Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. METHODS: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. RESULTS: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. CONCLUSIONS: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.

Use of Optimal Medical Therapy in Patients With Cardiovascular Disease Undergoing Cardiac Rehabilitation.

Optimal medical therapy (OMT) in patients with coronary artery disease (CAD) and/or heart failure (HF) is underused despite the established benefits of these medications. Cardiac rehabilitation (CR) may be one place where OMT could be promoted. We sought to describe the prevalence and characteristics of OMT use in patients with CAD or HF undergoing CR. We included patients with CAD (myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, angina) and HF enrolled in our CR program. For patients with CAD, we defined OMT to consist of aspirin or other antiplatelets, statins, and beta-blockers (BB). For patients with HF or EF ≤ 40%, OMT included BB, spironolactone, and either Angiotensin Converting Enzyme inhibitors (ACEi)/angiotensin receptor blockers or angiotensin receptor neprilysin inhibitor (ARNI). For CAD patients with normal EF, OMT also included ACEi/ARB/ARNI if they also had diabetes type 2. From January 2015 to December 2019, 828 patients were referred to CR and 743 attended. Among 612 patients (mean age: 65, 23% female) with CAD, 483 (79%) patients were on OMT. Of the 131 HF patients (mean age: 64, 21% female) enrolled in CR, only 23 (18%) met all 3 OMT criteria, whereas most patients were on only 1 (93 %) or 2 (76%) HF specific medications. Spironolactone was the least prescribed (22%) medication. Over the study period, we observed a steady increase in the use of ARNI (2015: 0% vs 2019: 27%, p < 0.01). Among the individuals, 69 patients experienced both CAD and HF, while only 7 patients were under OMT for both CAD and HF. Most patients attending CR with CAD are receiving OMT, but most patients with HF are not. Although OMT has improved over time, there remains room for improvement, particularly among patients with HF.

Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study.

BACKGROUND: Whether iron deficiency contributes to incident heart failure (HF) and cardiac dysfunction has important implications given the prevalence of iron deficiency and the availability of several therapeutics for iron repletion. OBJECTIVES: The aim of this study was to estimate the associations of plasma ferritin level with incident HF overall, HF phenotypes, and cardiac structure and function measures in older adults. METHODS: Participants in the ongoing, longitudinal ARIC (Atherosclerosis Risk In Communities) study who were free of prevalent HF and anemia were studied. The associations of plasma ferritin levels with incident HF overall and heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) were estimated using Cox proportional hazards regression models. Linear regression models estimated the cross-sectional associations of plasma ferritin with echocardiographic measures of cardiac structure and function. RESULTS: The cohort included 3,472 individuals with a mean age of 75 ± 5 years (56% women, 14% Black individuals). In fully adjusted models, lower ferritin was associated with higher risk for incident HF overall (HR: 1.20 [95% CI: 1.08-1.34] per 50% lower ferritin level) and higher risk for incident HFpEF (HR: 1.28 [95% CI: 1.09-1.50]). Associations with incident HFrEF were not statistically significant. Lower ferritin levels were associated with higher E/e' ratio and higher pulmonary artery systolic pressure after adjustment for demographics and HF risk factors but not with measures of left ventricular structure or systolic function. CONCLUSIONS: Among older adults without prevalent HF or anemia, lower plasma ferritin level is associated with a higher risk for incident HF, HFpEF, and higher measures of left ventricular filling pressure.

Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development.

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes.

Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis.

BACKGROUND: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms. OBJECTIVES: The aim of this study was to discover novel biomarkers with potentially causal associations with AS. METHODS: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue. RESULTS: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis. CONCLUSIONS: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.

Longitudinal Changes in Left Ventricular Diastolic Function in Late Life: The ARIC Study.

BACKGROUND: There is limited data regarding longitudinal changes of diastolic function in the very old, who are at the highest risk for heart failure (HF). OBJECTIVES: This study aims to quantify intraindividual longitudinal changes of diastolic function over 6 years in late life. METHODS: The authors studied 2,524 older adult participants in the prospective community-based ARIC (Atherosclerosis Risk In Communities) study who underwent protocol-based echocardiography at study visits 5 (2011-2013) and 7 (2018-2019). The primary diastolic measures were tissue Doppler e', E/e' ratio, and left atrial volume index (LAVI). RESULTS: Mean age was 74 ± 4 years at visit 5 and 80 ± 4 at visit 7, 59% were women, and 24% were Black. At visit 5, mean e'septal was 5.8 ± 1.4 cm/s, E/e'septal 11.7 ± 3.5, and LAVI 24.3 ± 6.7 mL/m2. Over a mean of 6.6 ± 0.8 years, e'septal decreased by 0.6 ± 1.4 cm/s, E/e'septal increased by 3.1 ± 4.4, and LAVI increased by 2.3 ± 6.4 mL/m2. The proportion with 2 or more abnormal diastolic measures increased from 17% to 42% (P < 0.001). Compared with participants free of cardiovascular (CV) risk factors or diseases at visit 5 (n = 234), those with prevalent CV risk factors or diseases but without prevalent or incident HF (n = 2,150) demonstrated greater increases in E/e'septal and LAVI. Increases of E/e'septal and LAVI were both associated with the development of dyspnea between visits in analyses adjusted for CV risk factors. CONCLUSIONS: Diastolic function generally deteriorates over 6.6 years in late life, particularly among persons with CV risk factors, and is associated with development of dyspnea. Further studies are necessary to determine if risk factor prevention or control will mitigate these changes.

Circulating neutrophil-related proteins associate with incident heart failure and cardiac dysfunction: The ARIC study.

AIMS: Neutrophil activity contributes to adverse cardiac remodelling in experimental acute cardiac injury and is modifiable with pharmacologic agents like colchicine. METHODS AND RESULTS: Neutrophil activity-related plasma proteins known to be affected by colchicine treatment were measured at Visit 3 (1993-1995) and Visit 5 (2011-2013) of the ARIC cohort study. A protein-based neutrophil activity score was derived from 10 candidate proteins using LASSO Cox regression. Associations with incident heart failure (HF) and with cardiac function using Cox proportional hazards regression and linear regression models, respectively. The mean ages at Visits 3 and 5 were 60 ± 6 and 75 ± 5 years, respectively, and 54% and 57% were women, respectively. Each 1-standard deviation increase in the neutrophil activity score was associated with a higher risk of incident HF in mid-life (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.25-1.37) and late-life (HR 1.23, 95% CI 1.14-1.34), with a higher HR for HF with preserved than reduced ejection fraction (HR 1.30, 95% CI 1.16-1.47 vs. HR 1.13, 95% CI 0.98-1.30). Higher neutrophil activity was associated with greater left ventricular end-diastolic volume index, mass index and diastolic and systolic dysfunction. CONCLUSIONS: Plasma proteins related to neutrophil function associate with incident HF in mid- and late-life and with adverse cardiac remodelling. Therapies that modify these proteins, such as colchicine, may represent promising targets for the prevention or treatment of HF.

MMP-2 Associates With Incident Heart Failure and Atrial Fibrillation: The ARIC Study.

BACKGROUND: MMP (matrix metalloproteinase)-2 participates in extracellular matrix regulation and may be involved in heart failure (HF), atrial fibrillation (AF), and coronary heart disease. METHODS: Among the 4693 ARIC study (Atherosclerosis Risk in Communities) participants (mean age, 75±5 years; 42% women) without prevalent HF, multivariable Cox proportional hazard models were used to estimate associations of plasma MMP-2 levels with incident HF, HF with preserved ejection fraction (≥50%), HF with reduced ejection fraction (<50%), AF, and coronary heart disease. Mediation of the association between MMP-2 and HF was assessed by censoring participants who developed AF or coronary heart disease before HF. Multivariable linear regression models were used to assess associations of MMP-2 with measures of left ventricular and left atrial structure and function. RESULTS: Compared with the 3 lower quartiles, the highest MMP-2 quartile associated with greater risk of incident HF overall (adjusted hazard ratio, 1.48 [95% CI, 1.21-1.81]), incident HF with preserved ejection fraction (1.44 [95% CI, 1.07-1.94]), incident heart failure with reduced ejection fraction (1.48 [95% CI, 1.08-2.02]), and incident AF (1.44 [95% CI, 1.18-1.77]) but not incident coronary heart disease (0.97 [95% CI, 0.71-1.34]). Censoring AF attenuated the MMP-2 association with HF with preserved ejection fraction. Higher plasma MMP-2 levels were associated with larger left ventricular end-diastolic volume index, greater left ventricular mass index, higher E/e' ratio, larger left atrial volume index, and worse left atrial reservoir and contractile strains (all P<0.001). CONCLUSIONS: Higher plasma MMP-2 levels associate with diastolic dysfunction, left atrial dysfunction, and a higher risk of incident HF and AF. AF is a mediator of MMP-2-associated HF with preserved ejection fraction risk.

Physical and Psychological Well-being Effects of Cardiac Rehabilitation on Patients Following Mitral Valve and Aortic Valve Procedures.

PURPOSE: Patients participating in cardiac rehabilitation (CR) following an aortic valve procedure demonstrate improvements in physical capacity and psychological well-being. The primary aim of this study is to evaluate baseline exercise capacity and psychological well-being for mitral valve patients participating in CR and to compare physical and psychological outcomes between mitral valve and aortic valve patients. METHODS: The primary endpoint was improvement in 6-min walk test (6MWT) distance. Secondary endpoints included change in exercise min/wk, depression scores (Patient Health Questionnaire-9 [PHQ-9]), anxiety scores (General Anxiety Disorder-7 [GAD-7]), and overall quality of life (Dartmouth Cooperative Functional Assessment [COOP]) scores. RESULTS: Between January 2015 and December 2019, 94 patients who underwent an aortic valve procedure and 46 patients who underwent mitral valve procedures were enrolled prospectively in CR. At the completion of their CR program, patients had similar improvements in their 6MWT (mitral valve: 173 ft [125, 238] vs aortic valve 197 ft [121, 295], P = .42); exercise min/wk (mitral valve: 90 min [45, 175] vs aortic valve: 80 min [40, 130], P = .44). Changes in anxiety (GAD-7), depression (PHQ-9), and COOP scores were smaller but similar between the two groups. CONCLUSIONS: CR participation resulted in similar improvements in physical activity between patients undergoing mitral valve and aortic valve procedures. Psychological well-being and quality of life scores improved minimally and similarly between the two groups.

Weight Loss and Its Predictors During Participation in Cardiac Rehabilitation.

We aimed to assess the prevalence and magnitude of clinically meaningful weight loss among cardiac rehabilitation (CR) participants who were overweight or obese and identify its predictors. We analyzed subjects with body mass index (BMI) ≥25 who were enrolled in a 12-week CR outpatient program from January 1, 2015, to December 31, 2019, and had paired pre- and post-CR weight data. Patients who lost 3% or more of their body weight by the end of the program were compared with the remaining participants. Multivariable logistic regression was used to determine predictors of weight loss. Overall, 129 of 485 subjects (27%) with overweight or obesity reduced their weight by at least 3% (average percent weight change: -5.0% ± 1.8% vs -0.02% ± 2.2%, average weight change: -10.9 ± 5.0 vs -0.1 ± 4.4 pounds, and average BMI change: -1.7 ± 0.7 vs -0.02 ± 0.7 kg/m2). Compared with the remaining 356 patients, those who achieved the defined weight loss were younger (p = 0.016) and had higher baseline weight (p = 0.002) and BMI (p <0.001). The weight loss group tended to be enrolled more likely for an acute myocardial infarction or percutaneous coronary intervention (p <0.001) and less likely for coronary artery bypass grafting (p = 0.001) or a heart valve procedure (p = 0.05). By the end of the CR program, the weight loss group demonstrated a greater increase in Rate Your Plate - Heart score (7 [3, 11] vs 4 [1, 8]; p <0.001) and a greater decrease in triglycerides (-20 ± 45 vs -7 ± 55 mg/dL; p = 0.026) and glycated hemoglobin (-0.1 [-0.5, 0.1] vs 0.1 [-0.3, 0.4] %; p = 0.05, among patients with diabetes or prediabetes). In a multivariable logistic regression model, baseline predictors of clinically meaningful weight loss included higher BMI and not being enrolled for a surgical CR indication (p = 0.001). In conclusion, throughout 12 weeks of CR participation, 129 of 485 subjects (27%) with BMI ≥25 had a 3% or more reduction in body weight. Patients with higher baseline BMI and participants without a surgical enrollment diagnosis were more likely to achieve the defined weight loss. Efforts to improve CR referral and enrollment for eligible patients with overweight and obesity should be encouraged, and suitable and efficient weight reduction interventions in CR settings need to be further studied.

Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.

AIMS: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. METHODS AND RESULTS: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (Pinteraction < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). CONCLUSIONS: Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.

An emerging role for the miR-26 family in cardiovascular disease.

In response to acute myocardial infarction (MI), a complex series of cellular and molecular signaling events orchestrate the myocardial remodeling that ensues weeks to months after injury. Clinical, epidemiological, and pathological studies demonstrate that inadequate or impaired angiogenesis after myocardial injury is often associated with decreased left ventricular (LV) function and clinical outcomes. The microRNA family, miR-26, plays diverse roles in regulating key aspects of cellular growth, development, and activation. Recent evidence supports a central role for the miR-26 family in cardiovascular disease by controlling critical signaling pathways, such as BMP/SMAD1 signaling, and targets relevant to endothelial cell growth, angiogenesis, and LV function post-MI. Emerging studies of the miR-26 family in other cell types including vascular smooth muscle cells, cardiac fibroblasts, and cardiomyocytes suggest that miR-26 may bear important implications for a range of cardiovascular repair mechanisms. This review examines the current knowledge of the miR-26 family's role in key cell types that critically control cardiovascular disease under pathological and physiological stimuli.