Abraham, William T.

Abstract Worldwide, valvular heart disease (VHD) is a common cause of hospitalization for acute heart failure. In acute heart failure caused by VHD, symptoms result from rapid haemodynamic changes and subsequent decline in cardiac function, and if left untreated, leads to acute decompensation and cardiogenic shock. Current evidence remains scarce and recommendations regarding the management of acute heart failure caused by VHD are lacking in most recent international guidelines. Herein, we review the management of acute heart failure caused by VHD with a focus on transcatheter therapies and describe currently available evidence based on a systematic literature search on the following valve pathologies: (i) aortic stenosis, (ii) aortic regurgitation, (iii) mitral regurgitation, and (iv) mitral stenosis. Articles reporting outcomes following urgent or emergent valve intervention in the setting of cardiogenic shock or acute heart failure were considered. After screening a total of 2234 articles, 76 published between 1994 and 2023 were included in subsequent analysis. Based on available evidence, proposed treatment algorithms to guide optimal management of acute heart failure caused by VHD were created. As the number of patients presenting with acute heart failure caused by VHD continues to rise and outcomes following transcatheter valve interventions continue to improve, it is inevitable that minimally invasive options will play an increasingly important role in the acute setting, especially given these patients are at an increased operative risk. This review aims to present an organized approach to the complex management and interventional treatment of patients with acute heart failure caused by VHD.

Background: Heart failure (HF), a leading cause of morbidity and mortality in women, continues to disproportionately affect African-American (AA) women compared to women of other races/ethnicities. In a large cohort of post-menopausal women, we investigated if AA women progress through HF stages and coronary heart disease (CHD) death more rapidly than Caucasian (Cau) or Hispanic/Latina (HL) women. Methods: We assessed the American College of Cardiology/American Heart Association (ACC/AHA) HF stage A upon enrollment into the Women’s Health Initiative (1993-1998) and the progression from Stage A to Stage C, Stage C to CHD death, up to the last date of follow-up (2010). Cox proportional hazard regressions models were used to assess disease progression risk. We adjusted for age, baseline comorbidities, duration of comorbidities, interval development of myocardial infarction, ejection fraction at HF diagnosis, socioeconomic factors, and sex specific variables. Results: At baseline, AA women were younger and had a higher percentage of Stage A HF (76%) than Cau (54%) and HL (55%) women. Overall, AA and HL women had significantly lower risk of progressing from Stage A to Stage C compared to Cau women [AA vs. Cau adjusted Hazard Ratio (HR) 0.77 (95% Confidence Interval (CI) 0.64 -0.93) p = 0.0055; HL vs. Cau HR 0.54 (95% CI 0.40 -0.71) p < 0.0001]. After stratifying by age groups(<65, 65-69, >70 years), AA women had a similar risk of progression from stage A to C compared to Cau women. When compared to Cau women, AA had an insignificant increased risk of progressing from Stage C to CHD death [adjusted HR 1.29 (95% CI 0.72 -2.32) p = 0.3883)]. Conclusions: Cau women were at higher risk for HF progression from Stage A to Stage C compared to HL women, but at similar risk as AA women. AA women had an insignificant but increased risk of progression from Stage C to CHD death compared to Cau women.

Background: Renal dysfunction has emerged as an important independent prognostic factor in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) improves functional status and left ventricular (LV) function in HF patients with ventricular dyssynchrony. We hypothesized that CRT would also improve glomerular filtration rate as estimated by the abbreviated MDRD equation (eGFR) in patients with reduced eGFR. Methods: This is a retrospective analysis of the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study, which evaluated CRT in HF patients with NYHA class III–IV, ejection fraction ≤35%, QRS ≥130 ms, and stable medical regimen. Patients were evaluated before implantation and 6 months after randomization to control (CRT device OFF, n=225) or CRT (n=228). Patients were categorized according to their baseline eGFR: ≥90 (category A), 60≤eGFR<90 (category B), and 30≤eGFR<60 (category C) mL/min per 1.73m 2 . Changes in eGFR were also correlated with changes in other parameters in univariate analysis. Results: At baseline, reduced eGFR was associated with ischemic etiology, increased age, mitral regurgitation, and neurohumoral activation. CRT increased LV ejection fraction and decreased LV volumes and mitral regurgitation in all categories. Importantly, CRT improved eGFR (p=0.003) and reduced blood urea nitrogen (p=0.008) compared to control in category C, but not A (p=0.75/p=0.41) and B (p=0.43/p=0.89). In addition, only in category C did atrial natriuretic peptide decrease, suggesting reduced atrial distention and filling pressures with CRT in this group with impaired eGFR. In univariate analysis, changes in eGFR correlated weakly but significantly with changes in aldosterone (r=−0.22), plasma renin activity (r=−0.19, norepinephrine (r=−0.16), and mean blood pressure (r=+0.14), a pattern consistent with reduced neurohumoral activation due to increased systemic and renal perfusion pressure. Conclusions: CRT increased eGFR and reduced blood urea nitrogen in HF patients with reduced baseline eGFR. By improving cardiac function, CRT can indirectly improve renal function, underscoring the importance of cardiorenal interaction and providing another mechanism for the beneficial effects of CRT.

Background: In the randomized COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation), among 614 patients with heart failure with 3+ or 4+ secondary mitral regurgitation (MR), transcatheter mitral valve repair (TMVr) with the MitraClip reduced MR, heart failure hospitalizations, and mortality and improved quality of life compared with guideline-directed medical therapy (GDMT) alone. We aimed to examine the prognostic relationship between MR reduction and outcomes after TMVr and GDMT alone. Methods: Outcomes in COAPT between 30 days and 2 years were examined on the basis of the severity of residual MR at 30 days. Results: TMVr-treated patients had less severe residual MR at 30 days than GDMT-treated patients (0/1+, 2+, and 3+/4+: 72.9%, 19.9%, and 7.2% versus 8.2%, 26.1%, and 65.8%, respectively [ P <0.0001]). The rate of composite death or heart failure hospitalizations between 30 days and 2 years was lower in patients with 30-day residual MR of 0/1+ and 2+ compared with patients with 30-day residual MR of 3+/4+ (37.7% versus 49.5% versus 72.2%, respectively [ P <0.0001]). This relationship was consistent in the TMVr and GDMT arms ( P interaction =0.92). The improvement in Kansas City Cardiomyopathy Questionnaire score from baseline to 30 days was maintained between 30 days and 2 years in patients with 30-day MR ≤2+ but deteriorated in those with 30-day MR 3+/4+ (–0.3±1.7 versus –9.4±4.6 [ P =0.0008]) consistently in both groups ( P interaction =0.95). Conclusions: In the COAPT trial, reduced MR at 30 days was associated with greater freedom from death or heart failure hospitalizations and improved quality of life through 2-year follow-up whether the MR reduction was achieved by TMVr or GDMT. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01626079.

Background: Atrial fibrillation (AF), mitral regurgitation (MR), and left ventricular (LV) ejection fraction have a complex interplay. We evaluated the role of AF in patients with heart failure and moderate-to-severe or severe secondary MR enrolled in the randomized COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) and its impact on mechanisms and outcomes with the MitraClip. Methods: Patients in the COAPT trial were stratified by the presence (n=327) or absence (n=287) of a history of AF and by assignment to treatment group. Clinical, echocardiographic, and outcome measures were assessed. The primary outcome was the composite rate of death or heart failure hospitalization at 24 months. Results: Patients with history of AF were older and more often male. They had a higher LV ejection fraction, larger left atrial volumes and mitral valve orifice areas, smaller LV volumes, and similar MR severity. Patients with AF compared with those without a history of AF had a higher unadjusted (hazard ratio [HR], 1.32 [95% CI, 1.06–1.64], P =0.01) and adjusted (HR, 1.30 [1.03–1.64], P =0.03) 2-year rate of the primary outcome. Treatment with the MitraClip compared with guideline-directed medical therapy alone reduced death or heart failure hospitalization in both those with (HR, 0.61 [0.46–0.82]) and without (HR, 0.46 [0.33–0.66]) a history of AF ( P int =0.18). Treatment with the MitraClip was associated with a lower risk of stroke in patients with a history of AF (HR, 0.18 [0.04–0.86]) but not in those without a history of AF (HR, 1.64 [0.58–4.62]; P int =0.02). Conclusions: In the COAPT trial, patients with a history of AF had larger left atrial and mitral valve orifice areas with higher LV ejection fraction and smaller LV volumes, suggesting an atrial mechanism contribution to functional MR. Despite the worse prognosis of heart failure patients with a history of AF, MR reduction with the MitraClip still afforded substantial clinical benefits. Treatment with MitraClip was associated with a lower risk of stroke in patients with a history of AF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01626079.

Abstract Aims More evidence is needed to quantify the association between tricuspid regurgitation (TR) and mortality in patients with heart failure (HF). Methods and results Between 2008–2017, using the Optum longitudinal database, a patient-level database that integrates multiple US-based electronic health and claim records from several health care providers, we identified 435 679 patients with new HF diagnosis and both an assessment of the left ventricular ejection fraction and at least 1 year of history. TR was graded as mild, moderate or severe and classified as prevalent (at the time of the initial HF diagnosis) or incident (subsequent new cases thereafter). For prevalent TR, the analysis was performed using a Cox proportional hazards model with adjustment for patient covariates. Incident TR was modelled as a time-updated covariate, as were other non-fatal events during follow-up. Prevalence of mild, moderate and severe TR at baseline was 10.1%, 5.1% and 1.4%, respectively. Over a median follow-up of 1.5 years, 121 273 patients (27.8%) died and prevalent TR was independently associated with survival. Compared to patients with no TR at baseline, the adjusted hazard ratios for mortality were 0.99 [95% confidence interval (CI) 0.97–1.01], 1.17 (95% CI 1.14–1.20) and 1.34 (95% CI 1.28–1.39) for mild, moderate and severe TR, respectively. In the 363 270 patients free from TR at baseline, incident TR (at least mild, at least moderate, or severe) developed during follow-up in 12.1%, 5.1% and 1.1%, respectively. Adjusted mortality hazard ratios for such new cases were 1.48 (95% CI 1.44–1.52), 1.92 (95% CI 1.86–1.99) and 2.44 (95% CI 2.32–2.57), respectively. Findings were consistent across all patient subgroups based on age, gender, rhythm, associated comorbidities, prior cardiac surgery, B-type natriuretic peptide/N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction. Conclusions In this large contemporary patient-level database of almost half-million US patients with HF, TR was associated with a marked increases in mortality risk overall and in all subgroups. Future randomized controlled trials will evaluate the impact of TR correction on clinical outcomes and the causal relationship between TR and mortality.

Objective Implantable cardioverter defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and the combination therapy (CRT-D) have been shown to reduce all-cause mortality compared with medical therapy alone in patients with heart failure and reduced EF. Our aim was to synthesise data from major randomised controlled trials to estimate the comparative mortality effects of these devices and how these vary according to patients’ characteristics. Methods Data from 13 randomised trials (12 638 patients) were provided by medical technology companies. Individual patient data were synthesised using network meta-analysis. Results Unadjusted analyses found CRT-D to be the most effective treatment (reduction in rate of death vs medical therapy: 42% (95% credible interval: 32–50%), followed by ICD (29% (20–37%)) and CRT-P (28% (15–40%)). CRT-D reduced mortality compared with CRT-P (19% (1–33%)) and ICD (18% (7–28%)). QRS duration, left bundle branch block (LBBB) morphology, age and gender were included as predictors of benefit in the final adjusted model. In this model, CRT-D reduced mortality in all subgroups (range: 53% (34–66%) to 28% (−1% to 49%)). Patients with QRS duration ≥150 ms, LBBB morphology and female gender benefited more from CRT-P and CRT-D. Men and those <60 years benefited more from ICD. Conclusions These data provide estimates for the mortality benefits of device therapy conditional upon multiple patient characteristics. They can be used to estimate an individual patient's expected relative benefit and thus inform shared decision making. Clinical guidelines should discuss age and gender as predictors of device benefits.

Background— Cardiac resynchronization therapy (CRT) is an effective therapy for patients with moderate to severe heart failure and prolonged QRS duration. The purpose of this study was to determine whether reverse left ventricular (LV) remodeling and symptomatic benefit from CRT were sustained at 12 months, and if so, in what proportion of patients this occurred. Methods and Results— Serial Doppler echocardiograms were obtained at baseline and 6 and 12 months after CRT in 228 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Measurements were made of LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E wave) and late (A wave) diastolic filling, and myocardial performance index. At both 6 and 12 months, respectively, CRT was associated with reduced LV EDV ( P <0.0001 and P =0.007) and LV ESV ( P <0.0001 and P <0.0001), improved ejection fraction ( P <0.0001 and P <0.0001), regression of LV mass ( P =0.012 and P <0.0001), and reduced MR ( P <0.0001 and P <0.0001). LV filling time, transmitral E/A ratio, and myocardial performance index all improved at 12 months compared with baseline ( P <0.001, P =0.031, and P <0.0001). Reverse LV remodeling with CRT occurred in more patients at 6 than at 12 months (74% versus 60%, respectively; P <0.05) and was greater in patients with a nonischemic than an ischemic etiology. Conclusions— Reverse LV remodeling and symptom benefit with CRT are sustained at 12 months in patients with New York Heart Association class III/IV heart failure but occur to a lesser degree in patients with an ischemic versus a nonischemic etiology, most likely owing to the inexorable progression of ischemic disease.

Background— Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. Methods and Results— Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the β-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the β-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant ( P <0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. Conclusions— In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation β-blocker.