Impact of first-line antihypertensive drug class and intensity on NT-proBNP improvement and cardiovascular outcomes among hypertensive patients with pre-heart failure: findings from SPRINT trial.

Five first-line classes of antihypertensive drugs are recommended for hypertension treatment. However, it is unclear which class should be chosen for hypertensive patients with pre-heart failure (pre-HF). The study aimed to investigate the association between antihypertensive drug classes and intensity with probability of NT-proBNP (N-terminal pro-B-type natriuretic peptide) improvement and risk of cardiovascular events among pre-HF hypertensive patients. Utilizing the data from SPRINT, we included pre-HF hypertensive patients, identified by NT-proBNP ≥125 pg/mL at baseline. NT-proBNP improvement is defined as a reduction of ≥50% to a level below 125 pg/mL. A total of 3293 patients (mean age: 71.9 years; female: 43.8%) were included. NT-proBNP improvement was observed in 415 patients (12.6%) over 1-year follow up. Thiazide-type diuretics users were associated with a higher likelihood of NT-proBNP improvement (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.05-1.70), a lower risk of HF (hazard ratio [HR], 0.54; 95% CI, 0.37-0.78) and primary composite outcome (HR, 0.72; 95% CI, 0.57-0.89). ACEI/ARB users were only associated with a lower risk of primary composite outcome (HR, 0.80; 95% CI, 0.63-0.99). In contrast, beta-blockers users were associated with a lower likelihood of NT-proBNP improvement (OR, 0.43; 95% CI, 0.34-0.55), while a higher risk of HF (HR, 1.79; 95% CI, 1.21-2.64) and primary composite outcome (HR, 1.48; 95% CI, 1.18-1.87). These associations varied across subgroups of different drug intensities. This post hoc analysis supports the use of thiazide-type diuretics and ACEI/ARB for prevention of cardiovascular events. The use of beta-blockers is associated with an increased risk of HF and primary outcomes, which requires further validation. Association between antihypertensive drug classes and intensity with NT-proBNP improvement and long-term clinical outcome.

The peptide neuromedin U (NMU) is elevated in NYHA II and III heart failure.

AIMS: Currently, there is no reliable biomarker to detect pre-heart failure in humans. An early risk signal is an elevated left atrial pressure (LAP) and preliminary results from animal studies strongly suggest the neuropeptide neuromedin U (NMU) is released in response to this increase in LAP. However, it is unknown whether NMU is elevated in patients with heart failure. Therefore, the aim of this study was to assess if NMU levels are elevated in human cases of heart failure. METHODS AND RESULTS: Twenty-four serum samples were obtained from patients in stage II and III heart failure from the Royal Papworth Hospital in Cambridge UK and tested using a selective NMU-ELISA; the data were compared with serum obtained commercially from self-declared healthy donors. NMU concentrations in serum from heart failure patients were significantly higher (P = 0.0007; unpaired Student's t-test) than control, 8.48 ± 0.67 ng/mL (mean ± SEM) versus 5.43 ± 0.46 ng/mL. There was no significant difference between NYHA stage II and III patients (P = 0.85, unpaired Student's t-test), which were 8.33 ± 0.89 ng/mL (n = 9) and 8.6 ± 0.95 ng/mL (n = 15), respectively. Only mean right atrial pressure was found to have a significant correlation with serum NMU (R = 0.81, P < 0.00001; regression analysis). CONCLUSIONS: NMU is elevated in serum from stage II and III heart failure patients, supporting data from our pre-heart failure animal model; however, further study is needed to determine whether NMU is a reliable biomarker for pre-heart failure.

Alcohol Consumption and Progression of Heart Failure in Those at Risk for or With Pre-heart Failure.

BACKGROUND: This study aimed to understand the dose-response relationship between alcohol consumption, progression of left ventricular dysfunction (LVD) and/or symptomatic heart failure (HF) in an older European population at risk for HF (stage A) or with pre-HF (stage B). METHODS: This longitudinal, observational, secondary analysis of the STOP-HF (St Vincent's Screening TO-Prevent Heart Failure) trial follow-up study excluded former alcohol drinkers and included patients with documented alcohol intake and echocardiography at baseline and follow-up ≥ 18 months. It evaluated the relationship between alcohol intake and progression of LVD/symptomatic (stage C) HF in those at risk for or with pre-HF. RESULTS: Of 744 patients (mean age 66.5 [SD 9.8] years), 395 (53.1%) were female, and 260 (34.9%) had pre-HF at baseline. Overall, 201 (27.0%) patients reported no alcohol usage, 356 (47.8%) reported ≤70 g/week (low) alcohol intake, and 187 (25.1%) reported > 70g/week (moderate-high). Over a median follow-up of 5.44 (IQR 4.33;6.73) years, 84 (11.3%) patients experienced progression of LVD/symptomatic HF. Alcohol usage of > 70g/week was associated with an adjusted 4.9-fold (95% CI 1.7-15.1; P < 0.01) increased risk of HF progression among those with pre-HF at baseline. The adverse relationship remained significant when adjusting for age, sex, diabetes, hypertension, body mass index, as well as further models with baseline liver function and alcohol dehydrogenase 1B gene variant rs1229984 status. The association remained when excluding those with high (> 140 g) weekly alcohol intake. In patients at risk for HF, there was no association of alcohol usage with progression of LVD/symptomatic HF. No protective associations of low alcohol usage (≤70 g/week) on progression of HF were found. CONCLUSION: Moderate to high alcohol (> 70 g/week) usage appears to be associated with progression of LVD/symptomatic HF in those with pre-HF, and we did not observe protective benefits of low alcohol usage.

Biomarkers for Heart Failure Prediction and Prevention.

Heart failure (HF) is a global pandemic affecting over 64 million people worldwide. Its prevalence is on an upward trajectory, with associated increasing healthcare expenditure. Organizations including the American College of Cardiology (ACC) and the American Heart Association (AHA) have identified HF prevention as an important focus. Recently, the ACC/AHA/Heart Failure Society of America (HFSA) Guidelines on heart failure were updated with a new Class IIa, Level of Evidence B recommendation for biomarker-based screening in patients at risk of developing heart failure. In this review, we evaluate the studies that have assessed the various roles and contributions of biomarkers in the prediction and prevention of heart failure. We examined studies that have utilized biomarkers to detect cardiac dysfunction or abnormality for HF risk prediction and screening before patients develop clinical signs and symptoms of HF. We also included studies with biomarkers on prognostication and risk prediction over and above existing HF risk prediction models and studies that address the utility of changes in biomarkers over time for HF risk. We discuss studies of biomarkers to guide management and assess the efficacy of prevention strategies and multi-biomarker and multimodality approaches to improve risk prediction.

Derivation and validation of a clinical predictive model of NT-proBNP ≥125 pg/mL to detect pre-heart failure.

BACKGROUND: Several guidelines recommend the measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) to diagnose heart failure (HF); however, no screening criteria for measuring NT-proBNP in asymptomatic patients exist. We develop/validate a clinical prediction model for elevated NT-proBNP to support clinical outpatient decision-making. METHODS: In this multicenter cohort study, we used a derivation cohort (24 facilities) from 2017 to 2021 and a validation cohort at one facility from 2020 to 2021. Patients were aged ≥65 years with at least one risk factor of HF. The primary endpoint was NT-proBNP ≥125 pg/mL. The final model was selected using backward stepwise logistic regression analysis. Diagnostic performance was evaluated for sensitivity and specificity, the area under the curve (AUC), and calibration. In total, 1645 patients (derivation cohort, n = 837; validation cohort, n = 808) were included, of whom 378 (23.0 %) had NT-proBNP ≥125 pg/mL. Body mass index, age, systolic blood pressure, estimated glomerular filtration rate, cardiothoracic ratio, and heart disease were used as predictors and aggregated into a BASE-CH score of 0-11 points. RESULTS: Internal validation resulted in an AUC of 0.74 and an external validation AUC of 0.70. CONCLUSIONS: Based on available clinical and laboratory variables, we developed and validated a new risk score to predict NT-proBNP ≥125 pg/mL in patients at risk for HF or with pre-HF.

Reclassification of Pre-Heart Failure Stages Using Cardiac Biomarkers: The ARIC Study.

BACKGROUND: The recent heart failure (HF) guideline recommends the inclusion of cardiac biomarkers in defining Stage B HF. OBJECTIVES: The authors evaluated the impact of incorporating cardiac biomarkers to reclassify HF in 5,324 participants (mean age: 75.8 years) without prevalent HF enrolled in the ARIC (Atherosclerosis Risk In Communities) study and assessed prognosis of Stage B using cardiac biomarkers. METHODS: Using N-terminal pro-B-type natriuretic peptide (<125 pg/mL or ≥125 pg/mL), high-sensitivity troponin T (<14 ng/L or ≥14 ng/L), and abnormal cardiac structure/function by echocardiography, individuals were classified as Stage Anew and Stage Bnew HF, respectively. Stage Bnew was further evaluated as elevated biomarker only, abnormal echocardiogram only, and abnormalities in both (echo + biomarker). The authors assessed risk for incident HF and all-cause death using Cox regression. RESULTS: Overall, 4,326 (81.3%) individuals were classified as Stage Bnew with 1,123 (21.1%) meeting criteria for elevated biomarkers only. Compared with Stage Anew, Stage Bnew was associated with increased risk for incident HF (HR: 3.70 [95% CI: 2.58-5.30]) and death (HR: 1.94 [95% CI: 1.53-2.46]). Stage Bbiomarkers only and Stage Becho only were associated with increased HF risk, whereas Stage Bbiomarkers only was also associated with increased death. Stage Becho+biomarker had the highest risk for HF (HR: 6.34 [95% CI: 4.37-9.19]) and death (HR: 2.53 [95% CI: 1.98-3.23]). CONCLUSIONS: Incorporating biomarkers based on the new HF guideline reclassified approximately 1 in 5 older adults without prevalent HF to Stage B. The routine measurement of biomarkers can help to identify individuals at higher HF risk who may benefit most from HF prevention efforts.

Risk factors for pre-heart failure or symptomatic heart failure based on NT-proBNP.

AIMS: Evidence on the risk factors for incident heart failure in Asia has been limited. We sought to identify the risk factors for pre-heart failure or symptomatic heart failure, based on N-terminal pro-B-type natriuretic peptide (NT-proBNP), in the Japanese general population. METHODS: We performed a retrospective cohort study based on the Circulatory Risk in Communities Study involving 5335 Japanese individuals whose NT-proBNP levels were measured between 2010 and 2015. Of these, 2768 people aged between 30 and 69 years who undertook annual cardiovascular risk surveys at least once between 1990 and 2000 were retrospectively eligible to be participants in this study. We performed multivariable logistic regression analyses to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of pre-heart failure or symptomatic heart failure defined as NT-proBNP >400 pg/mL or as having a diagnosis of heart failure and taking medication for heart failure for several cardiovascular risk factors (body mass index, blood pressure, diabetes mellitus, total cholesterol, triglyceride, smoking status, drinking status). RESULTS: We identified 85 cases of heart failure. The multivariable ORs (95% CIs) were 5.70 (2.70-12.0) for body mass index of 27-29.9 kg/m2 and 5.91 (2.19-16.0) for ≥30 kg/m2 compared with 21-22.9 kg/m2 ; 2.49(1.01-6.13) for systolic blood pressure of ≥160 mmHg vs. <130 mmHg; 2.87(1.23-6.68) for diastolic blood pressure of ≥100 mmHg vs. <80 mmHg; 5.16(2.14-12.4) for diabetes vs. non-diabetes; and 2.24 (0.92-5.49) for current smokers of ≥20 cigarettes/day vs. never smokers. The multivariable ORs (95% CIs) of the number of risk factors, defined as the sum of four risk factors (obesity, hypertension, diabetes, and current smoker) was 6.80 (3.69-12.5) for ≥2 risk factors vs. no risk factors. CONCLUSIONS: The accumulation of these risk factors was associated with a graded higher risk of pre-heart failure or symptomatic heart failure.

Development and Challenges of Pre-Heart Failure with Preserved Ejection Fraction.

Pre-heart failure with preserved ejection fraction (Pre-HFpEF) is a critical link to the development of heart failure with preserved ejection fraction (HFpEF). Early recognition and early intervention of pre-HFpEF will halt the progression of HFpEF. This article addresses the concept proposal, development, and evolution of pre-HFpEF, the mechanisms and risks of pre-HFpEF, the screening methods to recognize pre-HFpEF, and the treatment of pre-HFpEF. Despite the challenges, we believe more focus on the topic will resolve more problems.