In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).

Cardiogenic shock is a high-acuity, potentially complex, and hemodynamically diverse state of end-organ hypoperfusion that is frequently associated with multisystem organ failure. Despite improving survival in recent years, patient morbidity and mortality remain high, and there are few evidence-based therapeutic interventions known to clearly improve patient outcomes. This scientific statement on cardiogenic shock summarizes the epidemiology, pathophysiology, causes, and outcomes of cardiogenic shock; reviews contemporary best medical, surgical, mechanical circulatory support, and palliative care practices; advocates for the development of regionalized systems of care; and outlines future research priorities. Cardiogenic shock (CS) is a low-cardiac-output state resulting in life-threatening end-organ hypoperfusion and hypoxia.1,2 Acute myocardial infarction (MI) with left ventricular (LV) dysfunction remains the most frequent cause of CS. 1,3 Advances in reperfusion therapy have been associated with improvements in survival, but significant regional disparities in evidence-based care have been reported, and in-hospital mortality remains high (27%-51%).1,4-9 Management recommendations are distributed between disease-specific statements and guidelines, and a dedicated and comprehensive clinical resource in this area is lacking. Thus, consolidating the evidence to define contemporary best medical and surgical CS practices for both MI-associated CS and other types of CS may be an important step in knowledge translation to help attenuate disparities in evidence-based care.Regional systems of care coupled with treatment algorithms have improved survival in high-acuity time-sensitive conditions such as MI, out-of-hospital cardiac arrest (OHCA), and trauma.10-12 Applying a similar framework to CS management may lead to similar improvements in survival, and CS systems of care are emerging within existing regional cardiovascular emergency care networks; however, guidance from a national expert group on structure and systems of care has not been available. 13,14 Accordingly, the purposes of this American Heart Association (AHA) scientific statement on CS are to summarize our contemporary understanding of the epidemiology, pathophysiology, and in-hospital best care practices into a single clinical resource document; to suggest a stepwise management algorithm that integrates medical, surgical, and mechanical circulatory support (MCS) therapies; and to propose a Mission: Lifelinesupported pathway for the development of integrated regionalized CS systems of care. DEFINITION OF CSAcute cardiac hemodynamic instability may result from disorders that impair function of the myocardium, valves, conduction system, or pericardium, either in isolation HISTORICAL PERSPECTIVESBefore the routine use of early revascularization, MIassociated CS had an in-hospital mortality exceeding 80%. A registry trial of 250 patients with acute MI described the association between bedside physical examination (Killip classification) for the as...

Background— Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas). Methods and Results— To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P <0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. Conclusions— This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00094302.

NCT00094302.

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone–system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78–0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76–0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77–0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81–0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Background Impairment in left ventricular (LV) systolic function has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic relevance is not known. We determined whether LV longitudinal strain (LS) is predictive of cardiovascular (CV) outcomes in HFpEF beyond clinical and conventional echocardiographic measures. Methods and Results LS was assessed by 2D speckle-tracking echocardiography at baseline in 447 HFpEF patients enrolled in the Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. At a median follow-up of 2.6 (IQR 1.5–3.9) years, 115 patients experienced the primary composite outcome of CV 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 HR 2.14, 95% CI 1.26–3.66; p=0.005), CV death alone (adjusted HR 3.20, 95% CI 1.44–7.12; p=0.004), and HF hospitalization alone (adjusted HR 2.23, 95% CI 1.16–4.28; p=0.016) after adjusting 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 12–18 months demonstrated a trend towards improvement in LS associated with spironolactone in patients enrolled in the Americas but not in Russia or Georgia. Conclusions Impaired LV systolic function is a powerful predictor of HF hospitalization, CV death, or aborted cardiac arrest in HFpEF, independent of clinical predictors. Impaired LS represents a novel imaging biomarker to identify HFpEF patients at particularly high risk for CV morbidity and mortality. Clinical Trial Registration Information Clinicaltrials.gov. Identifier NCT00094302.

Background Soluble ST2 reflects activity of an IL-33 dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results We determined the association between ST2 level and risk of death or transplantation in a multi-center prospective cohort of 1,141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic (ROC) analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2>36.3ng/ml) had a markedly increased risk of adverse outcomes compared to the lowest tertile (ST2≤22.3ng/ml), with an unadjusted hazard ratio (HR) of 3.2 (95%CI:2.2-4.7;p<0.0001) that remained significant after multivariable adjustment (adjusted HR 1.9[95%CI:1.3-2.9];p=0.002). In ROC analyses, the area under the curve (AUC) for ST2 was 0.75 (95%CI:0.69-0.79), which was similar to NT-proBNP (AUC 0.77 [95%CI:0.72-0.81];p=0.24 versus ST2), but lower than the Seattle Heart Failure Model (SHFM; AUC 0.81 ([95%CI:0.77-0.85];p=0.014 versus ST2). Addition of ST2 and NT-proBNP to the SHFM reclassified 14.9% of patients into more appropriate risk categories (p=0.017). Conclusions ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

Background-Unexplained left ventricular hypertrophy (LVH) is considered diagnostic of hypertrophic cardiomyopathy (HCM) but fails to identify all genetically affected individuals. Altered diastolic function has been hypothesized to represent an earlier manifestation of HCM before the development of LVH; however, data regarding the clinical utility of imaging techniques that assess this parameter are limited. Methods and Results-Echocardiographic studies including Doppler tissue imaging (DTI) were performed in a genotypedHCM population with ␤-myosin heavy chain (␤-MHC) mutations. Genotype (ϩ) individuals with LVH (Gϩ/LVHϩ; nϭ18) and genotype (ϩ) individuals without LVH (Gϩ/LVHϪ; nϭ18) were compared with normal control subjects (nϭ36). Left ventricular ejection fraction (EF) was significantly higher in both genotype (ϩ) groups (75Ϯ5% and 71Ϯ6%, respectively, versus 64Ϯ5% in control subjects; PϽ0.0001). Mean early diastolic myocardial velocities (Ea) were significantly lower in both genotype (ϩ) subgroups, irrespective of LVH (PϽ0.02). However, there was substantial overlap in Ea velocities between the Gϩ/LVHϪ and control groups. An Ea velocity of Յ13.5 cm/s had 86% specificity and 75% sensitivity for identifying genotype-positive subjects. The combination of EF Ն68% and Ea velocity Ͻ15 cm/s was 100% specific and 44% sensitive in predicting affected genotype. Conclusions-Abnormalities of diastolic function assessed by Doppler tissue imaging precede the development of LVH in individuals with HCM caused by ␤-MHC mutations. Although Ea velocity alone was not sufficiently sensitive as a sole diagnostic criterion, the combination of Ea velocity and EF was highly predictive of affected genotype in individuals without overt manifestations of HCM.