Browsing by Subject "Stroke Volume"
Now showing 1 - 20 of 21
- Results Per Page
- Sort Options
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 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 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 Comparison of long-term postoperative sequelae in patients with tetralogy of Fallot versus isolated pulmonic stenosis.(Am J Cardiol, 2014-07-15) Zdradzinski, Michael J; Qureshi, Athar M; Stewart, Robert; Pettersson, Gosta; Krasuski, Richard APatients with tetralogy of Fallot (TOF) after complete repair and pulmonic stenosis (PS) after surgical valvotomy often develop significant pulmonic regurgitation (PR) that eventually requires valve replacement. Although criteria exist for the timing of pulmonary valve replacement in TOF, it remains less clear when to intervene in valvotomy patients and whether TOF recommendations can be applied. Our aim was to compare the structural and functional sequelae of valvotomy for PS with complete repair for TOF. We compared the clinical characteristics, electrocardiograms, echocardiograms, cardiac magnetic resonance imaging (MRI), and invasive hemodynamics of 109 adults (34 PS and 75 TOF) newly referred to a congenital heart disease center for evaluation of PR between 2005 and 2012. Both cohorts were similar in terms of baseline demographics and presenting New York Heart Association function class. Valvotomy patients had a slightly greater degree of PR by echocardiogram, although it was similar by cardiac MRI. Electrocardiography QRS width was greater in patients with TOF (114±27 vs 150±28 ms, p<0.001). MRI right ventricular ejection fraction (49±8 vs 41±11%, p=0.001) and left ventricular ejection fraction (59±7 vs 52±10%, p=0.002) were lower in patients with TOF. Pacemaker or defibrillator implantation was significantly greater in patients with TOF (3% vs 23%, p=0.011). In conclusion, patients postvalvotomy and complete repair present with similar degrees of PR and severity of symptoms. Biventricular systolic function and electrocardiography QRS width appear less affected, suggesting morphologic changes in TOF and its repair that extend beyond the effects of PR. These findings suggest the need for developing disease-specific guidelines for patients with PR postvalvotomy.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 Effect at One Year of Adjuvant Trastuzumab for HER2+ Breast Cancer Combined with Radiation or an Anthracycline on Left Ventricular Ejection Fraction.(The American journal of cardiology, 2020-06) Andersen, Mousumi M; Ayala-Peacock, Diandra; Bowers, Jessie; Kooken, Banks W; D'Agostino, Ralph B; Jordan, Jennifer H; Vasu, Sujethra; Thomas, Alexandra; Klepin, Heidi D; Brown, Doris R; Hundley, W GregoryTo determine the impact of radiation therapy (XRT) in addition to trastuzumab (TZB) adjuvant chemotherapy for HER2+ breast cancer on left ventricular systolic function, we assessed demographics, oncologic treatment history including XRT exposure, and serial measurements of left ventricular ejection fraction (LVEF) in 135 consecutively identified women receiving TZB for treatment of adjuvant breast cancer. Longitudinal mixed effects models were fit to identify baseline to treatment changes in LVEF among those receiving TZB with or without concomitant anthracycline or XRT. Women averaged 53 ± 3 years in age, 77% were white, 62% patients had 1 or more cardiovascular risk factors at baseline, and mean duration of TZB was 11 ± 5 months. Seventy-seven women were treated with XRT and received between 4000 and 5500 cGy of radiation. The LVEF declined by an average of 3.4% after 1 year for those in the study. Relative to baseline upon completion of adjuvant TZB, LVEF remained reduced for those receiving anthracycline with or without XRT (p=0.002 for both), or XRT alone (p=0.002), but not in those without these therapies. Amongst patients treated only with XRT and TZB, LVEF declined 3.1% on average in those with left-sided disease and 6.9% on average in those with right-sided disease (p= 0.06, p= 0.008 respectively). Among women receiving TZB for adjuvant treatment of HER-2 positive breast cancer, the administration of XRT, anthracycline, or the combination of the 2 is associated with a persistent post-treatment as opposed to a temporary treatment related decline in LVEF.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.Item Open Access Heart failure with preserved ejection fraction: New approaches to diagnosis and management.(Clinical cardiology, 2020-02) Upadhya, Bharathi; Kitzman, Dalane WThe majority of older patients who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). Patients with HFpEF have severe symptoms of exercise intolerance, poor quality-of-life, frequent hospitalizations, and increased mortality. The prevalence of HFpEF is increasing and its prognosis is worsening. However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Originally viewed as a disorder due solely to abnormalities in left ventricular (LV) diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome, involving multiple organ systems, likely triggered by inflammation and with an important contribution of aging, lifestyle factors, genetic predisposition, and multiple-comorbidities, features that are typical of a geriatric syndrome. HFpEF is usually progressive due to complex mechanisms of systemic and cardiac adaptation that vary over time, particularly with aging. In this review, we examine evolving data regarding HFpEF that may help explain past challenges and provide future directions to care patients with this highly prevalent, heterogeneous clinical syndrome.Item Open Access International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS.(American heart journal, 2019-12) Bhatt, Ankeet S; Luo, Nancy; Solomon, Nicole; Pagidipati, Neha J; Ambrosio, Giuseppe; Green, Jennifer B; McGuire, Darren K; Standl, Eberhard; Cornel, Jan H; Halvorsen, Sigrun; Lopes, Renato D; White, Harvey D; Holman, Rury R; Peterson, Eric D; Mentz, Robert J; TECOS Study GroupInternational differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. β-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials.Item Open Access Myocardial Function in Premenopausal Women Treated With Ovarian Function Suppression and an Aromatase Inhibitor.(JNCI cancer spectrum, 2021-08) Jordan, Jennifer H; D'Agostino, Ralph B; Ansley, Katherine; Douglas, Emily; Melin, Susan; Sorscher, Steven; Vasu, Sujethra; Park, Sung; Kotak, Anuj; Romitti, Paul A; O'Connell, Nathanial S; Hundley, William G; Thomas, AlexandraPremenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) with aromatase inhibitor therapy; however, abrupt menopause induction, together with further decrements in estrogen exposure through aromatase inhibition, may affect cardiovascular microcirculatory function. We examined adenosine-induced changes in left ventricular (LV) myocardial T1, a potential subclinical marker of LV microcirculatory function in premenopausal women undergoing treatment for breast cancer. Twenty-one premenopausal women (14 with HR-positive breast cancer receiving OFS with an aromatase inhibitor and 7 comparator women with triple-negative breast cancer [TNBC] who had completed primary systemic therapy) underwent serial resting and adenosine cardiovascular magnetic resonance imaging measurements of LV myocardial T1 and LV volumes, mass, and ejection fraction. All statistical tests were 2-sided. After a median of 4.0 months (range = 3.1-5.7 months), the stress to resting ratio of LV myocardial T1 declined in women with HR-positive breast cancer (-1.3%, 95% confidence interval [CI] = -3.4% to 0.7%) relative to those with TNBC (3.2%, 95% CI = -1.2% to 7.6%, P = .02). After accounting for age, LV stroke volume, LV ejection fraction, diastolic blood pressure, and breast cancer subtype women with HR-positive breast cancer experienced a blunted T1 response after adenosine relative to women with TNBC (difference = -4.7%, 95% CI = -7.3% to -2.1%, Pdifference = .002). Over the brief interval examined, women with HR-positive breast cancer receiving OFS with an aromatase inhibitor experienced reductions in adenosine-associated changes in LV myocardial T1 relative to women who received nonhormonal therapy for TNBC. These findings suggest a possible adverse impact on LV myocardial microcirculatory function in premenopausal women with breast cancer receiving hormone deprivation therapy.Item Open Access Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.(Hypertension (Dallas, Tex. : 1979), 2014-02) Bathgate-Siryk, Ashley; Dabul, Samalia; Pandya, Krunal; Walklett, Karlee; Rengo, Giuseppe; Cannavo, Alessandro; De Lucia, Claudio; Liccardo, Daniela; Gao, Erhe; Leosco, Dario; Koch, Walter J; Lymperopoulos, Anastasiosβ-Arrestin (βarr)-1 and β-arrestin-2 (βarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac β-adrenergic receptor (βAR) function via βAR desensitization and downregulation. In addition, they mediate G-protein-independent βAR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac βAR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal βarr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of βarr1 in post-myocardial infarction (MI) HF by testing the effects of βarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied βarr1 knockout (βarr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) βarr1KO mice display enhanced βAR-dependent contractility and post-MI βarr1KO mice enhanced overall cardiac function (and βAR-dependent contractility) compared with wild type. Post-MI βarr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac βAR signaling and function, as evidenced by increased βAR density and procontractile signaling, via reduced cardiac βAR desensitization because of cardiac βarr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal βarr1 absence. Thus, βarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.Item Open Access Outcomes of Cardiac Resynchronization Therapy with Image-Guided Left Ventricular Lead Placement at the Site of Latest Mechanical Activation: A Systematic Review and Meta-Analysis.(Journal of interventional cardiology, 2022-01) Allen LaPointe, Nancy M; Ali-Ahmed, Fatima; Dalgaard, Frederik; Kosinski, Andrzej S; Schmidler, Gillian Sanders; Al-Khatib, Sana MAim
To assess evidence for an image-guided approach for cardiac resynchronization therapy (CRT) that targets left ventricular (LV) lead placement at the segment of latest mechanical activation.Methods
A systematic review of EMBASE and PubMed was performed for randomized controlled trials (RCTs) and prospective observational studies from October 2008 through October 2020 that compared an image-guided CRT approach with a non-image-guided approach for LV lead placement. Meta-analyses were performed to assess the association between the image-guided approach and NYHA class improvement or changes in end-systolic volume (LVESV), end-diastolic volume (LVEDV), and ejection fraction (LVEF).Results
From 5897 citations, 5 RCTs including 818 patients (426 image-guided and 392 non-image-guided) were identified. The mean age ranged from 66 to 71 years, 76% were male, and 53% had ischemic cardiomyopathy. Speckle tracking echocardiography was the primary image-guided method in all studies. LV lead placement within the segment of the latest mechanical activation (concordant) was achieved in the image-guided arm in 45% of the evaluable patients. There was a statistically significant improvement in the NYHA class at 6 months (odds ratio 1.66; 95% confidence interval (CI) [1.02, 2.69]) with the image-guided approach, but no statistically significant change in LVESV (MD -7.1%; 95% CI [-16.0, 1.8]), LVEDV (MD -5.2%; 95% CI [-15.8, 5.4]), or LVEF (MD 0.68; 95% CI [-4.36, 5.73]) versus the non-image-guided approach.Conclusion
The image-guided CRT approach was associated with improvement in the NYHA class but not echocardiographic measures, possibly due to the small sample size and a low rate of concordant LV lead placement despite using the image-guided approach. Therefore, our meta-analysis was not able to identify consistent improvement in CRT outcomes with an image-guided approach.Item Open Access PINOT NOIR: pulmonic insufficiency improvement with nitric oxide inhalational response.(J Cardiovasc Magn Reson, 2013-09-04) Hart, Stephen A; Devendra, Ganesh P; Kim, Yuli Y; Flamm, Scott D; Kalahasti, Vidyasagar; Arruda, Janine; Walker, Esteban; Boonyasirinant, Thananya; Bolen, Michael; Setser, Randolph; Krasuski, Richard ABACKGROUND: Tetralogy of Fallot (TOF) repair and pulmonary valvotomy for pulmonary stenosis (PS) lead to progressive pulmonary insufficiency (PI), right ventricular enlargement and dysfunction. This study assessed whether pulmonary regurgitant fraction measured by cardiovascular magnetic resonance (CMR) could be reduced with inhaled nitric oxide (iNO). METHODS: Patients with at least moderate PI by echocardiography undergoing clinically indicated CMR were prospectively enrolled. Patients with residual hemodynamic lesions were excluded. Ventricular volume and blood flow sequences were obtained at baseline and during administration of 40 ppm iNO. RESULTS: Sixteen patients (11 with repaired TOF and 5 with repaired PS) completed the protocol with adequate data for analysis. The median age [range] was 35 [19-46] years, BMI was 26 ± 5 kg/m(2) (mean ± SD), 50% were women and 75% were in NYHA class I. Right ventricular end diastolic volume index for the cohort was 157 ± 33 mL/m(2), end systolic volume index was 93 ± 20 mL/m(2) and right ventricular ejection fraction was 40 ± 6%. Baseline pulmonary regurgitant volume was 45 ± 25 mL/beat and regurgitant fraction was 35 ± 16%. During administration of iNO, regurgitant volume was reduced by an average of 6 ± 9% (p=0.01) and regurgitant fraction was reduced by an average of 5 ± 8% (p=0.02). No significant changes were observed in ventricular indices for either the left or right ventricle. CONCLUSION: iNO was successfully administered during CMR acquisition and appears to reduce regurgitant fraction in patients with at least moderate PI suggesting a potential role for selective pulmonary vasodilator therapy in these patients. TRIALS REGISTRATION: ClinicalTrials.gov, NCT00543933.Item Open Access Projected Clinical Benefits of Implementation of SGLT-2 Inhibitors Among Medicare Beneficiaries Hospitalized for Heart Failure.(Journal of cardiac failure, 2022-04) Vaduganathan, Muthiah; Greene, Stephen J; Zhang, Shuaiqi; Solomon, Nicole; Chiswell, Karen; Devore, Adam D; Butler, Javed; Heidenreich, Paul A; Huang, Joanna C; Kittleson, Michelle M; Joynt Maddox, Karen E; Mcdermott, James J; Owens, Anjali Tiku; Peterson, Pamela N; Solomon, Scott D; Vardeny, Orly; Yancy, Clyde W; Fonarow, Gregg CBackground
The sodium-glucose cotransporter-2 (SGLT-2) inhibitors form the latest pillar in the management of heart failure with reduced ejection fraction (HFrEF) and appear to be effective across a range of patient profiles. There is increasing interest in initiating SGLT-2 inhibitors during hospitalization, yet little is known about the putative benefits of this implementation strategy.Methods
We evaluated Medicare beneficiaries with HFrEF (≤ 40%) hospitalized at 228 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry in 2016 who had linked claims data for ≥ 1 year postdischarge. We identified those eligible for dapagliflozin under the latest U.S. Food and Drug Administration label (excluding estimated glomerular filtration rates < 25 mL/min per 1.73 m2, dialysis and type 1 diabetes). We evaluated 1-year outcomes overall and among key subgroups (age ≥ 75 years, gender, race, hospital region, kidney function, diabetes status, triple therapy). We then projected the potential benefits of implementation of dapagliflozin based on the risk reductions observed in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial.Results
Among 7523 patients hospitalized for HFrEF, 6576 (87%) would be candidates for dapagliflozin (mean age 79 ± 8 years, 39% women, 11% Black). Among eligible candidates, discharge use of β-blockers, ACEi/ARB, MRA, ARNI, and triple therapy (ACEi/ARB/ARNI+β-blocker+MRA) was recorded in 88%, 64%, 29%, 3%, and 20%, respectively. Among treatment-eligible patients, the 1-year incidence (95% CI) of mortality was 37% (36-38%) and of HF readmission was 33% (32-34%), and each exceeded 25% across all key subgroups. Among 1333 beneficiaries eligible for dapagliflozin who were already on triple therapy, the 1-year incidence of mortality was 26% (24%-29%) and the 1-year readmission due to HF was 30% (27%-32%). Applying the relative risk reductions observed in DAPA-HF, absolute risk reductions with complete implementation of dapagliflozin among treatment-eligible Medicare beneficiaries are projected to be 5% (1%-9%) for mortality and 9% (5%-12%) for HF readmission by 1 year. The projected number of Medicare beneficiaries who would need to be treated for 1 year to prevent 1 death is 19 (11-114), and 12 (8-21) would need to be treated to prevent 1 readmission due to HF.Conclusions
Medicare beneficiaries with HFrEF who are eligible for dapagliflozin after hospitalization due to HF, including those well-treated with other disease-modifying therapies, face high risks of mortality and HF readmission by 1 year. If the benefits of reductions in death and hospitalizations due to HF observed in clinical trials can be fully realized, the absolute benefits of implementation of SGLT-2 inhibitors among treatment-eligible candidates are anticipated to be substantial in this high-risk postdischarge setting.Item Open Access Rehabilitation Intervention in Older Patients With Acute Heart Failure With Preserved Versus Reduced Ejection Fraction.(JACC. Heart failure, 2021-10) Mentz, Robert J; Whellan, David J; Reeves, Gordon R; Pastva, Amy M; Duncan, Pamela; Upadhya, Bharathi; Nelson, M Benjamin; Chen, Haiying; Reed, Shelby D; Rosenberg, Paul B; Bertoni, Alain G; O'Connor, Christopher M; Kitzman, Dalane WObjectives
This study assessed for treatment interactions by ejection fraction (EF) subgroup (≥45% [heart failure with preserved ejection fraction (HFpEF); vs <45% [heart failure with reduced ejection fraction (HFrEF)]).Background
The REHAB-HF trial showed that an early multidomain rehabilitation intervention improved physical function, frailty, quality-of-life, and depression in older patients hospitalized with acute decompensated heart failure (ADHF).Methods
Three-month outcomes were: Short Physical Performance Battery (SPPB), 6-min walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ). Six-month end points included all-cause rehospitalization and death and a global rank of death, all-cause rehospitalization, and SPPB. Prespecified significance level for interaction was P ≤ 0.1.Results
Among 349 total participants, 185 (53%) had HFpEF and 164 (47%) had HFrEF. Compared with HFrEF, HFpEF participants were more often women (61% vs 43%) and had significantly worse baseline physical function, frailty, quality of life, and depression. Although interaction P values for 3-month outcomes were not significant, effect sizes were larger for HFpEF vs HFrEF: SPPB +1.9 (95% CI: 1.1-2.6) vs +1.1 (95% CI: 0.3-1.9); 6MWD +40 meters (95% CI: 9 meters-72 meters) vs +27 (95% CI: -6 meters to 59 meters); KCCQ +9 (2-16) vs +6 (-2 to 14). All-cause rehospitalization rate was nominally lower with intervention in HFpEF but not HFrEF [effect size 0.83 (95% CI: 0.64-1.09) vs 0.99 (95% CI: 0.74-1.33); interaction P = 0.40]. There were significantly greater treatment benefits in HFpEF vs HFrEF for all-cause death [interaction P = 0.08; intervention rate ratio 0.63 (95% CI: 0.25-1.61) vs 2.21 (95% CI: 0.78-6.25)], and the global rank end point (interaction P = 0.098) with benefit seen in HFpEF [probability index 0.59 (95% CI: 0.50-0.68)] but not HFrEF.Conclusions
Among older patients hospitalized with ADHF, compared with HFrEF those with HFpEF had significantly worse impairments at baseline and may derive greater benefit from the intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).Item Open Access Relationship of physical function with quality of life in older patients with acute heart failure.(Journal of the American Geriatrics Society, 2021-07) Aladin, Amer I; Whellan, David; Mentz, Robert J; Pastva, Amy M; Nelson, M Benjamin; Brubaker, Peter; Duncan, Pamela; Reeves, Gordon; Rosenberg, Paul; Kitzman, Dalane WBackground
Older patients with acute decompensated heart failure (ADHF) have severely impaired physical function (PF) and quality of life (QOL). However, relationships between impairments in PF and QOL are unknown but are relevant to clinical practice and trial design.Methods
We assessed 202 consecutive patients hospitalized with ADHF in the multicenter Rehabilitation Therapy in Older Acute HF Patients (REHAB-HF) Trial. PF measures included Short Physical Performance Battery (SPPB) and 6-min walk distance (6MWD). Disease-specific QOL was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). General QOL was assessed by the Short Form-12 (SF-12) and EuroQol-5D-5L. PF was evaluated as a predictor of QOL using stepwise regression adjusted for age, sex, race, and New York Heart Association class.Results
Participants were 72 ± 8 years, 54% women, 55% minority race, 52% with reduced ejection fraction, and body mass index 33 ± 9 kg/m2 . Participants had severe impairments in PF (6MWD 185 ± 99 m, SPPB 6.0 ± 2.5 units) and disease-specific QOL (KCCQ Overall Score 41 ± 21 and Physical Score 47 ± 24) and general QOL (SF-12 Physical Score 28 ± 9 and EuroQol Visual Analog Scale 57 ± 23). There were modest, statistically significant correlations between 6MWD and KCCQ Overall, KCCQ Physical Limitation, and SF-12 Physical Scores (r = 0.23, p < 0.001; r = 0.30, p < 0.001; and r = 0.24, p = 0.001, respectively); and between SPPB and KCCQ Physical and SF-12 Physical Scores (r = 0.20, p = 0.004, and r = 0.19, p = 0.007, respectively). Both 6MWD and SPPB were correlated with multiple components of the EuroQol-5D-5L. 6MWD was a significant, weak predictor of KCCQ Overall Score and SF-12 Physical Score (estimate = 0.05 ± 0.01, p < 0.001 and estimate = 0.05 ± 0.02, p = 0.012, respectively). SPPB was a significant, weak predictor of KCCQ Physical Score and SF-12 Physical Score (estimate = 1.37 ± 0.66, p = 0.040 and estimate = 0.54 ± 0.25, p = 0.030, respectively).Conclusion
In older, hospitalized ADHF patients, PF and QOL are both severely impaired but are only modestly related, suggesting that PF and QOL provide complementary information and assessment of both should be considered to fully assess clinically meaningful patient-oriented outcomes.Item Open Access Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial.(Lancet, 2024-08-24) Deanfield, John; Verma, Subodh; Scirica, Benjamin M; Kahn, Steven E; Emerson, Scott S; Ryan, Donna; Lingvay, Ildiko; Colhoun, Helen M; Plutzky, Jorge; Kosiborod, Mikhail N; Hovingh, G Kees; Hardt-Lindberg, Søren; Frenkel, Ofir; Weeke, Peter E; Rasmussen, Søren; Goudev, Assen; Lang, Chim C; Urina-Triana, Miguel; Pietilä, Mikko; Lincoff, A Michael; SELECT Trial InvestigatorsBACKGROUND: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. METHODS: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. FINDINGS: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. INTERPRETATION: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. FUNDING: Novo Nordisk.Item Open Access The Association Between Beta-blocker and Renin-Angiotensin System Inhibitor Use After Heart Failure With Reduced Ejection Fraction Hospitalization and Outcomes in Older Patients.(Journal of cardiac failure, 2023-04) Gilstrap, Lauren; Solomon, Nicole; Chiswell, Karen; James O'Malley, A; Skinner, Jonathan S; Fonarow, Gregg C; Bhatt, Deepak L; Yancy, Clyde W; Devore, Adam DIntroduction
Beta-blockers (BB) and renin-angiotensin system inhibitors (RASi) are foundational for the treatment of heart failure with reduced ejection fraction (HFrEF). However, given the increased risk of side effects in older patients, uncertainty remains as to whether, on net, older patients benefit as much as the younger patients studied in trials.Methods and results
Using the Get With The Guidelines-Heart Failure registry linked with Medicare data, overlap propensity weighted Cox proportional hazard models were used to examine the association between BB and RASi use at hospital discharge and 30-day and 1-year outcomes among patients with HFrEF. Among the 48,711 patients (aged ≥65 years) hospitalized with HFrEF, there were significant associations between BB and/or RASi use at discharge and lower rates of 30-day and 1-year mortality, including those over age 85 (30-day hazard ratio 0.56, 95% confidence interval 0.45-0.70; 1-year hazard ratio 0.69, 95% confidence interval 0.61-0.78). In addition, the magnitude of benefit associated with BB and/or RASi use after discharge did not decrease with advancing age. Even among the oldest patients, those over age 85, with hypotension, renal insufficiency or frailty, BB and/or RASi use at discharge was still associated with lower 1-year mortality or readmission.Conclusions
Among older patients hospitalized with HFrEF, BB and/or RASi use at discharge is associated with lower rates of 30-day and 1-year mortality across all age groups and the magnitude of this benefit does not seem to decrease with advancing age. These data suggest that, absent a clinical contraindication, BB and RASi should be considered in all patients hospitalized with HFrEF before or at hospital discharge, regardless of age.Item Open Access The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes.(Clinical epigenetics, 2022-12) Jiang, Rong; Hauser, Elizabeth R; Kwee, Lydia Coulter; Shah, Svati H; Regan, Jessica A; Huebner, Janet L; Kraus, Virginia B; Kraus, William E; Ward-Caviness, Cavin KBackground
Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures.Methods
We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach.Results
PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065).Conclusions
Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks.Item Open Access Ultrafiltration in Acute Heart Failure: Implications of Ejection Fraction and Early Response to Treatment From CARRESS-HF.(Journal of the American Heart Association, 2020-12-08) Fudim, Marat; Brooksbank, Jeremy; Giczewska, Anna; Greene, Stephen J; Grodin, Justin L; Martens, Pieter; Ter Maaten, Jozine M; Sharma, Abhinav; Verbrugge, Frederik H; Chakraborty, Hrishikesh; Bart, Bradley A; Butler, Javed; Hernandez, Adrian F; Felker, G Michael; Mentz, Robert JBackground Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (≤40% or >40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (≤24 hours) response to ultrafiltration. Cox-proportional hazards models were used to identify associations between fluid removal <24 hours and composite of death, hospitalization, or unscheduled outpatient/emergency department visit during study follow-up. The intention-to-treat analysis included 93 patients. Within 24 hours, median fluid removal was 1.89 L (Q1, Q3: 1.22, 3.16). The high fluid removal group had a greater urine output (9.08 versus 6.23 L, P=0.027) after 96 hours. Creatinine change from baseline to 96 hours was similar in both groups (0.10 mg/dL increase, P=0.610). The EF >40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy.