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The PARAGON-HF trial studied the effect of sacubitril/valsartan (Sac/Val) compared with valsartan (Val) on clinical outcomes in patients with chronic heart failure with preserved ejection fraction (HFpEF) or mildly reduced EF (HFmrEF). Further data are needed regarding the use of Sac/Val in these groups with EF and with recent worsening heart failure (WHF) events and in key populations not broadly represented in the PARAGON-HF trial, including those with de novo HF, the severely obese and Black patients. T he PARAGLIDE-HF trial is a multicenter, double-blind, randomized, controlled trial of Sac/Val vs Val that enrolled patients at 100 sites. Medically stable patients ≥ 18 years old with EF > 40%, amino terminal-pro B-type natriuretic peptide (NT-proBNP) levels ≥ 500 pg/mL and within 30 days of a WHF event were eligible for participation. Patients were randomly assigned 1:1 to Sac/Val vs Val. The primary efficacy endpoint is time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. Secondary endpoints include clinical outcomes during follow-up and additional biomarker assessments. Safety endpoints include symptomatic hypotension, worsening renal function and hyperkalemia. The trial enrolled 467 participants from June 2019 through October 2022 (52% women, 22% Black, age 70 ± 12 years, median (IQR) BMI 33 (27–40) kg/m2). The median (IQR) EF was 55% (50%–60%), 23% with HFmrEF (LVEF 41%–49%), 24% with EF > 60% and 33% with de novo HFpEF. Median screening NT-proBNP was 2009 (1291–3813) pg/mL, and 69% were enrolled in the hospital. The PARAGLIDE-HF trial enrolled a broad and diverse range of patients with heart failure with mildly reduced or preserved ejection fraction and will inform clinical practice by providing evidence about the safety, tolerability and efficacy of Sac/Val vs Val in those with a recent WHF event. • PARAGLIDE-HF is a randomized, controlled trial of sacubitril/valsartan vs valsartan that enrolled 467 participants with heart failure (52% women, 22% Black) and ejection fraction > 40% stabilized after a recent worsening heart failure event. • The primary efficacy endpoint was time-averaged proportional change in NT-proBNP from baseline through weeks 4 and 8; secondary endpoints included clinical outcomes during follow-up. • PARAGLIDE-HF enrolled a broad and diverse range of patients with heart failure with mildly reduced or preserved ejection fraction and will inform clinical practice by providing evidence on the safety, tolerability and efficacy of sacubitril/valsartan vs valsartan in those with a recent worsening heart failure event. [ABSTRACT FROM AUTHOR]

Acute Heart failure (AHF) is among the most frequent causes of hospitalization in the United States, contributing to substantial health care costs, morbidity, and mortality. Inpatient initiation of guideline-directed medical therapy (GDMT) is recommended for patients with heart failure with reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death or HF hospitalization. However, underutilization of GDMT prior to discharge is pervasive, representing a valuable missed opportunity to optimize evidence-based care. The PR agmatic Trial O f Messaging to P roviders about T reatment of A cute H eart F ailure tests the effectiveness of an electronic health record embedded clinical decision support system that informs providers during hospital management about indicated but not yet prescribed GDMT for eligible AHF patients with HFrEF. PR agmatic Trial O f Messaging to P roviders about T reatment of A cute H eart F ailureis an open-label, multicenter, pragmatic randomized controlled trial of 1,012 patients hospitalized with HFrEF. Eligible patients randomized to the intervention group are exposed to a tailored best practice advisory embedded within the electronic health record that alerts providers to prescribe omitted GDMT. The primary outcome is an increase in the proportion of additional GDMT medication classes prescribed at the time of discharge compared to those in the usual care arm. [ABSTRACT FROM AUTHOR]

The Surgical Treatment for Ischemic Heart Failure (STICH) trial found that routine use of coronary artery bypass surgery (CABG) improved mean quality of life (QoL) scores relative to guideline-directed medical therapy (GDMT) in patients with ischemic cardiomyopathy. However, mean differences in QoL scores do not provide what patients want to know when facing a high-risk/high-benefit treatment choice. We analyzed Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary scores in CABG and GDMT patients over 36 months using a combination of statistical methods to group QoL data into clinically relevant outcome patterns (phenotype trajectories) and to then identify the main baseline predictors of each phenotype. QoL outcome phenotypes were developed using mixture models to define the dominant phenotype trajectories present in STICH QoL data. Logistic regression models were used to predict each patient's probability of achieving each outcome pattern with each treatment. In STICH, 592 patients underwent CABG and 607 were managed with GDMT. Our analyses identified 3 phenotype trajectory patterns in both treatment groups. Two of the 3 trajectories showed improving patterns, and were classified as "good QoL trajectories," seen in 498 (84.1%) CABG and 449 (73.9%) GDMT patients. Defining a consequential CABG-GDMT treatment difference as a >10% higher absolute predicted probability of belonging to good QoL trajectories, 277 (23.5%) patients were more likely to have good outcome with CABG while 45 (3.8%) patients were more likely to have a good outcome with GDMT. For 644 (54.7%) patients, CABG and GDMT probabilities of a good outcome were within 5% of each other. The pattern of QoL outcomes after CABG compared with GDMT in STICH followed 3 main phenotypic trajectories, which could be predicted based on individual baseline features. Patient-specific predictions about expected QoL outcomes with different treatment choices provide an intuitive framework for personalizing patient decision making. [ABSTRACT FROM AUTHOR]

Background: Death ascertainment can be challenging for pragmatic clinical trials that limit site follow-up activities to usual clinical care.Methods and Results: We used blinded aggregate data from the ongoing ToRsemide comparison with furoSemide FOR Management of Heart Failure (TRANSFORM-HF) pragmatic clinical trial in patients with heart failure to evaluate the agreement between centralized call center death event identification and the United States National Death Index (NDI). Of 2284 total patients randomized through April 12, 2021, 1480 were randomized in 2018-2019 and 804 in 2020-2021. The call center identified 416 total death events (177 in 2018-2019 and 239 in 2020-2021). The NDI 2018-2019 final file identified 178 death events, 165 of which were also identified by the call center. The study's inter-rater reliability metric (Cohen's kappa coefficient, 0.920; 95% confidence interval, 0.889-0.951) demonstrates a high level of agreement. The time between a death event and its identification was less for the call center (median, 47 days; interquartile range, 11-103 days) than for the NDI (median, 270 days; interquartile range, 186-391 days).Conclusions: There is substantial agreement between deaths identified by a centralized call center and the NDI. However, the time between a death event and its identification is significantly less for the call center. [ABSTRACT FROM AUTHOR]

Heart failure with reduced ejection fraction (HFrEF) is one of the most common chronic illnesses in the United States and carries significant risk of morbidity and mortality. Use of guideline-directed medical therapy (GDMT) for patients with HFrEF has been shown to dramatically improve outcomes, but adoption of these treatments remains generally low. Possible explanations for poor GDMT uptake include lack of knowledge about recommended management strategies and provider reluctance due to uncertainties regarding application of said guidelines to real-world practice. One way to overcome these barriers is by harnessing the electronic health record (EHR) to create patient-centered "best practice alerts" (BPAs) that can guide clinicians to prescribe appropriate medical therapies. If found to be effective, these low-cost interventions can be rapidly applied across large integrated healthcare systems. The PRagmatic Trial Of Messaging to Providers about Treatment of Heart Failure (PROMPT-HF) trial is a pragmatic, cluster randomized controlled trial designed to test the hypothesis that tailored and timely alerting of recommended GDMT in heart failure (HF) will result in greater adherence to guidelines when compared with usual care. PROMPT-HF has completed enrollment of 1,310 ambulatory patients with HFrEF cared for by 100 providers who were randomized to receive a BPA vs usual care. The BPA alerted providers to GDMT recommended for their patients and displayed current left ventricular ejection fraction (LVEF) along with the most recent blood pressure, heart rate, serum potassium and creatinine levels, and estimated glomerular filtration rate. It also linked to an order set customized to the patient that suggests medications within each GDMT class not already prescribed. Our goal is to examine whether tailored EHR-based alerting for outpatients with HFrEF will lead to higher rates of GDMT at 30 days post randomization when compared with usual care. Additionally, we are assessing clinical outcomes such as hospital readmissions and death between the alert versus usual care group. Trial Registration: Clinicaltrials.gov NCT04514458. [ABSTRACT FROM AUTHOR]

Background and Objective: Few data exist on trends in acute myocardial infarction (AMI) patterns spanning recent epidemiological shifts in low middle-income countries (LMICs). To understand temporal disease patterns of AMI characteristics and outcomes between 1988--2018, we used digitized legacy clinical data at a large tertiary care centre in Pakistan. Methods: We reviewed digital health information capture systems maintained across the Aga Khan University Hospital and obtained structured elements to create a master dataset. We included index admissions of patients >18 years that were discharged between January 1, 1988, and December 31, 2018, with a primary discharge diagnosis of AMI (using ICD-9 diagnoses). The outcome evaluated was in-hospital mortality. Clinical characteristics derived from the electronic database were validated against chart review in a random sample of cases (k 0.53--1.00). Results: The final population consisted of 14,601 patients of which 30.6% (n = 4,470) were female, 52.4% (n = 7,651) had ST elevation MI and 47.6% (n = 6,950) had non- ST elevation MI. The median (IQR) age at presentation was 61 (52--70) years. Overall unadjusted in-hospital mortality was 10.3%. Across the time period, increasing trends were noted for the following characteristics: age, proportion of women, prevalence of hypertension, diabetes, proportion with NSTEMI (all ptrend < 0.001). In-hospital mortality rates declined significantly between 1988--1997 and 2008--2018 (13.8% to 9.2%, p < 0.001). Conclusions: The patterns of AMI have changed over the last three decades with a concomitant decline in in-hospital mortality at a tertiary care centre in Pakistan. Clinical digitized data presents a unique opportunity for gaining insights into disease patterns in LMICs. [ABSTRACT FROM AUTHOR]

Background: It remains unclear why depression is associated with adverse outcomes in patients with heart failure (HF). We examine the relationship between depression and clinical outcomes among patients with HF with reduced ejection fraction managed with guideline-directed medical therapy (GDMT).Methods and Results: Using the GUIDE-IT trial, 894 patients with HF with reduced ejection fraction were stratified according to a history of depression, and Cox proportional hazards regression modeling was used to examine the association with outcomes. There were 140 patients (16%) in the overall cohort who had depression. They tended to be female (29% vs 46%, P < .001) and White (67% vs 53%, P = .002). There were no differences in GDMT rates at baseline or at 90 days; nor were there differences in target doses of these therapies achieved at 90 days (NS, all). amino-terminal pro-B-type natriuretic peptide levels at all time points were similar between the cohorts (P > .05, all). After adjustment, depression was associated with all-cause hospitalizations (hazard ratio, 1.42, 95% confidence interval 1.11-1.81, P < .01), cardiovascular death (hazard ratio, 1.69, 95% confidence interval 1.07-2.68, P = .025), and all-cause mortality (hazard ratio, 1.54, 95% confidence interval 1.03-2.32, P = .039).Conclusions: Depression impacts clinical outcomes in HF regardless of GDMT intensity and amino-terminal pro-B-type natriuretic peptide levels. This finding underscores the need for a focus on mental health in parallel to achievement of optimal GDMT in these patients.Trial Registration: NCT01685840, https://clinicaltrials.gov/ct2/show/NCT01685840. [ABSTRACT FROM AUTHOR]

BACKGROUND: The TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) found no significant difference in all-cause mortality or hospitalization among patients randomized to a strategy of torsemide versus furosemide following a heart failure (HF) hospitalization. However, outcomes and responses to some therapies differ by left ventricular ejection fraction (LVEF). Thus, we sought to explore the effect of torsemide versus furosemide by baseline LVEF and to assess outcomes across LVEF groups. METHODS: We compared baseline patient characteristics and randomized treatment effects for various end points in TRANSFORM-HF stratified by LVEF: HF with reduced LVEF, ≤40% versus HF with mildly reduced LVEF, 41% to 49% versus HF with preserved LVEF, ≥50%. We also evaluated associations between LVEF and clinical outcomes. Study end points were all-cause mortality or hospitalization at 30 days and 12 months, total hospitalizations at 12 months, and change from baseline in Kansas City Cardiomyopathy Questionnaire clinical summary score. RESULTS: Overall, 2635 patients (median 64 years, 36% female, 34% Black) had LVEF data. Compared with HF with reduced LVEF, patients with HF with mildly reduced LVEF and HF with preserved LVEF had a higher prevalence of comorbidities. After adjusting for covariates, there was no significant difference in risk of clinical outcomes across the LVEF groups (adjusted hazard ratio for 12-month all-cause mortality, 0.91 [95% CI, 0.59–1.39] for HF with mildly reduced LVEF versus HF with reduced LVEF and 0.91 [95% CI, 0.70–1.17] for HF with preserved LVEF versus HF with reduced LVEF; P =0.73). In addition, there was no significant difference between torsemide and furosemide (1) for mortality and hospitalization outcomes, irrespective of LVEF group and (2) in changes in Kansas City Cardiomyopathy Questionnaire clinical summary score in any LVEF subgroup. CONCLUSIONS: Despite baseline demographic and clinical differences between LVEF cohorts in TRANSFORM-HF, there were no significant differences in the clinical end points with torsemide versus furosemide across the LVEF spectrum. There was a substantial risk for all-cause mortality and subsequent hospitalization independent of baseline LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296813. [ABSTRACT FROM AUTHOR]

The role of surgical ventricular reconstruction (SVR) in patients with ischemic cardiomyopathy is controversial. Observational series and the Surgical Treatment of IsChemic Heart failure (STICH) trial reported contradictory results. SVR is highly dependent on operator experience. The aim of this study is to compare the long-term results of SVR between a high-volume SVR institution and the STICH trial using individual patient data. Patients undergoing SVR at San Donato Hospital (Milan) were compared with patients undergoing SVR in STICH (as-treated principle) by inverse probability treatment-weighted Cox regression. The primary outcome was all-cause mortality. The San Donato cohort included 725 patients, whereas the STICH cohort included 501. Compared with the STICH-SVR cohort, San Donato patients were older (66.0, lower quartile, upper quartile [Q1, Q3: 58.0, 72.0] vs 61.9 [Q1, Q3: 55.1, 68.8], P <.001) and with lower left ventricular end-systolic volume index at baseline (LVESVI: 77.0 [Q1, Q3: 59.0, 97.0] vs 80.8 [Q1, Q3: 58.5, 106.8], P =.02). Propensity score weighting yielded 2 similar cohorts. At 4-year follow-up, mortality was significantly lower in the San Donato cohort compared with the STICH-SVR cohort (adjusted hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P =.001). Greater postoperative LVESVI was independently associated with mortality (hazard ratio, 1.02; 95% confidence interval, 1.01-1.03). At 4 to 6 months of follow-up, the mean reduction of LVESVI in the San Donato cohort was 39.6%, versus 10.7% in the STICH-SVR cohort (P <.001). Patients with postinfarction LV remodeling undergoing SVR at a high-volume SVR institution had better long-term results than those reported in the STICH trial, suggesting that a new trial testing the SVR hypothesis may be warranted. Visual summary of the study findings highlighting significantly better long-term results of SVR in an experienced center than those reported in the STICH trial, and its implications. SVR , Surgical ventricular reconstruction; STICH , Surgical Treatment for Ischemic Heart Failure trial; AHR , adjusted hazard ratio; CI , confidence interval. [Display omitted] [ABSTRACT FROM AUTHOR]

BACKGROUND: In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile. METHODS: PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mmHg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219). RESULTS: The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each). CONCLUSIONS: In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated. [ABSTRACT FROM AUTHOR]

Background: The evolution and clinical impact of cardiac remodeling after large ST-elevation myocardial infarction (STEMI) is not well delineated in the current therapeutic era.Methods: The PRESERVATION I trial longitudinally assessed cardiac structure and function in STEMI patients receiving primary percutaneous coronary intervention (PCI). Echocardiograms were performed immediately post-PCI and at 1, 3, 6 and 12 months after STEMI. The extent of cardiac remodeling was assessed in patients with ejection fraction (EF) ≤ 40% after PCI. Patients were stratified by the presence or absence of reverse remodeling, defined as an increase in end-diastolic volume (EDV) of ≤10 mL or decrease in EDV at 1 month, and evaluated for an association with adverse events at 1 year.Results: Of the 303 patients with large STEMI enrolled in PRESERVATION I, 225 (74%) had at least moderately reduced systolic function (mean EF 32 ± 5%) immediately after primary PCI. In the following year, there were significant increases in EF and LV volumes, with the greatest magnitude of change occurring in the first month. At 1 month, 104 patients (46%) demonstrated reverse remodeling, which was associated with a significantly lower rate of death, recurrent myocardial infarction and repeat cardiovascular hospitalization at 1 year (HR 0.44; 95% CI: 0.19-0.99).Conclusion: Reduced EF after large STEMI and primary PCI is common in the current therapeutic era. The first month following primary reperfusion is a critical period during which the greatest degree of cardiac remodeling occurs. Patients demonstrating early reverse remodeling have a significantly lower rate of adverse events in the year after STEMI. [ABSTRACT FROM AUTHOR]

Background: Diastolic dysfunction (DD) is common and occurs at an earlier age among human immunodeficiency virus-infected (HIV+) individuals, but the mechanisms and consequences of DD among HIV+ individuals are unclear.Methods and Results: The Characterization of Heart Function on Antiretroviral Therapy (CHART) study was a multicenter cross-sectional case-control study of treated and virally suppressed HIV+ individuals with (DD+) and without DD (DD-). All patients had normal ejection fraction (>50%), no significant valvular disease, and no history of coronary revascularization or persistent atrial fibrillation. Overall, 94 DD+ and 101 DD- patients were included. DD+ patients were older with higher body mass index (BMI) and more likely to have hypertension, renal dysfunction, and dyslipidemia. Groups were similar with respect to sex, race, CD4 count, and HIV RNA copies. N-terminal pro-B-type natriuretic peptide levels (median 36 [23, 85] vs 26 [12, 49] pg/mL, P < .01) and high-sensitivity troponin I (3.6 [2.6, 5.1] vs 2.5 [1.8, 3.5] pg/mL, P < .01) were higher among DD+ patients. The latter had similar left atrial size, but increased stiffness (conduit strain: 23.5 [17.5, 36.9] vs 30.0 [22.9, 37.0], P < .01) and impaired relaxation (reservoir strain: 39.7 [32.0, 58.0] vs 45.9 [37.0, 60.6], P = .04). On cardiac magnetic resonance, the prevalence of focal fibrosis was higher among DD+ patients (19.0% vs 5.3%, P < .01). DD+ patients demonstrated higher levels of carboxyl-terminal telopeptide of collagen type I (P = .04), and trends toward higher interleukin-6 and oxidized low-density lipoprotein levels (P ≤ .08). Kansas City Cardiomyopathy Questionnaire physical limitation (87.1±21.4 vs 93.1±18.1, P = .01) and symptom frequency scores were lower among DD+ patients (86.0±21.5 vs 92.5±16.8, P = .01).Conclusions: In this contemporary HIV+ population receiving antiretroviral therapy, DD was associated with multiple alterations in cardiac structure and function, including myocardial fibrosis and left atrial abnormalities, and worse quality of life. Further studies are needed to assess longitudinal changes in these parameters and their potential as therapeutic targets to prevent progressive cardiac remodeling and dysfunction in HIV. [ABSTRACT FROM AUTHOR]

Background: Although left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear.Methods and Results: We evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10%-22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P < .05 for all). At baseline, higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin I were independently associated with lower LA reservoir and contractile strain (Padjusted < .05 for all comparisons). Higher LA reservoir strain (β coefficient per 1-unit increase: -21.2, 95% CI: -38.8, -3.7; P = .02) was independently associated with reduction in NT-proBNP at 24 weeks.Conclusion: In HFpEF, LA myopathy is characterized by elevation in biomarkers of neurohormonal activation and myocardial necrosis. Lower LA function is associated with continued elevation in NT-proBNP over time, suggesting that LA myopathy is associated with persistent congestion in HFpEF. [ABSTRACT FROM AUTHOR]

Objective: To identify temporal trends in the use of exercise treadmill testing (ETT) and cardiorespiratory fitness (CRF) estimated by ETT in metabolic equivalents (METs).Patients and Methods: We compiled an ETT database of all available treadmill tests-including those with concomitant stress echocardiography and nuclear perfusion imaging studies-performed at Duke University Hospital from January 1, 1970- December 31, 2012. Six different ramp protocols were used in these combined modalities. CRF at maximal exertion was estimated using established metrics. Eligible patients were required to have no missing data on maximal treadmill speed, grade, and protocol.Results: The most commonly used ETT protocol was the Bruce (n = 28,877), followed by manual test (n = 7390). Since the 1980's, the use of ETT for clinical purposes declined substantially; there was a decreased trend in utilization of 9.4% over the decades 1990-1999 and 2000-2009. When standard protocol (Bruce) was assessed in isolation, trends in CRF decreased progressively from 1970 to 2012 (mean METs (standard deviation): 11.7 (4.3) to 10.5 (3.5)). After adjusting for baseline comorbidities, the trend was reduced to a lesser degree.Conclusions: The use of ETT at our institution has declined over time, perhaps due to changes in clinical practice. In patients undergoing ETT using the standard Bruce protocol, CRF decreased progressively over the last five decades. Future studies are needed to clarify the etiology of the decrease in use of such a powerful predictor of clinical outcomes in our medical care environment. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the association of MR severity and type with all-cause death in a large, real-world, clinical setting.Methods: We reviewed full echocardiography studies at Duke Echocardiography Laboratory (01/01/1995-12/31/2010), classifying MR based on valve morphology, presence of coronary artery disease, and left ventricular size and function. Survival was compared among patients stratified by MR type and baseline severity.Results: Of 93,007 qualifying patients, 32,137 (34.6%) had ≥mild MR. A total of 8094 (8.7%) had moderate/severe MR, which was primary myxomatous (14.1%), primary non-myxomatous (6.2%), secondary non-ischemic (17.0%), and secondary ischemic (49.4%). At 10 years, patients with primary myxomatous MR or MR due to indeterminate cause had survival rates of >60%; primary non-myxomatous, secondary ischemic, and non-ischemic MR had survival rates <50%. While mild (HR 1.06, 95% CI 1.03-1.09), moderate (HR 1.31, 95% CI 1.27-1.37), and severe (HR 1.55, 95% CI 1.46-1.65) MR were independently associated with all-cause death, the relationship of increasing MR severity with mortality varied across MR types (P ≤ .001 for interaction); the highest risk associated with worsening severity was seen in primary myxomatous MR followed by secondary ischemic MR and primary non-myxomatous MR.Conclusions: Although MR severity is independently associated with increased all-cause death risk for most forms of MR, the absolute mortality rates associated with worse MR severity are much higher for primary myxomatous, non-myxomatous, and secondary ischemic MR. The findings from this study support carefully defining MR by type and severity. [ABSTRACT FROM AUTHOR]

Objective: The aim of this work was to investigate determinants of structural myocardial abnormalities in persons living with human immunodeficiency virus (PLWH).Methods and Results: We reviewed archived transthoracic echocardiograms (TTEs) performed on PLWH at Duke University Medical Center from 2001 to 2012. The primary outcomes were presence of left ventricular hypertrophy (LVH) or diastolic dysfunction (DD). TTEs for 498 human immunodeficiency virus-infected persons were reviewed (median age 44 years, 38% female, 72% black, 34% with hypertension, 15% with diabetes). Among those with usable images, LVH was detected in 174 of 473 persons (37%) according to LV mass criteria and in 99 of 322 persons (31%) according to American Society of Echocardiography LV mass index criteria. Definite DD was detected in 18 of 224 persons (8%). LVH was more common in PLWH with a CD4 count ≤ 200 cells/mm3 proximal to TTE (adjusted OR 1.68, 95% CI 1.08-2.62), CD4 nadir ≤ 200 cells/mm3 (adjusted OR 1.63, 95% CI 1.04-2.54) and less common in persons with viral suppression (OR 0.46, 95% CI 0.27-0.80). Lower CD4 nadirs (P = .002) and proximal CD4 counts (P = .002) were also associated with DD.Conclusions: Persons with a history of advanced human immunodeficiency virus-associated immune suppression are at higher risk of LVH and DD than infected persons with preserved immune function. [ABSTRACT FROM AUTHOR]

Background: Left ventricular ejection fraction (LVEF) is used to select patients for primary prevention implantable cardioverter defibrillators (ICDs). The relationship between baseline and long-term follow-up LVEF and clinical outcomes among primary prevention ICD patients remains unclear.Methods: We studied 195 patients with a baseline LVEF ≤35% ≤6 months prior to ICD implantation and follow-up LVEF 1-3 years after ICD implantation without intervening left ventricular assist device (LVAD) or transplant. The co-primary study endpoints were: (1) a composite of time to death, LVAD, or transplant and (2) appropriate ICD therapy. We examined multivariable Cox proportional hazard models with a 3-year post-implant landmark view; the LVEF closest to the 3-year mark was considered the follow-up LVEF for analyses. Follow-up LVEF was examined using 2 definitions: (1) ≥10% improvement compared to baseline or (2) actual value of ≥40%.Results: Fifty patients (26%) had a LVEF improvement of ≥10% and 44 (23%) had a follow-up LVEF ≥40%. Neither baseline nor follow-up LVEF was significantly associated with the composite endpoint. In contrast, both baseline and follow-up LVEF were associated with risk for long-term ICD therapies, whether follow-up LVEF was modeled as a ≥10% absolute improvement (baseline LVEF HR 0.87, CI 0.91-0.93, P < .001; follow-up LVEF HR 0.18, CI 0.06-0.53, P = .002) or a ≥40% follow-up value (baseline LVEF HR 0.89, CI 0.83-0.96, P = .001, follow-up LVEF HR 0.26, CI 0.08-0.87, P = .03).Conclusions: Among primary prevention ICD recipients, both baseline and follow-up LVEF were independently associated with long-term risk for appropriate ICD therapy, but they were not associated with time to the composite of LVAD, transplant, or death. [ABSTRACT FROM AUTHOR]

Objective The authors aimed to assess determinants of intubation time and evaluate its impact on 30-day and 1-year postoperative survival in Surgical Treatment for Ischemic Heart Failure (STICH) trial patients. Design, Setting, Participants, and Interventions A multivariable Cox proportional hazards model was used among the 1,446 surgical patients from the STICH trial who survived 36 hours after operation, in order to identify perioperative factors associated with 30-day and 1-year postoperative mortality. A multivariable logistic regression model was used to determine risk factors associated with intubation time. Measurements and Main Results At 36 hours post-operation, 1,298 (out of 1,446) were extubated and 148 (10.2%) still intubated. Median postoperative intubation time was 11.4 hours. Among patients surviving 36 hours, a multivariable model was developed to predict 30-day (c-index = 0.88) and 1-year (c-index = 0.78) mortality. Intubation time was the strongest independent predictor of 30-day (hazard ratio [HR] 5.50) and 1-year mortality (HR 3.69). Predictors of intubation time >36 hours included mitral valve procedure, New York Heart Association class, left ventricular systolic volume index, creatinine, previous coronary artery bypass grafting (CABG), and age. Results were similar in patients surviving 24 hours post-operation, where intubation time was also the strongest predictor of 30-day (HR 4.18, c-index 0.87) and 1-year (HR 2.81, c-index 0.78) mortality. Conclusions Intubation time is the strongest predictor of 30-day and 1-year mortality among patients with ischemic heart failure undergoing CABG. Combining intubation time with other mortality risk factors may allow the identification of patients at the highest risk for whom the development of specific strategies may improve outcomes. [ABSTRACT FROM AUTHOR]

Objective: The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF.Background: Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF.Methods: PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia.Conclusion: The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) has been associated with a shift in the epidemiology of human immunodeficiency virus (HIV)-associated cardiomyopathy from a phenotype of primarily left ventricular (LV) systolic dysfunction to LV diastolic dysfunction (DD). Patients with HIV receiving ART have higher rates of DD compared with age-matched control subjects and develop DD at a younger age. However, little is known about the natural history and pathogenesis of DD in virally suppressed HIV-infected patients. Current evidence suggests that immune processes modulate the risk for cardiac involvement in HIV-infected persons. Ongoing inflammation appears to have myocardial effects, and accelerated myocardial fibrosis appears to be a key mediator of HIV-induced DD. The Characterizing Heart Function on Antiretroviral Therapy (CHART) study aims to systematically investigate determinants, mechanisms, and consequences of DD in HIV-infected patients. We will compare ART-treated virally suppressed HIV-infected individuals with and without DD and HIV- individuals with DD regarding (1) systemic inflammation, myocardial stress, and subclinical myocardial necrosis as indicated by circulating biomarkers; (2) immune system activation as indicated by cell surface receptors; (3) myocardial fibrosis according to cardiac magnetic resonance examination; (4) markers of fibrosis and remodeling, oxidative stress, and hypercoagulability; (5) left atrial function according to echocardiographic examination; (6) myocardial stress and subclinical necrosis as indicated by circulating biomarkers; (7) proteomic and metabolic profiles; and (8) phenotype signatures derived from clinical, biomarker, and imaging data. [ABSTRACT FROM AUTHOR]

Background: Evidence continues to demonstrate increasing prevalence, cost, and mortality implications of heart failure with preserved ejection fraction (HFpEF), but clearly defined parameters that distinguish between control subjects and HFpEF have not been established.Objectives: This study was designed to detect differences in markers associated with Ventricular-arterial coupling and HFpEF when comparing matched case and control groups.Methods: A study cohort of case (incident patients with HFpEF; n = 155) and matched control (patients with no prior heart failure; n = 155) groups was retrospectively identified. Matching criteria included race, sex, age, and date of echocardiography (within 1 year). Physiologic and echocardiographic markers were collected from previously acquired transthoracic echocardiograms. These echocardiographic images were reanalyzed, and measures of ventricular-arterial coupling were calculated. Using conditional logistic regression and controlling for covariates, models were fitted to detect differences in HFpEF markers between case and control subjects.Results: Statistically significant differences in markers that reflect ventricular elastance (Ees; P = .007) and left atrial diameter (LAdiam; P = .04) were detected when comparing the case and control groups. Conditional logistic regression analyses suggested a 40% higher odds of being in the case group with every 1-unit increase in Ees (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.10-1.79) and a 2.92 times higher odds of being in the case group for every 1 cm increase in LAdiam (OR 2.92, 95% CI 1.064-7.994).Conclusions: Ees and LAdiam are easily measurable echocardiographic markers that may have a role in identifying and tracking the progression toward incident HFpEF without increasing cost or risk to the patient. Prospective studies are indicated to explore the use of Ees and LAdiam as predictors of impending HFpEF. [ABSTRACT FROM AUTHOR]

Background Coronary computed tomography angiography (CTA) and functional testing strategies for stable chest pain yield similar outcomes; one aspect that may guide test choice is safety. Methods We compared test safety (test complications, incidental findings, and effective radiation dose) between CTA and functional testing as-tested in PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain). In the subgroup whose physicians intended nuclear stress over other functional tests if randomized to the functional arm, we compared radiation dose of CTA versus nuclear stress and identified characteristics associated with dose. Results Of 9470 patients, none had major and <1% had minor complications (CTA: 0.8% [37/4633] vs. functional: 0.6% [27/4837]). CTA identified more incidental findings (11.6% [539/4633] vs. 0.7% [34/4837], p < 0.001), most commonly pulmonary nodules (9.4%, 437/4633). CTA had similar 90-day cumulative radiation dose to functional testing. However, in the subgroup whose physicians intended nuclear stress (CTA 3147; nuclear 3203), CTA had lower median index test (8.8 vs. 12.6 mSv, p < 0.001) and 90-day cumulative (11.6 vs. 13.1 mSv, p < 0.001) dose, independent of patient characteristics. The lowest nuclear doses employed 1-day Tc-99m protocols (12.2 mSv). The lowest CTA doses were at sites performing ≥500 CTAs/year (6.9 mSv) and with advanced (latest available) CT scanners (5.5 mSv). Conclusion Complications were negligibly rare for both CTA and functional testing. CTA detects more incidental findings. Compared to nuclear stress testing, CTA's lower radiation dose, independent of patient characteristics, makes it an attractive test choice. Radiation dose varies with imaging protocol, indicating opportunities to further reduce dose. (ClinicalTrials.gov number, NCT01174550 ). [ABSTRACT FROM AUTHOR]

Corresponding Author [ABSTRACT FROM AUTHOR]

Optimal medical therapy in patients with heart failure and coronary artery disease is associated with improved outcomes. However, whether this association is influenced by the performance of coronary artery bypass grafting is less well established. Thus, the aim of this study was to determine the possible relationship between coronary artery bypass grafting and optimal medical therapy and its effect on the outcomes of patients with ischemic cardiomyopathy. The Surgical Treatment for Ischemic Heart Failure trial randomized 1212 patients with coronary artery disease and left ventricular ejection fraction 35% or less to coronary artery bypass grafting with medical therapy or medical therapy alone with a median follow-up over 9.8 years. For the purpose of this study, optimal medical therapy was collected at baseline and 4 months, and defined as the combination of 4 drugs: angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, statin, and 1 antiplatelet drug. At baseline and 4 months, 58.7% and 73.3% of patients were receiving optimal medical therapy, respectively. These patients had no differences in important parameters such as left ventricular ejection fraction and left ventricular volumes. In a multivariable Cox model, optimal medical therapy at baseline was associated with a lower all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.66-0.91; P =.001). When landmarked at 4 months, optimal medical therapy was also associated with a lower all-cause mortality (hazard ratio, 0.82; 95% confidence interval, 0.62-0.99; P =.04). There was no interaction between the benefit of optimal medical therapy and treatment allocation. Optimal medical therapy was associated with improved long-term survival and lower cardiovascular mortality in patients with ischemic cardiomyopathy and should be strongly recommended. Kaplan–Meier rates of all-cause mortality by OMT 58.8% versus non-OMT 67.6%. P less than.001 at baseline in patients with CAD and ejection fraction 35% or less. OMT , Optimal medical therapy; STICH , Surgical Treatment for Ischemic Heart Failure; CAD , coronary artery disease; EF , ejection fraction. [Display omitted] [ABSTRACT FROM AUTHOR]

Background-The management of aortic stenosis rests on accurate echocardiographic diagnosis. Hence, it was chosen as a test case to examine the utility of continuous quality improvement (CQI) approaches to increase echocardiographic data accuracy and reliability. A novel, multistep CQI program was designed and prospectively used to investigate whether it could minimize the difference in aortic valve mean gradients reported by echocardiography when compared with cardiac catheterization. Methods and Results-The Duke Echo Laboratory compiled a multidisciplinary CQI team including 4 senior sonographers and MD faculty to develop a mapped CQI process that incorporated Intersocietal Accreditation Commission standards. Quarterly, the CQI team reviewed all moderate-or greater-severity aortic stenosis echocardiography studies with concomitant catheterization data, and deidentified individual and group results were shared at meetings attended by cardiologists and sonographers. After review of 2011 data, the CQI team proposed specific amendments implemented over 2012: the use of nontraditional imaging and Doppler windows as well as evaluation of aortic gradients by a second sonographer. The primary outcome measure was agreement between catheterization-and echocardiography-derived mean gradients calculated by using the coverage probability index with a prespecified acceptable echocardiography-catheterization difference of <10 mm Hg in mean gradient. Between January 2011 and January 2014, 2093 echocardiograms reported moderate or greater aortic stenosis. Among cases with available catheterization data pre-and post-CQI, the coverage probability index increased from 54% to 70% (P=0.03; 98 cases, year 2011; 70 cases, year 2013). The proportion of patients referred for invasive valve hemodynamics decreased from 47% pre-CQI to 19% post-CQI (P<0.001). Conclusions-A laboratory practice pattern that was amenable to reform was identified, and a multistep modification was designed and implemented that produced clinically valuable performance improvements. The new protocol improved aortic stenosis mean gradient agreement between echocardiography and catheterization and was associated with a measurable decrease in referrals of patients for invasive studies. [ABSTRACT FROM AUTHOR]

Background Although risk factors for heart failure are increasingly common worldwide, the contribution of atherosclerosis to heart failure in sub-Saharan Africa is largely unknown. Objective This study assessed the association between atherosclerotic risk factors and heart failure in a developing country. Methods We performed a case-control study of heart failure in rural Kenya. We assessed the risk factors for heart failure by using international criteria based on electrocardiogram (ECG), echocardiogram, physical examination findings, and laboratory testing. Atherosclerotic risk factors were determined by ECG, echocardiogram, ankle-brachial index (ABI), and lipid testing. We described the relationship of wall motion abnormalities on echocardiogram, ABI <0.9, and ischemic pattern on ECG with the presence of heart failure with multivariable logistic regression adjusting for age and sex and using adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Results There were 125 cases and 191 controls (n = 316); 49% were male. The mean age was 60 (SD = 13) years. Most patients had hypertension (53%), and 16% had human immunodeficiency virus infection. Lipids were in the normal range for all. Cases were older than controls (62 years vs. 58 years, respectively). The most common abnormality associated with heart failure was dilated cardiomyopathy. Ischemic heart failure was the second most common cause in men. Cases were more likely to have an ABI <0.9 (46% vs. 31%; AOR: 1.99; 95% CI: 1.19 to 3.32), ischemia or infarct on ECG (68% vs. 43%; AOR: 3.01; 95% CI: 1.43 to 6.34), and wall motion abnormalities on echocardiogram (54% vs. 15%; AOR: 7.00; 95% CI: 3.95 to 12.39). Conclusions Ischemic heart failure is more common in Kenya than previously recognized. Noninvasive markers of atherosclerosis are routinely found among patients with heart failure. Treatment and prevention of heart failure in sub-Saharan Africa must consider many causes including those related to atherosclerosis. [ABSTRACT FROM AUTHOR]

Objectives This study sought to test the hypothesis that end-systolic volume (ESV), as a marker of severity of left ventricular (LV) remodeling, influences the relationship between myocardial viability and survival in patients with coronary artery disease and LV systolic dysfunction. Background Retrospective studies of ischemic LV dysfunction suggest that the severity of LV remodeling determines whether myocardial viability predicts improved survival with surgical compared with medical therapy, with coronary artery bypass grafting (CABG) only benefitting patients with viable myocardium who have smaller ESV. However, this has not been tested prospectively. Methods Interactions of end-systolic volume index (ESVI), myocardial viability, and treatment with respect to survival were assessed in patients in the prospective randomized STICH (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease) trial of CABG versus medical therapy who underwent viability assessment (n = 601; age 61 ± 9 years; ejection fraction ≤35%), with a median follow-up of 5.1 years. Median ESVI was 84 ml/m 2 . Viability was assessed by single-photon emission computed tomography or dobutamine echocardiography using pre-specified criteria. Results Mortality was highest among patients with larger ESVI and nonviability (p < 0.001), but no interaction was observed between ESVI, viability status, and treatment assignment (p = 0.491). Specifically, the effect of CABG versus medical therapy in patients with viable myocardium and ESVI ≤84 ml/m 2 (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.56 to 1.29) was no different than in patients with viability and ESVI >84 ml/m 2 (HR: 0.87; 95% CI: 0.57 to 1.31). Other ESVI thresholds yielded similar results, including ESVI ≤60 ml/m 2 (HR: 0.87; 95% CI: 0.44 to 1.74). ESVI and viability assessed as continuous rather than dichotomous variables yielded similar results (p = 0.562). Conclusions Among patients with ischemic cardiomyopathy, those with greater LV ESVI and no substantial viability had worse prognosis. However, the effect of CABG relative to medical therapy was not differentially influenced by the combination of these 2 factors. Lower ESVI did not identify patients in whom myocardial viability predicted better outcome with CABG relative to medical therapy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595 ) [ABSTRACT FROM AUTHOR]