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.
Associations of colchicine‐related plasma proteins, incident heart failure (HF) and cardiac structure and function. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Aims
Narrower retinal arterioles and wider retinal venules have been associated with macrovascular forms of cardiovascular disease (CVD). However, whether they are predictive of the development of ...heart failure (HF) independent of atherosclerotic CVD is unclear. We aimed to describe long‐term associations of retinal vessel calibres with incident HF, in those with and without prevalent macrovascular disease, and how they relate to cardiac structure and function.
Methods and results
This analysis included Atherosclerosis Risk in Communities Study participants who underwent retinal photography between 1993 and 1995. HF outcomes were followed in these participants until the end of 2013. Returning participants underwent echocardiography between 2011 and 2013. Participants with retinal vessel measurements who were free of CVD at baseline (n = 10 692) were followed for a mean of 16 years (baseline mean age 60 ± 6 years). Wider central retinal venular equivalent (CRVE) and narrower central retinal arteriolar equivalent (CRAE), adjusted for age, gender, and race, were significantly linearly associated with incident HF; however, a non‐linear association was detected with CRVE and incident HF (P‐value for overall trend < 0.001; P‐value for non‐linearity = 0.002). After adjustment with clinical risk factors, CRVE association with incident HF remained significant (P‐value for overall trend = 0.025). Adjusted for age, gender, and race, CRVE widening and CRAE narrowing were associated with larger left ventricular size, higher prevalence of left ventricular hypertrophy, and worse measures of diastolic and systolic function.
Conclusion
Retinal vessel calibre imaging, which characterizes retinal microvasculature, is a simple, non‐invasive test that predicts incident HF and adverse cardiac structure/function 18 years in the future, thereby providing insight into systemic cardiovascular health.
•Lung ultrasound B-lines differ between hypertensive patients and those with HF.•B-Lines are associated with echocardiographic markers of cardiovascular risk.•In ambulatory HF patients, B-lines may ...be associated with adverse events.
Although pulmonary congestion can be quantified in heart failure (HF) by means of lung ultrasonography (LUS), little is known about LUS findings (B-lines) in different HF phenotypes. This prospective cohort study investigated the prevalence and clinical and echocardiographic correlates of B-lines in ambulatory HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared with hypertensive patients. We related LUS findings to 12-month HF hospitalizations and all-cause mortality.
We used LUS to examine hypertensive (n = 111), HFpEF (n = 46), and HFrEF (n = 73) patients (median age 66 y, 56% male, 79% white, and median EF 55%) undergoing clinically indicated outpatient echocardiography. B-line number was quantified offline, across 8 chest zones, blinded to clinical and echocardiographic characteristics. The proportion of patients with ≥3 B-lines was lower in hypertensive patients (13.5%) compared with both HFrEF (45.2%, P < .001) and HFpEF (34.8%; P = .05). HF patients with ≥3 B-lines had a higher risk of the composite outcome (age- and sex-adjusted hazard ratio 2.62, 95% confidence interval 1.15–5.96; P = .022).
When performed at the time of outpatient echocardiography, LUS findings of pulmonary congestion differ between patients with known HF and those with hypertension, and may be associated with adverse outcomes.
Some patients with heart failure may experience transient changes in kidney function upon transition to sacubitril/valsartan. Whether such changes portend adverse outcomes or influence long-term ...treatment benefits with sacubitril/valsartan continuation is unknown.
This investigation aimed to evaluate the association between the occurrence of moderate estimated glomerular filtration rate (eGFR) decline (>15%) after initial exposure to sacubitril/valsartan and subsequent cardiovascular outcomes and its treatment benefits in PARADIGM-HF and PARAGON-HF.
In sequential run-in phases, patients were titrated to enalapril 10 mg twice daily and then sacubitril/valsartan 97 mg/103 mg twice daily (in PARADIGM-HF) or valsartan 80 mg twice daily and then sacubitril/valsartan 49 mg/51 mg twice daily (in PARAGON-HF).
Among randomized participants, 11% in PARADIGM-HF and 10% in PARAGON-HF experienced eGFR decline (>15%) during sacubitril/valsartan run-in. eGFR partially recovered (from nadir to postrandomization week 16) regardless of sacubitril/valsartan continuation or switch to renin-angiotensin system inhibitor (RASi) postrandomization. Initial eGFR decline was not consistently associated with clinical outcomes in either trial. Treatment benefits of sacubitril/valsartan vs RASi on primary outcomes were similar irrespective of run-in eGFR decline in PARADIGM-HF (eGFR decline, HR: 0.69; 95% CI: 0.53-0.90; and no eGFR decline, HR: 0.80; 95% CI: 0.73-0.88; Pinteraction = 0.32) and PARAGON-HF (eGFR decline, rate ratio RR: 0.84; 95% CI: 0.52-1.36 and no eGFR decline, RR: 0.87; 95% CI: 0.75-1.02, Pinteraction = 0.92). The treatment effect of sacubitril/valsartan remained consistent across a range of eGFR declines.
Moderate eGFR decline when transitioning from RASi to sacubitril/valsartan is not consistently associated with adverse outcomes, and its long-term benefits are retained in heart failure across a broad range of eGFR declines. Early eGFR changes should not deter continuation of sacubitril/valsartan or stall uptitration. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction PARAGON-HF; NCT01920711; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitors with Angiotensin-Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure PARADIGM-HF; NCT01035255)
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Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) experience a high burden of symptoms, physical limitations, and ...poor quality of life; improving health status is a key goal of management.
In a prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, we examine effects of dapagliflozin on health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ).
The DELIVER trial randomized patients with symptomatic HFmrEF/HFpEF to dapagliflozin 10 mg or placebo. KCCQ was evaluated at randomization, 1, 4, and 8 months; KCCQ Total Symptom Score (TSS) was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles; Cox models examined effects of dapagliflozin on clinical outcomes. We evaluated the effects of dapagliflozin on KCCQ-TSS, Physical Limitations (PLS), Clinical Summary (CSS), and Overall Summary (OSS) domains. Responder analyses compared proportions of dapagliflozin vs placebo-treated patients with clinically meaningful changes in KCCQ.
A total of 5,795 patients had baseline KCCQ (median KCCQ-TSS 72.9). The effects of dapagliflozin on reducing cardiovascular death/worsening HF appeared more pronounced in patients with greater baseline symptom burden (lowest-to-highest KCCQ-TSS tertile: HR: 0.70 95% CI: 0.58-0.84; 0.81 95% CI: 0.65-1.01; 1.07 95% CI: 0.83-1.37; Pinteraction = 0.026). Dapagliflozin improved KCCQ-TSS, -PLS, -CSS, and -OSS at 8 months (2.4, 1.9, 2.3, and 2.1 points higher vs placebo; P < 0.001 for all). Dapagliflozin-treated patients experienced improvements in KCCQ-TSS regardless of EF (Pinteraction = 0.85). Fewer dapagliflozin-treated patients had deterioration, and more had improvements in all KCCQ domains at 8 months.
The clinical benefits of dapagliflozin in HFmrEF/HFpEF appear especially pronounced in those with greater baseline symptom impairment. Dapagliflozin improved all KCCQ domains and the proportion of patients experiencing clinically meaningful changes in health status. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure DELIVER; NCT03619213)
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Aims
Hospitalizations for heart failure (HF) are common and are associated with significant morbidity, mortality and cost. However, precipitating factors leading to HF hospitalization and their ...importance with respect to subsequent outcomes are not well understood.
Methods and results
The symptoms and signs present at admission and investigator‐identified factors thought to have contributed to the first adjudicated HF hospitalization in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) programme were prospectively collected and stratified by ejection fraction (EF). Potential precipitants were collected using a specifically designed case report form and categorized according to the presence of cardiovascular (CV), non‐CV and unknown factors. Associations between these factors and subsequent rehospitalization and mortality rates were examined. Of 1668 patients who experienced HF hospitalization, 1152 had reduced EF (≤40%, HFrEF) and 516 had preserved EF (HFpEF). Overall, 54% had CV, 32% had non‐CV and 14% had unknown factors thought to have precipitated HF, with similar proportions in the HFrEF and HFpEF groups. The most common precipitants were arrhythmia (15%), other non‐CV factors (11%) and respiratory infection (10%). Subsequent CV readmission rates were highest in those whose initial HF hospitalization was precipitated by CV factors. However, mortality rates were similar among patients with any of the three categories of precipitating factors. Results were similar in HFrEF and HFpEF.
Conclusions
Among chronic HF patients hospitalized for decompensation, the investigator‐reported precipitating factor was not associated with the subsequent mortality rate, but was associated with type of readmission: readmissions for CV reasons were more likely when the index precipitant was CV.
The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, ...and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction.
We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399 and PARAGON-HF Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality.
Higher scores of the cardiac domain were observed in PARADIGM-HF (10 7-13 versus 5 3-6,
<0.001) and higher scores of the demographic domain in PARAGON-HF (10 8-13 versus 5 2-9,
<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (
<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (
<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction
<0.05 for both outcomes).
Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.
High-throughput metabolomics investigations, when conducted in large human cohorts, represent a potentially powerful tool for elucidating the biochemical diversity underlying human health and ...disease. Large-scale metabolomics data sources, generated using either targeted or nontargeted platforms, are becoming more common. Appropriate statistical analysis of these complex high-dimensional data will be critical for extracting meaningful results from such large-scale human metabolomics studies. Therefore, we consider the statistical analytical approaches that have been employed in prior human metabolomics studies. Based on the lessons learned and collective experience to date in the field, we offer a step-by-step framework for pursuing statistical analyses of cohort-based human metabolomics data, with a focus on feature selection. We discuss the range of options and approaches that may be employed at each stage of data management, analysis, and interpretation and offer guidance on the analytical decisions that need to be considered over the course of implementing a data analysis workflow. Certain pervasive analytical challenges facing the field warrant ongoing focused research. Addressing these challenges, particularly those related to analyzing human metabolomics data, will allow for more standardization of as well as advances in how research in the field is practiced. In turn, such major analytical advances will lead to substantial improvements in the overall contributions of human metabolomics investigations.
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