Incidence Of Heart Failure Research Articles

Accelerometer-Measured Sedentary Behavior and Risk of Future Cardiovascular Disease.

Beyond serving as a marker for insufficient physical activity, sedentary behavior may directly affect future cardiovascular (CV) disease risk. This study sought to examine associations between accelerometer-measured sedentary behavior with risk of specific CV outcomes, including potential relations with moderate to vigorous physical activity (MVPA). Among participants of the UK Biobank prospective cohort study, we fit Cox models adjusted for demographic and lifestyle factors to assess associations between accelerometer-measured daily sedentary time with incident atrial fibrillation (AF), myocardial infarction (MI), heart failure (HF), and CV mortality. We assessed the potential effect of MVPA on associations between sedentary time and CV disease by including MVPA as an adjustment variable, as well as performing subgroup analyses stratified at the guideline-recommended MVPA threshold (ie,≥150min/wk). We then performed compositional analyses to estimate the effects of reallocating sedentary time to other activities. Among 89,530 individuals (age 62 ± 8 years, 56.4% women) undergoing 1week of accelerometry, median sedentary time was 9.4 h/d (Q1-Q3: 8.2-10.6). In multivariable models, using the second quartile (8.2-9.4 h/d) as a referent, sedentary time in the top quartile (>10.6 h/d) was associated with greater risks of HF (HR: 1.45; 95%CI: 1.28-1.65) and CV mortality (HR: 1.62; 95%CI: 1.34-1.96), with an inflection of risk at 10.6 h/d. Higher sedentary time was also associated with greater risks of incident AF (HR: 1.11; 95%CI: 1.01-1.21) and MI (HR: 1.15; 95%CI: 1.00-1.32), with an approximately linear relation. Associations with HF and CV mortality persisted among individuals meeting guideline-recommended MVPA levels. Among individuals with >10.6 h/d of sedentary time, reallocating sedentary behavior to other activities substantially reduced the excess CV risk conferred by sedentary behavior (eg, 30-minute decrease in sedentary time for HF: HR: 0.93; 95%CI: 0.90-0.96), even among individuals meeting guideline-recommended MVPA (HR: 0.93; 95%CI: 0.87-0.99). Sedentary behavior is broadly associated with future adverse CV outcomes, with particularly prominent effects on HF and CV mortality, where risk inflected at approximately 10.6 h/d. Although guideline-adherent MVPA partially mitigates excess risk, optimizing sedentary behavior appears to be important even among physically active individuals.

Shedding of membrane complement inhibitors CD59 and CD46 into the circulation is associated with poor prognosis in acute coronary syndrome patients: a cohort study

IntroductionThe role of the complement inhibitory proteins CD46 and CD59 in the immune response to an acute coronary syndrome (ACS) is unknown. We investigated the relationships between the shedding of CD46 and CD59 into the circulation, reflected by plasma levels of soluble CD46 and CD59, and the risk for post-ACS complications.MethodsWe measured plasma sCD46 and sCD59 in a cohort of 546 ACS patients within 24 h after hospital admission, and after 6-weeks in a subgroup of 114 patients. Study outcomes were incident heart failure (HF), major adverse cardiovascular events (MACE) and mortality during a median follow-up period of up to 3.3 years. Echocardiography at 1-year was performed in the follow-up subgroup.ResultsElevated sCD46 and sCD59 were correlated with increased levels of inflammatory mediators and metalloproteinases in plasma, and were associated with increased risk for MACE in Cox proportional hazard models adjusted for cardiovascular risk factors and revascularization [HR 95% CI 1.24 (1.02–1.52), p = 0.034 for sCD46 and 1.18 (1.00–1.38), p = 0.049 for sCD59]. Elevated sCD59 was also associated with higher incidence of HF [HR 95% CI 1.41 (1.15–1.74), p = 0.001], and with lower left ventricular ejection fraction at 1-year post-ACS (Spearman r = − 0.234, p = 0.020). We found no associations between plasma levels of the proteins at 6 weeks and outcomes.ConclusionsShedding of the complement regulators CD46 and CD59 in plasma in the acute phase of ACS is associated with a negative prognosis. Plasma sCD46 and sCD59 could reflect the degree of local immune activation and serve as prognostic biomarkers in ACS patients.

Benefits and Harms of Coronary Revascularization in Non-Dialysis-Dependent Chronic Kidney Disease and Ischemic Heart Disease: A Systematic Review and Meta-Analysis.

Key Points In people with non–dialysis-dependent CKD, revascularization may lower all-cause mortality and risk of cardiovascular events.Adverse kidney events, which are often cited as a reason to avoid revascularization, were uncommon.Additional research on the effect of revascularization on patient-reported outcomes in people with non–dialysis-dependent CKD is needed. Background Cardiovascular disease is the leading cause of death in people with CKD. Coronary revascularization can improve cardiac function and prognosis in people with ischemic heart disease; however, in people with CKD, there is concern that potential harms could outweigh benefits of revascularization. Evidence on the balance of these risks and benefits, specifically in people with non–dialysis-dependent CKD, is lacking. Methods We conducted a systematic review of randomized controlled trials to assess the risks and benefits of revascularization, compared with medical management, among adults or children with ischemic heart disease and CKD not requiring KRT (dialysis or transplantation). We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials through December 12, 2023. Two people independently screened titles and abstracts followed by full-text review, serially extracted data using standardized forms, independently assessed risk of bias, and graded the certainty of evidence (COE). Results Evaluating data from nine randomized controlled trials, we found that people with CKD and ischemic heart disease treated with revascularization may experience lower all-cause mortality compared with people receiving medical management (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.64 to 0.98; COE, low). Revascularization may reduce incidence of myocardial infarction (RR, 0.81; 95% CI, 0.64 to 1.04; COE, low) and heart failure (RR, 0.80; 95% CI, 0.52 to 1.23; COE, low). The effect on cardiovascular mortality is uncertain (hazard ratio, 0.67; 95% CI, 0.37 to 1.20; COE, very low). Evidence was insufficient for patient-reported outcomes and adverse kidney events. Data were limited by heterogeneity of patient populations and the limited number of trials. Conclusions In people with non–dialysis-dependent CKD, revascularization may be associated with lower all-cause mortality compared with medical management and may also lower the risk of cardiovascular events. Additional data surrounding kidney and patient-reported outcomes are needed to comprehensively engage in shared decision making and determine optimal treatment strategies for people with CKD and ischemic heart disease. Clinical Trial registry name and registration number: CRD42022349820 (PROSPERO).

Timing of coronary angiography in high-risk non-ST-elevation acute coronary syndrome: results from the Portuguese Registry for Acute Coronary Syndromes (ProACS).

Current guidelines recommend an early invasive coronary angiography (ICA) within 24 h of admission for high-risk patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Nevertheless, meta-analyses failed to demonstrate a clear advantage of this strategy in reducing hard endpoints such as death or nonfatal myocardial infarction compared to a delayed approach. Thus, the optimal timing of ICA in high-risk NSTE-ACS remains undetermined. This study aimed to determine the optimal timing for ICA in high-risk NSTE-ACS, regarding 1-year all-cause mortality and cardiovascular rehospitalizations. We conducted a national multicenter retrospective study of high-risk NSTE-ACS patients included in the Portuguese Registry for Acute Coronary Syndromes. Patients were divided into three groups according to the time of ICA: within the first 24 h, between 24 and 48 h, and between 48 and 72 h. The incidence of in-hospital complications and mortality, 1-year mortality, and cardiovascular rehospitalizations were assessed. Of the 9949 patients included, 46.7% underwent early ICA. This was associated with a lower incidence of acute heart failure (8.5% vs. 11.1% vs. 11.5%, P < 0.001) and shorter length of stay (3 vs. 4 vs. 6 days, P = 0.012). It, however, did not reduce in-hospital complications or mortality (1.2 vs. 0.7 vs. 0.8%, P = 0.066). We also found no significant association with the composite endpoint of 1-year mortality or cardiovascular rehospitalization (15.1 vs. 15.9 vs. 15.7%, P = 0.887). Early ICA was associated with a lower incidence of acute heart failure and shorter length of stay, without a significant impact on 1-year mortality risk or cardiovascular rehospitalizations.

A Bayesian method for adverse effects estimation in observational studies with truncation by death.

Death among subjects is common in observational studies evaluating the causal effects of interventions among geriatric or severely ill patients. High mortality rates complicate the comparison of the prevalence of adverse events between interventions. This problem is often referred to as outcome "truncation" by death. A possible solution is to estimate the survivor average causal effect, an estimand that evaluates the effects of interventions among those who would have survived under both treatment assignments. However, because the survivor average causal effect does not include subjects who would have died under one or both arms, it does not consider the relationship between adverse events and death. We propose a Bayesian method which imputes the unobserved mortality and adverse event outcomes for each participant under the intervention they did not receive. Using the imputed outcomes we define a composite ordinal outcome for each patient, combining the occurrence of death and the adverse event in an increasing scale of severity. This allows for the comparison of the effects of the interventions on death and the adverse event simultaneously among the entire sample. We implement the procedure to analyze the incidence of heart failure among geriatric patients being treated for Type II diabetes with sulfonylureas or dipeptidyl peptidase-4 inhibitors.

Morbidity Burden in Patients With Ebstein Anomaly: The Natural History.

The lifetime morbidity burden of patients with Ebstein anomaly (EA) has not been well described. Through an extensive 2-country register-based collaboration, patients diagnosed with EA who were born between 1930 and 2017 were identified in Danish and Swedish nationwide medical registries. Each patient was matched by age and sex with 10 control subjects from the general population. Cox proportional-hazards regression, Fine-Gray competing risk regression, and Kaplan-Meier failure function were used to estimate the morbidity burden. The study included 794 patients diagnosed with EA and 7940 controls, with a median follow-up period of 33 years. Among patients with EA, approximately half (n=442) had isolated EA, and 28% (n=218) had concomitant atrial septal defect. Patients with complex anatomy demonstrated the highest cardiovascular morbidity burden, followed by those with concomitant atrial septal defect and isolated EA. The lifetime cumulative incidence of supraventricular arrhythmia and ventricular preexcitation in patients with EA, with or without atrial septal defect, was approximately 70% and 19%, respectively. Supraventricular arrhythmia substantially increased the risk of ischemic stroke (hazard ratio [HR] 22.6 [95% CI, 11.1-45.9]). Presence of atrial septal defect significantly affected arrhythmia and heart failure burden compared with isolated EA. In the total cohort of patients with EA, supraventricular arrhythmia onset led to an immediate high incidence of heart failure, with a 10-year cumulative incidence of 18%. The natural history of EA, whether isolated or not, involves a substantial burden of cardiovascular morbidity and thus a highly vulnerable long-term prognosis.

Association of innate versus specific immunity with heart failure incidence: a prospective study.

Immune disorders are key heart failure (HF) triggers, but little is known about whether the status of immunity affects the incidence of HF. To explore this, we used blood cell counts and derived ratios to investigate the association between immunity status markers and HF incidence. The number and proportion of peripheral blood leucocytes in a physiological state are related to the body's immune status. Neutrophils, monocytes, SII (systemic immune-inflammatory index), NLR (neutrophil-to-lymphocyte ratio), and PLR (platelet-to-lymphocyte ratio) serve as innate immunity status markers, while lymphocytes and LMR (lymphocyte-to-monocyte ratio) serve as specific immunity status markers. 330 362 UK Biobank (UKB) participants were finally examined. Cox proportional hazard models were used to explore the relationship between immunity status markers and HF incidence. Flexible parametric survival models were used to capture time-varying relationships between blood cell ratios and HRs for HF. Subgroup analyses were conducted by age, sex, and body mass index. Finally, sensitivity analyses were performed to validate the results. During a median follow-up of 14.1 years, 9611 (2.9%) participants developed HF. Neutrophils, monocytes, SII, and NLR were positively associated with HF incidence, with fully adjusted per SD increment HR (95% CI) of 1.20 (1.17 to 1.22), 1.09 (1.07 to 1.12), 1.12 (1.10 to 1.14), and 1.16 (1.14 to 1.18), respectively. Platelets, lymphocytes, and LMR were inversely correlated with HF incidence, with fully adjusted per SD increment HR (95% CI) of 0.97 (0.95 to 1.00), 0.97 (0.95 to 0.99), and 0.90 (0.88 to 0.92), respectively. The innate immunity status markers were positively associated with HF incidence, while specific immunity status markers exhibited an inverse association, offering novel insights for HF prediction and intervention.

Association Between Different Insulin Resistance Indices and Heart Failure in US Adults With Diabetes Mellitus.

This study aims to scrutinize the association between various Insulin Resistance (IR) indices and heart failure (HF) risk in adult diabetics within the United States. The National Health and Nutrition Examination Survey (NHANES) (2005-2018) dataset was used in this study. Weighted logistic regression analysis and restricted cubic spline were employed to ascertain the correlation between IR indices and the incidence of HF in diabetic patients. The predictive capability of the IR indices was evaluated using the Receiver Operating Characteristic curve. This study included a total of 2574 diabetic patients, out of which 209 (8.1%) were diagnosed with HF. After the adjustment of potential confounders, TyG-BMI (OR: 1.005, 95% CI: 1.002-1.009), TG/HDL-C (OR: 1.138, 95% CI: 1.024-1.265), and METS-IR index (OR: 1.035, 95% CI: 1.015-1.057) were significantly associated with HF risk. RCS curves revealed nonlinear dose-response relationship between TyG, TyG-BMI, TG/HDL-C, and the occurrence of HF in diabetic patients. Subgroup analyses showed that four IR indices were positively associated with the risk of HF in the elderly diabetic population. Unfortunately, all IR indices failed to improve the predictive performance of the underlying risk model for HF in diabetic patients. Four IR markers may be important predictors of HF risk in diabetics.

Effect of vitamin D supplementation on cardiovascular outcomes: an updated meta-analysis of RCTs.

To evaluate the effect of vitamin D supplementation on cardiovascular outcomes. After searching different databases, we retrieved and included randomized controlled trials on long-term supplementation of vitamin D (≥1-year intervention) and reporting cardiovascular outcomes. We calculated risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes. Compared to the control group, the vitamin D group was not associated with a statistically significant decrease in the incidence of major adverse cardiovascular events (MACE) [risk ratio=0.99; 95% CI: 0.94-1.03]. We found no difference between the vitamin D group and the control group for the outcomes of incidences of myocardial infarction, heart failure, coronary revascularization, cardiovascular death, and all-cause mortality. The heterogeneity was low for all outcomes. According to our meta-analysis, vitamin D supplementation did not reduce major adverse cardiovascular events, other cardiovascular parameters, and all-cause mortality.

Incident Myocardial Infarction, Heart Failure, and Oncologic Outcomes in Breast Cancer Survivors

Incident Myocardial Infarction, Heart Failure, and Oncologic Outcomes in Breast Cancer Survivors

IGF-1 levels in the general population, heart failure patients, and individuals with acromegaly: differences and projections from meta-analyses-a dual perspective.

The complex relationship between insulin-like growth factor 1 (IGF-1) levels and heart failure (HF) is not fully understood, particularly across different populations and conditions. This meta-analysis aims to elucidate the dual perspectives of IGF-1 levels in the general population, HF patients, and individuals with treatment-naïve acromegaly, highlighting IGF-1 as a biomarker and potential therapeutic target in HF management. Studies were searched across multiple electronic databases up to January 2024 and independently identified by reviewers. The outcomes were analyzed using RevMan 5.4 and STATA 15. A total of 25 articles were ultimately included in the analysis. Six studies compared IGF-1 levels between HF patients and non-HF controls, revealing significantly lower IGF-1 levels in HF patients (mean difference -20.93; 95% CI -37.88 to -3.97; p = 0.02). This reduction was consistent across various HF subtypes and severities. In addition, individuals with intermediate IGF-1 levels had a lower risk of developing HF [risk ratio (RR) 0.78; 95% CI 0.74-0.83; p < 0.01] and HF-related mortality (RR 0.98; 95% CI 0.97, 0.99; p < 0.01) compared to those with low IGF-1 levels, suggesting a protective role for maintaining adequate IGF-1 levels. Conversely, treatment-naïve acromegaly patients, characterized by excessively high IGF-1 levels, showed a significantly higher incidence of both diastolic HF [odds ratio (OR) 9.08; 95% CI 6.20-13.29; p < 0.01] and systolic HF (OR 13.1; 95% CI 6.64-25.84; p < 0.01), implicating supraphysiological IGF-1 levels in adverse cardiac outcomes. Our meta-analysis highlights the complex interplay between IGF-1 levels and HF. We found that reduced IGF-1 levels are commonly observed in HF patients and are associated with an increased risk of HF and higher HF-related mortality. Conversely, excessively high levels, as observed in acromegaly, are linked to a higher incidence of HF. Based on these results, it is recommended that cardiac function be closely monitored in patients with reduced IGF-1 levels and in those with acromegaly. These findings suggest that IGF-1 could hold potential prognostic value for risk stratification in HF.

Temporal trends and prognostic significance of heart failure after acute myocardial infarction

Abstract Background There are limited and conflicting data regarding the incidence and prognostic impact of in-hospital heart failure (HF) complicating acute myocardial infarction (MI). The aim of this study was to examine temporal trends in the incidence and outcomes of systolic HF after acute MI in a large national cohort in South Korea. Methods The nationwide Korea Acute Myocardial Infarction Registry records baseline characteristics, treatments, and outcome of consecutive patients with acute MI admitted to hospitals capable of primary percutaneous coronary intervention (PCI) in South Korea. Systolic HF was defined as an ejection fraction ≤40% by echocardiography at admission. This study included 68,123 patients admitted for index acute MI between 2005 and 2020 (phase 1: 2005-2007, n=14,735; phase 2: 2008-2011, n=24,656; phase 3: 2012-2015, n=13,104; phase 4: 2016-2020, n=15,628). Results In all patients, the incidence of HF declined from 19.4% in phase 1 to 14.1% in phase 4 (p&amp;lt;0.001). This decrease was more pronounced in patients with ST-segment elevation MI (STEMI, from 20.9% to 15.8%) compared to those with non-ST-segment elevation MI (NSTEMI, from 17.9% to 12.3%). The use of PCI and of statins at discharge increased from 86% to 91.2% and from 75.1% to 92.2%, respectively (p&amp;lt;0.001 for all). Previous history of MI increased from 8.4% to 10.4% (p&amp;lt;0.001) whereas previous history of HF and stroke decreased from 6.3% to 1.3% and from 17.4% to 6.4%, respectively (p&amp;lt;0.001). The median symptom-to-door time decreased from 3.5 hours to 2.1 hours for STEMI and from 6.3 hours to 5.5 hours for NSTEMI (p&amp;lt;0.001). The median door-to-balloon time decreased from 107 min to 64 min for STEMI and from 26 hours to 14 hours for NSTEMI (p&amp;lt;0.001). The in-hospital and 12-month mortality rates for all patients decreased over the years from 5.0% to 3.3% and from 7.6% to 6.1%, respectively (p&amp;lt;0.001). However, in those who developed HF during the index MI, no significant declining trends were observed in in-hospital mortality (phase 1: 8.8%, phase 2: 7.95%, phase 3: 8.3%, phase 4: 7.3%, p=0.123) and 12-month mortality (phase 1: 15.4%, phase 2: 12.6%, phase 3: 19.4%, phase 4: 15.2%, p=0.270). Independent predictors of developing in-hospital HF were age &amp;gt;75 years, body mass index &amp;lt;18.5 kg/m2, symptom-to-door and door-to-balloon times, systolic blood pressure &amp;lt;100 mmHg at presentation, heart rate &amp;gt;90 min at presentation, presence of atrial fibrillation or diabetes, and previous history of MI, HF or stroke. Conclusions A marked reduction was found in the incidence of HF after acute MI between 2005 and 2020 in South Korea. However, in-hospital and 12-month mortality rates in HF patients remain unchanged, warranting intensive post-MI management with more aggressive efforts for secondary prevention.

Prevalence and incidence of heart failure in patients with type 2 diabetes mellitus. Results of the prospective DIABET-IC study

Abstract Introduction Heart failure (HF) is one of the major health problems in our environment today. Type 2 diabetes mellitus (DM2) is an important cardiovascular risk factor and can increase the burden of HF through various mechanisms. The incidence of HF in DM2 has not been well studied. Purpose The aim of our study was to evaluate the prevalence and incidence of HF in patients with DM2 followed in hospital cardiology and endocrinology departments. Methods The DIABET-IC study is a longitudinal cohort, prospective, multicenter follow-up study that included 1,249 consecutive patients with DM2 in 2018-2019 in 30 Spanish centers in cardiology and endocrinology outpatient clinics. HF was diagnosed according to the clinical records and following the criteria of the European Society of Cardiology. The prevalence of HF at the inclusion visit was analyzed, as well as the incidence of HF (new diagnoses) during a 3-year follow-up. Results Mean age was 67.3±+9.9 years, with 31.7% of the patients being women. Cardiology clinics included 61.9% of patients and endocrinology clinics the remaining 38.1%. There was a previous history of coronary artery disease in 38.6%, hypertensive heart disease in 21% and atrial fibrillation in 31.9%. Cardiovascular and antidiabetic drugs prescribed at the baseline and 3-year visits are shown in figure 1. Figure 2 summarizes the results of the study. The prevalence of HF at the baseline visit was 39.2%, 490 cases (with reduced LVEF 17.3%, mildly reduced 8.1% and preserved 13.8%). After a follow-up of 1,935/100 persons-year of cases without baseline HF, 58 incident cases of HF were diagnosed, 7.6% (32 in the first year, 13 in the second and 13 in the third year of follow-up). The incidence rate was 3.01/100 person-years (95%CI: 2.30-3.92). Of these 58 cases, 23.7% were with reduced LVEF, 28.9% with slightly reduced LVEF and 47.4% preserved. The incidence was higher in patients followed by endocrinology (3.90 vs 2.90/100 persons-year; p=0.042). At the end of the 3-year follow-up, including baseline prevalence, 46.8% of all patients had HF. Conclusions The prevalence and incidence of HF in patients with DM2 are very high. The incidence of HF is around 3% per year, which is almost 8 times higher than the rate found in large studies in the general population. Approximately half of the new cases were HF with preserved LVEF, and the other half with LVEF &amp;lt; 50%. The use of new antidiabetic drugs, such as iSGLT2, which have been shown to reduce the incidence of HF, should be encouraged.

Hyponatremia and risk of new-onset heart failure in patients with type 2 diabetes - a real-world study of 70,000 patients

Abstract Background Hyponatremia is common in patients with heart failure and in patients with type 2 diabetes (T2D), and is a risk marker for increased morbidity and mortality. However, it is unclear whether hyponatremia in patients with T2D is associated with an increased risk of new-onset heart failure. Purpose To investigate whether hyponatremia is associated with an increased risk of new-onset heart failure in patients with T2D. Methods From Danish nationwide registers, all patients with T2D with no history of heart failure were identified from 2013-2021. Patients with at least two samples of plasma sodium measured (at least one month apart), during the first six months following their T2D diagnosis, were included with follow-up start six months after T2D diagnosis as well. Patients were categorized in two groups according to the mean plasma sodium concentration at baseline: 1) sodium &amp;gt;137 mmol/L; and 2) sodium &amp;lt;137mmol/L. Cumulative incidence curves and Cox proportional hazards models (crude and adjusted for age, sex, comorbidities, and potential hyponatremia-inducing medications including diuretics, anticonvulsants, and antidepressants) were used to investigate the association of sodium concentration with the incidence of heart failure during follow-up. Incidence rates of heart failure per 1000 person-years were calculated across the spectrum of the measured sodium levels. Results We included 69,750 patients where 57% were male and the median age was 63 (interquartile range: 54-71). At index, 57,723 (83%) patients had a mean sodium concentration of &amp;gt;137 mmol/L and 12,027 (17%) patients had a mean sodium concentration &amp;lt;137 mmol/L (hyponatremia). Patients with a sodium level &amp;lt;137 mmol/L were associated with a significantly higher hazard rate of heart failure compared to patients with sodium concentrations &amp;gt;137 mmol: adjusted hazard ratio (HR) 1.27 (95% confidence interval 1.15-1.41, p-value &amp;lt;0.001). In analyses where sodium concentration was considered a continuous variable, increasing concentration of 1 mmol/L was associated with a decreasing hazard rate of heart failure: adjusted HR 0.96 (0.94-0.97, p-value &amp;lt;0.001). Conclusions Hyponatremia was common and associated with a significantly higher risk of new-onset heart failure in patients newly diagnosed with T2D. Whether hyponatremia could be a new treatment target to prevent heart failure in T2D remains to be determined.Cumulative incidence of heart failureIncident heart failure

Proteomic biomarkers and pathway analysis for progression to heart failure in three epidemiological representative cohorts.

Biomarkers associated with asymptomatic ventricular dysfunction might improve risk stratification and identify pathways leading to heart failure (HF). We explored the association between proteomic biomarkers and left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and incident HF in three population-based cohorts. A chip was used to measure 92 protein biomarkers in blood samples from >1500 Malmö Preventive Project (MPP) participants, of whom 514 had LVH (34%), 462 had DD (32.4%) and, over a median follow-up of 13 (11-14) years, 130 developed HF (7.7%). Findings were confirmed in the STANISLAS (n > 1500, 238 participants with LVH, 76 with DD) and HOMAGE case-control (562 cases of incident HF, 871 controls) cohorts. In multivariable logistic or Cox regression analyses adjusted for age, sex and cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with LVH, DD and incident HF in all cohorts: MPP (LVH odds ratio [OR] [95% confidence interval] 1.48 [1.28-1.71]; DD OR 1.71 [1.53-1.92]; HF HR 1.98 [1.66-2.36]); STANISLAS (LVH OR 1.20 [1.02-1.41]; DD OR 1.46 [1.12-1.90]); HOMAGE (HF HR 1.85 [1.62-2.12]). Galectin-4, growth differentiation factor 15 and suppression of tumorigenicity-2 were associated with incident HF in MPP and HOMAGE. A pathway enrichment analysis suggested that inflammation and viral infection were related to incident HF. In conclusion, our study reinforces the role of NT-proBNP as a key biomarker for asymptomatic cardiac dysfunction and incident HF, consistent with its established use in clinical practice. This underscores the value of NT-proBNP for identifying patients at high risk for HF, and provides insights into pathways leading to HF and potential therapeutic targets.

Validation of existing risk scores for worsening renal function in patients with newly diagnosed heart failure: a longitudinal population cohort study

Abstract Background Worsening renal function (WRF) is one of the strongest predictors of outcome in patients with heart failure (HF). The presence of WRF often influences the decision to start, up-titrate, or discontinue disease-modifying HF therapies and is one of the key determinants of suboptimal guideline-directed medical therapy. However, there are now potential cardiovascular pharmacotherapies that have favourable cardiorenal outcomes and reduce the risk of renal decline. It is therefore important to identify patients with HF early in their disease trajectory who are at risk of developing WRF. Purpose The aim of this study was to evaluate two existing WRF risk scores (the Forman risk score and the Basel risk score) in a population-based longitudinal cohort diagnosed with incident HF. Methods Data for individuals with incident HF between 2016 to 2021 were extracted and analysed from the NELSON study conducted in Tayside, Scotland. WRF was defined as a composite event of (i) having two consecutive eGFRs declined by 40% or greater; (ii) having an eGFR &amp;lt; 15mL/min/1.73m2; (iii) initiation of sustained dialysis; (iv) development of end-stage kidney disease; or (v) receiving kidney transplantation. The primary outcome was the occurrence of WRF within 180 days of diagnosis of HF. Among patients hospitalised with HF, in-hospital WRF was also assessed. The area under the curve (AUC) was used to assess the discrimination performance of the two risk scores in individuals with incident HF diagnosed as either in-patients or out-patients. Results 4076 individuals (mean age 72.8 ± 13.2; 58% male; 1081 HFrEF, 646 HFmrEF, 1348 HFpEF, and 1001 HF with unknown ejection fraction (EF)) who were WRF-free at incident HF diagnosis were identified. Of these, 2095 (51.4%) were diagnosed as in-patients, and 1981 (48.6%) were diagnosed as out-patients. 285 (7%) patients developed WRF within 180 days post HF diagnosis. Among the 2,095 HF in-patients, 75 (3.6%) developed WRF before discharge. The Forman risk score had an AUC of 0.618 (95% CI: 0.585 – 0.651) in predicting 180-day WRF, and an AUC of 0.650 (0.587 – 0.713) for in-hospital WRF. The Basel risk score showed similar discriminating performance with an AUC of 0.618 (0.585 – 0.651) for 180-day WRF, and 0.656 (0.593 – 0.719) for in hospital WRF. Conclusions In a contemporary population, conventional risk scores such as the Forman or Basel risk scores have limited discrimination in predicting WRF in incident HF. New models with better discrimination for WRF prediction are therefore needed.

Serum metabolomics improve risk stratification for incident heart failure

Abstract Background The prediction and early detection of heart failure (HF) is vital to reduce its substantial impact on quality of life, survival and healthcare expenditure. Current incident HF risk stratification strategies achieve only modest performance. Moreover, state-of-the-art risk scores focus on commonly acknowledged clinical risk factors, thus necessitating the integration of heterogenous data sources and prioritizing individuals with obvious risk constellations. Purpose Here, we explored the predictive value of serum metabolomics (168 metabolites detected by proton nuclear magnetic resonance (1H-NMR) spectroscopy) for incident HF. Methods Leveraging data of n = 68,311 individuals and &amp;gt; 0.8 million person-years of follow-up from the UK Biobank (UKB) cohort, we (I) evaluated the association of individual metabolites with incident HF via fitting of per-metabolite COX proportional hazards models and (II) trained and validated elastic net (EN) models to predict incident HF using the serum metabolome. Discriminative performance was benchmarked against a comprehensive, well-validated clinical risk score (Pooled Cohort Equations to Prevent HF, PCP-HF). External validation was conducted in the independent FINRISK study. Results Several metabolites were independently associated with incident HF (90/168 adjusting for age and sex, 48/168 adjusting for PCP-HF). Performance-optimized risk models effectively retained key predictors representing highly correlated clusters (≈ 80 % feature reduction). The addition of metabolomics to PCP-HF improved predictive performance (Harrel’s C: 0.768 vs. 0.755, ΔC = 0.013 (95% confidence interval (CI) 0.004 – 0.022), continuous net reclassification improvement (NRI) = 0.287 (95% CI 0.200 – 0.367), relative integrated discrimination improvement (IDI): 17.47 % (95% CI 9.463 - 27.825)). Simplified models only including age, sex and metabolomics performed almost as well as the PCP-HF model (Harrel’s C: 0.745 vs. 0.755, ΔC = 0.010 (95% CI -0.004 - 0.027), continuous NRI: 0.097 (95% CI -0.025 - 0.217), relative IDI: 13.445 % (95% CI -10.608 - 41.454)). Risk and survival stratification was improved by integrating metabolomics. External validation within FINRISK revealed similar patterns using the original model coefficients. Conclusions Serum metabolomics improve the prediction of incident HF risk. Scores obtained from the combination of age, sex and metabolomics exhibit similar predictive power as clinical risk models. Offering serum metabolomics to a middle-aged cohort might significantly improve HF risk stratification, thus facilitating preventive efforts. Via a single blood draw, serum metabolomics displays a highly cost- and time-effective, standardizable, and scalable alternative to clinical risk scores involving physical measurements and history taking in addition to clinical chemistry.Relative performance (test split)ROC &amp; DCA plots (test split)

Large-scale proteomic profiling reveals characteristic HIV-specific druggable protein signatures associated with incident heart failure

Abstract Background Compared with the general population, persons with HIV suffer from an augmented risk of both systolic and diastolic heart failure despite effective antiretroviral therapy [1]. While inflammatory and coagulation markers are thought to be involved in this increased risk, other contributing mechanisms, such as pro-inflammatory protein networks, remain to be elucidated. Purpose To identify novel protein predictors of incident heart failure events in the longitudinal Veterans Aging Cohort Study Biomarker Cohort of United States Veterans with HIV (PLWH; n = 1525) and without HIV (PWoH; n = 853) and to assess the functional relatedness of these proteins in PLWH. Methods We characterized the plasma proteome of PLWH and PWoH using an aptamer-based platform and assessed univariable associations with incident heart failure. Druggable proteins were identified using the Therapeutic Target Database [2]. We built a protein interaction network querying significant proteins (q-value &amp;lt;0.05) using Cytoscape for the Retrieval of Interacting Genes/Proteins (STRING) database [3]. To focus on densely connected core proteins, we used the mcl clustering method and identified a subnetwork of approximately 77 proteins. Over-representation analysis was performed for the core network by identifying enriched gene sets using Gene Ontology biological processes and WikiPathways. Final results are filtered based on a false discovery rate (FDR) threshold of 0.05. Results Of 4926 plasma proteins, 441 proteins in all PLWH and 706 in those with well-controlled HIV (viral load &amp;lt;200 copies/mL) were significantly associated with incident heart failure, compared with only 142 among PWoH (Figure 1A). Of the top 50 proteins most significantly associated with heart failure, 21 were druggable in PLWH and 14 in PWoH; only 5 druggable markers were shared, while 16 were unique to HIV (Table 1). Pleiotrophin, a pro-angiogenic, pro-inflammatory cytokine that induces tumor necrosis factor- (TNF) α, interleukin- (IL) 1β, and IL-6 expression and has been implicated in cardiomyocyte apoptosis [4,5], had the highest hazard ratio (HR) for incident heart failure (HR = 4.7; p = 1.6E-20; q = 1.7E-18) in PLWH. The most significant enriched protein pathway included 36 genes involved in chemotaxis (FDR = 1.3E-30); 3 of the 21 druggable targets (pleiotrophin, ephrin-A5, and ephrin type-A receptor 2) were represented in this pathway (Figure 1B). Ephrin signaling pathways, which are involved in cell adhesion, differentiation, and proliferation [6], have not previously been implicated in heart failure, nor in HIV. Subnetwork analysis of druggable proteins demonstrated that ephrin-signaling, IL-15, and TNF pathways were functionally interconnected (Figure 1C). Conclusions Our findings indicate that there may be unique pro-inflammatory pathways characteristic of HIV-associated cardiomyopathy that merit further study as dedicated pharmacologic targets and/or risk markers in this population.

Differences in risk profiles and clinical outcomes according to age in patients with high-risk myocardial infarction: insights from the PARADISE-MI trial

Abstract Introduction Temporal declines in rates of rehospitalization and death after acute myocardial infarction (MI) have not been uniform across age groups. A better understanding of how risk profiles and clinical outcomes differ after MI by age may allow for targeted treatment and prevention strategies. Aims To investigate risk profiles and clinical outcomes following high-risk MI according to age in the Prospective ARNI vs ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI). Methods Adults without prior heart failure (HF) were randomized to sacubitril/valsartan versus ramipril within 0.5 to 7 days of a MI complicated by transient pulmonary congestion and/or left ventricular systolic dysfunction and additional risk-augmenting factors. Associations between age and clinical outcomes were analyzed using Cox proportional hazards regression models, which were additionally adjusted for baseline demographic and clinical covariates (Figure). Results The mean age of the 5,661 PARADISE-MI participants was 64 ± 11 years. Patients aged ≥75 years (n=1051) were more likely women, had more hypertension and atrial fibrillation and lower estimated glomerular filtration rate, were less likely to present with ST-segment elevation MI and regardless of type of MI were less likely to receive primary reperfusion and guideline-based medical therapy (Table). Age was significantly associated with all-cause death (HR 1.54 per 10-year increase; 95% CI, 1.41-1.68) and was more strongly associated with non-CV death (HR 2.09; 95% CI, 1.70-2.56) than with CV death (HR 1.43; 95% CI, 1.29-1.57). Age was also associated with incident HF (HR 1.37; 95% CI, 1.25-1.49) (Figure). Multivariable adjustment attenuated the risk relationship of age with recurrent fatal or non-fatal MI (HR 1.08; 95% CI, 0.96-1.21) and the coronary composite outcome (HR 1.01; 95% CI, 0.93-1.09). The relative treatment effect of sacubitril/valsartan versus ramipril on the primary composite outcome of CV death or incident HF was not significantly modified by age (p-interaction = 0.19). Conclusions Following high-risk MI, age was most strongly associated with subsequent non-CV death followed by CV death and incident HF, but was not independently associated with recurrent coronary events. The heightened risk of CV death and HF with advancing age was not explained by differences in clinical characteristics. Older patients may require closer surveillance and more aggressive treatment after MI to mitigate the elevated risk of CV death and HF.

A liberal blood transfusion strategy is safe in patients with myocardial infarction, anemia, and heart failure: lessons from MINT

Abstract Background In patients with acute myocardial infarction (MI) and anemia, the Myocardial Ischemia and Transfusion (MINT) trial found a trend toward increased 30-day death or recurrent MI with a restrictive compared with a liberal blood transfusion strategy. Patients with and without heart failure (HF) may respond differently to blood transfusion. Purpose To characterize the effects of restrictive vs. liberal transfusion strategies on clinical outcomes in patients with MI and anemia with and without baseline HF. Methods In the MINT trial, 3504 patients with MI and hemoglobin &amp;lt;10 g/dL were randomized to restrictive (7-8 g/dL) or liberal (10 g/dL) transfusion thresholds. We compared outcomes between patients with and without baseline HF, defined as any history of HF, acute HF, or baseline left ventricular ejection fraction (LVEF) &amp;lt;45%. Outcomes included death or incident HF, death or recurrent MI, death, and incident HF, all at 30 days. Results Compared with patients without baseline HF (n=1633), patients with baseline HF (overall n=1871 (history of HF n=1066, acute HF n=780, LVEF &amp;lt;45% n= 1099) were older, more frequently male and Black, and had higher rates of prior PCI, diabetes, and hypertension. In the restrictive strategy, patients with and without baseline HF received an average of 0.63 and 0.80 units of blood and had a median LOS of 6 and 4 days, respectively. In the liberal strategy, patients with and without baseline HF received an average of 2.44 and 2.49 units of blood and had a median LOS of 5 and 4 days, respectively. Patients with baseline HF had higher rates of death or incident HF (18.0% vs. 10.0%, risk ratio [RR]=1.79 [95% confidence interval {CI} 1.50-2.13]), death or recurrent MI (17.6% vs. 13.5%, RR=1.31 [95% CI 1.12-1.53]), and death (10.5% vs. 7.5%, RR 1.41 [95% CI 1.14-1.75]). Among patients with baseline HF, a restrictive transfusion strategy resulted in a trend toward an increase in death or HF and death or MI compared with a liberal transfusion strategy (Table, Figure). Among patients without baseline HF, the risk of incident HF was lower with restrictive than with liberal transfusion strategy. Conclusions Among patients with MI and anemia, a restrictive transfusion strategy resulted in a greater increase in death or HF, death or MI, and death in patients with baseline HF than in patients without baseline HF. A liberal transfusion strategy is safe for patients with MI and anemia, including those with prior or acute HF.TableFigure