Coronary Microvascular Abnormalities Research Articles

THE NON-INVASIVE ASSESSMENT OF PERIPHERAL MICROVASCULAR AND ENDOTHELIAL FUNCTION IN WOMEN WITH NON-OBSTRUCTIVE CORONARY ARTERY DISEASE

THE NON-INVASIVE ASSESSMENT OF PERIPHERAL MICROVASCULAR AND ENDOTHELIAL FUNCTION IN WOMEN WITH NON-OBSTRUCTIVE CORONARY ARTERY DISEASE

Effectiveness of an Educational Program through Mobile Health Application on Knowledge and Adherence to a Healthy Lifestyle in Cardiac Syndrome X Patients

Background: Cardiac syndrome X (CSX) is a form of ischemic heart disease with functional coronary microvascular abnormalities. The symptoms are often debilitating and sufferers have a poor quality of life, with costly demand for healthcare services. Therefore, an educational intervention contributes to the increase of knowledge about CSX risk factors and adherence to a healthy lifestyle. Objectives: This study aimed to investigate the effectiveness of educational interventions on knowledge and adherence to a healthy lifestyle in CSX Patients. Methods: A simple, two-arm, parallel, randomized control trial was conducted in the Heart Clinic on 100 CSX outpatients who were selected through randomized sampling and divided into experimental (n=50) and control (n=50) groups. This study assessed an educational program that has been provided through the Mobile Health application (mHealth app) to the experimental group. The data were collected using the Heart Disease Fact Questionnaire (HDFQ) and Adherence to a Healthy lifestyle questionnaire (AHLQ). Results: In the intervention group, the difference between the pre-test and post-test mean scores of knowledge on CSX risk factors was statistically significant (SD=1.77; P<0.05). However, there was no significant difference between pre-test and post-test means scores in the control group (SD=3.12; P>0.05). Conclusion: Patients with CSX have high morbidity and health care expenditure; therefore, the provision of an educational program through the mHealth app as well as lifestyle modification can be considered a highly effective and low-cost intervention contributing to an increase of knowledge about CSX risk factors in patients and adoption of a healthy lifestyle.

Coronary microvascular dysfunction in stable ischaemic heart disease (non-obstructive coronary artery disease and obstructive coronary artery disease).

Diffuse and focal epicardial coronary disease and coronary microvascular abnormalities may exist side-by-side. Identifying the contributions of each of these three players in the coronary circulation is a difficult task. Yet identifying coronary microvascular dysfunction (CMD) as an additional player in patients with coronary artery disease (CAD) may provide explanations of why symptoms may persist frequently following and why global coronary flow reserve may be more prognostically important than fractional flow reserve measured in a single vessel before percutaneous coronary intervention. This review focuses on the challenges of identifying the presence of CMD in the context of diffuse non-obstructive CAD and obstructive CAD. Furthermore, it is going to discuss the pathophysiology in this complex situation, examine the clinical context in which the interaction of the three components of disease takes place and finally look at non-invasive diagnostic methods relevant for addressing this question.

P1401 The prognostic value of the reduction of coronary flow velocity reserve in non-ischemic heart failure patients

Abstract OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background Coronary microvascular abnormalities determining a reduction of coronary flow velocity reserve (CFVR) have been described in patients (pts) with non-ischemic heart failure (HF). Aim To assess the prognostic value of CFVR in HF. Methods In a prospective, observational, multicenter study, we recruited 333 pts with angiographically normal coronary arteries: 105 patients with HF and preserved (>50%) ejection fraction (HFpEF); 71 with HF and mid-range (40-50%) ejection fraction (HFmrEF); 157 with HF and reduced (<40%) ejection fraction (HFrEF). All patients underwent vasodilator SE with dipyridamole (0.84 mg/kg) in 10 accredited laboratories of 5 countries (Argentina, Brazil, Italy, Mexico, Serbia). CFVR was calculated as the stress/rest ratio of diastolic peak flow velocity pulsed wave-Doppler assessment of LAD flow. In all patients we also assessed left ventricular contractile reserve (LVCR) based on force (systolic blood pressure/end-systolic volume) Abnormal cutoff values were ≤2.0 for CFVR and ≤1.1 for LVCR. All pts were followed-up. Results After a median follow-up time of 15 months, 78 events occurred: 36 hospital admissions for acute decompensated heart failure, 23 deaths, 16 worsening in NYHA functional class, 2 stroke and 1 late revascularization. Event-free survival was best in patients with preserved CFVR and LVCR and worst in pts with reduced CFVR and impaired LVCR, with intermediate values for patients with either one (CFVR or LVCR) abnormal results: see figure. A preserved CFVR was associated with a better 24-month event-free survival than reduced CFVR in a subset analysis in pts with HFpEF (HR = 16.2, 95% CI, 1.8-145.1, p = 0.001) and in HFrEF (HR = 3.06, 95% CI, 1.6-5.6, p < 0.001). A multivariable analysis in the overall group of HF pts identified a reduced CFVR as the only independent predictor of event-free survival (HR = 3.455,95% CI 1.723-6.929). Conclusions A reduction in CFVR identifies a high risk subset in HF patients, outlining a shared role of coronary microvascular abnormalities as a marker and potential therapeutic target of HF, independently of underlying EF. Abstract P1401 Figure. Event-free survival based on CFVR-LVCR

Coronary microvascular dysfunction may be related to IGF-1 in acromegalic patients and can be restored by therapy

Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly. We studied 40 acromegalic patients (23 male, age 52 ± 11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity. CFR was lower in patients than in controls (2.9 ± 0.8 vs. 3.7 ± 0.6, p < 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) (p < 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = -0.5, p < 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381-898] μg/l versus 246 [186-484] μg/l, p < 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8-13.7] μg/l versus 5 [2.8-8.9] μg/l, p = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR (p < 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 (p = 0.009). In four patients with active disease (all with CFR<2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder. Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly.

Role of Coronary Microvascular Dysfunction in Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TTC) is a relatively frequent acute cardiac condition, but its pathogenesis has not been established as yet. Since the first descriptions of TTC, microvascular dysfunction has been advocated as a possible pathophysiological mechanism underlying the left ventricular wall motion abnormalities that characterize the syndrome. Several noninvasive and invasive methods have confirmed the involvement of coronary microvascular abnormalities in the pathogenesis of TTC, but whether microvascular dysfunction is the primary cause or a secondary phenomenon is still debated. The greater prevalence of TTC among postmenopausal women, along with the relationship identified between physical and emotional triggers and other "neuro-cardiac" mechanisms, suggest that increased microvascular reactivity, possibly sympathetically mediated, may play a pathogenic role in susceptible individuals. This review critically evaluates the possible role of microvascular dysfunction in the development of TTC.

Abstract 15194: Multiple Co-morbidities Produce Left Ventricular Diastolic Dysfunction in a Large Animal Model

More than 50% of patients with heart failure have preserved ejection fraction (HFpEF) characterized by diastolic dysfunction. HFpEF usually occurs in female patients with multiple comorbidities such as obesity, hypercholesterolemia, diabetes mellitus (DM) and hypertension. Here we studied the effects of DM, high fat diet (HFD), and chronic kidney disease (CKD) on diastolic dysfunction in swine. In 11 female swine, DM type 2 (3x50mg/kg iv streptozotocin), hypercholesterolemia (HFD 1% cholesterol) and CKD by renal artery embolization (38-42μm polyethylene beads), were induced (DM+HFD+CKD). Swine were followed for 6 months. Eight female healthy swine on normal pig-chow, matched for age were used as controls (CON). The DM+HFD+CKD showed hyperglycemia (22.7±0.9mmol/l in DM+HFD+CKD vs 6.1±0.67mmol/l in CON), hypercholesterolemia (16.9±3.4 vs 2.2±0.1mmol/l), hypertriglyceridemia (1.20±0.36 vs 0.28±0.05mmol/l) and hypertension (awake mean arterial pressure: 108±6 vs 84±3mmHg; all P≤0.05). These co-morbidities resulted in chronic systemic inflammation (TNF-α: 231±64 vs 74±24pg/ml), impaired coronary small artery endothelium-dependent vasodilation to bradykinin, capillary rarefaction (cap./fiber ratio 0.58 vs 0.99) and increased myocardial superoxide production (14.8±0.9 vs 6.4±0.3 RLU/sec/g), due to increased NOX activity (all P≤0.05). The coronary microvascular abnormalities were associated with increased myocardial collagen content (4.7±0.3 vs 2.4±0.2%) and elevated passive cardiomyocyte force, (both P≤0.05), resulting in reduced E/A ratio (0.99±0.14 vs 1.53±0.23), measured with cardiac MRI, and increased LV end-diastolic stiffness (0.79±0.19 vs 0.29±0.03 mmHg/ml/mg) derived from LV pressure-volume relations obtained with a conductance catheter (both P≤0.05). In contrast, ejection fraction was maintained, (45±4 vs 54±3%, P=NS). In summary, multiple comorbidities, including DM, hypercholesterolemia, CKD and hypertension in female swine trigger a series of events, starting with systemic inflammation, increased oxidative stress and coronary microvascular dysfunction, resulting in myocardial stiffening, and leading to diastolic dysfunction.

Arrhythmias in chagasic cardiomyopathy.

Chagas disease, a chronic parasitosis caused by the protozoa Trypanosoma cruzi, is an increasing worldwide problem because of the number of cases in endemic areas and the migration of infected individuals to more developed regions. Chagas disease affects the heart through cardiac parasympathetic neuronal depopulation, immune-mediated myocardial injury, parasite persistence in cardiac tissue with secondary antigenic stimulation, and coronary microvascular abnormalities causing myocardial ischemia. A lack of knowledge exists for risk stratification, management, and prevention of ventricular arrhythmias in patients with chagasic cardiomyopathy. Catheter ablation can be effective for the management of recurrent ventricular tachycardia.

Pharmacological approaches to coronary microvascular dysfunction.

In recent decades coronary microvascular dysfunction has been increasingly identified as a relevant contributor to several cardiovascular conditions. Indeed, coronary microvascular abnormalities have been recognized in patients suffering acute myocardial infarction, chronic stable angina and cardiomyopathies, and also in patients with hypertension, obesity and diabetes. In this review, we will examine pathophysiological information needed to understand pharmacological approaches to coronary microvascular dysfunction in these different clinical contexts. Well-established drugs and new pharmacological agents, including those for which only preclinical data are available, will be covered in detail.

Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients

Plasma concentration of asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is considered a novel risk factor for endothelial dysfunction associated with enhanced atherosclerosis. Coronary microcirculation abnormalities have been demonstrated in patients with early rheumatoid arthritis (ERA) without any signs or symptoms of coronary artery disease (CAD). The aim of the study was to compare the ERA and control groups with ADMA, intima-media thickness (IMT) and coronary flow reserve (CFR) levels. It assessed whether ERA patients have more cardiovascular risk (endothelial dysfunction and coronary microvascular abnormalities), and evaluated whether any difference in IMT/CFR between ERA and controls can be explained by any difference in ADMA levels between the groups. The study involved 25 ERA patients (female/male 21/4; mean age 52.04 +/- 14.05 years; disease duration <or=12 months) and 25 healthy volunteers with no history or current signs of CAD or other traditional risk factors. Dipyridamole trans-thoracic stress echocardiography was preformed to evaluate CFR, and carotid ultrasound to measure the IMT of the common carotid arteries. Blood samples were obtained in order to assess ADMA levels before the patients had received any biological or non-biological DMARDs, or steroid therapy. CFR was significantly reduced in the ERA patients (2.5 +/- 0.5 vs 3.5 +/- 0.8; P <0.01). In particular, 6/25 (24%) had a CFR of <2 consistent with potentially dangerous coronary flow impairment. Common carotid IMT was significantly greater in the ERA patients, although still within the normal range (0.68 +/- 0.1 vs 0.56 +/- 0.11 mm; P <0.01). There was a significant correlation between CFR and plasma ADMA levels in the ERA population (r = -0.53; P <0.01). IMT was negatively associated with CFR (P <0.05). Plasma ADMA levels were significantly higher in the ERA patients. A statistically significant negative effect of ADMA levels on CFR value was observed. The effect of ADMA levels on IMT is not significant.

The non-invasive documentation of coronary microcirculation impairment: role of transthoracic echocardiography

Transthoracic Doppler echocardiographic-derived coronary flow reserve is an useful hemodynamic index to assess dysfunction of coronary microcirculation. Isolated coronary microvascular abnormalities are overt by reduced coronary flow reserve despite normal epicardial coronary arteries. These abnormalities may occur in several diseases (arterial hypertension, diabetes mellitus, hypercholesterolemia, syndrome X, aortic valve disease, hypertrophic cardiomyopathy and idiopathic dilated cardiomyopathy). The prognostic role of impaired microvascular coronary flow reserve has been shown unfavourable especially in hypertrophic or idiopathic dilated cardiomyopathies. Coronary flow reserve reduction may be reversible, for instance after regression of left ventricular hypertrophy subsequent to valve replacement in patients with aortic stenosis, after anti-hypertensive treatment or using cholesterol lowering drugs. Coronary flow reserve may increase by 30% or more after pharmacological therapy and achieve normal level >3.0. In contrast to other non invasive tools as positron emission tomography, very expensive and associated with radiation exposure, transthoracic Doppler-derived coronary flow reserve is equally non invasive but cheaper, very accessible and prone to a reliable exploration of coronary microvascular territories, otherwise not detectable by invasive coronary angiography, able to visualize only large epicardial arteries.

Myocardial perfusion and coronary microcirculation: From pathophysiology to clinical application

In the past 2 decades, enough evidence has been produced by different centers and by means of different methodologies to demonstrate the existence of coronary microvascular abnormalities in various cardiovascular diseases. Unfortunately, because of the technical difficulties in exploring coronary microcirculation, studies currently available on this subject are limited to relatively small groups of patients, preventing a definitive conclusion on the clinical relevance of peculiar microvascular alterations in each disease in terms of prevalence, incidence, and prognosis. Despite this limitation, available information strongly calls for caution in the binary attribution of perfusion abnormalities to coronary stenosis or, by exclusion, to technical artifacts. In this respect, it is now clear that perfusion defects secondary to microcirculatory dysfunction are frequent and indistinguishable from the defects commonly observed in ischemic heart disease, relative to regionality, extension, and severity. With regard to the physiopathology of microvascular disorders, it should be considered that the models of coronary pathology in “healthy” animals, developed in the last half century, are largely inadequate for the reproduction of human pathology, in light of new acquisitions in the field of vascular and molecular biology. It appears evident that the classical model of coronary circulation suffers from oversimplification and that the regional increase in microvascular resistance observed in patients cannot simply be attributed to extrinsic factors such as hemodynamics or ventricular hypertrophy. Understanding the nature and significance of functional and structural intrinsic factors as they relate to human coronary pathology requires a greater research effort, primarily in clinical models.

Effects of Long-term Treatment with Verapamil on Left Ventricular Function and Myocardial Blood Flow in Patients with Dilated Cardiomyopathy Without Overt Heart Failure

Myocardial blood flow (MBF) abnormalities are present in early stage dilated cardiomyopathy (DCM) and have been attributed to coronary microvascular abnormalities. The favorable effects of verapamil on coronary microcirculation might indicate its use in early stage DCM. We assessed the safety of long-term combination therapy of verapamil and enalapril and its effects on both left ventricular function and myocardial perfusion compared with enalapril alone in 18 patients with DCM (15 men, 3 women; mean age, 50+/-9 years) without overt heart failure (NYHA class I-II). At baseline and after 6 months of randomized treatment with either enalapril (10-20 mg) (nine patients, group 1) or enalapril (10-20 mg) and verapamil (120-240 mg) (nine patients, group 2), left ventricular function was assessed at rest, during handgrip, and during bicycle exercise by equilibrium radionuclide angiography. Mean MBF was measured at rest and after dipyridamole by positron emission tomography (PET) and 13N-ammonia as a flow tracer. At baseline, the two groups had reduced left ventricular ejection fraction at rest, which was further impaired during isometric exercise, but increased at peak bicycle exercise. MBF was similarly reduced in the two groups at rest and during dipyridamole. During treatment, no adverse events occurred in either group. After 6 months there was no significant difference in the main study variables either between the two groups or within each group before and after treatment. Long-term combination therapy with verapamil and enalapril is safe in patients with DCM without overt heart failure. Despite no favorable effect on myocardial perfusion, combined treatment prevented deterioration of left ventricular function, similarly to enalapril alone.

An antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs.

Ischemia and reperfusion cause coronary vascular and myocardial injury, which may be due to leukocyte-mediated processes. Antileukocyte measures have reduced injury after brief reperfusion periods of 1-3 h, but there has been little information on whether benefits are apparent after longer periods of reperfusion. We examined the effect of pretreatment with a monoclonal antibody (R15.7) to the CD18 family of leukocyte adhesion molecules (beta2-integrins) in dogs exposed to regional coronary ischemia for 1 h of left anterior descending coronary artery ligation and then reperfused for 48 h. Coronary microvascular permeability was assessed in vivo by measurement of protein leak index (PLI), using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilators bradykinin (BK) and ADP and the endothelium-independent vasodilator nitroprusside. At 48 h of reperfusion in untreated dogs there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. These abnormalities were decreased, but not abolished, in the dogs treated with R15.7. Relaxation of rings from the ischemic/reperfused artery to BK and ADP were blunted in the untreated dogs. R15.7 resulted in improvement in some, but not all, indexes of relaxation in response to BK and ADP. Relaxation to nitroprusside was normal in ischemic/reperfused coronary rings from both treated and untreated dogs. Therefore, after 1 h of regional coronary ischemia and 48 h of reperfusion, coronary endothelial injury, which was manifested by increased coronary microvascular permeability and abnormalities in coronary endothelium-dependent relaxation, was reduced by pretreatment with the anti-CD18 integrin antibody R15.7.

Role of coronary microvascular abnormalities in coronary artery disease—implications for perfusion imaging

The exact role and relative importance of the microvascular dysfunction in the pathophysiology and natural history of CAD is still to be defined. However, this disorder might affect imaging of both baseline and stress myocardial perfusion. A resting perfusion defect should not always be considered a marker of severe coronary stenosis not adequately counterbalanced by a maximal distal vasodilation. In fact, resting hypoperfusion does not necessarily imply exhaustion of vasodilator reserve and may be observed even in regions supplied by angiographically normal coronary arteries. Similarly, the absence of a perfusion defect during stress might indicate the presence of either a nonsignificant stenosis or a diffuse impairment in microcirculatory function. The possibility of obtaining absolute measurements of regional myocardial perfusion by positron emission tomography allows identification of mechanisms affecting myocardial blood flow regulation, providing a more precise characterization of CAD beyond simple agreement with the morphologic angiographic picture.

Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy.

When angina occurs in patients with hypertension, it is usually attributed to coronary artery disease or left ventricular hypertrophy. To determine the contribution of coronary microvascular abnormalities to angina in patients with hypertension, we evaluated hypertensive patients without coronary artery disease or left ventricular hypertrophy by measuring the coronary responses to rapid atrial pacing before and after administration of ergonovine. We compared 12 hypertensive patients who had pacing-induced angina with 13 normotensive subjects without such angina. The two groups had similar coronary flow (in the great cardiac vein) at rest; however, pacing increased coronary flow less in hypertensive patients with angina than in normotensive subjects (48 vs. 83 percent; P = 0.05). In the hypertensive patients with angina, pacing after ergonovine increased coronary flow by only 32 percent (as compared with 48 percent before ergonovine; P less than 0.05) and decreased coronary resistance by 15 percent (as compared with 28 percent before ergonovine; P less than 0.05), indicating the presence of ergonovine-induced vasoconstriction. In normotensive subjects, in contrast, cardiac pacing after ergonovine increased coronary flow by 112 percent (P less than 0.001), and its effect on coronary resistance was not different from that of pacing before ergonovine. The hypertensive patients with angina had a significant increase in myocardial oxygen extraction during pacing after ergonovine and less of an increase in myocardial lactate consumption - a response consistent with the presence of myocardial ischemia. Thus, angina in hypertensive patients without epicardial coronary disease may be caused by myocardial ischemia, which appears to be due to an abnormally elevated resistance of the coronary microvasculature.