Muhammad Hammadah

Soluble Urokinase Plasminogen Activator Receptor Level Is an Independent Predictor of the Presence and Severity of Coronary Artery Disease and of Future Adverse Events

Introduction Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Whether suPAR level predicts the presence and the severity of coronary artery disease (CAD), and of incident death and myocardial infarction (MI) in subjects with suspected CAD, is unknown. Methods and Results We measured plasma suPAR levels in 3367 subjects (67% with CAD) recruited in the Emory Cardiovascular Biobank and followed them for adverse cardiovascular (CV) outcomes of death and MI over a mean 2.1±1.1 years. Presence of angiographic CAD (≥50% stenosis in ≥1 coronary artery) and its severity were quantitated using the Gensini score. Coxs proportional hazard survival and discrimination analyses were performed with models adjusted for established CV risk factors and C‐reactive protein levels. Elevated suPAR levels were independently associated with the presence of CAD (P<0.0001) and its severity (P<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youdens index) predicted future risk of MI (hazard ratio [HR]=3.2; P<0.0001), cardiac death (HR=2.62; P<0.0001), and the combined endpoint of death and MI (HR=1.9; P<0.0001), even after adjustment of covariates. The C‐statistic for a model based on traditional risk factors was improved from 0.72 to 0.74 (P=0.008) with the addition of suPAR. Conclusion Elevated levels of plasma suPAR are associated with the presence and severity of CAD and are independent predictors of death and MI in patients with suspected or known CAD.

Spotty calcification and plaque vulnerability in vivo : frequency-domain optical coherence tomography analysis

BACKGROUND Spotty calcification is a morphological characteristic of a vulnerable plaque phenotype. While this calcium pattern is considered an active process, promoted by inflammation, it is unknown whether spotty calcification associates with development of microstructures observed in vulnerable plaques. As frequency-domain optical coherence tomography (FD-OCT) enables visualization of microstructures associated with plaque vulnerability, we investigated the association between spotty calcification and plaque microstructures by using FD-OCT. METHODS A total of 300 patients with stable coronary artery disease (CAD), having clinical indication for percutaneous coronary intervention (PCI), were analyzed. Totally 280 non-culprit lipid plaques within the target vessel requiring PCI were evaluated by FD-OCT. Spotty calcification was defined as a presence of lesion <4 mm in length, containing an arc of calcification <90° on FD-OCT. Plaque microstructures were compared in non-culprit lipid-rich plaques with and without spotty calcification. RESULTS Spotty calcification was observed in 39.6% of non-culprit lipid-rich plaques, with 30.6% of these plaques demonstrating multiple spotty calcifications. Plaques containing spotty calcification exhibited a greater lipid index (= averaged lipid arc × lipid length); 1,511.8±1,522.3 vs. 815.2±1,040.3 mm°, P<0.0001), thinner fibrous caps (89.0±31.6 vs. 136.5±32.5 µm, P=0.002) and a higher prevalence of microchannels (45.9% vs. 17.7%, P=0.007). A significant association was observed between the number of spotty calcifications per plaque and fibrous cap thickness (r=-0.40, P=0.006). Increased number of spotty calcification was also associated with a higher prevalence of microchannel within plaques (P=0.01). CONCLUSIONS In patients with stable CAD requiring PCI, the presence of spotty calcification imaged by FD-OCT was associated with features of greater plaque vulnerability.

Sex Differences in Mental Stress‐Induced Myocardial Ischemia in Patients With Coronary Heart Disease

Background Emerging data suggest that young women with coronary heart disease (CHD) are disproportionally vulnerable to the adverse cardiovascular effects of psychological stress. We hypothesized that younger, but not older, women with stable CHD are more likely than their male peers to develop mental stress‐induced myocardial ischemia (MSIMI). Methods and Results We studied 686 patients (191 women) with stable coronary heart disease (CHD). Patients underwent 99mTc‐sestamibi myocardial perfusion imaging at rest and with both mental (speech task) and conventional (exercise/pharmacological) stress testing. We compared quantitative (by automated software) and visual parameters of inducible ischemia between women and men and assessed age as an effect modifier. Women had a more‐adverse psychosocial profile than men whereas there were few differences in medical history and CHD risk factors. Both quantitative and visual indicators of ischemia with mental stress were disproportionally larger in younger women. For each 10 years of decreasing age, the total reversibility severity score with mental stress was 9.6 incremental points higher (interaction, P<0.001) and the incidence of MSIMI was 82.6% higher (interaction, P=0.004) in women than in men. Incidence of MSIMI in women ≤50 years was almost 4‐fold higher than in men of similar age and older patients. These results persisted when adjusting for sociodemographic and medical risk factors, psychosocial factors, and medications. There were no significant sex differences in inducible ischemia with conventional stress. Conclusions Young women with stable CHD are susceptible to MSIMI, which could play a role in the prognosis of this group.

Reverse remodeling and prognosis following kidney transplantation in contemporary patients with cardiac dysfunction

BACKGROUND Cardiac dysfunction influences candidate selection for kidney transplantation. There is a paucity of data regarding predictors of myocardial recovery following kidney transplantation and long-term outcomes. OBJECTIVES The purpose of this study was to identify the extent of reverse remodeling in our kidney transplant population and the predictors of such changes, and to assess outcomes in these patients. METHODS We reviewed 232 patients who underwent kidney transplantation at the Cleveland Clinic from 2003 to 2013 and who had baseline and post-transplant echocardiograms; patients with simultaneous heart transplantation were excluded. RESULTS Post-transplantation mean left ventricular ejection fraction (LVEF) improved in those with LV dysfunction (increased from 41% to 50%; p < 0.0001; n = 66). There was significant improvement in other parameters, including diastolic function, LV end-diastolic dimension, LV mass, and right ventricular systolic pressure. After adjusting for multiple clinical variables, increased hemoglobin following transplantation was associated with an improved LVEF (odds ratio: 1.50; 95% confidence interval [CI]: 1.07 to 2.14; p = 0.016) and reduced mortality (hazard ratio [HR]: 0.65; 95% CI: 0.49 to 0.87; p = 0.004). An improved LVEF ≥10% predicted survival independently of a pre-transplantation LVEF (HR: 0.46; 95% CI: 0.21 to 0.93; p = 0.031). CONCLUSIONS Kidney transplantation is associated with improved cardiac structure and function. A rise in post-transplantation hemoglobin was a significant factor associated with such changes, in addition to conferring a survival advantage.

Age and Human Regenerative Capacity Impact of Cardiovascular Risk Factors

RATIONALE We investigated aging of human endogenous reparative capacity and aimed to clarify whether it is affected by presence of cardiovascular disease or its risk factors (RFs). OBJECTIVE Circulating progenitor cell (PC) levels reflect endogenous regenerative potential. The effect on PC of healthy aging compared with aging with RFs or cardiovascular disease (CVD) is unknown. We examined whether exposure to RF and CVD leads to an accelerated decline in circulating PC with increasing age. METHODS AND RESULTS In 2792 adult subjects, 498 were free of RFs (smoking, diabetes mellitus, hypertension, or hyperlipidemia), 1036 subjects had 1 to 2 RF, and 1253 had ≥3 RFs or CVD. PC were enumerated by flow cytometry as CD45(med+) mononuclear cells expressing CD34 and subsets coexpressing CD133, CXCR4, and vascular endothelial growth factor receptor-2 epitopes. Younger age, male sex, and larger body size correlated with higher PC counts (P<0.01). After multivariable adjustment, both age and RF categories were independently associated with PC counts (P<0.05), with lower PC counts in older subjects and those with higher RF burden or CVD. PC counts remained unchanged with increasing age in healthy individuals. There were significant interactions between age and RF categories (P≤0.005), such that for younger subjects (<40 years), RFs were associated with increased PC counts, whereas for older subjects (>60 years), RFs and CVD were associated with lower PC counts. CONCLUSIONS Circulating PC levels do not decline with healthy aging; RF exposure at a younger age stimulates PC mobilization, whereas continued exposure is associated with lower PC levels in later life. Over the lifespan, exposure to RFs and CVD is associated with an initial stimulation and subsequent decline in circulating PC levels, which reflect endogenous regenerative capacity.

Cholesterol crystals associate with coronary plaque vulnerability in vivo.

The high local concentration of cholesterol in foam cells has been reported to formulate cholesterol crystals, which trigger a local inflammatory response [(1)][1]. Intracellular crystals also induce apoptosis of foam cells, leading to further attraction of macrophages and development of a lipid-

Plaque microstructures in patients with coronary artery disease who achieved very low low-density lipoprotein cholesterol levels

OBJECTIVE Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces cardiovascular events and slows plaque progression. While this therapeutic approach has been reported to favorably modify plaque composition, this is not well characterized in humans. Also, the benefit of achieving LDL-C levels below current recommended targets remains unknown. Frequency-domain optical coherence tomography (FD-OCT) enables visualization of plaque microstructures associated with plaque instability. We investigated plaque morphologies in patients with low LDL-C levels by using FD-OCT. METHODS 293 and 122 non-obstructive lipid and fibrous plaques in 280 stable statin-treated CAD patients were evaluated by FD-OCT imaging in vessels requiring percutaneous coronary intervention. Study subjects were stratified according to achieved LDL-C levels (<50, 50-70, 70-100, <100 mg/dL). FD-OCT derived plaque microstructures were compared. RESULTS LDL-C levels <50 mg/dL and <70 mg/dL were observed in 13.9% (39/280) and 29.2% (82/280) of patients, respectively. Patients with LDL-C <50 mg/dL were more likely to be older (p < 0.001) and receive a high-dose statin (p = 0.01). On FD-OCT imaging, patients with LDL-C <50 mg/dL were more likely to have fibrous plaque (51.7, 43.2, 22.2 and 12.3%, p = 0.01) and less likely to have lipid plaques (48.2, 56.7, 77.7 and 87.6%, p = 0.01). In addition, LDL-C level was significantly associated with lipid arc (173 ± 76, 175 ± 88, 196 ± 102 and 234 ± 85°, p = 0.01) and fibrous cap thickness (139.9 ± 93.9, 103.1 ± 66.4, 92.5 ± 48.5 and 92.1 ± 47.8 um, p = 0.001). In particular, the smallest lipid arc and thickest fibrous cap were observed in patients who achieved LDL-C <50 mg/dL. Multivariable analysis revealed LDL-C levels (beta coefficient -0.254, p = 0.009) and high-dose statin use (beta coefficient 1.814, p = 0.003) to independently associate with fibrous cap thickness. CONCLUSIONS More stable plaque features were observed within non-obstructive atheromas in patients with very low LDL-C levels. These findings underscore LDL-C level to stabilize plaques in patients with CAD and high residual atherosclerotic risk.

The Impact of Changing Antiseptic Skin Preparation Agent used for Cardiac Implantable Electronic Device (CIED) Procedures on the Risk of Infection

Cardiac implantable electronic device (CIED) infection is a major complication that is associated with increased morbidity and mortality. Recent data suggested a relationship between the antiseptic agent used for skin preparation at time of CIED procedure and risk for infection.

Prognostic Value of Estimating Functional Capacity With the Use of the Duke Activity Status Index in Stable Patients With Chronic Heart Failure

BACKGROUND Over the years, several methods have been developed to reliably quantify functional capacity in patients with heart failure. Few studies have investigated the prognostic value of these assessment tools beyond cardiorenal prognostic biomarkers in stable patients with chronic heart failure. METHODS AND RESULTS We administered the Duke Activity Status Index (DASI) questionnaire, a self-assessment tool comprising 12 questions for estimating functional capacity, to 1,700 stable nonacute coronary syndrome patients with history of heart failure who underwent elective diagnostic coronary angiography with 5-year follow-up of all-cause mortality. In a subset of patients (n = 800), B-type natriuretic peptide (BNP) was measured. In our study cohort, the median DASI score was 26.2 (interquartile range [IQR] 15.5-42.7). Low DASI score provided independent prediction of a 3.3-fold increase in 5-year mortality risk (quartile 1 vs quartile 4: hazard ratio [HR] 3.33, 95% confidence interval [CI] 2.57-4.36; P < .0001). After adjusting for traditional risk factors, BNP, and estimated glomerular filtration rate, low DASI score still conferred a 2.6-fold increase in mortality risk (HR 2.57, 95% CI 1.64-4.15; P < .0001). CONCLUSIONS A simple self-assessment tool of functional capacity provides independent and incremental prognostic value for mortality prediction in stable patients with chronic heart failure beyond cardiorenal biomarkers.

Heart rate and the risk of adverse outcomes in patients with heart failure with preserved ejection fraction

Background Although high resting heart rates are associated with adverse outcomes in heart failure with reduced ejection, the reports for heart failure with preserved ejection fraction (HFpEF) are conflicting. Design A secondary analysis was conducted in order to examine the relationship between resting heart rate and adverse outcomes in 2705 patients (mean age = 68 ± 10 years; 47% men; 88% white) with HFpEF who were in sinus rhythm from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). Methods Baseline heart rate was obtained from baseline electrocardiogram data. Outcomes were adjudicated by a clinical end-point committee and included the following factors: hospitalisation, hospitalisation for heart failure, death and cardiovascular death. Results Over a median follow-up of 3.4 years (25th–75th percentiles = 2.0–4.9 years), a total of 1157 hospitalisations, 311 hospitalizations for heart failure, 369 deaths and 233 cardiovascular deaths occurred. An increased risk (per 5-beats per minute [bpm] increase) for hospitalisation (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 1.004–1.060), hospitalisation for heart failure (HR = 1.10, 95% CI = 1.05–1.15), death (HR = 1.10, 95% CI = 1.06–1.16) and cardiovascular death (HR = 1.13, 95% CI = 1.07–1.19) was observed. When the analysis was limited to those who did not report the use of β-blockers, the magnitude of the association for each outcome (per 5-bpm increase) was not materially altered (hospitalisation: HR = 1.03, 95% CI = 0.97–1.09; hospitalisation for heart failure: HR = 1.12, 95% CI = 0.98–1.27; death: HR = 1.16, 95% CI = 1.05–1.28; cardiovascular death: HR = 1.12, 95% CI = 0.99–1.27). Conclusion High resting heart rate is a risk factor for adverse outcomes in patients with HFpEF, and future studies are needed in order to determine whether reducing heart rate improves outcomes in HFpEF.