Diabetes mellitus is a metabolic disease with rapidly increasing prevalence. Sedentary lifestyle, ageing, overfeeding and obesity lead to diabetes mellitus and result in over 80% of cardiovascular deaths among these patients.
71 Clinical and experimental studies have demonstrated compromised cardiac function as a result of altered myocardial metabolism caused by diabetes, with a mismatch of myocardial supply and demand.
72 Cardiovascular consequences of diabetes are atherosclerotic epicardial CAD and cardiomyocyte and myocardium changes. Diabetes mellitus is a risk factor for cardiovascular disease, independent of age, hypertension, obesity and hyperlipidemia.
73 The term
diabetes-associated cardiovascular dysfunction includes a number of myocardial changes, including functional, metabolic and structural changes.
74,75
Subclinical level of disease
The subclinical level of diabetes-induced myocardial changes can be categorized as atherosclerotic changes of epicardial coronary arteries or microvascular coronary endothelial dysfunction with cardiomyocyte changes (schematically illustrated in
Figure 3). The endothelium is a central regulator of vascular homeostasis. This includes hormone transport and distribution, metabolic waste product disposal and regulation of regional blood flow by synthesis and release of different mediators with opposing vascular properties (NO, prostacyclin and endothelial-derived hyperpolarizing factor are balanced by Endothelin 1 (ET-1), angiotensin II and thromboxane A
2 to assure maintenance of nutrient and oxygen delivery to tissues by controlling vascular tone, vascular permeability and hemostasis).
76 The key pathophysiologic process of diabetes-induced coronary microvascular dysfunction is impaired coronary arteriole vasomotion, including impaired endothelial-mediated vasodilation, hypoxia-induced vasodilation and myogenic response.
72 Vasomotor dysfunction, affecting both smooth muscle- and endothelium-mediated mechanisms, is an early change, with long-term structural changes and diabetic microangiopathy development. Hyperglycaemia, as a primary pathogenic mechanism together with insulin resistance, hyperinsulinaemia, TNF-α overexpression and inflammation, supresses flow-mediated endothelial-dependent vasodilatation via decreased NO levels and increased ET-1 levels, causing acute intracellular changes.
72,76,77
One of the primary physiological stimuli involved in local regulation of arterial diameter is intraluminal blood flow, predominantly via NO endothelium-dependent vasodilation. NO production and vasodilation is reduced in diabetic animals and patients with diabetes, with reduced response to pharmacological and mechanical stimuli.
72,78 Structural changes in microvessels are a sign of chronicity, manifested as a thickened capillary basement membrane, microaneurisms, spiral deformation, medial arteriole thickening, perivascular fibrosis and constriction, reduced vascular density as a result of vascular endothelial cell growth factor disturbances, reduced angiogenesis and perivascular fibrosis.
79–81 Additional mechanisms of diabetes-related cardiomyocyte changes in contractility and stiffness include: altered Ca
2+ handling with decreased myofilament function; increased mitochondrial and non-mitochondrial reactive oxygen species formation and impaired antioxidant defenses that contribute to oxidative stress in type 1 and type 2 diabetes mellitus (with increased DNA damage and loss of activity DNA repair pathways promoting abnormal cardiac remodeling and cell death); decreased mitochondrial dysfunction as a result of functional and structural changes with reduced ATP production and contractility; decreased glucose oxidation and increased fatty acid oxidation; increased lipotoxicity; accumulation of ceramides; increased renin-angiotensin-aldosterone system activation with oxidative stress damage; endothelial/cardiomyocyte cell apoptosis and necrosis; and myocardial fibrosis, collagen formation, increased thrombosis, decreased fibrinolysis and autonomic dysfunction with sympathetic overdrive.
72,77,82–84
Elucidation of the molecular mechanisms underlying endothelial physiology is crucial for a better understanding of the pathophysiology involved in endothelial dysfunction during diabetes. Diabetic endothelial dysfunction involves a complex set of changes that includes metabolic and functional alterations, microvascular and neurohormonal disturbances and autonomic dysfunction. A better understanding of these processes may help in the development of novel approaches for early detection of resulting cardiovascular complications and eventual diabetic cardiomyopathy (DMCMP).
76,84
Coronary microvascular disease diagnosis requires the exclusion of abnormalities and significant stenosis of major epicardial vessels by coronary angiography. In patients with suspected coronary microvascular disease, attempts should not be made to rely on this exclusion, but rather to obtain objective evidence of coronary microvascular disease.
Non-invasive diagnostic methods
Microvascular disease should be suspected when chest pain persists after physical effort and shows slow or no response to short-acting nitrates.
85,86 Transthoracic Doppler echocardiography (TTDE) is an initial screening method to detect significant microcirculation impairment. It allows the measurement of coronary blood flow (CBF) velocity in the left anterior descending artery. With this method, coronary microvascular dilatator function is calculated as the ratio of diastolic CBF velocity at peak vasodilatation to CBF velocity at rest.
87 A ratio < 2.0 in response to adenosine or dipyridamole strongly suggests coronary microvascular dysfunction. Mild coronary microvascular dysfunction may not be identified by TTDE, and microvascular dysfunction can be assessed only in the left anterior descending artery perfusion area, because other coronary arteries are not well visualized.
87
Contrast stress echocardiography is promising for coronary microvascular disease detection and may be used when TTDE results are inconclusive or unreliable.
87 Yağmur et al.
88 demonstrated impaired longitudinal systolic strain on speckle tracking echocardiography despite normal systolic parameters. 2-D-speckle tracking echocardiography is a feasible technique that allows the evaluation of left ventricular regional systolic function in patients with microvascular dysfunction. This study contributed to our understanding of the relationship between fiber architecture, myocardial function and coronary microvascular disease. Leung et al.
89 demonstrated that left ventricle contractile reserve with low dose dobutamine echocardiography can be used to non-invasively estimate the index of microcirculatory resistance. Impaired contractile reserve in this study indicated coronary microvascular dysfunction.
Regional left ventricle myocardial perfusion reserve (ratio between maximal hyperemic and basal myocardial blood flow) can be estimated in patients with diabetes with single photon technology, which is broadly available. Myocardial blood flow index can be determined from gated Single-photon emission computed tomography (SPECT) images using
99 mTc-labelled tracers by measuring first transit counts in the pulmonary artery and myocardial count rate.
90
Coronary magnetic resonance imaging, with a pharmacological stress test and gadolinium as a flow tracer, is a relatively new noninvasive method to detect microvascular angina. Currently, this is still a complex, expensive and time-consuming technique for widespread utilization.
91,92 Positron emission tomography (PET) allows measurement of CBF per gram of myocardial tissue and can be used to identify coronary microvascular dysfunction.
93 However, coronary flow reserve (ratio of maximal hyperemic to basal CBF) may be preserved in mild forms of coronary microvascular disease. PET can also detect coronary vasomotor abnormalities caused by microvascular disease.
94,95 Recent studies suggest that
82Rb PET/CT is emerging as an important as well as rapid non-invasive assessment method of microvascular function and structure in asymptomatic patients with type 2 diabetes.
96 Some authors consider PET as the gold standard for myocardial flow reserve measurements and myocardial viability assessments.
97
The objective documentation of myocardial ischemia in patients with microvascular dysfunction can be obtained with the use of specific tests. For example, the assessment of lipid peroxidation products in the coronary sinus after stress tests represents a sensitive method to detect myocardial ischemia in patients with microvascular dysfunction.
87 Unfortunately, this method is invasive and cannot be proposed for routine application. Coronary magnetic resonance spectroscopy may detect phosphorus metabolism abnormalities after a stress test,
98 but this method is very expensive and can only detect anterior heart wall defects.
Invasive diagnostic methods
In patients with unstable microvascular angina, a standard ECG record can detect newly developing abnormalities, including ST depression, T-wave inversion and elevation of cardio-sensitive markers, especially troponin. Unstable microvascular angina diagnosis requires exclusion of coronary spasm and coronary thrombosis. Patients with coronary spasm typically have chest pain after physical effort and display ST elevation in an ECG. Thrombosis is unlikely when there is no evidence of atherosclerosis or coronary abnormalities, but some conditions can be associated with thrombus formation in vessels without atherosclerosis.
99 Coronary microvascular disease diagnosis can be confirmed with vasoconstrictor agents, such as ergonovine and acetylcholine, and should be performed during coronary angiography. An induction of angina and ST changes without epicardial vasoconstriction would be diagnostic for coronary microvascular disease.
Coronary angiography allows us to assess and analyze coronary microvascular function with several different methods. Some of these methods include thermodilution, the gas washout method and intracoronary Doppler wire flow. All of these methods allow CBF and coronary flow reserve quantification.
Intravascular Doppler ultrasonography (IVUS) allows us to visualize the state of arterial walls and to detect atherosclerotic plaques that cannot be adequately observed on angiograms. IVUS is a method that is primarily applied in the intracoronary recording of CBF using Doppler and pressure wires and allows exact measurement of CBF velocity. Using intracoronary Doppler and pressure sensors we can determine the index of microvascular resistance. This is defined as the distal coronary pressure multiplied by the exact transit time of reactive hyperemia.
100
It should not be forgotten that a “normal” coronary angiogram does not necessarily rule out an atherosclerotic plaque. With IVUS we can detect non-obstructive atherosclerotic plaques in coronary arteries. Often in diffuse CAD, the wall thickens outward without forming notches in the lumen. In patients who have diffuse epicardial artery disease but without significant proximal stenosis, fractional flow reserve analysis can be performed. Fractional flow reserve is the ratio between the distal coronary pressure and the aortic pressure during maximal coronary vasodilatation. A value <0.8 is suggestive of hemodynamically significant plaques that are perhaps not yet obstructive. Thus, we can avoid erroneously attributing patients’ symptoms to microvascular dysfunction.
101
Coronary angiography allows indirect evaluation of microvascular function by measurement of angiographic indexes. Myocardial blush is the myocardial opacification that results from injection of dye into the coronary circulation. We can determine the myocardial blush grade by counting the number of heart cycles required for the dye to fade out, which depends on the microcirculatory resistance to contrast passage and venous drainage efficiency.
100,102 The total myocardial blush score is the sum of the myocardial blush grade of each coronary territory and defines the overall microvascular functionality.
102
The TIMI frame count (TFC) can be calculated according to the number of frames that are required for contrast to reach the standardized distal coronary artery landmark and using a correction factor that depends on vessel length. TFC is related to the velocity of the contrast filling the epicardial vessel and the microvascular district resistance index.
103 TFC, similar to total myocardial blush score, represents the sum of three major epicardial artery scores and is useful for coronary microcirculation assessment.
104
Studies linking diabetes to coronary microvascular dysfunction in human patients
There is a high prevalence of coronary microvascular dysfunction in patients with type 2 diabetes who are free of overt cardiovascular disease.
96 Von Scholten et al. measured coronary flow reserve with cardiac
82Rb PET/computed tomography in a cross-sectional study. Reduced coronary flow reserve was significantly more common in patients with diabetes, particularly those with concomitant albuminuria, than in control subjects, suggesting that a common microvascular impairment is occurring in multiple microvascular beds. Di Carli and coworkers measured myocardial blood flow (using PET with N-13 ammonia as the flow tracer) at rest during adenosine-induced hyperaemia and in response to a cold pressor test in healthy control subjects and patients with type 1 and type 2 diabetes who were free of overt cardiovascular complications. They confirmed markedly reduced endothelium-dependent (adenosine-induced hyperaemia) and -independent (cold pressor test) coronary vasodilator function in subjects with diabetes, which were similarly reduced in both type 1 and type 2 diabetes. The differences compared with control subjects persisted after adjusting for diabetes mellitus duration, insulin treatment, metabolic abnormalities and autonomic neuropathy. The data suggest an important pathogenetic role of chronic hyperglycaemia in diabetic vascular dysfunction.
105 An impaired vasodilator response of coronary resistance vessels to increased sympathetic stimulation was associated with diabetic autonomic neuropathy and related to the degree of sympathetic nerve dysfunction.
106 Separate studies in young patients with type 1 diabetes without coronary heart disease suggested impairment of coronary vascular reactivity, as determined by PET and H
2O measurements of myocardial blood flow at rest and after dipyridamole administration.
107 In patients with type 2 diabetes, similar measurements (but using PET and N-13 ammonia) revealed reduced myocardial flow reserve.
108 Myocardial blood flow at rest was comparable between healthy controls and patients with type 2 diabetes, whereas myocardial blood flow after dipyridamole administration was significantly lower in patients with diabetes.
108 Moreover, myocardial flow reserve was inversely correlated with average haemoglobin A1C for 5 years and fasting plasma glucose levels, implying that glycaemic control is related to coronary microvascular function.
108 In patients with type 2 diabetes, application of the SPECT method also documented the presence of microvascular dysfunction, which was homogeneously distributed throughout the walls of the left ventricle and most frequently not associated with reversible perfusion defects.
90 Invasive studies in patients with diabetes with angiographically normal coronary arteries and normal left ventricular systolic function demonstrated impaired coronary vascular reserve (measured by intracoronary Doppler with an intracoronary maximally vasodilating dose of papaverine) and acetylcholine-induced coronary vasodilation.
109 These coronary microcirculatory alterations in diabetes may contribute to progressive myocardial deterioration and DMCMP pathogenesis.
109
DMCMP
DMCMP is a multifactorial disease and a result of complex pathophysiologic processes.
74 The impact of diabetes on atherosclerotic vascular disease has been well established, but non-ischemic heart failure in patients with diabetes has received less attention.
81 DMCMP is defined as structural and functional abnormalities of the myocardium in patients with diabetes who have no coronary disease or hypertension.
110
From a histological perspective, DMCMP is characterised by the loss of normal microvessels, extracellular matrix remodelling, capillary basement membrane thickening, interstitial and perivascular fibrosis, cardiomyocyte hypertrophy independent of hypertension and cardiomyocyte atrophy.
81,111 The Strong Heart Study reported that both men and women with type 2 diabetes mellitus have increased left ventricle mass and wall thickness,
112 because hyperinsulinaemia as a result of insulin resistance can act as a growth factor.
75 Obesity is an additional risk factor in type 2 diabetes mellitus, where increased intramyocardial lipid levels act as lipotoxic deposits that can contribute to cell death via as of yet unexplained mechanisms and, from a clinical point of view, lead to diastolic dysfunction.
113,114
After myocardial infarction, the diabetic myocardium possesses reduced compensatory mechanisms to restore cardiac function because of a complex set of intra- and extra-myocardial factors.
115 From a clinical perspective, type 1 and type 2 diabetes mellitus differ in aetiology, clinical presentation and metabolic profiles with adverse clinical presentation. However, the two types share many features of cardiomyopathy.
81 Systolic dysfunction is usually predominant in type 1 diabetes, where autoimmunity predisposes to a dilative phenotype and heart failure with reduced ejection fraction, or is related to atherosclerotic coronary and chronic ischemic heart diseases.
116 Coronary microvascular dysfunction in type 2 diabetes is predominantly the result of hyperglycaemia, lipotoxicity and hyperinsulinaemia. This occurs independently or in combination with other risk factors and leads primarily to diastolic dysfunction, concentric left ventricle remodelling and clinical presentation of heart failure with preserved ejection fraction. Furthermore, there is a progressive problem manifesting in myocardial stiffness (impaired relaxation and passive filling) and restrictive pattern development, with or without subclinical levels of depressed left ventricle systolic function.
71,116–118 Both types of diabetes have the same myocardial results, including coronary microvascular rarefaction and advanced glycation end-product depositions.
116
DMCMP is highly prevalent in asymptomatic patients with type 2 diabetes. Screening and early detection of myocardial changes may be crucial for slowing heart failure development and progression. Thus, early determination of myocardial manifestations can have major implications for prognosis in patients with diabetes. The most sensitive test for cardiac systolic and diastolic function is transthoracic echocardiography.
119 Schwanell and coworkers demonstrated that diastolic left ventricular dysfunction is a first sign of myocardial changes even in younger patients with normal systolic function detected by transthoracic echocardiography.
120 Poirer and coworkers confirmed this finding in male patients with well-controlled type 2 diabetes. The authors used the Valsava manoeuvre and pulmonary venous recordings, together with a standard echocardiographic transmitral left ventricular filling pattern of abnormal relaxation and/or pseudonormal filling, to unmask pseudonormal patterns of ventricular filling.
121 Tissue Doppler imaging, which can measure myocardial tissue velocities in the longitudinal direction, is more sensitive for the detection of left ventricular dysfunction. The peak early diastolic myocardial velocity reflects global left ventricular diastolic dysfunction.
81 Additional echocardiographic tools include strain echocardiography, in which measurement of global longitudinal strain can detect myocardial abnormalities before left ventricular ejection fraction declines.
122
Prognosis
A clear strategy for prevention or treatment of diabetes-induced/related cardiomyopathy and, consequently, a prognosis have not yet been established.
81 The increasing number of both basic research and clinical studies, particularly those that develop novel imaging techniques, are promising for detection of early microvascular functional changes and early changes in the myocardium in diabetes. Interestingly, there is evidence that patients with diabetes with a preserved coronary flow reserve have cardiac event rates similar to those of non-diabetic patients.\
123 Additionally, among diabetic patients without evident CAD, individuals with impaired coronary flow reserve (below the median) have mortality rates comparable to non-diabetic patients with prior CAD (cardiac death rate 2.8 vs. 2.0% per year).
123 This strongly implies that it is crucial to focus on the development and utilization of therapeutic strategies that will preserve normal coronary microvascular function in patients with diabetes. Cortigani et al.
124 demonstrated that coronary microvascular dysfunction before the occurrence of coronary artery involvement is an independent and strong predictor of adverse outcomes in patients with type 2 diabetes. They investigated Doppler-derived coronary flow velocity reserve of the left anterior descending coronary artery in 144 patients with type 2 diabetes who had chest pain or angina-like symptoms, with preserved left ventricular systolic function and without flow-limiting stenoses on angiography. During 29 months of follow-up, 17 hard events (five deaths and twelve nonfatal myocardial infarctions) occurred, with a 13.9% annual hard-event rate in patients with a reduced coronary flow velocity reserve and 2.0% in patients with a higher coronary flow velocity reserve. This finding illustrated the adverse effect of microvascular dysfunction on prognosis, while nonobstructive CAD was not an independent predictor.
124 Impaired coronary microvascular function was also implicated in a poor prognosis in the setting of acute myocardial infarction, where patients with diabetes have higher mortality rates.
125 The lack of microvascular reperfusion following revascularization in patients with diabetes with myocardial infarction appears to be one mechanism underlying a poor clinical outcome with major adverse cardiac events (death, reinfarction and congestive heart failure) that occurs more frequently in patients with a lack of microvascular reperfusion (30.8% vs. 15.9%).
126
Early detection of diastolic dysfunction in young patients with diabetes is also useful for detecting increased arrhythmia risk.
120 Subclinical levels of left ventricular dysfunction, detected by strain echo and global longitudinal strain, is another important parameter in asymptomatic patients with diabetes, because it is associated with adverse outcomes
122 and correlated with coronary microvascular dysfunction.
127 A DMCMP diagnosis requires impaired glucose metabolism as well as the exclusion of coronary, congenital, familial, infiltrative, viral, valvular and hypertensive heart disease.
116 It should be clarified that heart failure in patients with diabetes is not simply an advanced stage of DMCMP but results from a constellation of pathophysiologic processes.
128 Many unanswered questions need to be resolved, such as the issue of pathophysiologic and clinical differences between type 1 and type 2 diabetes mellitus and the lack of any pathognomonic histologic changes or imaging characteristics associated with the diagnosis.
128 Additionally, explanations of clinical manifestations of diabetes with respect to atherosclerotic coronary disease development or diabetic coronary microangiopathy/cardiomyopathy development are required. The big challenge in DMCMP diagnosis is how to exclude hypertension/hypertensive heart disease in patients with type 2 diabetes and metabolic syndrome.
Patients with comorbid heart failure and diabetes mellitus represent a growing patient population. Future clinical studies in both heart failure and diabetes are encouraged to refocus and differentially investigate the efficacy, safety and outcomes in patients with heart failure and concomitant diabetes mellitus.
84
Treatment options
There is a little research evaluating treatment options in patients with microvascular dysfunction. All patients should achieve optimal coronary risk factor control. Treatment options are empirical and arise from the experiences obtained from treatment of “classical” CAD.
Angiotensin is a potent vasoconstrictor. Inhibition of its action, by angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor 1 (AT
1) receptor blockade, counteracts its influence and promotes vessel dilation. Pauly et al.
129, in their study investigating quinapril in women with chest pain without obstructive coronary disease and reduced coronary flow reserve <2.5, identified significant changes in coronary flow reserve measured by intra IC Doppler. Other authors found similar results in their studies, demonstrating improved stress test parameters and coronary flow reserve.
130,131 Combination of eplerenone with angiotensin II inhibition did not improve endothelial dysfunction in a study by Bavry on women with signs and symptoms of ischemia in the setting of nonobstructive CAD.
132 However, investigation of microvascular dysfunction in patients with diabetes revealed that mineralocorticoid receptors might indeed be an appealing target to treat microvascular coronary dysfunction in diabetes.
133 It was demonstrated that interruption of the renin-angiotensin-aldosterone system with the use of ACE inhibitors improved coronary flow reserve (measured by quantitative PET) in patients with diabetes without ischemic heart disease. This effect was further enhanced by spironolactone.
133,134
Calcium channel blockade decreases microvascular spasm and tone, potentially improving coronary flow reserve in patients with coronary microvascular dysfunction.
135 Verapamil, nifedipine and lidoflazine have been demonstrated to improve exercise stress parameters.
136,137 Sütsch and colleagues did not determine that diltiazem improves coronary flow reserve.
138
Statins have anti-inflammatory and anti-atherogenic effects. Zhang et al.
139 demonstrated an improvement in coronary flow reserve and symptoms following fluvastatin treatment. Eshtehardi et al.
140 revealed improved coronary flow reserve in patients treated with atorvastatin. Additionally, some studies have indicated that an inability to reach target cholesterol values with statin therapy is associated with impaired coronary flow reserve and a worse prognosis.
141
NO is a crucial player in endothelium-dependent mediation of coronary microvasculature tone.
142 In one study, the authors evaluated the role of sildenafil in symptomatic patients with coronary flow reserve <2.5 compared with patients with coronary flow reserve >2.5. Patients with reduced coronary flow reserve displayed a significant increase in coronary flow reserve.
143 Considering the fact that L-arginine is a precursor of NO, Bottcher et al.
101 analysed a one-time infusion of L-arginine in 25 patients with chest pain without obstructive CAD or coronary microvascular dysfunction by PET. They noted no improvement in symptoms after infusion. In contrast, Egashira and Gellman noticed improved coronary flow reserve after a single L-arginine infusion.
144,145 However, Lerman identified improved symptoms but no change in coronary flow reserve after 6 months of supplementation.
146
Alpha-blockers reduce sympathetic activity and can thus potentially decrease microvascular tone. Botker, in his double-blind, placebo-controlled, crossover study, did not observe a change in exercise duration, time to angina onset or exercise time to > 0.1 mV ST segment depression between patients administered doxazosin and those receiving a placebo.
147
It has been theorized that an oestrogen deficiency could play a role in microvascular dysfunction. Bairey Merz et al.
148 demonstrated an improvement in anginal symptoms but without improvements in myocardial ischemia or brachial artery flow-mediated dilatation. In contrast, Knuuti et al.
149 revealed improved average myocardial perfusion reserve after oestrogen use.
Spinal cord stimulation modulates pain-related nerve signals and increases myocardial blood flow. Jessurun et al.
150 demonstrated an improvement in symptoms after the use of transcutaneous spinal cord stimulator therapy. Some other studies revealed similar results with angina symptom relief as well as improved coronary flow reserve.
151
Beta-blockers are the gold standard for the treatment of stable angina and CAD. They reduce myocardial oxygen demand and increase diastolic perfusion. However, there do not appear to be any studies investigating beta-blocker treatment in patients with diabetic microvascular dysfunction.
152 The first and second generation of beta-blockers (propranolol, atenolol, metoprolol and bisoprolol) reduce coronary flow at rest, but their action on hyperaemic coronary flow is controversial and variable. Third generation beta-blockers (carvedilol and nebivolol) have vasodilatatory effects through NO synthesis and alpha-adrenergic receptor blockade, ameliorating maximal hyperaemia of CBF.
153
Fukomoto and coworkers investigated the effect of the rho-kinase inhibitor, fasudil. Intracoronary fasudil (300 µg) administration reduced coronary sinus lactate production and improved myocardial ischemia parameters (ST segment changes and angina symptoms).
152
There are several types of antianginal drugs (ivabradine, ranolazine, mibefradil, nicorandil and trimetazidine) that have been investigated in patients with microvascular dysfunction. These drugs work through several different mechanisms to reduce myocardial oxygen demand and ischemia. Ranolazine has been extensively studied and was confirmed to improve myocardial perfusion reserve, as well as other symptomatic and stress test metrics.
155,156 Several studies have examined the role of nitrates in chest pain without obstructive CAD and have found no benefits. Russo et al.
157 observed no significant changes in stress test parameters following isosorbide dinitrate use, and some authors have observed worsened angina and reduced CBF with rapid atrial pacing.
158
Teophilline, an adenosine receptor blocker, was assessed in several small studies. The majority of these reports demonstrated improved exercise capacity.
152 Six-week exercise training versus a low cholesterol diet and relaxation techniques were also analysed. An improvement in coronary flow reserve in the exercise group was observed.
159 Some psychiatric therapy, such as the tricyclic antidepressant imipramine, can also improve symptoms.
Selective intracoronary endothelin A-receptor blockade (with the selective blocker BQ123) reversed the coronary microvascular dysfunction that is present during coronary stenting in patients with type 2 diabetes. Thus, therapeutic targeting of the endothelin system might be useful in protecting the myocardium against ischemic events during elective percutaneous coronary intervention in patients with diabetes.
160
Jadhav et al. compared metformin treatment (500 mg twice a day; n = 16) with placebo administration (n = 17) in women with normal results from a coronary angiogram, with two consecutive positive ergometry tests (positive defined as ST-segment depression ≥ 1 mm). Metformin treatment was associated with a significant reduction in weight and in homeostatic model assessment of insulin resistance.
161 Metformin treatment also improved the microvascular endothelial-dependent response to acetylcholine using laser Doppler devices, while a positive response was absent in the placebo group. Maximum ischemic ST denivelation, Duke score and reduced chest pain were also present in the metformin-treated group compared with those receiving the placebo.
161 Metformin has been demonstrated to have direct vascular effects. Treatment improves vascular function and dramatically reduces cardiovascular end points and mortality in patients with type 2 diabetes mellitus in large-scale clinical trials, but with incompletely elucidated mechanisms. Recently, it was determined that metformin treatment leads to increased NO production, which is induced by AMP protein kinase activation.
162
However, it is inconclusive whether glycaemic control can contribute to prevention or reversal of diabetic coronary microvascular dysfunction. Valenzuela-Garcia et al. analysed 100 patients with type 2 diabetes and 214 patients without diabetes and observed a lack of correlation between optimal glycaemic control and coronary microvascular dysfunction.
163 Furthermore, more intensive glycaemic control in patients with type 2 diabetes did not reduce the occurrence of heart failure.
164
A proposed diagnostic-therapeutic algorithm, based on the information provided earlier, is displayed in
Figure 4. The first steps are widely known preventive measures for type 2 diabetes. Patients with diabetic coronary microvascular dysfunction should minimize risk factors. It is recommended that all patients receive secondary prevention therapy, including aspirin and statins. Beta-blockers are recommended as a first-line therapy, and calcium channel blockers are recommended if beta-blockers do not achieve sufficient symptom control or are not tolerated. Other therapy options have lower level of recommendation. In patients with microvascular angina, the therapeutic response is highly variable and challenging, even without concomitant diabetes mellitus. Treatment often requires a combination of medications to control symptoms. There is still a lack of research evaluating therapies to relieve angina symptoms and reduce risk in populations suffering from microvascular dysfunction and, in particular, effective therapies targeting coronary microvascular dysfunction in diabetes. Future research should be focused on symptom improvement, improvement in quality of life and on the use of drugs that act directly on the pathophysiological processes.