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Clinical Phenotypes in Heart Failure With Preserved Ejection Fraction

Rohan Samson

Rohan Samson

Tulane University Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA

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Abhishek Jaiswal

Abhishek Jaiswal

Tulane University Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA

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Pierre V. Ennezat

Pierre V. Ennezat

Department of Cardiology, Centre Hospitalier Universitaire de Grenoble, Grenoble Cedex 09, France

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Mark Cassidy

Mark Cassidy

Tulane University Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA

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and

Thierry H. Le Jemtel

Thierry H. Le Jemtel

Tulane University Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA

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Originally published25 Jan 2016https://doi.org/10.1161/JAHA.115.002477Journal of the American Heart Association. 2016;5:e002477

Introduction

Over the past 2 decades, the syndrome of heart failure with preserved ejection fraction (HFpEF) received a lot of attention.¹^,²^,³^,⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹ However, little therapeutic progress was made.²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷ Among the issues that may account for the modest therapeutic progress, one appears to be overwhelming: HFpEF is not a well‐defined clinical entity: It is an amalgam of cardiovascular, metabolic, renal, and geriatric conditions.²⁸^,²⁹ Patients diagnosed with HFpEF currently, were until few years ago managed for systemic hypertension, coronary artery disease (CAD), obesity, renal impairment, pulmonary hypertension (PH), or age‐related deconditioning.

A rational approach for improving the outcome of patients with HFpEF may be to treat patients according to the conditions that led them to seek medical attention. As noted by others, a phenotype‐oriented approach to heart failure (HF) and, in particular, to HFpEF is needed.²⁹^,³⁰^,³¹ The diagnosis of HFpEF rests on the presence of signs and symptoms of HF and a normal left ventricular (LV) ejection fraction. Left ventricular diastolic dysfunction (LVDD) does not establish the presence of HF and may bias toward an exclusive role for the heart in the pathogenesis of HFpEF.³²^,³³

As a whole, HFpEF has been extensively reviewed.¹^,²^,³^,⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹ The present review focuses on 4 commonly encountered clinical phenotypes of HFpEF and their comorbid conditions (Figure). Therapeutic implications are discussed.

**Figure 1.** Hypertension is the steadfast underpinning of heart failure with preserved ejection ( HF p EF ). Aging, obesity, pulmonary hypertension ( PH ), and coronary artery disease ( CAD ) affect HF p EF presentation and progression. Their presence defines 4 common phenotypes that share atrial fibrillation, anemia, chronic obstructive pulmonary disease (COPD), frailty, diabetes, obstructive sleep apnea, and chronic kidney disease (CKD) as comorbid conditions. HTN indicates hypertension.

Aging Phenotype

Pathogenesis

Hypertension and age are major risk factors for HFpEF.³⁴^,³⁵ Community‐based studies have highlighted the high incidence of HFpEF in the elderly and very elderly (≥80 years of age).³⁶^,³⁷^,³⁸^,³⁹ Age‐related systemic changes contribute to myocardial molecular dysfunction and eventually to cardiac structural alterations and HFpEF.⁴⁰ Age‐related changes comprise neurohormonal dysregulation (angiotensin II, endothelin) and a proinflammatory state (tumor necrosis factor alpha, reactive oxygen species, and monocyte chemotractant protein). Age also affects the vasculature.⁴¹^,⁴² The major effect of age on the vasculature is systolic hypertension with widening of the pulse pressure that results from age‐related increase in arterial stiffness and early wave reflections.⁴³^,⁴⁴ Arterial stiffening and early wave reflections are steady vascular features in HFpEF.⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵² In the proximal arterial tree, vascular smooth cell loss of elastin increases systolic arterial pressure by lessening the “windkessel” effect.⁴⁴^,⁴⁵^,⁵³ In the distal arterial tree, several pathways contribute to early wave reflections.⁴⁴^,⁴⁵^,⁵³ In middle‐aged and elderly subjects, when the aortic lumen is no longer enlarging, arterial stiffness clearly predicts blood pressure progression.⁵⁴ Neuroendocrine activation (angiotensin II, aldosterone, and endothelin), metabolic alterations (insulin, hyperglycemia, and advanced glycation products), and inflammation (cytokines, oxidative stress, and nuclear factor kappa B) mediate collagen breakdown, cross‐linking, and glycation that promote early wave reflections by increasing peripheral arterial resistances.⁵⁵^,⁵⁶ Arterial stiffness is routinely assessed by carotid to femoral pulse wave velocity.⁵⁷^,⁵⁸^,⁵⁹ Common comorbid conditions in HFpEF (obesity, hypertension, diabetes, obstructive sleep apnea [OSA], anemia, and renal impairment) are independently associated with increased arterial stiffness.⁵⁸ However, arterial stiffness is consistently greater in HFpEF patients than in those who, with similar comorbidities, do not have HF.⁵¹^,⁶⁰^,⁶¹ Thus, age‐related increase in arterial stiffness is an important determinant of HFpEF.⁶²^,⁶³

By increasing systolic arterial pressure, arterial stiffening imposes an excessive load on the heart that leads to LVDD, ventricular‐vascular uncoupling, and afterload mismatch.⁴⁶^,⁶⁴ Aging greatly affects the efficiency of ventricular‐vascular coupling during exercise.⁶⁵ Of relevance to the preponderance of women in HFpEF, reduced efficiency of ventricular‐vascular coupling with age is related to increased effective arterial elastance in women, whereas it relates to increased ventricular systolic elastance in men.⁶⁵ With time, LVDD worsens and patients develop shortness of breath and fatigue.⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹ Symptoms correlate with LVDD severity that, in turn, results from progressive arterial stiffening.⁷⁰

A novel paradigm in HFpEF associates comorbid conditions to an inflammatory state that increases LV stiffness and promotes HF.⁷¹ The cellular and molecular mechanisms that lead from systemic inflammation to myocardial fibrosis (reduced nitric oxide bioactivity, cyclic guanosine monophosphate content, and protein kinase G) also promote arterial stiffening, with the endothelium being an essential component of vascular homeostasis.⁷²^,⁷³^,⁷⁴^,⁷⁵ The novel paradigm broadens our understanding of the mechanisms that underlie progression of LV remodeling in HFpEF with age‐related increase in arterial stiffness as the likely trigger of LV remodeling.

Therapeutic Implications

Lowering neurohormonal activation has unexpectedly failed to improve clinical outcome in large, placebo‐controlled, randomized HFpEF trials.²⁰^,²¹^,²²^,²³^,²⁴ Diagnostic uncertainties may partially account for the lack of therapeutic benefit.²⁹^,⁷⁶^,⁷⁷ However, the consistently neutral findings of these trials strongly suggest that neurohormonal modulation may not be beneficial in patients with HFpEF. In contrast to the well‐established effect of neurohormonal modulation on LV remodeling in heart failure with reduced ejection fraction (HFrEF), it may have only modest effect on LV remodeling in HFpEF, with LV mass decreasing by ≤10% in hypertensive patients.⁷⁸^,⁷⁹ Whether a modest reduction in LV mass reliably improves LVDD is unclear.

Reduced LV compliance and right ventricular (RV) remodeling are strong predictors of a poor outcome in HFpEF.⁸⁰^,⁸¹ Therapeutic trials in HFpEF have shown a greater prevalence of fatal outcome and HF hospitalizations than hypertension trials in elderly patients without HF.⁸² Although clinical events are clearly more prevalent when HFpEF is associated with severely reduced LV compliance and increased RV wall thickness, HFpEF may no longer be amenable to therapy at that stage. The lack of therapeutic success in patients with HFpEF suggests that the time to intervene may be earlier at the stage of preclinical diastolic dysfunction.⁸³ A critical prerequisite for earlier initiation of intensive antihypertensive therapy is identification of hypertensive patients who are at risk of progressing to HFpEF.

Circulating biomarkers and direct measurement of arterial stiffness may identify hypertensive patients at risk for HFpEF. Cardiac troponin T, alone or in combination with N‐terminal fragment of the prohormone of B‐type natriuretic peptide (NT‐proBNP), and products of collagen metabolism have been evaluated for identification of hypertensive patients at risk for HF.⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷

Baseline high‐sensitivity troponin and changes in troponin were found to be associated with incident HF or cardiovascular death in community‐dwelling older adults without known HF.⁸⁴ Elevation of troponin and NT‐proBNP above the age‐ and sex‐specific 75th percentile of the population identifies a malignant subphenotype of left ventricular hypertrophy (LVH) with high risk for progression to HF and cardiovascular death.⁸⁵ An increase in plasma troponin and NT‐proBNP by >50% in patients with low baseline levels identifies patients at risk for incident HF and cardiovascular death in the Cardiovascular Health Study.⁸⁴

Plasma tissue inhibitor of matrix metalloproteinase type 1 (TIMP‐1) is elevated in patients with LVDD and correlates with markers of LV filling in patients with untreated hypertension.⁸⁸ Circulating levels of carboxy‐terminal propeptide of procollagen type 1, carboxy terminal telopeptide of procollagen‐1, amino‐terminal peptide of procollagen type III, matrix metalloproteinase (MMP)‐2, and MMP‐9 levels are greater in hypertensive patients with LVDD than in those without LVDD.⁸⁹ In the Cardiovascular Health Study, the same makers of increased collagen turnover were elevated in patients with hypertension and LVDD.⁹⁰ In 2011, a panel of 17 biomarkers, including NT‐proBNP, cardiotrophin, osteopontin, and soluble receptor for advanced glycation products, in addition to markers of collagen metabolism, was found to have a greater discriminative value for identification of LVH and HF in patients with hypertension than any single marker.⁹¹ More recently, a meta‐analysis concluded that circulating levels of TIMP‐1, MMP‐2, and MMP‐9 identify hypertensive patients with LV remodeling, with circulating level of TIMP‐1 being the most specific for LVDD.⁹² In summary, serial determinations of circulating markers of collagen synthesis/degradation may allow identification of patients who, with preclinical diastolic dysfunction, are at risk for HF.

An alternative approach for identification of hypertensive patients with preclinical diastolic dysfunction or at risk for HF is to monitor arterial stiffness by serially measuring pulse wave velocity.⁹³^,⁹⁴ Recent European Society of Hypertension and Cardiology guidelines have endorsed this approach for detection of subclinical target organ damage.⁹⁵ Measurement of pulse wave velocity may be technically difficult in markedly obese patients with abundant adipose tissue over the groin. Arterial stiffness may be indirectly monitored by measuring circulating galectin‐3 given that it correlates with pulse wave velocity after adjustments for relevant variables.⁹⁶ Circulating levels of galectin‐3 do not appear to predict outcome in HFpEF after adjustment for age and renal function.⁹⁷

Identification of patients with preclinical diastolic dysfunction or at risk for HF is needed for the design and conduct of therapeutic interventions that may prevent/delay the development of HFpEF in hypertensive patients. Elderly hypertensive patients with preclinical diastolic dysfunction or at risk for HF may benefit from more‐intensive antihypertensive therapy than recommended in the latest guidelines.⁹⁸ A systolic blood pressure target goal of less than 120 mm Hg reduced the risk of incipient heart failure by 38%, as compared to the standard goal of less than 140 mm Hg, in the Systolic Blood Pressure Intervention Trial (SPRINT) trial.⁹⁹

Obesity Phenotype

Pathogenesis

North American urban HFpEF registries have highlighted a distinct subset of HFpEF patients.¹⁰⁰^,¹⁰¹ The subset consists of African American women with hypertension and obesity who, when diagnosed with HFpEF, are on average 10 to 15 years younger than their mainstream counterparts.¹⁰⁰^,¹⁰¹ Whereas the HFpEF obesity association was initially reported in African American women, it is not specific to sex or ethnicity.¹⁰² Obesity was reported in 34% of the Irbesartan in Heart Failure With Preserved Ejection Fraction (I‐PRESERVE) trial and in 40% of patients who, undergoing coronary angiography at the Mayo clinic, were found to have LV remodeling and diastolic dysfunction without obstructive epicardial CAD.¹⁰²^,¹⁰³ Sex‐related increase in LVH and proximal aortic stiffness with altered ventricular‐arterial coupling partly accounts for the preponderance of women in HFpEF.⁶³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷

An elevated body mass index (BMI; kg/m²) is a recognized risk factor for new‐onset HFrEF and HFpEF.¹⁰⁸^,¹⁰⁹^,¹¹⁰^,¹¹¹ Obesity has been associated with LVH and incipient LV dysfunction.¹¹²^,¹¹³ In the Dallas Heart Study, central adiposity was linked to concentric LVH and lower body obesity to eccentric LVH.¹¹⁴ Measurement of waist circumference and waist‐hip ratio may be preferred to BMI when evaluating patients with HFpEF and increased body weight.¹¹⁵^,¹¹⁶ Besides age and hypertension, obesity and especially central obesity is a major determinant of arterial stiffness.¹¹⁷^,¹¹⁸^,¹¹⁹ In an overfed mouse model of metabolic syndrome/obesity, weight gain precedes the increase in arterial stiffness, which can be reversed by caloric intake reduction and return to a normal weight.¹²⁰ Increased arterial stiffness in this mouse model is related to sympathetic nervous system activation, reduced nitric oxide bioactivity, and inflammation. Voluntary weight loss with a low‐calorie diet for 12 weeks is associated with a decrease in arterial stiffness in overweight/obese, middle‐aged, and elderly subjects.¹²¹ The decrease in arterial stiffness correlates with a reduction in total body weight and abdominal obesity.¹²¹ Aerobic exercise training and a low‐calorie diet for 7 weeks reduces arterial stiffness to a greater extent than diet alone in morbidly obese subjects.¹²² Two observations are relevant to obesity in HFpEF: (1) Obesity correlates with arterial stiffness in women and not in men.¹²³ Not unexpectedly, obesity and arterial stiffness did not correlate in an HFpEF population with nearly as many men as women.⁵⁰ (2) The duration of morbid obesity affects the LV response to weight loss.¹²⁴

In addition to increasing arterial stiffness, obesity is associated with 4‐fold greater prevalence of OSA, which contributes to the pathogenesis of HFpEF through multiple mechanisms: Sympathetic activation increases LV afterload, hypoxic pulmonary vasoconstriction reduces LV preload, oxidative stress stimulates inflammation, and hypoxia predisposes to atrial and ventricular arrhythmias.¹²⁵^,¹²⁶^,¹²⁷^,¹²⁸^,¹²⁹

When estimated by BMI, obesity is associated with a favorable outcome in patients with HF, a phenomenon that is referred to as the obesity paradox.¹³⁰^,¹³¹^,¹³²^,¹³³^,¹³⁴^,¹³⁵^,¹³⁶ However, when obesity is assessed by indices of visceral obesity, such as waist circumference and waist‐hip ratio, the obesity paradox is no longer apparent.¹³⁷ In the 4109 patients of the I‐PRESERVE trial, BMI and adverse clinical events were related, with the greatest rate of adverse outcomes in the lowest and highest BMI categories.¹⁰² The relationship between obesity and clinical outcome has not been specifically investigated in the obesity HFpEF phenotype.

Independently from body composition, African Americans are at high risk for HFpEF.¹³⁸^,¹³⁹ They are 2 to 3 times more likely to develop LVH than Caucasians.¹³⁸^,¹³⁹ African Americans remain at higher risk to develop HF than Caucasians after adjustment for many HF risk factors.¹⁴⁰^,¹⁴¹^,¹⁴² In a community‐based sample of middle‐aged African Americans, three quarters of ambulatory patients with HF had HFpEF.¹⁴³ Eighty‐five percent of HFpEF patients were women. The most common comorbid conditions were hypertension and obesity in 85% and 71% of patients, respectively.¹⁴³ In summary, central obesity appears to cause premature arterial stiffening and thereby to hasten the progression to HFpEF in hypertensive patients, particularly in African American women.

Therapeutic Implications

Obesity‐induced premature arterial stiffening is a clear target of therapy in obese patients with HFpEF. Exercise training reduces arterial stiffness.¹⁴⁴ However, obese patients may not be able to exercise at sufficient workloads to reverse vascular remodeling. Sustained and substantial weight loss is more reliably attained by bariatric surgery than by lifestyle modifications and medications.¹⁴⁵^,¹⁴⁶^,¹⁴⁷ Importantly, bariatric surgery improves LV relaxation and reverses concentric LV remodeling, with a substantial reduction in LV mass.¹⁴⁸^,¹⁴⁹^,¹⁵⁰ In addition to decreasing arterial stiffness and blood pressure, bariatric surgery improves/cures OSA and diabetes.¹⁵¹ In the absence of evidence‐based data, one cannot recommend gastric bypass surgery in obese HFpEF patients. The long‐term cardiovascular effects of bariatric surgery clearly need to be assessed in obese HFpEF patients.

PH Phenotype

Pathogenesis

The diagnosis and management of PH from left heart disease‐group 2 PH has been extensively reviewed.¹⁵²^,¹⁵³^,¹⁵⁴^,¹⁵⁵^,¹⁵⁶ Venous (postcapillary) PH, resulting from enduring elevation in left atrial (LA) pressure, is the most common cause of PH.¹⁵⁷^,¹⁵⁸ Functional mitral regurgitation and LVDD are associated with marked LA pressure elevation. Both are major determinants of PH in patients with HFrEF.¹⁵⁹ All patients with HFrEF have some degree of functional mitral regurgitation and LVDD as their condition deteriorates.⁹^,¹⁶⁰ However, only 60% of patients with advanced HFrEF develop PH.¹⁵² Tight control of LA pressure with loop diuretic therapy, sudden death before symptomatic deterioration, or both may account for near normal pulmonary artery (PA) pressure in 40% of patients with HFrEF. On the other hand, an arterial (precapillary) component contributes to PH in 25% to 30% of patients with HFrEF.¹⁵⁴^,¹⁵⁷ Impaired vascular reactivity with endothelin/nitric oxide imbalance, hypertrophy of vascular smooth muscle cells, extracellular matrix deposition, and genetic factors worsen precapillary PH in the setting of postcapillary PH.¹⁵⁴^,¹⁵⁷ An elevated mean or diastolic transpulmonary pressure gradient (TPG) provides direct evidence of a precapillary component to group 2 PH.¹⁵⁴^,¹⁶¹ The beneficial effect of phosphodiesterase type 5 inhibition (PDE5‐I) in HFrEF provides indirect evidence of a precapillary component to group 2 PH given that PDE5‐I is effective in patients with arterial PH.¹⁶²^,¹⁶³^,¹⁶⁴

The prevalence of PH is slightly greater in HFpEF than in HFrEF.¹⁵² Not surprisingly, the severity of LVDD is as much a determinant of PH in HFpEF as it is in HFrEF.¹⁶⁵^,¹⁶⁶^,¹⁶⁷ In addition, functional mitral regurgitation attributable to mitral leaflets tenting resulting from elevated LA pressure plays a role in the pathogenesis of PH in HFpEF.¹⁶⁸^,¹⁶⁹^,¹⁷⁰^,¹⁷¹^,¹⁷² The contribution of functional mitral regurgitation to PH is greater in the decompensated state, when LA pressure is markedly elevated, than in the compensated state.¹⁷² As noted in HFrEF, patients with HFpEF may exhibit PA pressures that are “out of proportion” to LA pressures secondary to impaired pulmonary vascular reactivity and structural alterations that add a precapillary component to postcapillary PH.¹⁶¹^,¹⁷³ The diagnosis of group 2 PH rests on the documentation of mean PA pressure ≥25 mm Hg and LV filling pressure >15 mm Hg. Direct measurement of LV diastolic pressure by left heart catheterization provides a more reliable measurement of LV filling pressure than pulmonary capillary wedge pressure in patients with severe PH or tachycardia.¹⁵⁷ Direct measurement of LV diastolic pressure may prevent to diagnose type II PH in a patient with type I PH.¹⁷⁴ Because pulmonary blood flow affects the TPG, diastolic TPG (when pulmonary flow substantially decreases) may be preferred to mean TPG to evaluate intrinsic changes in the pulmonary vasculature. A diastolic TPG <7 mm Hg denotes isolated postcapillary PH, and a diastolic TPG ≥7 mm Hg is indicative of combined pre‐ and postcapillary PH.¹⁷⁵

A caveat to the hemodynamic criteria of type II PH is that severe RV failure may result in elevated LV filling pressure attributable to ventricular interdependence with encroachment of a dilated RV into the LV.¹⁵⁷ In such instances, inotropic therapy may decompress the RV, thereby alleviating ventricular interdependence.¹⁵⁷ The converse caveat of type II PH hemodynamic criteria is that type II PH may be missed when in patients with intravascular depletion.¹⁷⁶ Fluid challenge or, preferably, supine exercise during right heart catheterization may ascertain the diagnosis.¹⁷⁶^,¹⁷⁷^,¹⁷⁸ Last, when PH cannot account for the severity of RV failure, transthyretin cardiac amyloidosis should be suspected.¹⁷⁹ In summary, HFpEF is a common cause of PH. When PH is “out of proportion” to the increase in LA pressure, it may be misdiagnosed as a primary arterial PH.

Therapeutic Implications

Management of PH in HFpEF presently rests on control of fluid accumulation and enhancement of LV filling.¹⁷⁵ Placebo‐controlled, randomized trials of endothelin antagonism with ambrisentan and bosentan have been terminated early because of poor enrollment or led to neutral findings, respectively (ClinicalTrials.gov Identifiers: NCT00840463, NCT00820352). The placebo‐controlled Phosphdiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial randomized 216 patients with HFpEF and moderate PH to PDE5‐I with sildenafil.²⁷ Compared to placebo, sildenafil did not significantly improve functional capacity and clinical status.²⁷ Notwithstanding that PDE5‐I may have failed to improve LV function, the selection of patients with moderate PH may partly account for the neutral findings of the RELAX trial.¹⁸⁰ Direct measurement of PA pressure and TPG by right heart catheterization was not required in the RELAX trial.¹⁸¹^,¹⁸² Recently, treatment with sildenafil failed to reduce PA pressure or hemodynamic parameters in a HFpEF cohort.¹⁸³ In contrast, a single‐center, placebo‐controlled, randomized trial reported significant improvements in PA pressure, RV function, and LV relaxation with sildenafil in patients with HFpEF and PH.¹⁸⁴ In the absence of evidence‐based data, PDE5‐I cannot be recommended for the treatment of PH in HFpEF.¹⁸⁵^,¹⁸⁶^,¹⁸⁷ Riociguat, a soluble guanylate cyclase stimulator that sensitizes guanylate cyclase through nitric oxide–dependent and –independent pathways, has been evaluated for the treatment of PH in HFpEF.¹⁸⁸^,¹⁸⁹ Riociguat increases stroke volume and cardiac output without changes in pulmonary vascular resistance and TPG.¹⁸⁸^,¹⁸⁹ The lack of US Food and Drug Administration–approved therapy makes the management of HFpEF patients with PH and particularly out of proportion PH extremely challenging. In summary, a subset of HFpEF patients seeks medical attention for PH‐related symptoms. The prognosis of HFpEF patients with PH is poor because no specific therapy is presently available to alleviate the progression of PH.

CAD Phenotype

Pathogenesis

In contrast to HFrEF, where obstructive CAD is a major consideration in the evaluation and management of patients, CAD has received little attention in HFpEF.¹⁹⁰^,¹⁹¹^,¹⁹²^,¹⁹³ Though abnormal relaxation is the first mechanical manifestation of myocardial ischemia,¹⁹⁴^,¹⁹⁵^,¹⁹⁶ acute coronary artery syndromes seldom precipitate HFpEF decompensation or present as HFpEF.¹⁰⁰^,¹⁹⁷ The prevalence of CAD ranges from 35% to 53% in large HFpEF registries.³⁴^,³⁵^,¹⁹⁸ The prevalence of CAD in HFpEF varies with the ethnic background of patients. When patients are mostly Caucasians, CAD appears to be highly prevalent and routine coronary artery angiography is recommended.¹⁹⁹ Noninvasive testing fails to detect the presence of CAD in at least one third of HFpEF patients.¹⁹⁹ In contrast, the prevalence of myocardial ischemia is less than 4% in a multiethnic population of patients presenting with shortness of breath and without wall motion abnormalities.²⁰⁰ Not surprisingly, patients with HFpEF and CAD experience a greater deterioration of LV function and a worse prognosis than patients with only HFpEF.¹⁹⁸^,²⁰¹^,²⁰²^,²⁰³ However, a fatal outcome does not appear to be related to the presence of CAD in patients hospitalized for a first episode of HFpEF decompensation.²⁰³ Patients with HFpEF and angina are at a significantly greater risk of myocardial infarction, coronary revascularization, stroke, and death than HFpEF patients without angina.²⁰¹ Surgical and percutaneous coronary revascularization improves clinical outcome in patients with HFpEF and symptomatic CAD.¹⁹⁹ Of note, coronary revascularization does not prevent the recurrence of flash pulmonary edema in patients with CAD and preserved LV systolic function.²⁰⁴

In addition to epicardial CAD, coronary microvascular rarefaction has been recently reported at postmortem examination of transmural LV specimens from HFpEF patients, compared to age‐appropriate control patients, who underwent autopsy after a noncardiac death.²⁰⁵ Coronary microvascular rarefaction was found to correlate with the ante mortem severity of LVH and diastolic dysfunction, as assessed by Doppler echocardiography.²⁰⁵ Whether coronary microvascular rarefaction and LV dyssynchrony are related in patients with HFpEF and narrow QRS has not been investigated.²⁰⁶ Microvascular dysfunction may not be limited to the myocardium given that the hyperemic response of the forearm subcutaneous microvasculature is impaired in HFpEF.⁶¹ In summary, when present CAD greatly affects the management and clinical course of HFpEF.

Therapeutic Implications

When HFpEF and CAD coexist, management needs to focus on CAD as well as on diuretic and antihypertensive therapy. Shortness of breath is unquestionably a cardinal symptom of HFpEF.²⁰⁷ However, when it fails to resolve with loop diuretic therapy, shortness of breath may be an angina equivalent. Focusing on HFpEF may delay stress imaging studies or coronary angiography in patients who, with HFpEF and equivocal response to loop diuretic, remain symptomatic because of ongoing myocardial ischemia.

Comorbid Conditions

All phenotypes of HFpEF have in common a multitude of comorbid conditions.²⁹^,²⁰⁸^,²⁰⁹ Rare is the HFpEF patient with only one comorbid condition.²¹⁰ Atrial fibrillation, anemia, chronic obstructive pulmonary disease (COPD) and frailty are common comorbidities of the aging phenotype. OSA, diabetes, and chronic kidney disease (CKD) are more prevalent in the obesity phenotype.

The presence of multiple comorbid conditions heavily affects the clinical course in HFpEF.²¹⁰^,²¹¹^,²¹² In an HF population of Medicare beneficiaries with a preponderance of women, comorbid conditions accounted for 45% of preventable hospitalizations.²¹³ An even greater clinical burden of noncardiac comorbid conditions has been reported in a mostly male population of HFpEF patients.²¹⁰ The risk of hospitalization is closely related to the number of comorbid conditions.²¹² The high prevalence of comorbid conditions also affects the mode of death in HFpEF patients.²¹⁴ In contrast to the findings of large, randomized therapeutic trials, registries have reported a preponderance of noncardiac deaths in HFpEF.²¹⁵^,²¹⁶^,²¹⁷

Aging‐Related Comorbid Conditions

Atrial fibrillation.

With hypertension as a steady background and aging as a common phenotype, atrial fibrillation (AF) is predictably a prevalent comorbid condition in HFpEF.²¹⁸ A history of AF was present in 29% of I‐PRESERVE and Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity (CHARM)‐Preserved patients.⁸² The prevalence of AF reached 44% and 51% in elderly I‐PRESERVE patients with a median age of 75 and 82 years, respectively.²¹⁹ AF is also highly prevalent in patients hospitalized for acutely decompensated HFpEF.²²⁰ Because of underlying diastolic dysfunction, AF may persist even after recovery of LV systolic function.²²¹

Despite some discordant findings, the presence of AF is now widely recognized to portend a poor outcome in HFpEF.²²²^,²²³^,²²⁴^,²²⁵ LA structural remodeling that provides the reentry substrate for AF clearly differs in HFpEF and HFrEF.²²⁶^,²²⁷ Increased LA stiffness and greater LA pulsatility may result in a higher AF burden in HFpEF than in HFrEF. In brief AF, a common comorbid condition of HFpEF, is particularly prevalent in the aging phenotype. AF increases hospitalizations and predicts a poor prognosis independent of the stroke risk.

Anemia.

Anemia is an independent predictor of mortality in patients with HFpEF.²²⁸ Its prevalence is similar to that of CKD, diabetes, and COPD.²²⁹^,²³⁰^,²³¹ Anemia is mostly prevalent in elderly women with advanced HFpEF, CKD, and diabetes.²³²^,²³³^,²³⁴ Anemia in HF has the same profile as in chronic disease with defective utilization of iron, impaired erythropoietin responsiveness, and depressed bone marrow function.²³²^,²³³^,²³⁴ Neurohormonal activation, renal dysfunction, hemodilution, and systemic inflammation contribute to the development of anemia in HFpEF.²³²^,²³³^,²³⁴ Functional iron deficiency with upregulation of myocardial transferrin receptor has been reported in the absence of anemia in HFpEF patients.²³⁵ The clinical implication of functional iron deficiency in HFpEF is presently unclear. It does not appear to correlate with function capacity or LV stiffness.²³⁵ A pooled analysis in a mixed population of HFpEF and HFrEF patients found that iron deficiency without anemia portends a worse prognosis than anemia without iron deficiency.²³⁶ From a therapeutic standpoint treatment with erythropoietin alpha does not improve functional capacity or reduce LV mass in elderly HFpEF patients.²³⁷

COPD.

In a mostly male elderly population of HFpEF, up to 45% of patients have been reported to have COPD.²¹⁰ The overall prevalence of COPD in HFpEF is 30%.²⁰⁸ When present, COPD is an independent predictor of mortality.²³⁸ Its impact on mortality is greater in HFpEF than HFrEF.²¹⁰ The link between HFpEF and COPD is incompletely understood.²³⁹ The proinflammatory state associated with COPD may hasten the development of myocardial fibrosis, and COPD may directly impair LV filling.²⁴⁰ In patients with atrial fibrillation, COPD hastens the development of HFpEF.²²⁵

Dyspnea is the cornerstone symptom of both HFpEF and COPD. A commonly faced therapeutic challenge is to determine whether dyspnea is attributable to COPD exacerbation, HFpEF decompensation, or both in patients who, with known HFpEF and COPD, present with symptomatic deterioration.²⁴¹ Because both conditions feed on each other, an efficient approach may be to initiate aggressive treatment of both conditions on presentation.

Frailty.

The concept of frailty refers to decreased homeostatic reserves, resulting in increased vulnerability to acute stress.²⁴² As a concept, frailty differs from comorbidity, which is the cooccurrence of multiple conditions.²⁴³^,²⁴⁴ Frailty can be primary as a consequence of aging or secondary attributable to the presence of comorbidity.²⁴⁵ However, given that the stress that reveals frailty is often the deterioration of comorbidity, one cannot, in most instances, definitely differentiate primary frailty from secondary frailty. Overall, frailty is a well‐recognized component of chronic conditions, with a prevalence of 60% and 40% in obstructive pulmonary and kidney diseases, respectively.²⁴⁵ The prevalence of HF‐related frailty is notably greater than that of age matched in community‐dwelling elders.²⁴⁵ It ranges from 20% to 74%, depending on age and criteria used to define frailty.²⁴⁵^,²⁴⁶ When older than 70 years, 52% of patients with HF are frail compared to 30% when they are younger than 70 years.²⁴⁷ Frailty is more prevalent in patients with HFpEF than HFrEF given that the former patients tend to be older and have more comorbidities.²⁴⁶ AF, a common comorbidity of the aging phenotype of HFpEF, hastens development and progression of frailty.²⁴⁸ After adjustment for confounders, including comorbidities, frailty was found to be an independent predictor of visits to the emergency department and hospitalizations in ambulatory patients with HF.²⁴⁶ Frailty increased emergency visits by 92% and hospitalizations by 65%. In summary, frailty, which commonly occurs in HFpEF, may be particularly prevalent in the aging phenotype.

Obesity‐Related Comorbid Conditions

OSA.

The prevalence of OSA ranges from 40% to 62% in obese patients with HFpEF compared to 10% in nonobese HFpEF patients.²⁴⁹^,²⁵⁰^,²⁵¹ Independently from hypertension and obesity, OSA impairs LV diastolic function, begets LVH, and thus may hasten HFpEF progression.¹²⁶^,¹²⁷^,²⁵²^,²⁵³^,²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷^,²⁵⁸ Repetitive sleep arousals and hypoxic episodes heighten sympathetic activity and promote endothelial dysfunction, systemic inflammation, and arterial stiffness that may further increase blood pressure and accelerate atherosclerosis progression.¹²⁸^,²⁵⁹^,²⁶⁰^,²⁶¹^,²⁶²^,²⁶³^,²⁶⁴^,²⁶⁵

Continuous positive airway pressure (CPAP) is the present standard of care for OSA.¹²⁸ In patients with HFrEF, CPAP improves functional class and reduces sympathetic activity, heart rate, and blood pressure.²⁶⁶^,²⁶⁷^,²⁶⁸ Furthermore, OSA therapy is associated with a trend toward improvement in survival.²⁶⁹ In contrast to HFrEF, CPAP therapy has not been extensively evaluated in HFpEF. Adherence to CPAP therapy is known to decrease systolic blood pressure, reduce arterial stiffness, and improve LV diastolic function in patients with hypertension and OSA.²⁷⁰^,²⁷¹^,²⁷²^,²⁷³ The effects of CPAP on morbidity and mortality have not been evaluated in large, randomized trials in patients with HFpEF. Nevertheless, because of the beneficial effect of CPAP therapy in hypertension, obese patients with HFpEF should undergo a sleep study to establish the presence of OSA and, if indicated, be initiated on CPAP therapy.

Diabetes.

The prevalence of diabetes averages 45% in HFpEF.²⁰⁸ It was as high as 61% in the Urban Baltimore Community Registry.¹⁰¹ Diabetes hastens the transition from preclinical diastolic dysfunction to HFpEF and is associated with a nearly 2‐fold increase in mortality and morbidity in HFpEF.²⁷⁴^,²⁷⁵^,²⁷⁶^,²⁷⁷ Insulin resistance and hyperglycemia affect HFpEF patients through multiple mechanisms.²⁷⁸ They include increased free fatty acid concentration, mitochondrial dysfunction, abnormal calcium homeostasis, oxidative stress, and advanced glycation endproducts.²⁷⁸ Besides its detrimental effect on myocardial relaxation and LV ventricular stiffness, diabetes increases arterial stiffness and accelerates wave reflections.²⁷⁸^,²⁷⁹ Pulse pressure is greater and renal dysfunction is more prevalent in diabetic than nondiabetic patients.²⁷⁹^,²⁸⁰ Diabetes and obesity are linked; obesity compounds diabetes’ effects on the myocardium and arterial wall.²⁷⁸^,²⁸¹ Aerobic capacity and walking distance were recently reported to be lower in diabetic than nondiabetic HFpEF patients.³¹ A similar observation had been previously reported in HFrEF patients.²⁸²^,²⁸³ As hypothesized in HFrEF patients with diabetes, skeletal muscle metabolic alterations are likely to contribute to the lower aerobic capacity of diabetic HFpEF patients.²⁸⁴

From a therapeutic standpoint, a joint endocrine‐HF clinic is an attractive approach given that diabetes is common in HFpEF patients who require frequent adjustments of their hypoglycemic regimen. Mitochondria‐targeted antioxidants may lower oxidative stress and improve LV diastolic function.¹⁹

CKD.

Renal dysfunction is common in HFpEF patients and especially prevalent in elderly obese/diabetic patients with hypertension.²⁰⁸^,²⁸⁵ Overall, renal dysfunction is present in 30% to 60% of patients with HFpEF.²⁰⁸^,²⁸⁶^,²⁸⁷ The prevalence of renal dysfunction is greater when defined by estimated glomerular filtration rate (eGFR) <60 mL/min/m² and high urinary albumin creatinine ratio than by eGFR alone.²⁸⁸ Low eGFR and high urinary albumin creatinine ratio are associated with cardiac remodeling and subtle LV systolic dysfunction in HFpEF.²⁸⁸ A high urinary albumin creatinine ratio alone has been associated with RV/LV remodeling and LV longitudinal systolic dysfunction in HFpEF.²⁸⁹ Renal dysfunction on presentation is associated with a poor prognosis in patients who are hospitalized for a first decompensation of HFpEF.²⁹⁰ Patients with worsening renal function during the index hospitalization have an even poorer prognosis.²⁹⁰ In contrast to HFrEF, worsening renal function after angiotensin receptor blockade is associated with a poor outcome in HFpEF.²⁹¹ Renal dysfunction increases the risk of adverse events during long‐term renin‐angiotensin system inhibition in HFpEF patients.²⁹¹ Renal dysfunction may lead to loop diuretic resistance and the need for ultrafiltration.²⁹² Besides being associated with a poor prognosis, renal dysfunction complicates the management of patients who, with HFpEF, require a tight control of fluid accumulation.

Future Directions

The large, all‐inclusive, randomized, placebo‐controlled therapeutic trials approach that led to great therapeutic progress in HFrEF has not worked so far in HFpEF.²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷ Such discrepancy is, in part, attributable to overt differences in the pathogenesis and progression of HFpEF and HFrEF. In that regard, marked clinical heterogeneity and multiple comorbidities argue in favor of a phenotyping approach to HFpEF.

Preliminary data derived from the I‐PRESERVE trial and validated in the CHARM‐Preserved trial suggest that latent class analysis can identify 6 subgroups of patients with HFpEF from 11 clinical variables.²¹⁹ These 6 subgroups exhibited significant differences in event‐free survival and, possibly, treatment response. Identification of HFpEF subgroups with different outcomes may help select specific endpoints and interventions that, in turn, will improve the likelihood of a positive treatment response. Whether latent class analysis is used to identify HFpEF subgroups or few clinical variables help define HFpEF phenotypes, delineation of the HFpEF syndrome into clinical cohorts may resolve the current therapeutic conundrum.

Conclusion

Any attempt at clinical classification is, by essence, arbitrary. Nevertheless, defining clinical phenotypes in HFpEF may help the management of patients with HFpEF and possibly lead to therapeutic progress. Elderly patients with long‐standing hypertension and HFpEF are likely to benefit from a different therapeutic approach than middle‐aged obese HFpEF patients. Patients who seek medical attention for PH‐related symptoms are clearly in need of specific therapy. When HFpEF and CAD coexist, great attention needs to be given to both conditions. Last, HFpEF is associated with a multitude of comorbid conditions that require specific therapies.

Disclosures

None.

Footnotes

*Correspondence to: Thierry H. Le Jemtel, MD, Tulane University School of Medicine, 1430 Tulane Ave, SL‐48, New Orleans, LA 70112. E‐mail: lejemtel@tulane.edu

References

1 Cohn JN, Johnson G. Heart failure with normal ejection fraction, the V‐HeFT study. Circulation. 1990; 81(suppl III):III‐48–III‐53.Google Scholar
2 Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol. 1995; 26:1656–1674.Crossref Google Scholar
3 Zile MR, Brustaert DL. New concepts in diastolic dysfunction and diastolic heart failure. Part I diagnosis, prognosis and measurements of diastolic function. Circulation. 2002; 105:1387–1393.Link Google Scholar
4 Zile MR, Brustaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part II. Causal mechanisms and treatment. Circulation. 2002; 105:1503–1508.Link Google Scholar
5 Kitzman DL, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marbuger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002; 288:2144–2150.Crossref Medline Google Scholar
6 Aurigemma GP, Gaasch WH. Diastolic heart failure. N Engl J Med. 2004; 351:1097–1105.Crossref Medline Google Scholar
7 Kass DA, Jean GF, Bronzwaer JG, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure?Circ Res. 2004; 94:1533–1542.Link Google Scholar
8 Zile MR, Baicu C, Gaasch WH. Diastolic heart failure‐ abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 350:1953–1959.Crossref Medline Google Scholar
9 Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic heart ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003; 289:194–202.Crossref Medline Google Scholar
10 Burkhoff D, Maurer MS, Packer M. Heart failure with a normal ejection fraction. Is it really a disorder of diastolic function?Circulation. 2003; 107:656–658.Link Google Scholar
11 Maurer MS, King DL, El‐Koury Rumbarger L, Packer M, Burkhoff D. Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms. J Card Fail. 2005; 11:177–187.Crossref Medline Google Scholar
12 Lester SJ, Tajik AJ, Nishimura RA, Oh JK, Kandherhia BK, Seward JB. Unlocking the mysteries of diastolic dysfunction. J Am Coll Cardiol. 2008; 51:679–689.Crossref Medline Google Scholar
13 Wang GW, Nagueh SF. Current perspectives on cardiac function in patients with diastolic heart failure. Circulation. 2009; 119:3044–3046.Link Google Scholar
14 De Keulenaer GW, Brutsaert DL. Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum. Circulation. 2011; 123:1996–2004.Link Google Scholar
15 Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis and treatment. Eur Heart J. 2011; 32:670–679.Crossref Medline Google Scholar
16 Ferrari R, Böhm M, Cleland JG, Paulus WJ, Pieske B, Rapezzi C, Tavazzi L. Heart failure with preserved ejection fraction: uncertainties and dilemmas. Eur J Heart Fail. 2015; 17:665–671.Crossref Medline Google Scholar
17 Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res. 2014; 115:79–96.Link Google Scholar
18 Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation. 2011; 123:2006–2013.Link Google Scholar
19 Jeong EM, Dudley SC. Diastolic dysfunction. Circ J. 2015; 79:470–477.Crossref Medline Google Scholar
20 Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J. Effects of candesartan in patients with chronic heart failure and preserved left‐ventricular ejection fraction: the CHARM‐Preserved Trial. Lancet. 2003; 362:777–781.Crossref Medline Google Scholar
21 Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008; 359:2456–2467.Crossref Medline Google Scholar
22 Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in elderly people with chronic heart failure (PEP‐CHF) study. Eur Heart J. 2006; 27:2338–2345.Crossref Medline Google Scholar
23 Kitzman DW, Hundley WG, Brubaker PH, Morgan T, Moore JB, Stewart KP, Little WC. A randomized double‐blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility. Circ Heart Fail. 2010; 3:477–485.Link Google Scholar
24 Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators . Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014; 370:1383–1392.Crossref Medline Google Scholar
25 Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF, Gheorghiade M. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006; 114:397–403.Link Google Scholar
26 Yip GWK, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO, Yu CM, Sanderson JE. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008; 94:573–580.Crossref Medline Google Scholar
27 Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E; RELAX Trial . Effect of phosphodiesterase‐5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013; 309:1268–1277.Crossref Medline Google Scholar
28 Borlaug BA. Heart failure with preserved and reduced ejection fraction: different risk profiles for different diseases. Eur Heart J. 2013; 34:1393–1395.Crossref Medline Google Scholar
29 Cleland JG, Pellicori P, Dierckx R. Clinical trials in patients with heart failure and preserved left ventricular ejection fraction. Heart Fail Clin. 2014; 10:511–523.Crossref Medline Google Scholar
30 De Keulenaer GW, Brustaert DL. The heart failure spectrum. Time for a phenotype‐oriented approach. Circulation. 2009; 119:3044–3046.Link Google Scholar
31 Lindman BR, Dávila‐Román VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, de las Fuentes L, Joseph SM, Vader J, Hernandez AF, Redfield MM. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol. 2014; 64:541–549.Crossref Medline Google Scholar
32 Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL, Ghali JK, Liebson PR. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?Circulation. 2001; 104:779–782.Link Google Scholar
33 Ennezat PV, Le Jemtel TH, Logeart D, Maréchaux S. Heart failure with preserved ejection fraction: a systemic disorder?Rev Med Interne. 2012; 33:370–380.Crossref Medline Google Scholar
34 Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006; 355:251–259.Crossref Medline Google Scholar
35 Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population‐based study. N Engl J Med. 2006; 355:260–269.Crossref Medline Google Scholar
36 Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, Redfield MM. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation. 1998; 98:2282–2289.Link Google Scholar
37 Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL; Cardiovascular Health Study Research Group . Importance of heart failure with preserved systolic function in patients ≥ 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol. 2001; 87:413–419.Crossref Medline Google Scholar
38 Banerjee P, Clark AL, Cleland JG. Diastolic heart failure: a difficult problem in the elderly. Am J Geriatr Cardiol. 2004; 13:16–21.Crossref Medline Google Scholar
39 Banerjee P, Banerjee T, Khand A, Clark AL, Cleland JGF. Diastolic heart failure: neglected or misdiagnosed?J Am Coll Cardiol. 2002; 39:138–141.Crossref Medline Google Scholar
40 Loffredo FS, Nikolova AP, Pancoast JR, Lee RT. Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res. 2014; 115:97–107.Link Google Scholar
41 Jei W. Mechanisms of disease: age and the cardiovascular system. N Engl J Med. 1992; 327:1735–1739.Crossref Medline Google Scholar
42 Nilsson PM. Hemodynamic aging as the consequence of structural changes associated with early vascular aging (EVA). Aging Dis. 2014; 5:109–113.Medline Google Scholar
43 Safar ME, Levy BI, Struijker‐Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation. 2003; 107:2864–2869.Link Google Scholar
44 Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin EJ, Vasan RS, Mitchell GF. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012; 308:875–881.Crossref Medline Google Scholar
45 Safar H, Chahwakilian A, Boudali Y, Debray‐Meignan S, Safar M, Blacher J. Arterial stiffness, isolated systolic hypertension, and cardiovascular risk in the elderly. Am J Geriatr Cardiol. 2006; 15:178–182.Crossref Medline Google Scholar
46 Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003; 107:714–720.Link Google Scholar
47 Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012; 60:1455–1469.Crossref Medline Google Scholar
48 Desai AS, Mitchell GF, Fang JC, Creager MA. Central aortic stiffness is increased in patients with heart failure and preserved ejection fraction. J Card Fail. 2009; 15:658–664.Crossref Medline Google Scholar
49 Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA, Redfield MM. Cardiac structure and ventricular‐vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007; 115:1982–1990.Link Google Scholar
50 Ikonomidis I, Tzortzis S, Papaioannou T, Protogerou A, Stamatelopoulos K, Papamichael C, Zakopoulos N, Lekakis J. Incremental value of arterial wave reflections in the determination of left ventricular diastolic dysfunction in untreated patients with essential hypertension. J Hum Hypertens. 2008; 22:687–698.Crossref Medline Google Scholar
51 Mohammed SF, Borlaug BA, Roger VL, Mirzoyev SA, Rodeheffer RJ, Chirinos JA, Redfield MM. Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community‐based study. Circ Heart Fail. 2012; 5:710–719.Link Google Scholar
52 Kitzman DW, Herrington DM, Brubaker PH, Moore JB, Eggebeen J, Haykowsky MJ. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction. Hypertension. 2013; 61:112–119.Link Google Scholar
53 London GM, Pannier B. Arterial functions: how to interpret the complex physiology. Nephrol Dial Transplant. 2010; 25:3815–3823.Crossref Medline Google Scholar
54 Mitchell GF. Arterial stiffness and hypertension: chicken or egg?Hypertension. 2014; 64:210–214.Link Google Scholar
55 Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005; 25:932–943.Link Google Scholar
56 Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, Seals DR. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium‐dependent dilation and upregulation of nuclear factor‐kappaB. Circ Res. 2007; 100:1659–1666.Link Google Scholar
57 Brunner‐La Rocca HP. Towards applicability of measures of arterial stiffness in clinical routine. Eur Heart J. 2010; 31:2320–2322.Crossref Medline Google Scholar
58 Nelson MR, Stepanek J, Cevette M, Covalciuc M, Hurst RT, Tajik AJ. Noninvasive measurement of central vascular pressures with arterial tonometry: clinical revival of the pulse pressure waveform?Mayo Clin Proc. 2010; 85:460–472.Crossref Medline Google Scholar
59 Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker‐Boudier H; European Network for Non‐invasive Investigation of Large Arteries . Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006; 27:2588–2605.Crossref Medline Google Scholar
60 Little WC, Zile MR. HFpEF: cardiovascular abnormalities not just comorbidities. Circ Heart Fail. 2012; 5:669–671.Link Google Scholar
61 Marechaux S, Samson R, Van Belle E, Susen S, Breyne J, de Monte J, Dedrie C, Chebai N, Menet A, Banfi C, Bouabdallaoui N, Le Jemtel TH, Ennezat PV. Vascular and microvascular endothelial function in heart failure with preserved ejection fraction. J Card Fail. 2015; 22:3–11.Crossref Medline Google Scholar
62 Cheriyan J, Wilkinson IB. Role of increased aortic stiffness in the pathogenesis of heart failure. Curr Heart Fail Rep. 2007; 4:121–126.Crossref Medline Google Scholar
63 Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age‐ and gender‐related ventricular‐vascular stiffening: a community‐based study. Circulation. 2005; 112:2254–2262.Link Google Scholar
64 Hart CY, Meyer DM, Tazelaar HD, Grande JP, Burnett JC, Housmans PR, Redfield MM. Load versus humoral activation in the genesis of early hypertensive heart disease. Circulation. 2001; 104:215–220.Link Google Scholar
65 Najjar SS, Schulman SP, Gerstenblith G, Fleg JL, Kass DA, O'Connor F, Becker LC, Lakatta EG. Age and gender affect ventricular‐vascular coupling during aerobic exercise. J Am Coll Cardiol. 2004; 44:611–617.Crossref Medline Google Scholar
66 Lam CS, Donal E, Kraigher‐Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail. 2011; 13:18–28.Crossref Medline Google Scholar
67 Gradman AH, Alfayoumi F. From left ventricular hypertrophy to congestive heart failure: management of hypertensive heart disease. Prog Cardiovasc Dis. 2006; 48:326–341.Crossref Medline Google Scholar
68 Zile MR, Gaasch WH, Patel K, Aban IB, Ahmed A. Adverse left ventricular remodeling in community‐dwelling older adults predicts incident heart failure and mortality. JACC Heart Fail. 2014; 2:512–522.Crossref Medline Google Scholar
69 Vogel MW, Slusser JP, Hodge DO, Chen HH. The natural history of preclinical diastolic dysfunction: a population‐based study. Circ Heart Fail. 2012; 5:144–151.Link Google Scholar
70 Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone. J Am Coll Cardiol. 1997; 30:8–18.Crossref Medline Google Scholar
71 Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013; 62:263–271.Crossref Medline Google Scholar
72 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87:840–844.Link Google Scholar
73 Jia G, Aroor AR, Sowers JR. Arterial stiffness: a nexus between cardiac and renal disease. Cardiorenal Med. 2014; 4:60–71.Crossref Medline Google Scholar
74 Tschöpe C, Van Linthout S. New insights in (inter)cellular mechanisms by heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2014; 11:436–444.Crossref Medline Google Scholar
75 Lam CS, Brutsaert DL. Endothelial dysfunction: a pathophysiologic factor in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2012; 60:1787–1789.Crossref Medline Google Scholar
76 Kristensen SL, Køber L, Jhund PS, Solomon SD, Kjekshus J, McKelvie RS, Zile MR, Granger CB, Wikstrand J, Komajda M, Carson PE, Pfeffer MA, Swedberg K, Wedel H, Yusuf S, McMurray JJ. International geographic variation in event rates in trials of heart failure with preserved and reduced ejection fraction. Circulation. 2015; 131:43–53.Link Google Scholar
77 McMurray JJ, O'Connor C. Lessons from the TOPCAT trial. N Engl J Med. 2014; 370:1453–1454.Crossref Medline Google Scholar
78 Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta‐analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med. 2003; 115:41–46.Crossref Medline Google Scholar
79 Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin‐converting enzyme inhibitor ramipril. Circulation. 2001; 104:1615–1621.Link Google Scholar
80 Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O'Meara E, Desai AS, Heitner JF, Li G, Fang J, Rouleau J, Zile MR, Markov V, Ryabov V, Reis G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial. Circ Heart Fail. 2014; 7:740–751.Link Google Scholar
81 Burke MA, Katz DH, Beussink L, Selvaraj S, Gupta DK, Fox J, Chakrabarti S, Sauer AJ, Rich JD, Freed BH, Shah SJ. Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2014; 7:288–299.Link Google Scholar
82 Campbell RT, Jhund PS, Castagno D, Hawkins NM, Petrie MC, McMurray JJ. What have we learned about patients with heart failure and preserved ejection fraction from DIG‐PEF, CHARM‐preserved, and I‐PRESERVE?J Am Coll Cardiol. 2012; 60:2349–2356.Crossref Medline Google Scholar
83 Wan SH, Vogel MW, Chen HH. Pre‐clinical diastolic dysfunction. J Am Coll Cardiol. 2014; 63:407–416.Crossref Medline Google Scholar
84 deFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M, Seliger SL. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA. 2010; 304:2494–2502.Crossref Medline Google Scholar
85 Neeland IJ, Drazner MH, Berry JD, Ayers CR, deFilippi C, Seliger SL, Nambi V, McGuire DK, Omland T, de Lemos JA. Biomarkers of chronic cardiac injury and hemodynamic stress identify a malignant phenotype of left ventricular hypertrophy in the general population. J Am Coll Cardiol. 2013; 61:187–195.Crossref Medline Google Scholar
86 Zile MR, Baicu CF, Ikonomidis J, Stroud RE, Nietert PJ, Bradshaw AD, Slater R, Palmer BM, Van Buren P, Meyer M, Redfield M, Bull D, Granzier H, LeWinter MM. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015; 131:1247–1259.Link Google Scholar
87 Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, McClure CD, Spinale FG, Zile MR. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006; 113:2089–2096.Link Google Scholar
88 González A, López B, Querejeta R, Zubillaga E, Echeverría T, Díez J. Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction. Hypertension. 2010; 55:1418–1424.Link Google Scholar
89 Martos R, Baugh J, Ledwidge M, O'Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007; 115:888–895.Link Google Scholar
90 Barash E, Gottdiener JS, Aurigemma G, Kitzman DW, Han J, Kop WJ, Tracy RP. Association between elevated fibrosis markers and heart failure in the elderly. The Cardiovascular Health Study. Circ Heart Fail. 2009; 2:303–310.Link Google Scholar
91 Zile MR, Desantis SM, Baicu CF, Stroud RE, Thompson SB, McClure CD, Mehurg SM, Spinale FG. Plasma biomarkers that reflect determinants of matrix composition identify the presence of left ventricular hypertrophy and diastolic heart failure. Circ Heart Fail. 2011; 4:246–256.Link Google Scholar
92 Marchesi C, Dentali F, Nicolini E, Maresca AM, Tayebjee MH, Franz M, Guasti L, Venco A, Schiffrin EL, Lip GY, Grandi AM. Plasma levels of matrix metalloproteinases and their inhibitors in hypertension: a systematic review and meta‐analysis. J Hypertens. 2012; 30:3–16.Crossref Medline Google Scholar
93 Abhayaratna WP, Srikusalanukul W, Budge MM. Aortic stiffness for the detection of preclinical left ventricular diastolic dysfunction: pulse wave velocity versus pulse pressure. J Hypertens. 2008; 26:758–764.Crossref Medline Google Scholar
94 Nilsson PM, Khalili P, Franklin SS. Blood pressure and pulse wave velocity as metrics for evaluating pathologic ageing of the cardiovascular system. Blood Press. 2014; 23:17–30.Crossref Medline Google Scholar
95 Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck‐Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Rydén L, Sirenko Y, Stanton A, Struijker‐Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013; 34:2159–2219.Crossref Medline Google Scholar
96 Libhaber E, Woodiwiss AJ, Raymond A, Gomes M, Maseko MJ, Sareli P, Norton GR. Independent association of circulating galectin‐3 concentrations with aortic pulse wave velocity and wave reflection in a community sample. Hypertension. 2015; 65:1356–1364.Link Google Scholar
97 AbouEzzeddine OF, Haines P, Stevens S, Nativi‐Nicolau J, Felker GM, Borlaug BA, Chen HH, Tracy RP, Braunwald E, Redfield MM. Galectin‐3 in heart failure with preserved ejection fraction: a RELAX trial substudy (Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure). JACC Heart Fail. 2015; 3:245–252.Crossref Medline Google Scholar
98 James PA, Oparil S, Carter BL, Cushman WC, Dennison‐Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Svetkey LP, Taler SJ, Townsend RR, Wright JT, Narva AS, Ortiz E. 2014 Evidence‐based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014; 311:507–520.Crossref Medline Google Scholar
99 SPRINT Research Group , Wright JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A randomized trial of intensive versus standard blood‐pressure control. N Engl J Med. 2015; 373:2103–2116.Crossref Medline Google Scholar
100 Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, Kalman J, Phillips RA, Steingart R, Brown EJ, Berkowitz R, Moskowitz R, Soni A, Mancini D, Bijou R, Sehhat K, Varshneya N, Kukin M, Katz SD, Sleeper LA, Le Jemtel TH; New York Heart Failure Consortium . Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol. 2004; 43:1432–1438.Crossref Medline Google Scholar
101 Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, Lakatta EG, Najjar SS, Kass DA. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol. 2007; 49:198–207.Crossref Medline Google Scholar
102 Haass M, Kitzman DW, Anand IS, Miller A, Zile MR, Massie BM, Carson PE. Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction. Results from the Ibesartan in Patients with Preserved Ejection Fraction (I‐PRESERVE) Trial. Circ Heart Fail. 2011; 4:324–331.Link Google Scholar
103 Powell BD, Redfield MM, Bybee KA, Freeman WK, Rihal CS. Association of obesity with left ventricular remodeling and diastolic dysfunction in patients with coronary artery disease. Am J Cardiol. 2006; 98:116–120.Crossref Medline Google Scholar
104 Douglas PS, Katz SE, Weinberg EO, Chen MH, Bishop SP, Lorell BH. Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload. J Am Coll Cardiol. 1998; 32:1118–1125.Crossref Medline Google Scholar
105 Gori M, Lam CS, Gupta DK, Santos AB, Cheng S, Shah AM, Claggett B, Zile MR, Kraigher‐Krainer E, Pieske B, Voors AA, Packer M, Bransford T, Lefkowitz M, McMurray JJ, Solomon SD; PARAMOUNT Investigators . Sex‐specific cardiovascular structure and function in heart failure with preserved ejection fraction. Eur J Heart Fail. 2014; 16:535–542.Crossref Medline Google Scholar
106 Regnault V, Thomas F, Safar ME, Osborne‐Pellegrin M, Khalil RA, Pannier B, Lacolley P. Sex difference in cardiovascular risk: role of pulse pressure amplification. J Am Coll Cardiol. 2012; 59:1771–1777.Crossref Medline Google Scholar
107 Coutinho T, Borlaug BA, Pellikka PA, Turner ST, Kullo IJ. Sex differences in arterial stiffness and ventricular‐arterial interactions. J Am Coll Cardiol. 2013; 61:96–103.Crossref Medline Google Scholar
108 Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med. 2002; 347:305–313.Crossref Medline Google Scholar
109 Ndumele CE, Coresh J, Lazo M, Hoogeveen RC, Blumenthal RS, Folsom AR, Selvin E, Ballantyne CM, Nambi V. Obesity, subclinical myocardial injury, and incident heart failure. JACC Heart Fail. 2014; 2:600–607.Crossref Medline Google Scholar
110 Peterson LR, Waggoner AD, Schechtman KB, Meyer T, Gropler RJ, Barzilai B, Dávila‐Román VG. Alterations in left ventricular structure and function in young healthy obese women: assessment by echocardiography and tissue Doppler imaging. J Am Coll Cardiol. 2004; 43:1399–1404.Crossref Medline Google Scholar
111 Wong CY, O'Moore‐Sullivan T, Leano R, Byrne N, Beller E, Marwick TH. Alterations of left ventricular myocardial characteristics associated with obesity. Circulation. 2004; 110:3081–3087.Link Google Scholar
112 Kishi S, Armstrong AC, Gidding SS, Colangelo LA, Venkatesh BA, Jacobs DR, Carr JJ, Terry JG, Liu K, Goff DC, Lima JA. Association of obesity in early adulthood and middle age with incipient left ventricular dysfunction and structural remodeling: the CARDIA study (Coronary Artery Risk Development in Young Adults). JACC Heart Fail. 2014; 2:500–508.Crossref Medline Google Scholar
113 Turkbey EB, McClelland RL, Kronmal RA, Burke GL, Bild DE, Tracy RP, Arai AE, Lima JA, Bluemke DA. The impact of obesity on the left ventricle: the Multi‐Ethnic Study of Atherosclerosis (MESA). JACC Cardiovasc Imaging. 2010; 3:266–274.Crossref Medline Google Scholar
114 Neeland IJ, Gupta S, Ayers CR, Turer AT, Rame JE, Das SR, Berry JD, Khera A, McGuire DK, Vega GL, Grundy SM, de Lemos JA, Drazner MH. Relation of regional fat distribution to left ventricular structure and function. Circ Cardiovasc Imaging. 2013; 6:800–807.Link Google Scholar
115 Després JP. Body fat distribution and risk of cardiovascular disease: an update. Circulation. 2012; 126:1301–1313.Link Google Scholar
116 Nordstrand N, Gjevestad E, Dinh KN, Hofsø D, Røislien J, Saltvedt E, Os I, Hjelmesæth J. The relationship between various measures of obesity and arterial stiffness in morbidly obese patients. BMC Cardiovasc Disord. 2011; 11:7.Crossref Medline Google Scholar
117 Zebekakis PE, Nawrot T, Thijs L, Balkestein EJ, van der Heijden‐Spek J, Van Bortel LM, Struijker‐Boudier HA, Safar ME, Staessen JA. Obesity is associated with increased arterial stiffness from adolescence until old age. J Hypertens. 2005; 23:1839–1846.Crossref Medline Google Scholar
118 Sutton‐Tyrrell K, Newman A, Simonsick EM, Havlik R, Pahor M, Lakatta E, Spurgeon H, Vaitkevicius P. Aortic stiffness is associated with visceral adiposity in older adults enrolled in the study of health, aging, and body composition. Hypertension. 2001; 38:429–433.Link Google Scholar
119 Wildman RP, Mackey RH, Bostom A, Thompson T, Sutton‐Tyrrell K. Measures of obesity are associated with vascular stiffness in young and older adults. Hypertension. 2003; 42:468–473.Link Google Scholar
120 Weisbrod RM, Shiang T, Al Sayah L, Fry JL, Bajpai S, Reinhart‐King CA, Lob HE, Santhanam L, Mitchell G, Cohen RA, Seta F. Arterial stiffening precedes systolic hypertension in diet‐induced obesity. Hypertension. 2013; 62:1105–1110.Link Google Scholar
121 Dengo AL, Dennis EA, Orr JS, Marinik EL, Ehrlich E, Davy BM, Davy KP. Arterial destiffening with weight loss in overweight and obese middle‐aged and older adults. Hypertension. 2010; 55:855–861.Link Google Scholar
122 Nordstrand N, Gjevestad E, Hertel JK, Johnson LK, Saltvedt E, Røislien J, Hjelmesaeth J. Arterial stiffness, lifestyle intervention and a low‐calorie diet in morbidly obese patients‐a nonrandomized clinical trial. Obesity (Silver Spring). 2013; 21:690–697.Crossref Medline Google Scholar
123 Wohlfahrt P, Redfield MM, Lopez‐Jimenez F, Melenovsky V, Kane GC, Rodeheffer RJ, Borlaug BA. Impact of general and central adiposity on ventricular‐arterial aging in women and men. JACC Heart Fail. 2014; 2:489–499.Crossref Medline Google Scholar
124 Alpert MA, Lambert CR, Panayiotou H, Terry BE, Cohen MV, Massey CV, Hashimi MW, Mukerji V. Relation of duration of morbid obesity to left ventricular mass, systolic function, and diastolic filling, and effect of weight loss. Am J Cardiol. 1995; 76:1194–1197.Crossref Medline Google Scholar
125 Otto ME, Belohlavek M, Romero‐Corral A, Gami AS, Gilman G, Svatikova A, Amin RS, Lopez‐Jimenez F, Khandheria BK, Somers VK. Comparison of cardiac structural and functional changes in obese otherwise healthy adults with versus without obstructive sleep apnea. Am J Cardiol. 2007; 99:1298–1302.Crossref Medline Google Scholar
126 Fung JW, Li TS, Choy DK, Yip GW, Ko FW, Sanderson JE, Hui DS. Severe obstructive sleep apnea is associated with left ventricular diastolic dysfunction. Chest. 2002; 121:422–429.Crossref Medline Google Scholar
127 Arias MA, García‐Río F, Alonso‐Fernández A, Mediano O, Martínez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation. 2005; 112:375–383.Link Google Scholar
128 Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, Young T. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology; American Heart Association Stroke Council; American Heart Association Council on Cardiovascular Nursing; American College of Cardiology Foundation. Circulation. 2008; 118:1080–1111. Erratum in: Circulation. 2009;119:e380.Link Google Scholar
129 Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med. 1994; 154:1705–1711.Crossref Medline Google Scholar
130 Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol. 2001; 38:789–795.Crossref Medline Google Scholar
131 Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura HO. Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. JACC Heart Fail. 2013; 1:93–102.Crossref Medline Google Scholar
132 Lavie CJ, Cahalin LP, Chase P, Myers J, Bensimhon D, Peberdy MA, Ashley E, West E, Forman DE, Guazzi M, Arena R. Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure. Mayo Clin Proc. 2013; 88:251–258.Crossref Medline Google Scholar
133 Clark AL, Fonarow GC, Horwich TB. Waist circumference, body mass index, and survival in systolic heart failure: the obesity paradox revisited. J Card Fail. 2011; 17:374–380.Crossref Medline Google Scholar
134 Levitan EB, Yang AZ, Wolk A, Mittleman MA. Adiposity and incidence of heart failure hospitalization and mortality: a population‐based prospective study. Circ Heart Fail. 2009; 2:202–208.Link Google Scholar
135 Shah R, Gayat E, Januzzi JL, Sato N, Cohen‐Solal A, diSomma S, Fairman E, Harjola VP, Ishihara S, Lassus J, Maggioni A, Metra M, Mueller C, Mueller T, Parenica J, Pascual‐Figal D, Peacock WF, Spinar J, van Kimmenade R, Mebazaa A; GREAT (Global Research on Acute Conditions Team) Network . Body mass index and mortality in acutely decompensated heart failure across the world: a global obesity paradox. J Am Coll Cardiol. 2014; 63:778–785.Crossref Medline Google Scholar
136 Khalid U, Ather S, Bavishi C, Chan W, Loehr LR, Wruck LM, Rosamond WD, Chang PP, Coresh J, Virani SS, Nambi V, Bozkurt B, Ballantyne CM, Deswal A. Pre‐morbid body mass index and mortality after incident heart failure: the ARIC Study. J Am Coll Cardiol. 2014; 64:2743–2749.Crossref Medline Google Scholar
137 Chrysant SG, Chrysant GS. New insights into the true nature of the obesity paradox and the lower cardiovascular risk. J Am Soc Hypertens. 2013; 7:85–94.Crossref Medline Google Scholar
138 Bibbins‐Domingo K, Pletcher MJ, Lin F, Vittinghoff E, Gardin JM, Arynchyn A, Lewis CE, Williams OD, Hulley SB. Racial differences in incident heart failure among young adults. N Engl J Med. 2009; 360:1179–1190.Crossref Medline Google Scholar
139 Okin PM, Kjeldsen SE, Dahlöf B, Devereux RB. Racial differences in incident heart failure during antihypertensive therapy. Circ Cardiovasc Qual Outcomes. 2011; 4:157–164.Link Google Scholar
140 Kizer JR, Arnett DK, Bella JN, Paranicas M, Rao DC, Province MA, Oberman A, Kitzman DW, Hopkins PN, Liu JE, Devereux RB. Differences in left ventricular structure between black and white hypertensive adults: the Hypertension Genetic Epidemiology Network study. Hypertension. 2004; 43:1182–1188.Link Google Scholar
141 Drazner MH, Dries DL, Peshock RM, Cooper RS, Klassen C, Kazi F, Willett D, Victor RG. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas Heart Study. Hypertension. 2005; 46:124–129.Link Google Scholar
142 Morris AA, Patel RS, Binongo JN, Poole J, Al Mheid I, Ahmed Y, Stoyanova N, Vaccarino V, Din‐Dzietham R, Gibbons GH, Quyyumi A. Racial differences in arterial stiffness and microcirculatory function between Black and White Americans. J Am Heart Assoc. 2013; 2:e002154 doi: 10.1161/JAHA.112.002154 .Link Google Scholar
143 Gupta DK, Shah AM, Castagno D, Takeuchi M, Loehr LR, Fox ER, Butler KR, Mosley TH, Kitzman DW, Solomon SD. Heart failure with preserved ejection fraction in African Americans: the ARIC (Atherosclerosis Risk In Communities) study. JACC Heart Fail. 2013; 1:156–163.Crossref Medline Google Scholar
144 Montero D, Roberts CK, Vinet A. Arterial stiffness in obese populations: is it reduced by aerobic training?Int J Cardiol. 2014; 176:280–281.Crossref Medline Google Scholar
145 Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi‐Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society . 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014; 63:2985–3023.Crossref Medline Google Scholar
146 Courcoulas AP, Christian NJ, Belle SH, Berk PD, Flum DR, Garcia L, Horlick M, Kalarchian MA, King WC, Mitchell JE, Patterson EJ, Pender JR, Pomp A, Pories WJ, Thirlby RC, Yanovski SZ, Wolfe BM; Longitudinal Assessment of Bariatric Surgery (LABS) Consortium . Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA. 2013; 310:2416–2425.Medline Google Scholar
147 Poirier P, Cornier MA, Mazzone T, Stiles S, Cummings S, Klein S, McCullough PA, Ren Fielding C, Franklin BA; American Heart Association Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism . Bariatric surgery and cardiovascular risk factors: a scientific statement from the American Heart Association. Circulation. 2011; 123:1683–1701.Link Google Scholar
148 Owan T, Avelar E, Morley K, Jiji R, Hall N, Krezowski J, Gallagher J, Williams Z, Preece K, Gundersen N, Strong MB, Pendleton RC, Segerson N, Cloward TV, Walker JM, Farney RJ, Gress RE, Adams TD, Hunt SC, Litwin SE. Favorable changes in cardiac geometry and function following gastric bypass surgery: 2‐year follow‐up in the Utah obesity study. J Am Coll Cardiol. 2011; 57:732–739.Crossref Medline Google Scholar
149 Leichman JG, Wilson EB, Scarborough T, Aguilar D, Miller CC, Yu S, Algahim MF, Reyes M, Moody FG, Taegtmeyer H. Dramatic reversal of derangements in muscle metabolism and left ventricular function after bariatric surgery. Am J Med. 2008; 121:966–973.Crossref Medline Google Scholar
150 Algahim MF, Sen S, Taegtmeyer H. Bariatric surgery to unload the stressed heart: a metabolic hypothesis. Am J Physiol Heart Circ Physiol. 2012; 302:H1539–H1545.Crossref Medline Google Scholar
151 Ashrafian H, le Roux CW, Darzi A, Athanasiou T. Effects of bariatric surgery on cardiovascular function. Circulation. 2008; 118:2091–2102.Link Google Scholar
152 Hoeper MM, Barberà JA, Channick RN, Hassoun PM, Lang IM, Manes A, Martinez FJ, Naeije R, Olschewski H, Pepke‐Zaba J, Redfield MM, Robbins IM, Souza R, Torbicki A, McGoon M. Diagnosis, assessment, and treatment of non‐pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol. 2009; 54:S85–S96.Crossref Medline Google Scholar
153 Guglin M, Khan H. Pulmonary hypertension in heart failure. J Card Fail. 2010; 16:461–474.Crossref Medline Google Scholar
154 Haddad F, Kudelko K, Mercier O, Vrtovec B, Zamanian RT, de Jesus Perez V. Pulmonary hypertension associated with left heart disease: characteristics, emerging concepts, and treatment strategies. Prog Cardiovasc Dis. 2011; 54:154–167.Crossref Medline Google Scholar
155 Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: part 1: epidemiology, pathophysiology, and definitions. Circ Heart Fail. 2013; 6:344–354.Link Google Scholar
156 Kalogeropoulos AP, Georgiopoulou VV, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: part 2: prognosis, noninvasive evaluation, treatment, and future research. Circ Heart Fail. 2013; 6:584–593.Link Google Scholar
157 Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non‐category 1) pulmonary hypertension. Circulation. 2008; 118:2190–2199.Link Google Scholar
158 Hill NS, Preston I, Roberts K. Defining the phenotypes for pulmonary hypertension associated with diastolic heart failure. Circ Heart Fail. 2011; 4:238–240.Link Google Scholar
159 Enriquez‐Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol. 1997; 29:153–159.Crossref Medline Google Scholar
160 Robbins JD, Maniar PB, Cotts W, Parker MA, Bonow RO, Gheorghiade M. Prevalence and severity of functional mitral regurgitation in chronic systolic heart failure. Am J Cardiol. 2003; 91:360–362.Crossref Medline Google Scholar
161 Gerges C, Gerges M, Lang MB, Zhang Y, Jakowitsch J, Probst P, Maurer G, Lang IM. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out‐of‐proportion” pulmonary hypertension. Chest. 2013; 143:758–766.Crossref Medline Google Scholar
162 Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1‐year, prospective, randomized, placebo‐controlled study. Circ Heart Fail. 2011; 4:8–17.Link Google Scholar
163 Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007; 116:1555–1562.Link Google Scholar
164 Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009; 361:1864–1871.Crossref Medline Google Scholar
165 Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community‐based study. J Am Coll Cardiol. 2009; 53:1119–1126.Crossref Medline Google Scholar
166 Thenappan T, Shah SJ, Gomberg‐Maitland M, Collander B, Vallakati A, Shroff P, Rich S. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2011; 4:257–265.Link Google Scholar
167 Perez VA, Haddad F, Zamanian RT. Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction. Pulm Circ. 2012; 2:163–169.Crossref Medline Google Scholar
168 Maréchaux S, Neicu DV, Braun S, Richardson M, Delsart P, Bouabdallaoui N, Banfi C, Gautier C, Graux P, Asseman P, Pibarot P, Le Jemtel TH, Ennezat PV; Lille HFpEF Study Group . Functional mitral regurgitation: a link to pulmonary hypertension in heart failure with preserved ejection fraction. J Card Fail. 2011; 17:806–812.Crossref Medline Google Scholar
169 Ennezat PV, Maréchaux S, Pibarot P, Le Jemtel TH. Secondary mitral regurgitation in heart failure with reduced or preserved left ventricular ejection fraction. Cardiology. 2013; 125:110–117.Crossref Medline Google Scholar
170 Maréchaux S, Pinçon C, Poueymidanette M, Verhaeghe M, Bellouin A, Asseman P, Le Tourneau T, Lejemtel TH, Pibarot P, Ennezat PV. Elevated left atrial pressure estimated by Doppler echocardiography is a key determinant of mitral valve tenting in functional mitral regurgitation. Heart. 2010; 96:289–297.Crossref Medline Google Scholar
171 Maréchaux S, Terrade J, Biausque F, Lefetz Y, Deturck R, Asseman P, Le Jemtel TH, Ennezat PV. Exercise‐induced functional mitral regurgitation in heart failure and preserved ejection fraction: a new entity. Eur J Echocardiogr. 2010; 11:E14.Medline Google Scholar
172 Ennezat PV, Maréchaux S, Bouabdallaoui N, Le Jemtel TH. Dynamic nature of pulmonary artery systolic pressure in decompensated heart failure with preserved ejection fraction: role of functional mitral regurgitation. J Card Fail. 2013; 19:746–752.Crossref Medline Google Scholar
173 Willens HJ, Kessler KM. Severe pulmonary hypertension associated with diastolic left ventricular dysfunction. Chest. 1993; 103:1877–1883.Crossref Medline Google Scholar
174 Halpern SD, Taichman DB. Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end‐diastolic pressure. Chest. 2009; 136:37–43.Crossref Medline Google Scholar
175 Guazzi M, Gomberg‐Maitland M, Arena R. Pulmonary hypertension in heart failure with preserved ejection fraction. J Heart Lung Transplant. 2015; 34:273–281.Crossref Medline Google Scholar
176 Robbins IM, Hemnes AR, Pugh ME, Brittain EL, Zhao DX, Piana RN, Fong PP, Newman JH. High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension. Circ Heart Fail. 2014; 7:116–122.Link Google Scholar
177 Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA. Differential hemodynamic effects of exercise and volume expansion in people with and without heart failure. Circ Heart Fail. 2015; 8:41–48.Link Google Scholar
178 Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010; 3:588–595.Link Google Scholar
179 Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T, Cruz M, Berk JL, Plante‐Bordeneuve V, Schmidt HH, Merlini G. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol. 2015; 66:2451–2466.Crossref Medline Google Scholar
180 Westermann D, Becher PM, Lindner D, Savvatis K, Xia Y, Fröhlich M, Hoffmann S, Schultheiss HP, Tschöpe C. Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II‐induced heart failure in vivo. Basic Res Cardiol. 2012; 107:308.Crossref Medline Google Scholar
181 Testani JM, St John Sutton MG, Wiegers SE, Khera AV, Shannon RP, Kirkpatrick JN. Accuracy of noninvasively determined pulmonary artery systolic pressure. Am J Cardiol. 2010; 105:1192–1197.Crossref Medline Google Scholar
182 Attaran RR, Ramaraj R, Sorrell VL, Movahed MR. Poor correlation of estimated pulmonary artery systolic pressure between echocardiography and right heart catheterization in patients awaiting cardiac transplantation: results from the clinical arena. Transplant Proc. 2009; 41:3827–3830.Crossref Medline Google Scholar
183 Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J. 2015; 36:2565–2573.Crossref Medline Google Scholar
184 Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase‐5 inhibition in a 1‐year study. Circulation. 2011; 124:164–174.Link Google Scholar
185 Kanwar M, Tedford RJ, Agarwal R, Clarke MM, Walter C, Sokos G, Murali S, Benza RL. Management of pulmonary hypertension due to heart failure with preserved ejection fraction. Curr Hypertens Rep. 2014; 16:501.Crossref Medline Google Scholar
186 Ohara T, Ohte N, Little WC. Pulmonary hypertension in heart failure with preserved left ventricular ejection fraction: diagnosis and management. Curr Opin Cardiol. 2012; 27:281–287.Crossref Medline Google Scholar
187 Waxman AB. Pulmonary hypertension in heart failure with preserved ejection fraction: a target for therapy?Circulation. 2011; 124:133–135.Link Google Scholar
188 Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ; Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) Study Group . Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double‐blind, randomized, placebo‐controlled, dose‐ranging hemodynamic study. Circulation. 2013; 128:502–511.Link Google Scholar
189 Bonderman D, Pretsch I, Steringer‐Mascherbauer R, Jansa P, Rosenkranz S, Tufaro C, Bojic A, Lam CS, Frey R, Ochan Kilama M, Unger S, Roessig L, Lang IM. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE‐1): a randomized, double‐blind, placebo‐controlled, single‐dose study. Chest. 2014; 146:1274–1285.Crossref Medline Google Scholar
190 Raftery EB, Banks DC, Oram S. Occlusive disease of the coronary arteries presenting as primary congestive cardiomyopathy. Lancet. 1969; 2:1146–1150.Medline Google Scholar
191 Burch GE, Giles TD, Colcolough HL. Ischemic cardiomyopathy. Am Heart J. 1970; 79:291–292.Crossref Medline Google Scholar
192 Burch GE, Tsui CY, Harb JM. Ischemic cardiomyopathy. Am Heart J. 1972; 83:340–350.Crossref Medline Google Scholar
193 Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow RO, Judd RM. The use of contrast‐enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med. 2000; 343:1445–1453.Crossref Medline Google Scholar
194 Ohara T, Little WC. Evolving focus on diastolic dysfunction in patients with coronary artery disease. Curr Opin Cardiol. 2010; 25:613–621.Crossref Medline Google Scholar
195 Bonow RO, Vitale DF, Bacharach SL, Frederick TM, Kent KM, Green MV. Asynchronous left ventricular regional function and impaired global diastolic filling in patients with coronary artery disease: reversal after coronary angioplasty. Circulation. 1985; 71:297–307.Link Google Scholar
196 Wijns W, Serruys PW, Slager CJ, Grimm J, Krayenbuehl HP, Hugenholtz PG, Hess OM. Effect of coronary occlusion during percutaneous transluminal angioplasty in humans on left ventricular chamber stiffness and regional diastolic pressure‐radius relations. J Am Coll Cardiol. 1986; 7:455–463.Crossref Medline Google Scholar
197 Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC; ADHERE Scientific Advisory Committee and Investigators . Clinical presentation, management, and in‐hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006; 47:76–84.Crossref Medline Google Scholar
198 Edelmann F, Stahrenberg R, Gelbrich G, Durstewitz K, Angermann CE, Düngen HD, Scheffold T, Zugck C, Maisch B, Regitz‐Zagrosek V, Hasenfuss G, Pieske BM, Wachter R. Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction. Clin Res Cardiol. 2011; 100:755–764.Crossref Medline Google Scholar
199 Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014; 63:2817–2827.Crossref Medline Google Scholar
200 Argulian E, Halpern DG, Agarwal V, Agarwal SK, Chaudhry FA. Predictors of ischemia in patients referred for evaluation of exertional dyspnea: a stress echocardiography study. J Am Soc Echocardiogr. 2013; 26:72–76.Crossref Medline Google Scholar
201 Mentz RJ, Broderick S, Shaw LK, Fiuzat M, O'Connor CM. Heart failure with preserved ejection fraction: comparison of patients with and without angina pectoris (from the Duke Databank for Cardiovascular Disease). J Am Coll Cardiol. 2014; 63:251–258.Crossref Medline Google Scholar
202 Greenberg B. Heart failure preserved ejection fraction with coronary artery disease: time for a new classification?J Am Coll Cardiol. 2014; 63:2828–2830.Crossref Medline Google Scholar
203 Rusinaru D, Houpe D, Szymanski C, Lévy F, Maréchaux S, Tribouilloy C. Coronary artery disease and 10‐year outcome after hospital admission for heart failure with preserved and with reduced ejection fraction. Eur J Heart Fail. 2014; 16:967–976.Crossref Medline Google Scholar
204 Kramer K, Kirkman P, Kitzman D, Little WC. Flash pulmonary edema: association with hypertension and reoccurrence despite coronary revascularization. Am Heart J. 2000; 140:451–455.Crossref Medline Google Scholar
205 Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015; 131:550–559.Link Google Scholar
206 Lee PW, Zhang Q, Yip GW, Wu L, Lam YY, Wu EB, Yu CM. Left ventricular systolic and diastolic dyssynchrony in coronary artery disease with preserved ejection fraction. Clin Sci (Lond). 2009; 116:521–529.Crossref Medline Google Scholar
207 Penicka M, Bartunek J, Trakalova H, Hrabakova H, Maruskova M, Karasek J, Kocka V. Heart failure with preserved ejection fraction in outpatients with unexplained dyspnea: a pressure‐volume loop analysis. J Am Coll Cardiol. 2010; 55:1701–1710.Crossref Medline Google Scholar
208 Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, Fiuzat M, Zannad F, Pitt B, O'Connor CM. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014; 64:2281–2293.Crossref Medline Google Scholar
209 Shah SJ, Heitner JF, Sweitzer NK, Anand IS, Kim HY, Harty B, Boineau R, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Lewis EF, Markov V, O'Meara E, Kobulia B, Shaburishvili T, Solomon SD, Pitt B, Pfeffer MA, Li R. Baseline characteristics of patients in the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail. 2013; 6:184–192.Link Google Scholar
210 Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, Wehrens XH, Deswal A. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012; 59:998–1005.Crossref Medline Google Scholar
211 Maréchaux S, Six‐Carpentier MM, Bouabdallaoui N, Montaigne D, Bauchart JJ, Mouquet F, Auffray JL, Le Tourneau T, Asseman P, LeJemtel TH, Ennezat PV. Prognostic importance of comorbidities in heart failure with preserved left ventricular ejection fraction. Heart Vessels. 2011; 26:313–320.Crossref Medline Google Scholar
212 Lund LH, Donal E, Oger E, Hage C, Persson H, Haugen‐Löfman I, Ennezat PV, Sportouch‐Dukhan C, Drouet E, Daubert JC, Linde C; KaRen Investigators . Association between cardiovascular vs. non‐cardiovascular co‐morbidities and outcomes in heart failure with preserved ejection fraction. Eur J Heart Fail. 2014; 16:992–1001.Crossref Medline Google Scholar
213 Braunstein JB, Anderson GF, Gerstenblith G, Weller W, Niefeld M, Herbert R, Wu AW. Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure. J Am Coll Cardiol. 2003; 42:1226–1233.Crossref Medline Google Scholar
214 Grigorian‐Shamagian L, Otero Raviña F, Abu Assi E, Vidal Perez R, Teijeira‐Fernandez E, Varela Roman A, Moreira Sayagues L, Gonzalez‐Juanatey JR. Why and when do patients with heart failure and normal left ventricular ejection fraction die? Analysis of >600 deaths in a community long‐term studyAm Heart J. 2008; 156:1184–1190.Crossref Medline Google Scholar
215 Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB, Lopez‐Sendon J, Teerlink JR, White M, McMurray JJ, Komajda M, McKelvie R, Ptaszynska A, Hetzel SJ, Massie BM, Carson PE; I‐Preserve Investigators . Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I‐Preserve) trial. Circulation. 2010; 121:1393–1405.Link Google Scholar
216 Lee DS, Gona P, Albano I, Larson MG, Benjamin EJ, Levy D, Kannel WB, Vasan RS. A systematic assessment of causes of death after heart failure onset in the community: impact of age at death, time period, and left ventricular systolic dysfunction. Circ Heart Fail. 2011; 4:36–43.Link Google Scholar
217 Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective. Circ Heart Fail. 2008; 1:91–97.Link Google Scholar
218 Magnani JW, Rienstra M, Lin H, Sinner MF, Lubitz SA, McManus DD, Dupuis J, Ellinor PT, Benjamin EJ. Atrial fibrillation: current knowledge and future directions in epidemiology and genomics. Circulation. 2011; 124:1982–1993.Link Google Scholar
219 Kao DP, Lewsey JD, Anand IS, Massie BM, Zile MR, Carson PE, McKelvie RS, Komajda M, McMurray JJ, Lindenfeld J, Kao DP. Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response. Eur J Heart Fail. 2015; 17:925–935.Crossref Medline Google Scholar
220 Maggioni AP, Dahlström U, Filippatos G, Chioncel O, Leiro MC, Drozdz J, Fruhwald F, Gullestad L, Logeart D, Fabbri G, Urso R, Metra M, Parissis J, Persson H, Ponikowski P, Rauchhaus M, Voors AA, Nielsen OW, Zannad F, Tavazzi L. EURObservational Research Programme: regional differences and 1‐year follow‐up results of the heart failure pilot survey (ESC‐HF Pilot). Eur J Heart Fail. 2013; 15:808–817.Crossref Medline Google Scholar
221 Seiler J, Stevenson WG. Atrial fibrillation in congestive heart failure. Cardiol Rev. 2010; 18:38–50.Crossref Medline Google Scholar
222 Rusinaru D, Leborgne L, Peltier M, Tribouilloy C. Effect of atrial fibrillation on long‐term survival in patients hospitalised for heart failure with preserved ejection fraction. Eur J Heart Fail. 2008; 10:566–572.Crossref Medline Google Scholar
223 Mamas MA, Caldwell JC, Chacko S, Garratt CJ, Fath‐Ordoubadi F, Neyses L. A meta‐analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur J Heart Fail. 2009; 11:676–683.Crossref Medline Google Scholar
224 Havmöller R, Chugh SS. Atrial fibrillation in heart failure. Curr Heart Fail Rep. 2012; 9:309–318.Crossref Medline Google Scholar
225 Lip GY, Laroche C, Popescu MI, Rasmussen LH, Vitali‐Serdoz L, Dan GA, Kalarus Z, Crijns HJ, Oliveira MM, Tavazzi L, Maggioni AP, Boriani G. Heart failure in patients with atrial fibrillation in Europe: a report from the EURObservational Research Programme Pilot survey on Atrial Fibrillation. Eur J Heart Fail. 2015; 17:570–582.Crossref Medline Google Scholar
226 Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res. 2014; 114:1453–1468.Link Google Scholar
227 Melenovsky V, Hwang SJ, Redfield MM, Zakeri R, Lin G, Borlaug BA. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ Heart Fail. 2015; 8:295–303.Link Google Scholar
228 Felker GM, Shaw LK, Stough WG, O'Connor CM. Anemia in patients with heart failure and preserved systolic function. Am Heart J. 2006; 151:457–462.Crossref Medline Google Scholar
229 Dunlay SM, Weston SA, Redfield MM, Killian JM, Roger VL. Anemia and heart failure: a community study. Am J Med. 2008; 121:726–732.Crossref Medline Google Scholar
230 Brucks S, Little WC, Chao T, Rideman RL, Upadhya B, Wesley‐Farrington D, Sane DC. Relation of anemia to diastolic heart failure and the effect on outcome. Am J Cardiol. 2004; 93:1055–1057.Crossref Medline Google Scholar
231 Abramov D, Cohen RS, Katz SD, Mancini D, Maurer MS. Comparison of blood volume characteristics in anemic patients with low versus preserved left ventricular ejection fractions. Am J Cardiol. 2008; 102:1069–1072.Crossref Medline Google Scholar
232 Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008; 52:501–511.Crossref Medline Google Scholar
233 Anand IS, Rector TS. Pathogenesis of anemia in heart failure. Circ Heart Fail. 2014; 7:699–700.Link Google Scholar
234 O'Meara E, Rouleau JL, White M, Roy K, Blondeau L, Ducharme A, Neagoe PE, Sirois MG, Lavoie J, Racine N, Liszkowski M, Madore F, Tardif JC, de Denus S; ANCHOR Investigators . Heart failure with anemia: novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes. Circ Heart Fail. 2014; 7:773–781.Link Google Scholar
235 Kasner M, Aleksandrov AS, Westermann D, Lassner D, Gross M, von Haehling S, Anker SD, Schultheiss HP, Tschöpe C. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. Int J Cardiol. 2013; 168:4652–4657.Crossref Medline Google Scholar
236 Klip IT, Comin‐Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, Lok DJ, Rosentryt P, Torrens A, Polonski L, van Veldhuisen DJ, van der Meer P, Jankowska EA. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013; 165:575–582.Crossref Medline Google Scholar
237 Maurer MS, Teruya S, Chakraborty B, Helmke S, Mancini D. Treating anemia in older adults with heart failure with a preserved ejection fraction with epoetin alfa: single‐blind randomized clinical trial of safety and efficacy. Circ Heart Fail. 2013; 6:254–263.Link Google Scholar
238 Tribouilloy C, Rusinaru D, Mahjoub H, Soulière V, Lévy F, Peltier M, Slama M, Massy Z. Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population‐based study. Eur Heart J. 2008; 29:339–347.Crossref Medline Google Scholar
239 Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol. 2007; 49:171–180.Crossref Medline Google Scholar
240 Barr RG, Bluemke DA, Ahmed FS, Carr JJ, Enright PL, Hoffman EA, Jiang R, Kawut SM, Kronmal RA, Lima JA, Shahar E, Smith LJ, Watson KE. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N Engl J Med. 2010; 362:217–227.Crossref Medline Google Scholar
241 Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, Hoes AW. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J. 2005; 26:1887–1894.Crossref Medline Google Scholar
242 Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G,McBurnie MA; Cardiovascular Health Study Collaborative Research Group . Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56:146–156.Crossref Medline Google Scholar
243 Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004; 59:255–263.Crossref Medline Google Scholar
244 Murad K, Kitzman DW. Frailty and multiple comorbidities in the elderly patient with heart failure: implications for management. Heart Fail Rev. 2012; 17:581–588.Crossref Medline Google Scholar
245 Goldwater DS, Pinney SP. Frailty in advanced heart failure: a consequence of aging or a separate entity?Clin Med Insights Cardiol. 2015; 9(suppl 2):39–46.Medline Google Scholar
246 McNallan SM, Singh M, Chamberlain AM, Kane RL, Dunlay SM, Redfield MM, Weston SA, Roger VL. Frailty and healthcare utilization among patients with heart failure in the community. JACC Heart Fail. 2013; 1:135–141.Crossref Medline Google Scholar
247 Lupón J, González B, Santaeugenia S, Altimir S, Urrutia A, Más D, Díez C, Pascual T, Cano L, Valle V. Prognostic implication of frailty and depressive symptoms in an outpatient population with heart failure. Rev Esp Cardiol. 2008; 61:835–842.Crossref Medline Google Scholar
248 Pardaens K, Van Cleemput J, Vanhaecke J, Fagard RH. Atrial fibrillation is associated with a lower exercise capacity in male chronic heart failure patients. Heart. 1997; 78:564–568.Crossref Medline Google Scholar
249 Herrscher TE, Akre H, Øverland B, Sandvik L, Westheim AS. High prevalence of sleep apnea in heart failure outpatients: even in patients with preserved systolic function. J Card Fail. 2011; 17:420–425.Crossref Medline Google Scholar
250 Bitter T, Faber L, Hering D, Langer C, Horstkotte D, Oldenburg O. Sleep‐disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail. 2009; 11:602–608.Crossref Medline Google Scholar
251 Sekizuka H, Osada N, Miyake F. Sleep disordered breathing in heart failure patients with reduced versus preserved ejection fraction. Heart Lung Circ. 2013; 22:104–109.Crossref Medline Google Scholar
252 Kim SH, Cho GY, Shin C, Lim HE, Kim YH, Song WH, Shim WJ, Ahn JC. Impact of obstructive sleep apnea on left ventricular diastolic function. Am J Cardiol. 2008; 101:1663–1668.Crossref Medline Google Scholar
253 Usui Y, Takata Y, Inoue Y, Tomiyama H, Kurohane S, Hashimura Y, Kato K, Saruhara H, Asano K, Shiina K, Yamashina A. Severe obstructive sleep apnea impairs left ventricular diastolic function in non‐obese men. Sleep Med. 2013; 14:155–159.Crossref Medline Google Scholar
254 Wachter R, Lüthje L, Klemmstein D, Lüers C, Stahrenberg R, Edelmann F, Holzendorf V, Hasenfuß G, Andreas S, Pieske B. Impact of obstructive sleep apnoea on diastolic function. Eur Respir J. 2013; 41:376–383.Crossref Medline Google Scholar
255 Chami HA, Devereux RB, Gottdiener JS, Mehra R, Roman MJ, Benjamin EJ, Gottlieb DJ. Left ventricular morphology and systolic function in sleep‐disordered breathing: the Sleep Heart Health Study. Circulation. 2008; 117:2599–2607.Link Google Scholar
256 Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea. J Hypertens. 1990; 8:941–946.Crossref Medline Google Scholar
257 Kraiczi H, Peker Y, Caidahl K, Samuelsson A, Hedner J. Blood pressure, cardiac structure and severity of obstructive sleep apnea in a sleep clinic population. J Hypertens. 2001; 19:2071–2078.Crossref Medline Google Scholar
258 Sukhija R, Aronow WS, Sandhu R, Kakar P, Maguire GP, Ahn C, Lehrman SG. Prevalence of left ventricular hypertrophy in persons with and without obstructive sleep apnea. Cardiol Rev. 2006; 14:170–172.Crossref Medline Google Scholar
259 Bradley TD, Floras JS. Sleep apnea and heart failure, part I: obstructive sleep apnea. Circulation. 2003; 107:1671–1678.Link Google Scholar
260 Kasai T, Bradley TD. Obstructive sleep apnea and heart failure: pathophysiologic and therapeutic implications. J Am Coll Cardiol. 2011; 57:119–127.Crossref Medline Google Scholar
261 Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995; 96:1897–1904.Crossref Medline Google Scholar
262 Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation. 2005; 112:2660–2667.Link Google Scholar
263 Drager LF, Bortolotto LA, Figueiredo AC, Silva BC, Krieger EM, Lorenzi‐Filho G. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007; 131:1379–1386.Crossref Medline Google Scholar
264 Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM, Lorenzi‐Filho G. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2005; 172:613–618.Crossref Medline Google Scholar
265 Doonan RJ, Scheffler P, Lalli M, Kimoff RJ, Petridou ET, Daskalopoulos ME, Daskalopoulou SS. Increased arterial stiffness in obstructive sleep apnea: a systematic review. Hypertens Res. 2011; 34:23e32.Crossref Google Scholar
266 Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, Ando S, Bradley TD. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med. 2003; 348:1233–1241.Crossref Medline Google Scholar
267 Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med. 2004; 169:361–366.Crossref Medline Google Scholar
268 Usui K, Bradley TD, Spaak J, Ryan CM, Kubo T, Kaneko Y, Floras JS. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol. 2005; 45:2008–2011.Crossref Medline Google Scholar
269 Wang H, Parker JD, Newton GE, Floras JS, Mak S, Chiu KL, Ruttanaumpawan P, Tomlinson G, Bradley TD. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol. 2007; 49:1625–1631.Crossref Medline Google Scholar
270 Butt M, Dwivedi G, Shantsila A, Khair OA, Lip GY. Left ventricular systolic and diastolic function in obstructive sleep apnea: impact of continuous positive airway pressure therapy. Circ Heart Fail. 2012; 5:226–233.Link Google Scholar
271 Marin JM, Agusti A, Villar I, Forner M, Nieto D, Carrizo SJ, Barbé F, Vicente E, Wei Y, Nieto FJ, Jelic S. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012; 307:2169–2176.Crossref Medline Google Scholar
272 Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, Foster GD, Maislin G, Saif H, Broderick P, Chittams J, Hanlon AL, Pack AI. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med. 2014; 370:2265–2275.Crossref Medline Google Scholar
273 Haentjens P, Van Meerhaeghe A, Moscariello A, De Weerdt S, Poppe K, Dupont A, Velkeniers B. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta‐analysis of placebo‐controlled randomized trials. Arch Intern Med. 2007; 167:757–764.Crossref Medline Google Scholar
274 From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre‐clinical diastolic dysfunction a population‐based study. J Am Coll Cardiol. 2010; 55:300–305.Crossref Medline Google Scholar
275 Aguilar D, Deswal A, Ramasubbu K, Mann DL, Bozkurt B. Comparison of patients with heart failure and preserved left ventricular ejection fraction among those with versus without diabetes mellitus. Am J Cardiol. 2010; 105:373–377.Crossref Medline Google Scholar
276 Tribouilloy C, Rusinaru D, Mahjoub H, Tartière JM, Kesri‐Tartière L, Godard S, Peltier M. Prognostic impact of diabetes mellitus in patients with heart failure and preserved ejection fraction: a prospective five‐year study. Heart. 2008; 94:1450–1455.Crossref Medline Google Scholar
277 MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, Solomon SD, Granger CB, Swedberg K, Yusuf S, Pfeffer MA, McMurray JJ; CHARM Investigators . Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008; 29:1377–1385.Crossref Medline Google Scholar
278 Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006; 98:596–605.Link Google Scholar
279 Sharman JE, Haluska BA, Fang ZY, Prins JB, Marwick TH. Association of arterial wave properties and diastolic dysfunction in patients with type 2 diabetes mellitus. Am J Cardiol. 2007; 99:844–848.Crossref Medline Google Scholar
280 Safar ME, Balkau B, Lange C, Protogerou AD, Czernichow S, Blacher J, Levy BI, Smulyan H. Hypertension and vascular dynamics in men and women with metabolic syndrome. J Am Coll Cardiol. 2013; 61:12–19.Crossref Medline Google Scholar
281 Creager MA, Lüscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation. 2003; 108:1527–1532.Link Google Scholar
282 Guazzi M, Brambilla R, Pontone G, Agostoni P, Guazzi MD. Effect of non‐insulin‐dependent diabetes mellitus on pulmonary function and exercise tolerance in chronic congestive heart failure. Am J Cardiol. 2002; 89:191–197.Crossref Medline Google Scholar
283 Tibb AS, Ennezat PV, Chen JA, Haider A, Gundewar S, Cotarlan V, Aggarwal VS, Talreja A, Le Jemtel TH. Diabetes lowers aerobic capacity in heart failure. J Am Coll Cardiol. 2005; 46:930–931.Crossref Medline Google Scholar
284 Scheuermann‐Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P, Radda GK, Neubauer S, Clarke K. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation. 2003; 107:3040–3046.Link Google Scholar
285 Nishio M, Sakata Y, Mano T, Ohtani T, Takeda Y, Hori M, Yamamoto K. Difference of clinical characteristics between hypertensive patients with and without diastolic heart failure: the roles of diastolic dysfunction and renal insufficiency. Hypertens Res. 2008; 31:1865–1872.Crossref Medline Google Scholar
286 McAlister FA, Ezekowitz J, Tarantini L, Squire I, Komajda M, Bayes‐Genis A, Gotsman I, Whalley G, Earle N, Poppe KK, Doughty RN; Meta‐analysis Global Group in Chronic Heart Failure (MAGGIC) Investigators . Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction: impact of the new Chronic Kidney Disease‐Epidemiology Collaboration Group formula. Circ Heart Fail. 2012; 5:309–314.Link Google Scholar
287 Sharma K, Hill T, Grams M, Daya NR, Hays AG, Fine D, Thiemann DR, Weiss RG, Tedford RJ, Kass DA, Schulman SP, Russell SD. Outcomes and worsening renal function in patients hospitalized with heart failure with preserved ejection fraction. Am J Cardiol. 2015; 116:1534–1540.Crossref Medline Google Scholar
288 Gori M, Senni M, Gupta DK, Charytan DM, Kraigher‐Krainer E, Pieske B, Claggett B, Shah AM, Santos AB, Zile MR, Voors AA, McMurray JJ, Packer M, Bransford T, Lefkowitz M, Solomon SD; PARAMOUNT Investigators . Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction. Eur Heart J. 2014; 35:3442–3451.Crossref Medline Google Scholar
289 Katz DH, Burns JA, Aguilar FG, Beussink L, Shah SJ. Albuminuria is independently associated with cardiac remodeling, abnormal right and left ventricular function, and worse outcomes in heart failure with preserved ejection fraction. JACC Heart Fail. 2014; 2:586–596.Crossref Medline Google Scholar
290 Rusinaru D, Buiciuc O, Houpe D, Tribouilloy C. Renal function and long‐term survival after hospital discharge in heart failure with preserved ejection fraction. Int J Cardiol. 2011; 147:278–282.Crossref Medline Google Scholar
291 Damman K, Perez AC, Anand IS, Komajda M, McKelvie RS, Zile MR, Massie B, Carson PE, McMurray JJ. Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol. 2014; 64:1106–1113.Crossref Medline Google Scholar
292 Jefferies JL, Bartone C, Menon S, Egnaczyk GF, O'Brien TM, Chung ES. Ultrafiltration in heart failure with preserved ejection fraction: comparison with systolic heart failure patients. Circ Heart Fail. 2013; 6:733–739.Link Google Scholar

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Journal of the American Heart Association, volume 5 issue 1 cover

January 13, 2016
Vol 5, Issue 1

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This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

https://doi.org/10.1161/JAHA.115.002477

PMID: 26811159

Originally publishedJanuary 25, 2016

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