Nancy K. Sweitzer

Prognostic Importance of Impaired Systolic Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone

Background— Impairment in left ventricular systolic function has been described in heart failure (HF) with preserved ejection fraction (HFpEF), but its prognostic relevance is not known. We determined whether left ventricular longitudinal strain (LS) is predictive of cardiovascular outcomes in HFpEF beyond clinical and conventional echocardiographic measures. Methods and Results— LS was assessed by 2-dimensional speckle-tracking echocardiography at baseline in 447 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. At a median follow-up of 2.6 years (interquartile range, 1.5–3.9 years), 115 patients experienced the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Impaired LS, defined as an absolute LS <15.8%, was present in 52% of patients and was predictive of the composite outcome (adjusted hazard ratio, 2.14; 95% confidence interval, 1.26–3.66; P=0.005), cardiovascular death alone (adjusted hazard ratio, 3.20; 95% confidence interval, 1.44–7.12; P=0.004), and HF hospitalization alone (adjusted hazard ratio, 2.23; 95% confidence interval, 1.16–4.28; P=0.016) after adjustment for clinical and conventional echocardiographic variables. LS was the strongest echocardiographic predictor of the composite outcome. Exploratory analysis in a subset of 131 patients with follow-up LS assessed after 12 to 18 months demonstrated a trend toward improvement in LS associated with spironolactone in patients enrolled in the Americas but not in Russia or Georgia. Conclusions— Impaired left ventricular systolic function is a powerful predictor of HF hospitalization, cardiovascular death, or aborted cardiac arrest in HFpEF independent of clinical predictors. Impaired LS represents a novel imaging biomarker to identify patients with HFpEF at particularly high risk for cardiovascular morbidity and mortality. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Advanced (stage D) heart failure: A statement from the heart failure society of america guidelines committee

We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patients wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure.

Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction

AIMSnWhile mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone.nnnMETHODS AND RESULTSnWe assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome (P = 0.046) and for heart failure hospitalization (P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30).nnnCONCLUSIONnIn patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum.nnnCLINICALTRIALSGOV NUMBERnNCT00094302.

Prognostic Relevance of Left Atrial Dysfunction in Heart Failure With Preserved Ejection Fraction

Background—Left atrial (LA) size is an established marker of risk for adverse outcomes in heart failure with preserved ejection fraction (HFpEF). However, the independent prognostic importance of LA function in HFpEF is not known. Methods and Results—We assessed LA function measured by speckle-tracking echocardiography in 357 patients with HFpEF enrolled in the Treatment Of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial who were in sinus rhythm at the time of echocardiography. Lower peak LA strain, indicating LA dysfunction, was associated with older age, higher prevalence of atrial fibrillation and left ventricular (LV) hypertrophy, worse LV and right ventricular systolic function, and worse LV diastolic function. At a mean follow-up of 31 months (interquartile range, 18–43months), 91 patients (25.5%) experienced the primary composite end point of cardiovascular death, HF hospitalization, and aborted sudden death. Lower peak LA strain was associated with a higher risk of the composite end point (hazard ratio, 0.96 per unit of reduction in strain; 95% confidence interval, 0.94–0.99; P=0.009) and of HF hospitalization alone (hazard ratio, 0.95 per unit of reduction in strain; 95% confidence interval, 0.92–0.98; P=0.003). The association of LA strain with incident HF hospitalization remained significant after adjustment for clinical confounders, but not after further adjustment for LV global longitudinal strain and the E/E′ ratio, parameters of LV systolic and diastolic function, respectively. Conclusions—LA dysfunction in HFpEF is associated with a higher risk of HF hospitalization independent of potential clinical confounders, but not independent of LV strain and filling pressure. Impairment in LV systolic and diastolic function largely explains the association between impaired LA function and higher risk of HF hospitalization in HFpEF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Prognostic Importance of Changes in Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone

Background—Limited data exist regarding the impact of aldosterone antagonist therapy on cardiac structure and function in heart failure with preserved ejection fraction and on the prognostic relevance of changes in cardiac structure and function in heart failure with preserved ejection fraction. Methods and Results—Cardiac structure and function were assessed by quantitative echocardiography at baseline and at 12- to 18-month follow-up in 239 patients with heart failure with preserved ejection fraction (left ventricular [LV] ejection fraction [LVEF] ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. The impact of spironolactone therapy on measures of cardiac structure and function was assessed in the study population overall, and change in echocardiographic measures was associated with the subsequent occurrence of the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. Spironolactone was not associated with alterations in cardiac structure and function compared with placebo. Decrease in left atrial volume at follow-up was associated with a lower risk of subsequent occurrence of the primary outcome. Conclusions—Twelve to 18 months of spironolactone therapy was not associated with alterations in cardiac structure or function in patients with heart failure with preserved ejection fraction. Reduction in left atrial volume at follow-up was associated with a lower risk of subsequent occurrence of the primary composite outcome. Clinical Trial Registration—URL: http:///www.clinicaltrials.gov. Unique identifier: NCT00094302.

Heart Failure in Non-Caucasians, Women, and Older Adults: A White Paper on Special Populations from the Heart Failure Society of America Guideline Committee

The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients.

Prognostic Value of Galectin-3 for Adverse Outcomes in Chronic Heart Failure

BACKGROUNDnClinical studies have suggested the prognostic value of galectin-3, a marker of fibrosis, in chronic heart failure. However, the specific role of galectin-3, compared with established biomarkers, remains uncertain.nnnMETHODS AND RESULTSnThe Penn Heart Failure Study was an ambulatory heart failure cohort that included 1385 participants with reduced (1141), preserved (106), and recovered (138) left ventricular ejection fraction (LVEF). Cox regression models determined the association between galectin-3 and risk of all-cause mortality, cardiac transplantation, or placement of a ventricular assist device. Receiver operating characteristic curves compared the prognostic accuracy of galectin-3, high-sensitivity soluble Toll-like receptor 2 (ST2), troponin I, and B-type natriuretic peptide (BNP) at 1 and 5 years. Higher galectin-3 levels were associated with an increased risk of adverse events (adjusted hazard ratio of 1.96 for each doubling in galectin-3; Pu2009<u2009.001). This association was most pronounced among participants with preserved LVEF (adjusted hazard ratio 3.30; Pu2009<u2009.001). At 5 years, galectin-3 was the most accurate discriminator of risk among participants with preserved LVEF (area under the curve 0.782; Pu2009=u2009.81 vs high-sensitivity ST2; Pu2009=u2009.029 vs troponin I; Pu2009=u2009.35 vs BNP). BNP was most accurate among participants with reduced and recovered LVEF (areas under the curves 0.716 and 0.728, respectively).nnnCONCLUSIONSnGalectin-3 could have prognostic value for long-term events among patients with heart failure and preserved ejection fraction.

Physical Activity and Prognosis in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial

Background: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized. Methods: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models. Results: The mean age at enrollment was 68.6±9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28–3.28; HR, 1.95; 95% CI, 1.15–3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16–3.22; HR, 1.84; 95% CI, 1.02–3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37–13.83; HR, 4.05; 95% CI, 1.17–14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44–6.02; HR, 2.05; 95% CI, 0.90–4.67) after multivariable adjustment for potential confounders. Conclusions: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.

Prognostic Importance of Temporal Changes in Resting Heart Rate in Heart Failure and Preserved Ejection Fraction: From the TOPCAT Study

OBJECTIVESnThe aim of this study was to examine the relationship between baseline heart rate (HR), change in HR from a preceding visit, and time-updated HR with subsequent outcomes in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial.nnnBACKGROUNDnHigher resting HR and increase in HR over time in patients with heart failure are associated with adverse outcomes. Whether these relationships between HR and prognosis are also observed in patients with HFpEF requires further assessment.nnnMETHODSnIn 1,767 patients enrolled in the TOPCAT trial from the Americas, the associations between baseline resting HR and change in HR from the preceding visit and clinical outcomes were examined using Cox proportional hazards models, along with the association between HR at each visit and outcome.nnnRESULTSnBoth baseline HR (adjusted hazard ratio: 1.08; 95% confidence interval: 1.04 to 1.12) and change in HR from the preceding visit (adjusted hazard ratio: 1.09; 95% confidence interval: 1.05 to 1.14; pxa0< 0.001 per 5 beats/min higher HR), after adjusting for covariates, were associated with a higher risk for the primary endpoint of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Time-updated resting HR at each visit was also associated with risk (adjusted hazard ratio: 1.11; 95% confidence interval: 1.07 to 1.15; pxa0< 0.001 per 5 beats/min higher HR). Furthermore, axa0risexa0in resting HR of approximately 10 beats/min, beginning approximately 10 days prior to the primary endpoint, wasxa0observed.nnnCONCLUSIONSnBaseline resting HR and change in HR over time predict outcomes in patients with HFpEF, as does time-updated HR during follow-up. These data suggest that frequent outpatient monitoring of HR, possibly with remote technologies, may identify patients with HFpEF who may be at increased risk for rehospitalization or death.

Effect of Heart Failure With Preserved Ejection Fraction on Nitric Oxide Metabolites.

Endothelial function may be deranged in heart failure with preserved ejection fraction (HFpEF). Serum NO-derived metabolites (NOm) might provide a biochemical surrogate of endothelial function in patients with heart failure (HF). We measured serum NOm in 415 participants in the Penn HF Study. Participants with HFpEF (nxa0= 82) and those whose EF had recovered (Recovered-HF, nxa0= 125) were matched 1:1 to heart failure with reduced ejection fraction (HFrEF) participants based on age, gender, race, tobacco use, and eGFR. Serum NOm levels were quantified after chemical reduction coupled with gas-phase chemiluminescence detection. After adjustment for matching covariates and BMI, HFpEF (34.5 μM; interquartile range [IQR] 25.0, 51.5) participants had lower NOm levels than HFrEF (41.0 μM; IQR 28.3, 58.0; ratio of HFpEF:HFrEF 0.82, 95% confidence interval [CI] 0.67 to 0.99; pxa0= 0.04), which further decreased when adjusted for covariates that affect endothelial function (ratio 0.79, 95% CI 0.65 to 0.98; pxa0= 0.03). There were no differences between HFrEF (34.0; IQR 25.3, 49.0) and matched Recovered-HF (36.0 μM; IQR 25.0, 55.0) or HFpEF and Recovered-HF. Age (+21%/10-year increase, p <0.001) and black race (-28%, pxa0= 0.03) associated with NOm in HFpEF, whereas age (+11%/10-year increase, pxa0= 0.03), current tobacco use (+67%, pxa0= 0.01), and eGFR (pxa0= 0.01) associated with NOm in Recovered-HF. In conclusion, HFpEF participants have reduced NOm compared with HFrEF in this matched cohort. This might suggest either compromised endothelial function or poor dietary intake. Black race was associated with lower NOm in HFpEF.