Macrovascular Coronary Artery Disease Research Articles

Relationship between myocardial strain, coronary microvascular dysfunction, and myocardial extracellular volume in patients with type 2 diabetes: a cross-sectional CMR study

Abstract Background Patients with diabetes often develop heart failure with preserved ejection and often demonstrate early indications of myocardial dysfunction by decreased strain, notably the global longitudinal (GLS). The underlying myocardial phenotypical changes in patients with diabetes are coronary microvascular dysfunction and myocardial interstitial fibrosis. The relation of these to strain-indicators of early systolic dysfunction is not established. Purpose We hypothesized that coronary microvascular function and interstitial fibrosis contribute to the subclinical myocardial dysfunction seen in patients with diabetes. Method With gadolinium contrast and adenosine-stress magnetic resonance imaging, we determined myocardial blood flow (MBF) and perfusion ratio (MPR) and extracellular volume (ECV; an imaging biomarker of diffuse fibrosis) in 211 patients with type 2 diabetes without macrovascular coronary artery disease and 25 control subjects. Left ventricular (LV) function was determined from its ejection fraction and 3D feature tracking of GLS, circumferential (GCS), and radial strains (GRS). Results Without a significant age- or sex-differences to control subjects, patients (median age 57 years [IQR 50, 67], 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. LV ejection fraction was normal and similar to controls. Compared to control subjects (GLS -13.9±2.0%), GLS, GCS and GRS were reduced in the total diabetes cohort, and GLS was reduced also in the subgroup of patients without any diabetes complications (total -11.6±3.0%; without-complications -12.3±2.6%). GLS, but not GCS or GRS or LVEF, was associated with albuminuria (b (95%CI) 1.09 (0.22-1.96)) and autonomic neuropathy (b (95%CI) 1.43 (0.54-2.31)). Independently of ECV, a 10% increase in MBF at adenosine-stress and MPR was associated with improved GLS in uni- and multivariable regression analyses. A 10% increase in ECV was associated with a decrease in GLS in univariable and multivariable regression analysis, but this was abolished when adjusted for MPR. GLS showed a moderate ability to discriminate a significantly lowered myocardial blood flow at stress defined as <1.49 mL/min/g (AUC 0.72, GLS threshold -11.5%; sensitivity 75% and specificity 53%) and myocardial perfusion ratio defined as as <2.1 (AUC 0.73, GLS threshold -10.8% resulted in a sensitivity of 71% and a specificity of 70%). GLS had a poor ability to predict increased extracellular volume defined as > 31% (AUC 0.60, GLS threshold -13.5 resulted in a sensitivity of 72% and a specificity of 34%). Conclusion Of the two important phenotypical changes seen with type 2 diabetes, microvascular dysfunction and fibrosis, coronary microvacular dysfunction demonstrates the more important relation to early systolic compromise as determined from the left ventricle global longitudinal strain.Associations of Systolic parametersROC curve

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction.

In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow)<2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.

Abstract P304: Coronary Flow Reserve In Primary Aldosteronism

Introduction: Primary aldosteronism (PA) is characterized by excess cardiovascular risk, underpinned by evidence of microvascular dysfunction. Whether this extends to the coronary vasculature and, as such, regresses after appropriate treatment remains to be determined. Aim: To investigate the presence of coronary microvascular dysfunction and its reversibility in PA patients. Methods: Fifteen PA patients with evidence of lateralized aldosterone overproduction at adrenal vein sampling underwent Doppler echocardiography for the assessment of Coronary flow reserve (CFR: diastolic peak flow on the anterior descending coronary artery during pharmacological [dipyridamole, n=14] or physical stress [n=1] -induced hyperaemia/basal flow) and the ratio between diastolic peak flow and left ventricle mass (FMR), at the time of diagnosis (after withdrawal of RAAS-interfering drugs and normalization of kalemia with K supplementation) and 4-6 months after specific treatment. In case CFR was ≤ 2.5 or the stress protocol suggested potential ischemia, regardless of CFR, a coronary CT angiography (coroCT) was performed to exclude underlying macrovascular coronary artery disease. Results: Out of 15 PA patients (5F; 52±10 yo; BP:149/91±17/11 mmHg; sK + =3.5±0.6 at diagnosis and 3.8±0.3 mmol/L on KCl supplements; DRC=3.0 [2.0-5.5] mIU/L; PAC=747 [417-1430] pmol/L), 14 were cured by unilateral adrenalectomy (127/81±13/11 mmHg; sK + =4.3±0.4 mmol/L; DRC=11.8 [6.7-19.2] mIU/L; PAC=200 [136-244] pmol/L, p&lt;0.05 for all); one patient experienced incomplete biochemical cure and was managed with long-term mineralocorticoid receptor antagonism. At the time of diagnosis, n=7 (46%), n=3 (20%) and n=1 (7%) patients showed CFR ≤ 3.0, 2.5 and 2.0, respectively; none had evidence of macrovascular disease at coroCT. In parallel to a reduction in left ventricular mass (trend; p=0.084), both CFR and FRM significantly increased after treatment (CFR=3.1 [2.6-3.3] vs. 3.4 [3.1-4.6], p=0.013; FMR=0.71±0.33 vs. 0.91±0.32 cm x g/sec x m 2 , p=0.038). Conclusions: Treatment of PA improves coronary microvascular function, as assessed by established prognostic indices like CFR and FMR.

Fractal analysis of 4D dynamic myocardial stress-CT perfusion imaging differentiates micro- and macrovascular ischemia in a multi-center proof-of-concept study

Fractal analysis of dynamic, four-dimensional computed tomography myocardial perfusion (4D-CTP) imaging might have potential for noninvasive differentiation of microvascular ischemia and macrovascular coronary artery disease (CAD) using fractal dimension (FD) as quantitative parameter for perfusion complexity. This multi-center proof-of-concept study included 30 rigorously characterized patients from the AMPLIFiED trial with nonoverlapping and confirmed microvascular ischemia (nmicro = 10), macrovascular CAD (nmacro = 10), or normal myocardial perfusion (nnormal = 10) with invasive coronary angiography and fractional flow reserve (FFR) measurements as reference standard. Perfusion complexity was comparatively high in normal perfusion (FDnormal = 4.49, interquartile range [IQR]:4.46–4.53), moderately reduced in microvascular ischemia (FDmicro = 4.37, IQR:4.36–4.37), and strongly reduced in macrovascular CAD (FDmacro = 4.26, IQR:4.24–4.27), which allowed to differentiate both ischemia types, p < 0.001. Fractal analysis agreed excellently with perfusion state (κ = 0.96, AUC = 0.98), whereas myocardial blood flow (MBF) showed moderate agreement (κ = 0.77, AUC = 0.78). For detecting CAD patients, fractal analysis outperformed MBF estimation with sensitivity and specificity of 100% and 85% versus 100% and 25%, p = 0.02. In conclusion, fractal analysis of 4D-CTP allows to differentiate microvascular from macrovascular ischemia and improves detection of hemodynamically significant CAD in comparison to MBF estimation.

Cardiovascular imaging of women and men visiting the outpatient clinic with chest pain or discomfort: design and rationale of the ARGUS Study

IntroductionChest pain or discomfort affects 20%–40% of the general population over the course of their life and may be a symptom of myocardial ischaemia. For the diagnosis of obstructive macrovascular...

Circulating neuregulin1-β in heart failure with preserved and reduced left ventricular ejection fraction.

AimsNeuregulin1‐β (NRG1‐β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1‐β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF).Methods and resultsCirculating NRG1‐β was quantified in 86 stable patients with HFpEF (EF ≥45% and N‐terminal pro‐brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1‐β and the composite outcome of all‐cause mortality/HF hospitalization in HFpEF and all‐cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th–75th percentile) NRG1‐β was 6.5 (2.1–11.3) ng/mL; in HFrEF, 3.6 (2.1–7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9–3.6) ng/mL; after HTx 2.1 (1.4–3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1–34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1‐β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04–2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1‐β with outcomes was modified by ischaemia (log‐rank P = 0.020; P interaction = 0.553) such that only in ischaemic patients, higher NRG1‐β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1‐β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48–1.05, P = 0.085).ConclusionsNeuregulin1‐β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1‐β with outcomes in non‐ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1‐β from microvascular endothelial dysfunction in the former (non‐ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

Correlation of Microvascular Ophthalmic Disease With Macrovascular Coronary Artery Disease in Trinidad

Correlation of Microvascular Ophthalmic Disease With Macrovascular Coronary Artery Disease in Trinidad

Sex differences in heart failure

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF.

To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

Epicardial Adipose Tissue Removal Potentiates Outward Remodeling and Arrests Coronary Atherogenesis

Pericoronary epicardial adipose tissue (cEAT) serves as a metabolic and paracrine organ thatcontributes to inflammation and is associated with macrovascular coronary artery disease (CAD) development. Although there is a strong correlation in humans between cEAT volume and CAD severity, there remains a paucity of experimental data demonstrating a causal link of cEAT to CAD. The current study tested the hypothesis that surgical resection ofcEAT attenuates inflammation and CAD progression. Female Ossabaw miniature swine (n= 12) were fed an atherogenic diet for 8 months and randomly allocated into sham (n= 5) or adipectomy (n= 7) groups. Both groups underwent a thoracotomy, opening of the pericardial sac, and placement of radioopaque clips to mark the proximal left anterior descending artery. Adipectomy swine underwent removal of 1 to 1.5 cm2 of cEAT from the proximal artery. After sham or adipectomy, CAD severity was assessed with intravascular ultrasonography. Swine recovered for an additional 3 months on an atherogenic diet, and CAD was assessed immediately before euthanasia. Artery sections were processed for histologic and immunohistochemical analysis. Severity of CAD as assessed by percent stenosis was reduced in the adipectomy cohort compared with shams; however, plaque size remained unaltered, whereas larger plaque sizes developed in sham-operated swine. Adipectomy resulted in an expanded arterial diameter, similar to the Glagov phenomenon of positive outward remodeling. No differences in inflammatory marker expression were observed. These data indicate that cEAT resection did not alter inflammatory marker expression, but arrested CAD progression through increased positive outward remodeling and arrest of atherogenesis.

Coronary Microvascular Dysfunction - Epidemiology, Pathogenesis, Prognosis, Diagnosis, Risk Factors and Therapy.

Angina has traditionally been thought to be caused by obstructive coronary artery disease (CAD). However, a substantial number of patients with angina are found to not have obstructive CAD when undergoing coronary angiography. A significant proportion of these patients have coronary microvascular dysfunction (CMD), characterized by heightened sensitivity to vasoconstrictor stimuli and limited microvascular vasodilator capacity. With the advent of non-invasive and invasive techniques, the coronary microvasculature has been more extensively studied in the past 2 decades. CMD has been identified as a cause of cardiac ischemia, in addition to traditional atherosclerotic disease and vasospastic disease. CMD can occur alone or in the presence obstructive CAD. CMD shares many similar risk factors with macrovascular CAD. Diagnosis is achieved through detection of an attenuated response of coronary blood flow in response to vasodilatory agents. Imaging modalities such as cardiovascular magnetic resonance, positron emission tomography, and transthoracic Doppler echocardiography have become more widely used, but have not yet completely replaced the traditional intracoronary vasoreactivity testing. Treatment of CMD starts with lifestyle modification and risk factor control. The use of traditional antianginal, antiatherosclerotic medications and some novel agents may be beneficial; however, clinical trials are needed to assess the efficacy of the pharmacologic and non-pharmacologic therapeutic modalities. In addition, studies with longer-term follow-up are needed to determine the prognostic benefits of these agents. We review the epidemiology, prognosis, pathogenesis, diagnosis, risk factors and current therapies for CMD.

Takotsubo cardiomyopathy associated with the administration of intranasal phenylephrine/lignocaine for epistaxis

1as a reversible form of left ventricular dysfunction, followed up by a case series in five patients. Although previously considered rare, over the past two decades there has been a marked rise in the number of publications relating to TTC, with the current estimation being that the condition accounts for over 1% of all cases of acute coronary syndrome presentations. The condition is defined by transient, reversible left ventricular systolic dysfunction with no macrovascular coronary artery disease, as confirmed by coronary angiography. Epidemiologically, postmenopausal women seem to be at highest risk, however the condition has been seen in multiple different patient populations. Although classically described in the setting of acute emotional or physical stress and associated with catecholamine overstimulation, exogenous administration of sympathomimetic agents has been reported to cause stress induced left ventricular dysfunction, particularly when administered intravenously. A 67 year old lady with a background of hypertension, Raynaud’s phenomenon and gastroparesis requiring PEJ (percutaneous endoscopic jejunostomy) feeding, presented with persistent recurrent epistaxis to the emergency department on a Friday evening. She had previously had episodes of nitrate responsive angina over the past decade, and previous coronary angiography in 2008 had demonstrated no significant lesions, with a diagnosis of presumptive microvascular disease noted in the history. She also had a history of ventricular tachycardia, for which she had been treated with flecainide, with a structurally normal heart on previous echocardiography, and no other significant cardiovascular risk factors.

Adenosine stress native T1 mapping detects microvascular disease in diabetic cardiomyopathy, without the need for gadolinium-based contrast

Background Patients with diabetes mellitus (DM) are known to have microvascular coronary artery disease (CAD), in the absence of hypertension and flow limiting stenoses on epicardial coronary arteries. Microvascular coronary dysfunction can be detected on CMR using adenosine stress perfusion imaging. Native T1 values can detect tissue water content of intra/extracellular or intra/extravascular origin. We hypothesised that increased myocardial blood volume in the intravascular space under adenosine vasodilator stress will have a measurable effect on T1 values. Therefore, we compared adenosine stress T1 response and myocardial perfusion reserve in patients with type-2 DM (T2DM) without macrovascular CAD against controls.

Likelihood of obstructive coronary disease in metabolic syndrome patients with abnormal stress echocardiography

BackgroundMetabolic syndrome (MetSx) encompasses several risk factors for macrovascular coronary artery disease. An association between MetSx and coronary syndrome X has also been reported, suggesting that patients with MetSx are more likely to have endothelial dysfunction in the setting of angiographically normal coronary arteries. It remains unknown whether MetSx patients with abnormal stress echocardiography (SE) are more likely to have obstructive coronary disease (CAD) compared to patients without MetSx. MethodsWe identified symptomatic patients without known CAD and abnormal SE who underwent coronary angiography within 4weeks after the SE. Patients were grouped according to their MetSx and impaired fasting glucose (IFG) status. We compared the proportion of patients with obstructive CAD in each subgroup using the x2 test. Multivariate regression analysis was used to adjust for the pre-test probability of underlying coronary artery disease. ResultsAmong 583 consecutive symptomatic patients who had an abnormal SE and were referred for angiography, 158 (36%) met the NCEP definition of MetSx. MetSx patients had a trend towards having more obstructive CAD than those without MetSx (OR 1.44, p=0.07). After adjusting for pre-test probability of coronary disease, smoking and LDL-C, MetSx/IFG combination was an independent predictor of obstructive CAD (OR 2.06 [1.24-3.44], p<0.001) but MetSx with normal fasting blood glucose was not (OR 0.91 [0.47-1.70], p 0.09). ConclusionSymptomatic patients with MetSx and IFG are more likely to have angiographically significant CAD after abnormal SE than patients without MetSx or those with normal fasting blood glucose.

The utility of cardiopulmonary exercise testing in the assessment of suspected microvascular ischemia

Evidence demonstrating the potential value of cardiopulmonary exercise testing (CPET) to accurately detect myocardial ischemia secondary to macro-vascular disease is beginning to emerge. Despite distinct mechanisms mediating ischemia in micro-vascular and macrovascular coronary artery disease (CAD), the net physiologic effect of exercise-induced left ventricular (LV) dysfunction is common to both. The abnormal physiologic response to CPET may, therefore, be similar in patients with macro- and micro-vascular ischemia. The following case report describes the CPET abnormalities in a patient with suspected microvascular CAD and the subsequent improvement in LV function following three weeks of medical therapy with the anti-ischemic drug ranolazine.

Women's Ischemic Syndrome Evaluation: current status and future research directions: report of the National Heart, Lung and Blood Institute workshop: October 2-4, 2002: Section 1: diagnosis of stable ischemia and ischemic heart disease.

The WISE workshop was convened to review results from the Women’s Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment. This section addresses research needs in improved diagnosis of myocardial ischemia in women. The chronic stable ischemia syndrome was traditionally viewed as reversible myocardial ischemia and obstructive macrovascular coronary artery disease (CAD) that limits blood flow during periods of increased myocardial oxygen demand. The symptom, typical angina pectoris, usually had a predictable, effort-induced threshold for provocation and a characteristic chest discomfort. Unless they had diabetes, women were thought to be generally spared from this syndrome until they became elderly.1 Relatively “fixed” stenoses were central to this syndrome, and dynamic changes in coronary size were believed infrequent and contributing to only occasional variability in the threshold for ischemia provocation. Finally, the smaller arteries and arterioles were thought to be relatively spared from disease, and hence, they were not likely to participate in the pathophysiology of the ischemic syndrome. Our more contemporary view includes both men and women (with the latter being more prevalent2,3) who have variable thresholds for ischemia and symptoms that may be typical or atypical for angina pectoris. This view also includes patients (more frequently women, but also men) who have symptoms but no flow-limiting large-vessel coronary stenoses. The pathophysiology of this variability, as well as of ischemia without flow-limiting stenoses, has now been confirmed to be due to dynamic changes in coronary size that also include the microcirculation.4 These findings often involve dysfunctional endothelium and have the potential to limit flow, causing ischemia …