Browsing by Subject "Heart Failure"
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Item Open Access Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial.(Circulation, 2021-04) Packer, Douglas L; Piccini, Jonathan P; Monahan, Kristi H; Al-Khalidi, Hussein R; Silverstein, Adam P; Noseworthy, Peter A; Poole, Jeanne E; Bahnson, Tristram D; Lee, Kerry L; Mark, Daniel B; CABANA InvestigatorsBackground
In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation).Methods
The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial's primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest.Results
Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2).Conclusions
In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.Item Open Access Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.(J Clin Invest, 2001-04) Freeman, K; Lerman, I; Kranias, EG; Bohlmeyer, T; Bristow, MR; Lefkowitz, RJ; Iaccarino, G; Koch, WJ; Leinwand, LAThe medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.Item Open Access Angina and Future Cardiovascular Events in Stable Patients With Coronary Artery Disease: Insights From the Reduction of Atherothrombosis for Continued Health (REACH) Registry.(Journal of the American Heart Association, 2016-09-28) Eisen, Alon; Bhatt, Deepak L; Steg, P Gabriel; Eagle, Kim A; Goto, Shinya; Guo, Jianping; Smith, Sidney C; Ohman, E Magnus; Scirica, Benjamin M; REACH Registry InvestigatorsThe extent to which angina is associated with future cardiovascular events in patients with coronary artery disease has long been debated.Included were outpatients with established coronary artery disease who were enrolled in the REACH registry and were followed for 4 years. Angina at baseline was defined as necessitating episodic or permanent antianginal treatment. The primary end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included heart failure, cardiovascular hospitalizations, and coronary revascularization. The independent association between angina and first/total events was examined using Cox and logistic regression models. Out of 26 159 patients with established coronary artery disease, 13 619 (52%) had angina at baseline. Compared with patients without angina, patients with angina were more likely to be older, female, and had more heart failure and polyvascular disease (P<0.001 for each). Compared with patients without angina, patients with angina had higher rates of first primary end-point event (14.2% versus 16.3%, unadjusted hazard ratio 1.19, CI 1.11-1.27, P<0.001; adjusted hazard ratio 1.06, CI 0.99-1.14, P=0.11), and total primary end-point events (adjusted risk ratio 1.08, CI 1.01-1.16, P=0.03). Patients with angina were at increased risk for heart failure (adjusted odds ratio 1.17, CI 1.06-1.28, P=0.002), cardiovascular hospitalizations (adjusted odds ratio 1.29, CI 1.21-1.38, P<0.001), and coronary revascularization (adjusted odds ratio 1.23, CI 1.13-1.34, P<0.001).Patients with stable coronary artery disease and angina have higher rates of future cardiovascular events compared with patients without angina. After adjustment, angina was only weakly associated with cardiovascular death, myocardial infarction, or stroke, but significantly associated with heart failure, cardiovascular hospitalization, and coronary revascularization.Item Open Access Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.(J Card Fail, 2015-09) Buggey, Jonathan; Mentz, Robert J; DeVore, Adam D; Velazquez, Eric JHeart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.Item Open Access Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation.(J Clin Invest, 2004-05) Freedman, Neil J; Lefkowitz, Robert JAntibodies specific for the beta(1)-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these antibodies actually contribute to the pathogenesis of chronic heart failure. This commentary discusses mechanisms by which these antibodies may engender cardiomyopathy.Item Open Access Association Between Comorbidities and Outcomes in Heart Failure Patients With and Without an Implantable Cardioverter-Defibrillator for Primary Prevention.(J Am Heart Assoc, 2015-08-06) Khazanie, Prateeti; Hellkamp, Anne S; Fonarow, Gregg C; Bhatt, Deepak L; Masoudi, Frederick A; Anstrom, Kevin J; Heidenreich, Paul A; Yancy, Clyde W; Curtis, Lesley H; Hernandez, Adrian F; Peterson, Eric D; Al-Khatib, Sana MBACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy is associated with improved outcomes in patients with heart failure (HF), but whether this association holds among older patients with multiple comorbid illnesses and worse HF burden remains unclear. METHODS AND RESULTS: Using the National Cardiovascular Data Registry's ICD Registry and the Get With The Guidelines-Heart Failure (GWTG-HF) registry linked with Medicare claims, we examined outcomes associated with primary-prevention ICD versus no ICD among HF patients aged ≥65 years in clinical practice. We included patients with an ejection fraction ≤35% who received (ICD Registry) and who did not receive (GWTG-HF) an ICD. Compared with patients with an ICD, patients in the non-ICD group were older and more likely to be female and white. In matched cohorts, the 3-year adjusted mortality rate was lower in the ICD group versus the non-ICD group (46.7% versus 55.8%; adjusted hazard ratio [HR] 0.76; 95% CI 0.69 to 0.83). There was no associated difference in all-cause readmission (HR 0.99; 95% CI 0.92 to 1.08) but a lower risk of HF readmission (HR 0.88; 95% CI 0.80 to 0.97). When compared with no ICD, ICDs were also associated with better survival in patients with ≤3 comorbidities (HR 0.77; 95% CI 0.69 to 0.87) and >3 comorbidities (HR 0.77; 95% CI 0.64 to 0.93) and in patients with no hospitalization for HF (HR 0.75; 95% CI 0.65 to 0.86) and at least 1 prior HF hospitalization (HR 0.69; 95% CI 0.58 to 0.82). In subgroup analyses, there were no interactions between ICD and mortality risk for comorbidity burden (P=0.95) and for prior HF hospitalization (P=0.46). CONCLUSION: Among older HF patients, ICDs for primary prevention were associated with lower risk of mortality even among those with high comorbid illness burden and prior HF hospitalization.Item Open Access Blood Pressure Response during Cardiopulmonary Exercise Testing in Heart Failure.(Medicine and science in sports and exercise, 2018-07) Il'giovine, Zachary J; Solomon, Nicole; Devore, Adam D; Wojdyla, Daniel; Patel, Chetan B; Rogers, Joseph GIntroduction
The prognostic value of peak V˙O2 and V˙E/V˙CO2 slope measured during cardiopulmonary exercise (CPX) testing has been well established in patients with advanced heart failure, but blood pressure response to exercise is less well characterized.Methods
We retrospectively studied 151 outpatients who underwent CPX testing as part of an advanced heart failure evaluation. The outcome of interest was failure of medical management, defined by death, cardiac transplantation, or left ventricular assist device placement. Patients were stratified into tertiles by change in systolic blood pressure (SBP) (<13, 13-26, and ≥27 mm Hg) during exercise.Results
Patients in the lowest tertile had the lowest peak V˙O2 (10.2 vs 10.6 vs 13.6 mL·kg·min, P = <0.001), the highest V˙E/V˙CO2 slope (42.8 vs 42.1 vs 36.3, P = 0.030), the shortest mean exercise time (5.1 vs 6.0 vs 7.0 min, P = <0.001), and the highest probability of failure of medical management at 1.5 yr (0.69 vs 0.41 vs 0.34, P = 0.011). After multivariate adjustment, increased SBP <20 mm Hg during exercise was associated with a lower hazard of medical management failure (hazard ratio = 0.96, 95% confidence interval [CI] = 0.934-0.987), whereas SBP increases >20 mm Hg were associated with an increased hazard (hazard ratio = 1.046, 95% CI = 1.018-1.075).Conclusion
In conclusion, changes in SBP during CPX testing provide additional prognostic information above standard clinical variables. The peculiar increase in risk noted in those with a rise in SBP >20 mm Hg is less clear and needs to be investigated further.Item Open Access Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial.(American heart journal, 2019-02) Held, Claes; White, Harvey D; Stewart, Ralph AH; Davies, Richard; Sampson, Shani; Chiswell, Karen; Silverstein, Adam; Lopes, Renato D; Heldestad, Ulrika; Budaj, Andrzej; Mahaffey, Kenneth W; Wallentin, Lars; STABILITY InvestigatorsBackground
Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.Methods
Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.Results
In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).Conclusions
The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.Item Open Access Chest pain in patients with heart failure: why history may matter.(Eur Heart J, 2014-12-21) DeVore, Adam D; Hernandez, Adrian FItem Open Access Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure and Diabetes.(JACC. Heart failure, 2022-03) Khan, Muhammad Shahzeb; Solomon, Nicole; DeVore, Adam D; Sharma, Abhinav; Felker, G Michael; Hernandez, Adrian F; Heidenreich, Paul A; Matsouaka, Roland A; Green, Jennifer B; Butler, Javed; Yancy, Clyde W; Peterson, Pamela N; Fonarow, Gregg C; Greene, Stephen JObjectives
The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype).Background
Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these therapies on clinical outcomes among patients with comorbid HF and diabetes is unclear.Methods
The authors evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure Registry between 2006 and 2014 with diabetes and not prescribed metformin or sulfonylurea before admission. In parallel separate analyses for metformin and sulfonylurea, patients with newly prescribed therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between prescription of therapy, and mortality and hospitalization for HF (HHF) at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleed, and influenza vaccination. Prespecified subgroup analyses were stratified by EF ≤40% versus >40%.Results
Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was independently associated with reduced risk of composite mortality/HHF (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but individual components were not statistically significant. Findings among patients with EF >40% accounted for associations with mortality/HHF (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) endpoints (all P for interaction ≤0.04). After adjustment, sulfonylurea initiation was associated with increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with nominal statistical significance. Associations between sulfonylurea initiation and endpoints were consistent regardless of EF (all P for interaction >0.11). Neither metformin initiation nor sulfonylurea initiation were associated with negative control endpoints.Conclusions
In this population of older U.S. adults hospitalized for HF with comorbid diabetes, metformin initiation was independently associated with substantial improvements in 12-month clinical outcomes, driven by findings among patients with EF >40%. By contrast, sulfonylurea initiation was associated with excess risk of death and HF hospitalization, regardless of EF.Item Open Access Clinical Predictors of Adherence to Exercise Training Among Individuals With Heart Failure: THE HF-ACTION STUDY.(Journal of cardiopulmonary rehabilitation and prevention, 2023-05) Collins, Katherine A; Reeves, Gordon R; Miller, Nancy Houston; Whellan, David J; O'Connor, Christopher M; Marcus, Bess H; Kitzman, Dalane W; Kraus, William E; HF-ACTION InvestigatorsPurpose
Suboptimal adherence is a major limitation to achieving the benefits of exercise interventions, and our ability to predict and improve adherence is limited. The purpose of this analysis was to identify baseline clinical and demographic characteristics predicting exercise training adherence in the HF-ACTION study cohort.Methods
Adherence to exercise training, defined by the total duration of exercise performed (min/wk), was evaluated in 1159 participants randomized to the HF-ACTION exercise intervention. More than 50 clinical, demographic, and exercise testing variables were considered in developing a model of the min/wk end point for 1-3 mo (supervised training) and 10-12 mo (home-based training).Results
In the multivariable model for 1-3 mo, younger age, lower income, more severe mitral regurgitation, shorter 6-min walk test distance, lower exercise capacity, and Black or African American race were associated with poorer exercise intervention adherence. No variable accounted for >2% of the variance and the adjusted R2 for the final model was 0.14. Prediction of adherence was similarly limited for 10-12 mo.Conclusions
Clinical and demographic variables available at the initiation of exercise training provide very limited information for identifying patients with heart failure who are at risk for poor adherence to exercise interventions.Item Open Access Clinician's guide to the updated ABCs of cardiovascular disease prevention.(Journal of the American Heart Association, 2014-09) Kohli, Payal; Whelton, Seamus P; Hsu, Steven; Yancy, Clyde W; Stone, Neil J; Chrispin, Jonathan; Gilotra, Nisha A; Houston, Brian; Ashen, M Dominique; Martin, Seth S; Joshi, Parag H; McEvoy, John W; Gluckman, Ty J; Michos, Erin D; Blaha, Michael J; Blumenthal, Roger STo facilitate the guideline-based implementation of treatment recommendations in the ambulatory setting and to encourage participation in the multiple preventive health efforts that exist, we have organized several recent guideline updates into a simple ABCDEF approach. We would remind clinicians that evidence-based medicine is meant to inform recommendations but that synthesis of patient-specific data and use of appropriate clinical judgment in each individual situation is ultimately preferred.Item Open Access Control beliefs and risk for 4-year mortality in older adults: a prospective cohort study.(BMC geriatrics, 2017-01) Duan-Porter, Wei; Hastings, Susan Nicole; Neelon, Brian; Van Houtven, Courtney HaroldBackground
Control beliefs are important psychological factors that likely contribute to heterogeneity in health outcomes for older adults. We evaluated whether control beliefs are associated with risk for 4-year mortality, after accounting for established "classic" biomedical risk factors. We also determined if an enhanced risk model with control beliefs improved identification of individuals with low vs. high mortality risk.Methods
We used nationally representative data from the Health and Retirement Study (2006-2012) for adults 50 years or older in 2006 (n = 7313) or 2008 (n = 6301). We assessed baseline perceived global control (measured as 2 dimensions-"constraints" and "mastery"), and health-specific control. We also obtained baseline data for 12 established biomedical risk factors of 4-year mortality: age, sex, 4 medical conditions (diabetes mellitus, cancer, lung disease and heart failure), body mass index less than 25 kg/m2, smoking, and 4 functional difficulties (with bathing, managing finances, walking several blocks and pushing or pulling heavy objects). Deaths within 4 years of follow-up were determined through interviews with respondents' family and the National Death Index.Results
After accounting for classic biomedical risk factors, perceived constraints were significantly associated with higher mortality risk (third quartile scores odds ratio [OR] 1.37, 95% CI 1.03-1.81; fourth quartile scores OR 1.45, 95% CI, 1.09-1.92), while health-specific control was significantly associated with lower risk (OR 0.69-0.78 for scores above first quartile). Higher perceived mastery scores were not consistently associated with decreased risk. The enhanced model with control beliefs found an additional 3.5% of participants (n = 222) with low predicted risk of 4-year mortality (i.e., 4% or less); observed mortality for these individuals was 1.8% during follow-up. Compared with participants predicted to have low mortality risk only by the classic biomedical model, individuals identified by only the enhanced model were older, had higher educational status, higher income, and higher prevalence of diabetes mellitus and cancer.Conclusion
Control beliefs were significantly associated with risk for 4-year mortality; accounting for these factors improved identification of low-risk individuals. More work is needed to determine how assessment of control beliefs could enable targeting of clinical interventions to support at-risk older adults.Item Open Access Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling.(Circulation, 2011-08) Li, Xue; Chan, Tung O; Myers, Valerie; Chowdhury, Ibrul; Zhang, Xue-Qian; Song, Jianliang; Zhang, Jin; Andrel, Jocelyn; Funakoshi, Hajime; Robbins, Jeffrey; Koch, Walter J; Hyslop, Terry; Cheung, Joseph Y; Feldman, Arthur MBackground
[Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor.Methods and results
The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG(Ind)), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα(q) protein, we blocked Gα(q) signaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα(q). Gα(q) blockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline.Conclusions
Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.Item Open Access Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure.(JACC Heart Fail, 2015-02) Mentz, Robert J; Stevens, Susanna R; DeVore, Adam D; Lala, Anuradha; Vader, Justin M; AbouEzzeddine, Omar F; Khazanie, Prateeti; Redfield, Margaret M; Stevenson, Lynne W; O'Connor, Christopher M; Goldsmith, Steven R; Bart, Bradley A; Anstrom, Kevin J; Hernandez, Adrian F; Braunwald, Eugene; Felker, G MichaelOBJECTIVES: The purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes. BACKGROUND: High-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation. METHODS: This study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes. RESULTS: Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5). CONCLUSIONS: High-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491).Item Open Access Dengue Myocarditis: A Case Report and Major Review.(Global heart, 2023-01) Cristodulo, Roberto; Luoma-Overstreet, Gracia; Leite, Fernando; Vaca, Manuel; Navia, Michelle; Durán, Gustavo; Molina, Fernando; Zonneveld, Bozorg; Perrone, Sergio Víctor; Barbagelata, Alejandro; Kaplinsky, EdgardoDengue is a viral disease transmitted by the bite of a female arthropod, prevalent primarily in tropical and subtropical regions. Its manifestations include asymptomatic infections, dengue fever, and a severe form called hemorrhagic dengue or dengue shock syndrome. Atypical manifestations can also occur, called expanded dengue syndrome. We describe the case of a 43-year-old man with an unusual presentation of dengue, demonstrating a workup suggestive of myocardial and pericardial damage. Symptoms and markers indicative of cardiac compromise improved after five days on anti-inflammatory treatment. Dengue myocarditis is considered an uncommon complication of dengue, although its reported incidence is likely an underestimation. In general, most cases of dengue myocarditis are self-limited, with only a minority at risk of progressing to heart failure. In order to improve recognition and prevent progression, healthcare providers should maintain a high degree of suspicion regarding potential cardiac complications in patients with dengue.Item Open Access Depressive Symptoms and Incident Heart Failure in the Jackson Heart Study: Differential Risk Among Black Men and Women.(Journal of the American Heart Association, 2022-03) Gaffey, Allison E; Cavanagh, Casey E; Rosman, Lindsey; Wang, Kaicheng; Deng, Yanhong; Sims, Mario; O'Brien, Emily C; Chamberlain, Alanna M; Mentz, Robert J; Glover, LáShauntá M; Glover, LáShauntá M; Burg, Matthew MBackground Associations between depression, incident heart failure (HF), and mortality are well documented in predominately White samples. Yet, there are sparse data from racial minorities, including those who are women, and depression is underrecognized and undertreated in the Black population. Thus, we examined associations between baseline depressive symptoms, incident HF, and all-cause mortality across 10 years. Methods and Results We included Jackson Heart Study (JHS) participants with no history of HF at baseline (n=2651; 63.9% women; median age, 53 years). Cox proportional hazards models tested if the risk of incident HF or mortality differed by clinically significant depressive symptoms at baseline (Center for Epidemiological Studies-Depression scores ≥16 versus <16). Models were conducted in the full sample and by sex, with hierarchical adjustment for demographics, HF risk factors, and lifestyle factors. Overall, 538 adults (20.3%) reported high depressive symptoms (71.0% were women), and there were 181 cases of HF (cumulative incidence, 0.06%). In the unadjusted model, individuals with high depressive symptoms had a 43% greater risk of HF (P=0.035). The association remained with demographic and HF risk factors but was attenuated by lifestyle factors. All-cause mortality was similar regardless of depressive symptoms. By sex, the unadjusted association between depressive symptoms and HF remained for women only (P=0.039). The fully adjusted model showed a 53% greater risk of HF for women with high depressive symptoms (P=0.043). Conclusions Among Black adults, there were sex-specific associations between depressive symptoms and incident HF, with greater risk among women. Sex-specific management of depression may be needed to improve cardiovascular outcomes.Item Open Access Diminishment of respiratory sinus arrhythmia foreshadows doxorubicin-induced cardiomyopathy.(Circulation, 1991-08) Hrushesky, WJ; Fader, DJ; Berestka, JS; Sommer, M; Hayes, J; Cope, FOBACKGROUND: The development of a microcomputer-based device permits quick, simple, and noninvasive quantification of the respiratory sinus arrhythmia (RSA) during quiet breathing. METHODS AND RESULTS: We prospectively and serially measured the radionuclide left ventricular ejection fraction and the RSA amplitude in 34 cancer patients receiving up to nine monthly bolus treatments with doxorubicin hydrochloride (60 mg/m2). Of the eight patients who ultimately developed symptomatic doxorubicin-induced congestive heart failure, seven (87.5%) demonstrated a significant decline in RSA amplitude; five of 26 subjects without clinical symptoms of cardiotoxicity (19.2%) showed a similar RSA amplitude decline. On average, significant RSA amplitude decline occurred 3 months before the last planned doxorubicin dose in patients destined to develop clinical congestive heart failure. CONCLUSION: Overall, RSA amplitude abnormality proved to be a more specific predictor of clinically significant congestive heart failure than did serial resting radionuclide ejection fractions.Item Open Access Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.(Circulation, 2011-03) Van Oort, RJ; Garbino, A; Wang, W; Dixit, SS; Landstrom, AP; Gaur, N; De Almeida, AC; Skapura, DG; Rudy, Y; Burns, AR; Ackerman, MJ; Wehrens, XHTExcitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca(2+)-induced Ca(2+) release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy.To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance.Loss of JPH2 had profound effects on Ca2+ release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca2+ release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA-mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca2+ release in the heart.Item Open Access Effectiveness and Safety of Aldosterone Antagonist Therapy Use Among Older Patients With Reduced Ejection Fraction After Acute Myocardial Infarction.(J Am Heart Assoc, 2016-01-21) Wang, Tracy Y; Vora, Amit N; Peng, S Andrew; Fonarow, Gregg C; Das, Sandeep; de Lemos, James A; Peterson, Eric DBACKGROUND: While aldosterone antagonists have proven benefit among post-myocardial infarction (MI) patients with low ejection fraction (EF), how this treatment is used among older MI patients in routine practice is not well described. METHODS AND RESULTS: Using ACTION Registry-GWTG linked to Medicare data, we examined 12 080 MI patients ≥65 years with EF ≤40% who were indicated for aldosterone antagonist therapy per current guidelines and without documented contraindications. Of these, 11% (n=1310) were prescribed aldosterone antagonists at discharge. Notably, 10% of patients prescribed an aldosterone antagonist were eligible for, but not concurrently treated with, an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Spironolactone was the predominantly prescribed aldosterone antagonist. At 2-year follow-up, aldosterone antagonist use was not associated with lower mortality (unadjusted 39% versus 38%; HR 0.99, 95% CI 0.88-1.33 using inverse probability-weighted propensity adjustment) except in symptomatic HF patients (HR 0.84, 95% CI 0.72-0.99, Pinteraction=0.009). Risks of hyperkalemia were low at 30 days, but significantly higher among patients prescribed aldosterone antagonists (unadjusted 2.3% versus 1.5%; adjusted HR 2.04, 95% CI 1.16-3.60), as was 2-year risk of acute renal failure (unadjusted 6.7% versus 4.8%; adjusted HR 1.39, 95% CI 1.01-1.92) compared with patients not prescribed aldosterone antagonists. CONCLUSIONS: Aldosterone antagonist use among eligible older MI patients in routine clinical practice was not associated with lower mortality except in patients with HF symptoms, but was associated with increased risks of hyperkalemia and acute renal failure. These results underscore the importance of close post-discharge monitoring of this patient population.