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Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction: The PARALLAX Randomized Clinical Trial.
Pieske, B, Wachter, R, Shah, SJ, Baldridge, A, Szeczoedy, P, Ibram, G, Shi, V, Zhao, Z, Cowie, MR, ,
JAMA. 2021;(19):1919-1929
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Abstract
IMPORTANCE There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). OBJECTIVE To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. DESIGN, SETTING, AND PARTICIPANTS A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). INTERVENTIONS Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. MAIN OUTCOMES AND MEASURES Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. RESULTS Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%). CONCLUSIONS AND RELEVANCE Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03066804.
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Associations Between Dietary Patterns and Subclinical Cardiac Injury: An Observational Analysis From the DASH Trial.
Juraschek, SP, Kovell, LC, Appel, LJ, Miller, ER, Sacks, FM, Christenson, RH, Rebuck, H, Chang, AR, Mukamal, KJ
Annals of internal medicine. 2020;(12):786-794
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BACKGROUND The DASH diet has been found to lower blood pressure (BP) and low-density lipoprotein cholesterol levels. OBJECTIVE To compare diets rich in fruits and vegetables with a typical American diet in their effects on cardiovascular injury in middle-aged adults without known preexisting cardiovascular disease (CVD). DESIGN Observational study based on a 3-group, parallel-design, randomized trial conducted in the United States from 1994 to 1996. (ClinicalTrials.gov: NCT00000544). SETTING 3 of the 4 original clinical trial centers. PARTICIPANTS 326 of the original 459 trial participants with available stored specimens. INTERVENTION Participants were randomly assigned to 8 weeks of monitored feeding with a control diet typical of what many Americans eat; a diet rich in fruits and vegetables but otherwise similar to the control diet; or the DASH diet, which is rich in fruits, vegetables, low-fat dairy, and fiber and has low levels of saturated fat and cholesterol. Weight was kept constant throughout feeding. MEASUREMENTS Biomarkers collected at baseline and 8 weeks: high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). RESULTS The mean age of participants was 45.2 years, 48% were women, 49% were black, and mean baseline BP was 131/85 mm Hg. Compared with the control diet, the fruit-and-vegetable diet reduced hs-cTnI levels by 0.5 ng/L (95% CI, -0.9 to -0.2 ng/L) and NT-proBNP levels by 0.3 pg/mL (CI, -0.5 to -0.1 pg/mL). Compared with the control diet, the DASH diet reduced hs-cTnI levels by 0.5 ng/L (CI, -0.9 to -0.1 ng/L) and NT-proBNP levels by 0.3 pg/mL (CI, -0.5 to -0.04 pg/mL). Levels of hs-CRP did not differ among diets. None of the markers differed between the fruit-and-vegetable and DASH diets. LIMITATION Short duration, missing specimens, and an inability to isolate the effects of specific foods or micronutrients. CONCLUSION Diets rich in fruits and vegetables given over 8 weeks were associated with lower levels of markers for subclinical cardiac damage and strain in adults without preexisting CVD. PRIMARY FUNDING SOURCE National Institutes of Health, National Heart, Lung, and Blood Institute.
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Novel Biomarkers, ST-Elevation Resolution, and Clinical Outcomes Following Primary Percutaneous Coronary Intervention.
Shavadia, JS, Granger, CB, Alemayehu, W, Westerhout, CM, Povsic, TJ, Van Diepen, S, Defilippi, C, Armstrong, PW
Journal of the American Heart Association. 2020;(13):e016033
Abstract
Background Despite restoration of epicardial flow following primary percutaneous coronary intervention (PPCI), microvascular reperfusion as reflected by ST-elevation resolution (ST-ER) resolution remains variable and its pathophysiology remains unclear. Methods and Results Using principal component analyses, we explored associations between 91 serum biomarkers drawn before PPCI clustered into 14 pathobiologic processes (including NT-proBNP [N-terminal pro-B-type natriuretic peptide] as an independent cluster), and (1) ST-ER resolution ≥50% versus <50%; and (2) 90-day composite of death, shock, and heart failure. Network analyses were performed to understand interbiomarker relationships between the ST-ER groups. Among the 1160 patients studied, 861 (74%) had ST-ER ≥50% at a median 40 (interquartile range, 23-70) minutes following PPCI, yet both groups had comparable post-PPCI TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow (86.6% versus 82.9%; P=0.25). ST-ER ≥50% was associated with significantly lower pre-PPCI concentrations of platelet activation cluster (particularly P-selectin, von Willebrand factor, and platelet-derived growth factor A) and NT-proBNP, including after risk adjustment. Across both ST-ER groups, strong interbiomarker relationships were noted between pathways indicative of myocardial stretch, platelet activation, and inflammation, whereas with ST-ER <50% correlations between iron homeostasis and inflammation were observed. Of all 14 biomarker clusters, only NT-proBNP was significantly associated with the 90-day clinical composite. Conclusions Suboptimal ST-ER is common despite achieving post-PPCI TIMI grade 3 flow. The cluster of platelet activation proteins and NT-proBNP were strongly correlated with suboptimal ST-ER and NT-proBNP was independently associated with 90-day outcomes. This analysis provides insights into the pathophysiology of microvascular reperfusion in ST-segment-elevation myocardial infarction and suggests novel pre-PPCI risk targets potentially amenable to enhancing tissue-level reperfusion following PPCI.
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Prognostic Value of Lactate Dehydrogenase for Mid-Term Mortality in Acute Decompensated Heart Failure: A Comparison to Established Biomarkers and Brain Natriuretic Peptide.
Yamaguchi, S, Abe, M, Arakaki, T, Arasaki, O, Shimabukuro, M
Heart, lung & circulation. 2020;(9):1318-1327
Abstract
BACKGROUND Enzyme biomarkers-such as creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase-are associated with acute decompensated heart failure (ADHF) severity and, therefore, have a prognostic value in ADHF. However, the prognostic value of lactate dehydrogenase (LDH) is unclear. This study aimed to investigate the prognostic value of LDH in ADHF. METHODS This single-centre observational retrospective study enrolled 396 patients with ADHF between June 2014 and July 2016. The patients were categorised into groups based on the tertile values of serum LDH (LDH-low [<196 U/L], LDH-intermediate [196≤ LDH <239 U/L] and LDH-high [LDH ≥239 U/L]). Survival analysis for all-cause mortality was performed. This study also examined the ability of adding log-transformed LDH (LogLDH) on Get With The Guideline score, which is an established risk score to predict 90-day, 180-day and 365-day mortality using time-dependent receiver operating characteristic curves. RESULTS During the follow-up (median, 204 days), 100 (25%) patients died. The LDH-intermediate and LDH-high groups had worse survival (LDH-low vs LDH-intermediate, log-rank p=0.019; LDH-low vs LDH-high, log-rank p<0.001). Log LDH improved the ability to predict 90-day, 180-day and 365-day all-cause mortality, which was statistically significant (90 days, area under curve [AUC] = 0.79, p=0.012; 180 days, AUC = 0.79, p=0.017; and 365 days, AUC = 0.79, p=0.025). CONCLUSIONS Lactate dehydrogenase may be an important predictor of 90-day, 180-day and 365-day all-cause mortality in ADHF patients; however, further studies are needed to confirm these findings.
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Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.
Velazquez, EJ, Morrow, DA, DeVore, AD, Ambrosy, AP, Duffy, CI, McCague, K, Hernandez, AF, Rocha, RA, Braunwald, E
American heart journal. 2018;:145-151
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OBJECTIVE The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. BACKGROUND Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. METHODS PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. CONCLUSION The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.
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Does a run/walk strategy decrease cardiac stress during a marathon in non-elite runners?
Hottenrott, K, Ludyga, S, Schulze, S, Gronwald, T, Jäger, FS
Journal of science and medicine in sport. 2016;(1):64-8
Abstract
OBJECTIVES Although alternating run/walk-periods are often recommended to novice runners, it is unclear, if this particular pacing strategy reduces the cardiovascular stress during prolonged exercise. Therefore, the aim of the study was to compare the effects of two different running strategies on selected cardiac biomarkers as well as marathon performance. DESIGN Randomized experimental trial in a repeated measure design. METHODS Male (n=22) and female subjects (n=20) completed a marathon either with a run/walk strategy or running only. Immediately after crossing the finishing line cardiac biomarkers were assessed in blood taken from the cubital vein. Before (-7 days) and after the marathon (+4 days) subjects also completed an incremental treadmill test. RESULTS Despite different pacing strategies, run/walk strategy and running only finished the marathon with similar times (04:14:25±00:19:51 vs 04:07:40±00:27:15 [hh:mm:ss]; p=0.377). In both groups, prolonged exercise led to increased B-type natriuretic peptide, creatine kinase MB isoenzyme and myoglobin levels (p<0.001), which returned to baseline 4 days after the marathon. Elevated cTnI concentrations were observable in only two subjects. B-type natriuretic peptide (r=-0.363; p=0.041) and myoglobin levels (r=-0.456; p=0.009) were inversely correlated with the velocity at the individual anaerobic threshold. Run/walk strategy compared to running only reported less muscle pain and fatigue (p=0.006) after the running event. CONCLUSIONS In conclusion, the increase in cardiac biomarkers is a reversible, physiological response to strenuous exercise, indicating temporary stress on the myocyte and skeletal muscle. Although a combined run/walk strategy does not reduce the load on the cardiovascular system, it allows non-elite runners to achieve similar finish times with less (muscle) discomfort.
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High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
Everett, BM, Zeller, T, Glynn, RJ, Ridker, PM, Blankenberg, S
Circulation. 2015;(21):1851-60
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BACKGROUND Cardiac troponin and B-type natriuretic peptide (BNP) concentrations are associated with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood. METHODS AND RESULTS We measured high-sensitivity cardiac troponin I (hsTnI) in 12 956 and BNP in 11 076 participants without cardiovascular disease in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial before randomization to rosuvastatin 20 mg/d or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted hazard ratio [aHR], 2.19; 95% confidence interval, 1.56-3.06; P for trend <0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR, 1.94; 95% confidence interval, 1.41-2.68; P for trend <0.001). The risk of all-cause mortality was elevated for the highest versus the lowest tertiles of hsTnI (aHR, 2.61; 95% confidence interval, 1.81-3.78; P for trend <0.001) and BNP (aHR, 1.45; 95% confidence interval, 1.03-2.04; P for trend 0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range, 0.50-0.60) and BNP (aHR range, 0.42-0.67) with no statistically significant evidence of interaction (P for interaction=0.53 and 0.20, respectively). CONCLUSIONS In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the Trial of Intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF).
Maeder, MT, Rickenbacher, P, Rickli, H, Abbühl, H, Gutmann, M, Erne, P, Vuilliomenet, A, Peter, M, Pfisterer, M, Brunner-La Rocca, HP, et al
European journal of heart failure. 2013;(10):1148-56
Abstract
AIMS: To assess the effects of an NT-proBNP-guided medical management on 18-month outcomes in patients with heart failure (HF) and preserved LVEF ( HFpEF). METHODS AND RESULTS Patients with HFpEF (LVEF >45%; n = 123) and HF with reduced LVEF (HFrEF; LVEF ≤45%; n = 499) with age ≥60 years, NYHA class ≥ II, and elevated NT-proBNP (>400 ng/L or >800 ng/L depending on age) were randomized to medical therapy titrated only to reduce symptoms to NYHA ≤II (symptom-guided) or also to reduce NT-proBNP below the inclusion threshold (NT-proBNP-guided) during a 6-month period. Patients were followed for an additional 12 months. Despite similar treatment escalation, NT-proBNP reduction and symptom relief were less in HFpEF than in HFrEF. Hospitalization-free survival at 18 months was worse in HFpEF than in HFrEF (P = 0.02), while survival and HF hospitalization-free survival did not differ. Among HFpEF patients, NT-proBNP reduction and symptom relief were similar in the symptom-guided (n = 59) and NT-proBNP-guided (n = 64) group despite more aggressive treatment in the NT-proBNP-guided group. In contrast to effects in HFrEF, NT-proBNP-guided management tended to worsen 18-month outcomes in HFpEF, with P-values for the interactions between LVEF stratum and management strategy of 0.2 for hospitalization-free survival, 0.03 for survival, and 0.01 for HF hospitalization-free survival. CONCLUSIONS Outcomes in HFpEF were not better than in HFrEF, and opposite effects of NT-proBNP-guided management were observed in HFpEF compared with HFrEF. These preliminary findings suggest that, in contrast to HFrEF, NT-proBNP-guided therapy may not be beneficial in HFpEF. Trial registration ISRCTN43596477.
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Combined use of the novel biomarkers high-sensitivity troponin T and ST2 for heart failure risk stratification vs conventional assessment.
Lupón, J, de Antonio, M, Galán, A, Vila, J, Zamora, E, Urrutia, A, Bayes-Genis, A
Mayo Clinic proceedings. 2013;(3):234-43
Abstract
OBJECTIVE To assess an innovative multimarker strategy for risk stratification of death in a real-life ambulatory heart failure (HF) cohort. PATIENTS AND METHODS The study included 876 consecutive outpatients (median age, 70.3 years; left ventricular ejection fraction, 34%) between May 22, 2006, and July 7, 2010, prospectively followed up in a structured HF unit. A combination of biomarkers reflecting myocardial stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), myocyte injury (high-sensitivity cardiac troponin T [hs-cTnT]), and ventricular fibrosis and remodeling (high-sensitivity ST2 [hs-ST2]) were added to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes mellitus, estimated glomerular filtration rate, ischemic etiology, sodium level, hemoglobin level, and pharmacologic treatment). RESULTS During median follow-up of 41.4 months, 311 patients died. The combined addition of hs-cTnT and hs-ST2 to the model yielded good measurements of performance (C statistic, 0.789; Bayesian information criterion, 3611; integrated discrimination improvement, 4.1 [95% CI, 2.5-5.6]; and net reclassification index, 13.9% [95% CI, 6.2-21.6]). Reclassification did not significantly benefit after NT-proBNP addition into the full model; some indices even worsened with all 3 biomarkers. Separate addition of NT-proBNP provided prognostic discrimination only in the subgroup of patients with either hs-cTnT or hs-ST2 levels below the cutoff points (hazard ratio, 2.97; 95% CI, 2.24-9.39; P<.001). CONCLUSION A multimarker strategy seems useful for stratifying risk in chronic HF. However, NT-proBNP in addition to the new-generation biomarkers hs-cTnT and hs-ST2 had a limited effect on risk stratification.
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Does continuous endurance exercise in water elicit a higher release of ANP and BNP and a higher plasma concentration of FFAs in pre-obese and obese men than high intensity intermittent endurance exercise? - study protocol for a randomized controlled trial.
Karner-Rezek, K, Knechtle, B, Fenzl, M, Gredig, J, Rosemann, T
Trials. 2013;:328
Abstract
BACKGROUND Atrial natriuretic peptides (ANP) and Brain natriuretic peptides (BNP) stimulate fat cell plasma membrane receptors. They are potent lipolytic agents on isolated fat cells from subcutaneous adipose tissue. The physiological effects of continuous endurance exercise on ANP release and plasma free fatty acids (FFA) concentrations have been well described. The enhancement of fat metabolism using high intensity intermittent exercise protocols has been assessed in more recent investigations. The combined effects of endurance exercise and water immersion on ANP and FFA plasma concentration and the magnitude of excess post-exercise oxygen consumption (EPOC) might be further enhanced by choosing the most effective exercise protocol. Exercise modalities may play a significant role in the future prevention and treatment of obesity. METHODS/DESIGN The two testing trials will be performed according to a randomized and cross-over design. Twenty healthy sedentary pre-obese and obese class-1 men will be scrutinized with regard to their metabolic responses to continuous exercise in water and to high intensity endurance exercise in water. Both trials will be matched for energy expenditure. After preliminary testing, the tests will be conducted as repeated measurements. The two different exercise protocols will be compared. The aims of the study are to investigate (1) whether continuous endurance exercise or high intensity intermittent endurance exercise in water elicits both a higher release of ANP and BNP and a higher plasma concentration of glycerol and (2) to determine whether continuous endurance exercise in water or a high intensity intermittent endurance exercise in water would lead to a more pronounced short term (two hours) EPOC effect. DISCUSSION If our hypothesis would be confirmed, the most effective exercise protocol based on the combined effects of high intensity endurance exercise and water immersion on ANP and BNP release and glycerol plasma concentrations can be identified. Moreover, the magnitude of the EPOC effect can be augmented. Our study would provide a major contribution for creating optimized exercise modalities in the prevention and treatment of obesity. TRIAL REGISTRATION Current controlled trials, ISRCTN95488515.