Identifying the molecular and cellular signature of cardiac dilation following myocardial infarction.

Establishing molecular and cellular indicators that reflect the extent of dilation of the left ventricle (LV) after myocardial infarction (MI) may improve diagnostic and prognostic capabilities. We queried the Mouse Heart Attack Research Tool (mHART) 1.0 for day 7 post-MI mice (age 3-9 months, untreated males and females) with serial echocardiographic data at days 0, 1, and 7 (n = 51). Mice were classified into two subgroups determined by a median fold change of 1.6 in end-diastolic dimensions (EDD) normalized to pre-MI values; n = 26 fell below (moderate; mean of 1.42 ±â€¯0.01) and n = 25 fell above this cut-off (extreme; mean of 1.79 ±â€¯0.01; p < 0.001 vs. moderate). Plasma proteomic profiling of 34 analytes measured at day 7 post-MI from male mice (n = 12 moderate and 12 extreme) were evaluated as the test dataset, and receiver operating curve (ROC) analysis was used to assess strength of biomarkers. Females (n = 6 moderate and 9 extreme) were used as the validation dataset. Both by t-test and characteristic (ROC) curve analysis, lower macrophage inflammatory protein-1 gamma (MIP-1γ), lymphotactin, and granulocyte chemotactic protein-2 (GCP-2) were identified as plasma indicators for dilation status (p < 0.05 for all). Macrophage numbers were decreased and complement C5, laminin 1, and Ccr8 gene levels were significantly higher in the LV infarcts of the extreme dilation group (p < 0.05 for all). A composite panel including plasma MIP-1γ, lymphotactin, and GCP-2, and LV infarct Ccr8 and macrophage numbers strongly mirrored LV dilation status (AUC = 0.92; p < 0.0001). Using the mHART 1.0 database, we determined that a failure to mount sufficient macrophage-mediated inflammation was indicative of exacerbated LV dilation.

Energy Drinks: Another Cause of QT Prolongation?

See Article Shah et al.

Higher plasma leptin levels are associated with reduced left ventricular mass and left ventricular diastolic stiffness in black women: insights from the Genetic Epidemiology Network of Arteriopathy (GENOA) study.

Our previous experimental animal data suggest a beneficial effect of leptin on LV structure and function. We hypothesized that leptin levels are associated with lower LV mass and myocardial stiffness which are important risk factors for the development of heart failure with preserved ejection fraction (HFpEF). We evaluated 1172 blacks, in which the prevalence of HFpEF is quite high, with preserved LV ejection fraction (EF > 50%) from the Genetic Epidemiology Network of Arteriopathy Study (mean age 62.9 years, 72% women), a community-based study to identify genes influencing blood pressure and target organ damage due to hypertension. Associations between leptin levels and indices of LV structure and function were evaluated using generalized estimating equations accounting for clustering in siblings. LV myocardial stiffness was evaluated using diastolic wall strain (DWS) measured by echocardiography. Analyses were stratified by sex because leptin levels were three times higher in women than men (p < 0.001). After adjustment for confounders, higher leptin levels were associated with lower LV mass (coefficient for 1 s.d. increase of leptin level: -5.825 g, 95% CI: -9.755 to -1.895 g, P = 0.004) and higher DWS (lower LV stiffness) (coefficient for 1 s.d. increase of leptin level: 0.009, 95% CI: 0.002-0.015, P = 0.007) in women. There were no statistically significant associations in men. In women, there were interactions between leptin levels and body mass index quartiles on LV mass and stiffness (p < 0.05 for both). Higher leptin levels were associated with lower LV mass and stiffness in obese but not lean black women.

Cigarette Smoking and Incident Heart Failure: Insights From the Jackson Heart Study.

BACKGROUND: Cigarette smoking has been linked with several factors associated with cardiac dysfunction. We hypothesized that cigarette smoking is associated with left ventricular (LV) structure and function, and incident heart failure (HF) hospitalization. METHODS: We investigated 4129 (never smoker n=2884, current smoker n=503, and former smoker n=742) black participants (mean age, 54 years; 63% women) without a history of HF or coronary heart disease at baseline in the Jackson Heart Study. We examined the relationships between cigarette smoking and LV structure and function by using cardiac magnetic resonance imaging among 1092 participants, cigarette smoking and brain natriuretic peptide levels among 3325 participants, and incident HF hospitalization among 3633 participants with complete data. RESULTS: After adjustment for confounding factors, current smoking was associated with higher mean LV mass index and lower mean LV circumferential strain (P<0.05, for both) in comparison with never smoking. Smoking status, intensity, and burden were associated with higher mean brain natriuretic peptide levels (all P<0.05). Over 8.0 years (7.7-8.0) median follow-up, there were 147 incident HF hospitalizations. After adjustment for traditional risk factors and incident coronary heart disease, current smoking (hazard ratio, 2.82; 95% confidence interval, 1.71-4.64), smoking intensity among current smokers (≥20 cigarettes/d: hazard ratio, 3.48; 95% confidence interval, 1.65-7.32), and smoking burden among ever smokers (≥15 pack-years: hazard ratio, 2.06; 95% confidence interval, 1.29-3.3) were significantly associated with incident HF hospitalization in comparison with never smoking. CONCLUSIONS: In blacks, cigarette smoking is an important risk factor for LV hypertrophy, systolic dysfunction, and incident HF hospitalization even after adjusting for effects on coronary heart disease.

High-Intensity Cigarette Smoking Is Associated With Incident Diabetes Mellitus In Black Adults: The Jackson Heart Study.

BACKGROUND: Previous reports on whether smoking is associated with insulin resistance and diabetes mellitus have yielded inconsistent findings. We aimed to evaluate the relationship between cigarette smoking and incident diabetes mellitus in the Jackson Heart Study. METHODS AND RESULTS: Jackson Heart Study participants enrolled at baseline without prevalent diabetes mellitus (n=2991) were classified by self-report as current smokers, past smokers (smoked ≥400 cigarettes/life and no longer smoking), or never smokers. We quantified smoking intensity by number of cigarettes smoked daily; we considered ≥20 cigarettes per day (1 pack) "high-intensity." We defined diabetes mellitus as fasting glucose ≥126 mg/dL, hemoglobin A1c ≥6.5% or International Federation of Clinical Chemistry units HbA1c 48 mmol/mol, or use of diabetes mellitus medication. We estimated the adjusted associations of smoking status, intensity, and dose (pack-years) with incident diabetes mellitus using Poisson regression models. At baseline there were 361 baseline current (1-10 cigarettes per day [n=242]; ≥20 [n=119]), 502 past, and 2128 never smokers. From Visit 1 to Visit 3 (mean 8.0±0.9 years), 479 participants developed incident diabetes mellitus. After adjustment for covariates, baseline current smokers who smoked less than a pack/d and past smokers had similar rates of incident diabetes mellitus compared with never smokers (incidence rate ratios 1.04, 95% confidence interval, 0.69-1.58 and 1.08, 95% confidence interval, 0.82-1.42, respectively). Baseline current high-intensity smokers had a 79% (95% confidence interval, 1.14-2.81) higher incidence of diabetes mellitus compared with never smokers. Smoking dose (per 10 pack-years) was also associated with a higher incidence of diabetes mellitus (incidence rate ratios 1.10, 95% confidence interval, 1.03-1.19) in adjusted models. CONCLUSIONS: High-intensity cigarette smoking and smoking pack-years are associated with an increased risk of developing diabetes mellitus in blacks.

Diastolic wall strain is associated with incident heart failure in African Americans: Insights from the atherosclerosis risk in communities study.

BACKGROUND: Increased left ventricular (LV) myocardial stiffness may be associated with impaired LV hemodynamics and incident heart failure (HF). However, an indicator that estimates LV myocardial stiffness easily and non-invasively is lacking. The purpose of this study was to determine whether diastolic wall strain (DWS), an echocardiographic estimator of LV myocardial stiffness, is associated with incident HF in a middle-aged community-based cohort of African Americans. METHODS AND RESULTS: We investigated associations between DWS and incident HF among 1528 African Americans (mean age 58.5 years, 66% women) with preserved LV ejection fraction (EF ≥50%) and without a history of cardiovascular disease in the Atherosclerosis Risk in Communities Study. Participants with the smallest DWS quintile (more LV myocardial stiffness) had a higher LV mass index, higher relative wall thickness, and lower arterial compliance than those in the larger four DWS quintiles (p<0.01 for all). Over a mean follow-up of 15.6 years, there were 251 incident HF events (incidence rate: 10.9 per 1000 person-years). After adjustment for traditional risk factors and incident coronary artery disease, both continuous and categorical DWS were independently associated with incident HF (HR 1.21, 95%CI 1.04-1.41 for 0.1 decrease in continuous DWS, p=0.014, HR 1.40, 95%CI 1.05-1.87 for the smallest DWS quintile vs other combined quintiles, p=0.022). CONCLUSIONS: DWS was independently associated with an increased risk of incident HF in a community-based cohort of African Americans. DWS could be used as a qualitative estimator of LV myocardial stiffness.

Left Ventricular False Tendons are Associated With Left Ventricular Dilation and Impaired Systolic and Diastolic Function.

BACKGROUND: Left ventricular false tendons (LVFTs) are chord-like structures that traverse the LV cavity and are generally considered to be benign. However, they have been associated with arrhythmias, LV hypertrophy and LV dilation in some small studies. We hypothesize that LVFTs are associated with LV structural and functional changes assessed by echocardiography. METHODS: We retrospectively evaluated echocardiographic and clinical parameters of 126 patients identified as having LVFTs within the past 2 years and compared them to 85 age-matched controls without LVFTs. RESULTS: There were no significant differences in age (52 ± 18 versus 54 ± 18 years, P = 0.37), sex (55% versus 59% men, P = 0.49), race (36% versus 23% white, P = 0.07), systolic blood pressure (131 ± 22 versus 132 ± 23mmHg, P = 0.76) or body mass index (BMI, 31 ± 8 versus 29 ± 10kg/m2, P = 0.07) between controls and patients with LVFTs, respectively. Patients with LVFTs had more prevalent heart failure (43% versus 21%, P = 0.001). Patients with LVFTs had more LV dilation, were 2.5 times more likely to have moderate-to-severe mitral regurgitation, had more severe diastolic dysfunction and reduced LV systolic function (18% lower) compared with controls (all P < 0.05). After adjustment for covariates, basal and middle LVFT locations were associated with reduced LV systolic function (P < 0.01), and middle LVFTs were associated with LV dilation (P < 0.01). CONCLUSIONS: Our findings suggest that LVFTs may not be benign variants, and basal and middle LVFTs may have more deleterious effects. Further prospective studies should be performed to determine their pathophysiological significance and whether they play a causal role in LV dysfunction.

Elevated serum osteoprotegerin is associated with increased left ventricular mass index and myocardial stiffness.

AIM: Osteoprotegerin (OPG) is associated with a poor prognosis in patients with heart failure with preserved ejection fraction (HFpEF). OPG has also been associated with fibrosis and collagen cross-linking, which increase arterial and left ventricle (LV) myocardial stiffness. Little is known about the relation of OPG and LV structure and function in African-Americans who are disproportionately affected by HFpEF. METHODS AND RESULTS: Our analysis included 1172 participants with preserved LV ejection fraction (>50%) from the African-American cohort in the Genetic Epidemiology Network of Arteriopathy Study (mean age 63 years, 72% female). We used diastolic wall strain indicator measured by echocardiography to assess LV myocardial stiffness. Diastolic wall strain was calculated as (LV posterior thickness at end-systole - LV posterior thickness at end-diastole)/LV posterior thickness at end-systole. Associations between OPG levels and indices of arterial and LV structure and function were evaluated by using generalized linear mixed models and adjusted for possible confounders. OPG levels were correlated with age, female sex, presence of hypertension and diabetes, and lower estimated glomerular filtration rate (P < 0.05 for all). Multivariable analysis revealed that higher OPG levels were associated with greater LV mass index, increased LV myocardial stiffness, and higher N-terminal prohormone brain natriuretic peptide levels (P < 0.05 for all). CONCLUSION: In African-Americans, higher OPG levels were associated with characteristics common in patients with HFpEF and were significantly associated with known precursors to HFpEF. These findings indicate a potential role for OPG in the pathophysiology of HFpEF in African-Americans.

Increased Left Ventricular Diastolic Stiffness Is Associated With Heart Failure Symptoms in Aortic Stenosis Patients With Preserved Ejection Fraction.

BACKGROUND: Clinical risk factors associated with heart failure (HF) symptoms in aortic stenosis (AS) patients with preserved ejection fraction (EF) have not been fully identified. We hypothesized that left ventricular (LV) diastolic stiffness is associated with HF symptoms in patients with AS. METHODS AND RESULTS: We retrospectively evaluated 275 patients with at least moderate AS (aortic valve area <1.5 cm2) and preserved EF (≥50%). LV diastolic stiffness was evaluated with the use of echocardiographic parameters, diastolic wall strain (DWS, a measure of LV wall stiffness), and KLV (a marker of LV chamber stiffness). There were 69 patients with HF. Patients with HF were older, were more likely to be African American, had a higher body mass index, and had more hypertension and coronary artery disease (P < .05 for all). Aortic valve area index and mean pressure gradient across the aortic valve were not different between patients with and without HF. Despite similar echocardiographic parameters of AS severity, patients with HF had stiffer LV (DWS 0.21 ± 0.06 vs 0.25 ± 0.06 [P < .01], KLV 0.17 ± 0.11 vs 0.13 ± 0.08 [P < .01]). Logistic regression analyses revealed that after adjusting for age, race, body mass index, history of hypertension, and coronary artery disease, LV diastolic stiffness parameters remained significantly associated with HF symptoms. CONCLUSIONS: LV diastolic stiffness is independently associated with HF in AS patients with preserved EF.

Cigarette Smoking and Chronic Kidney Disease in African Americans in the Jackson Heart Study.

BACKGROUND: Controversy exists regarding the association of cigarette smoking and renal dysfunction, particularly among African Americans, who are disproportionately affected by chronic kidney disease; therefore, we evaluated the relationship between cigarette smoking and rapid renal function (RRF) decline in the Jackson Heart Study. METHODS AND RESULTS: Rates of RRF decline were determined among 3648 African American participants enrolled at baseline in the Jackson Heart Study. RRF decline was defined as an absolute decline of estimated glomerular filtration rate of 30% from visit 1 to visit 3. There were 422 current, 659 past, and 2567 never smokers identified at visit 1. After adjustment for age, sex, body mass index, diabetes, hypertension, cholesterol, physical activity, education, alcohol consumption, and prevalent cardiovascular disease, current smokers demonstrated a significantly higher incidence of RRF decline compared with never smokers (incidence rate ratio 1.83, 95% CI 1.31-2.56). Current smokers using 1 to 19 and ≥20 cigarettes daily had an increased incidence of RRF decline (incidence rate ratios of 1.75 [95% CI 1.18-2.59] and 1.97 [95% CI 1.17-3.31], respectively). There was a significant, progressive reduction in estimated glomerular filtration rate from visit 1 to visit 3 in current and past smokers compared with never smokers. Finally, current smokers had a 1.38-fold increase in C-reactive protein compared with never smokers, after controlling for covariates. CONCLUSIONS: In a large African American cohort, current cigarette smoking was independently associated with RRF decline in a dose-dependent manner. There was also evidence of increased inflammation (C-reactive protein) in current smokers, suggesting a potential mechanism for these relationships.

Myocardial Infarction Superimposed on Aging: MMP-9 Deletion Promotes M2 Macrophage Polarization.

In this study, we examined the combined effect of aging and myocardial infarction on left ventricular remodeling, focusing on matrix metalloproteinase (MMP)-9-dependent mechanisms. We enrolled 55 C57BL/6J wild type (WT) and 85 MMP-9 Null (Null) mice of both sexes at 11-36 months of age and evaluated their response at Day 7 post-myocardial infarction. Plasma MMP-9 levels positively linked to age in WT mice (r = .46, p = .001). MMP-9 deletion improved survival (76% for WT vs 88% for Null, p = .021). Post-myocardial infarction, there was a progressive increase in left ventricular dilation with age in WT but not in Null mice. By inflammatory gene array analysis, WT mice showed linear age-dependent increases in three different proinflammatory genes (C3, CCl4, and CX3CL1; all p < .05), whereas Null mice showed increases in three proinflammatory genes (CCL5, CCL9, and CXCL4; all p < .05) and seven anti-inflammatory genes (CCL1, CCL6, CCR1, IL11, IL1r2, IL8rb, and Mif; all p < .05). Compared with WT, macrophages isolated from Null left ventricle infarct demonstrated enhanced expression of anti-inflammatory M2 markers CD163, MRC1, TGF-ß1, and YM1 (all p < .05), without affecting proinflammatory M1 markers. In conclusion, MMP-9 deletion stimulated anti-inflammatory polarization of macrophages to attenuate left ventricle dysfunction in the aging post-myocardial infarction.

Impact of clinical and therapeutic factors on incident cardiovascular and cerebrovascular events in a population-based cohort of HIV-infected and non-HIV-infected adults.

BACKGROUND: Cardiovascular and cerebrovascular (CVD) events/diseases are a common cause of non-acquired immunodeficiency syndrome (AIDS)-related mortality in the aging human immunodeficiency virus (HIV)-infected population. The incidence rate and clinical correlates of CVD in people living with HIV/AIDS compared to the general population warrants further investigation. HYPOTHESIS: HIV/AIDS is associated with increased risk CVD compared to general population. METHODS: CVD events in a matched cohort of HIV-infected and non-HIV-infected adults, ≥18 years old, served through the South Carolina Medicaid program during 1994 to 2011 were examined using time-dependent proportional hazards regression and marginal structural modeling. RESULTS: A retrospective cohort of 13,632 adults was followed longitudinally for an average of 51 months. The adjusted hazard ratio (aHR) of incident CVD events was higher among HIV-infected individuals exposed to combination antiretroviral therapy (cART) (aHR = 1.15) compared to the non-HIV-infected group, but did not differ from the subgroup of cART-naïve HIV-infected adults. A higher aHR of incident CVD was associated with comorbid hypertension (aHR = 2.18), diabetes (aHR = 1.38), obesity (aHR = 1.30), tobacco use (aHR = 1.47), and hepatitis C coinfection (aHR = 1.32), and older age (aHR = 1.26), but with a lower risk among females (aHR = 0.86). A higher risk of incident CVD events was also apparent in HIV-infected individuals with exposure to both protease inhibitors (adjusted risk ratio [aRR] = 1.99) and non-nucleoside reverse transcriptase inhibitors (aRR = 2.19) compared to those with no exposure. Sustained viral load suppression was associated with a lower risk of incident CVD events (aRR = 0.74). CONCLUSIONS: After adjusting for traditional risk factors and sociodemographic differences, there is higher risk of incident cardiovascular events among HIV-infected individuals exposed to combined antiretroviral medications compared to the general population.

Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling.

The cardiac extracellular matrix (ECM) fills the space between cells, supports tissue organization, and transduces mechanical, chemical, and biological signals to regulate homeostasis of the left ventricle (LV). Following myocardial infarction (MI), a multitude of ECM proteins are synthesized to replace myocyte loss and form a reparative scar. Activated fibroblasts (myofibroblasts) are the primary source of ECM proteins, thus playing a key role in cardiac repair. A balanced turnover of ECM through regulation of synthesis by myofibroblasts and degradation by matrix metalloproteinases (MMPs) is critical for proper scar formation. In this review, we summarize the current literature on the roles of myofibroblasts, MMPs, and ECM proteins in MI-induced LV remodeling. In addition, we discuss future research directions that are needed to further elucidate the molecular mechanisms of ECM actions to optimize cardiac repair.

A quality improvement framework for equity in cardiovascular care: results of a national collaborative.

Disparities in the quality of cardiovascular care provided to minorities have been well documented, but less is known about the use of quality improvement methods to eliminate these disparities. Measurement is also often impeded by a lack of reliable patient demographic data. The objective of this study was to assess the ability of hospitals with large minority populations to measure and improve the care rendered to Black and Hispanic patients. The Expecting Success: Excellence in Cardiac Care project utilized the standardized collection of self-reported patient race, ethnicity, and language data to generate stratified performance measures for cardiac care coupled with evidence-based practice tools in a national competitively selected sample of 10 hospitals with high cardiac volumes and largely minority patient populations. Main outcomes included changes in nationally recognized measures of acute myocardial infarction and heart failure quality of care and 2 composite measures, stratified by patient demographic characteristics. Quality improved significantly at 7 of the 10 hospitals as gauged by composite measures (p < .05), and improvements exceeded those observed nationally for all hospitals. Three of 10 hospitals found racial or ethnic disparities which were eliminated in the course of the project. Clinicians and institutions were able to join the standardized collection of self-reported patient demographic data to evidence-based measures and quality improvement tools to improve the care of minorities and eliminate disparities in care. This framework may be replicable to ensure equity in other clinical areas.