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Rationale & Objective Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. Study Design Observational retrospective cohort study. Setting & Participants We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. Exposures Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. Outcomes All-cause mortality. Analytical Approach Multivariable Cox proportional hazards analysis. Results In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). Limitations The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. Conclusions In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD

Objectives This study sought to determine whether age modifies the impact of key comorbidities on clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF). Background Comorbidities impact outcomes in HFrEF. However, the effect of age on the impact of comorbidities on prognosis is not clearly understood. Methods Cox proportional hazards models were used assessed interactions between age and comorbidities on the primary composite endpoint (all-cause mortality or hospitalization) and secondary endpoints in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) multicenter trial of 2,331 patients with HFrEF. Results Age did not significantly modify the effect of any comorbidity on the primary endpoint. However, age significantly modified the effect of body mass index (BMI) on all-cause mortality (interaction p = 0.02). Among patients ≥70 years of age, there was a U-shaped relationship between BMI and 1-year mortality, where BMI of 20 kg/m2 corresponded to 17.6%; a BMI of 30 kg/m2 corresponded to 7.0%; and a BMI of 40 kg/m2 corresponded to 11%. For patients Conclusions In chronic HFrEF, age markedly altered the impact of BMI and depressive symptoms on all-cause mortality, with much higher risk in older patients, but was not as strong a predictor of mortality/hospitalizations as cumulative comorbidity score. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

Background Pulmonary arterial hypertension (PAH) is a chronic disease that ultimately progresses to right-sided heart failure (HF) and death. Close monitoring of pulmonary artery pressure (PAP) and right ventricular (RV) function allows clinicians to appropriately guide therapy. However, the burden of commonly used methods to assess RV hemodynamics, such as right heart catheterization, precludes frequent monitoring. The CardioMEMS HF System (Abbott) is an ambulatory implantable hemodynamic monitor, previously only used in patients with New York Heart Association (NYHA) class III HF. In this study, we evaluate the feasibility and early safety of monitoring patients with PAH and right-sided HF using the CardioMEMS HF System. Methods The CardioMEMS HF sensors were implanted in 26 patients with PAH with NYHA class III or IV right-sided HF (51.3 ± 18.3 years of age, 92% women, 81% NYHA class III). PAH therapy was tracked using a minimum of weekly reviews of CardioMEMS HF daily hemodynamic measurements. Safety, functional response, and hemodynamic response were tracked up to 4 years with in-clinic follow-ups. Results The CardioMEMS HF System was safely used to monitor PAH therapy, with no device-related serious adverse events observed and a single preimplant serious adverse event. Significant PAP reduction and cardiac output elevation were observed as early as 1 month postimplant using trends of CardioMEMS HF data, coupled with significant NYHA class and quality of life improvements within 1 year. Conclusions The CardioMEMS HF System provided useful information to monitor PAH therapy, and demonstrated short- and long-term safety. Larger clinical trials are needed before its widespread use to guide therapy in patients with severe PAH with right-sided HF.

Background Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients. Methods This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis. Results The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p = 0.03 respectively), and ET-1 predicted future 6MWD (p = 0.02). ET-1 (p = 0.01) and cGMP/NT-proBNP ratio (p = 0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p = 0.03) and PAH patients on ERA therapy (p = 0.01). Conclusions ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

In the COVID-19 era, the heart failure community has witnessed an unprecedented reduction in heart failure related patient visits and hospitalizations. Social distancing measures present a dilemma for heart failure patients who require frequent surveillance of volume status and vital signs in order to minimize heart failure related symptoms and hospitalizations. With the rise of telemedicine comes an increased focus on remote monitoring technologies. This report describes use of a multisensor device algorithm in implantable cardioverter defibrillator devices by Boston Scientific, called HeartLogic. We present two cases of patients with advanced heart failure who were actively surveilled by the HeartLogic device algorithm to guide care., Graphical abstract

The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in heart failure with preserved ejection fraction. In this study, the authors summarize existing knowledge, persistent controversies, and gaps in evidence with regard to the understanding of heart failure with preserved ejection fraction. Our analysis is based on an expert panel discussion “Think Tank” meeting that included representatives from academia, the National Institutes of Health, the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, and industry.

BACKGROUND The Jackson Heart Study (JHS) assesses cardiovascular disease risk factors among African Americans in Jackson, Mississippi. Whether characteristics of JHS participants differ from those of a broader African American population are unknown. METHODS In a retrospective observational analysis, we compared characteristics and outcomes of JHS participants 65 years old and older and enrolled in Medicare (n = 1,105) to regional (n = 57,489) and national (n = 95,494) cohorts of African American Medicare beneficiaries. We weighted the regional and national cohorts to match the age and sex distributions of the JHS-Medicare cohort for pairwise baseline comparisons. Outcomes of interest included mortality and Medicare costs. We used Cox proportional hazards models to test associations between cohorts and outcomes. RESULTS The JHS-Medicare cohort was younger, included more women, and had fewer beneficiaries with dual Medicare-Medicaid eligibility, compared with regional and national Medicare cohorts. The cohort also had lower risks of stroke, lung disease, heart failure, diabetes, and renal disease. Mean Medicare costs were lower ($5,066 [SD = $11,932]) than in the regional ($7,419 [SD = $17,574]) and national ($8,013 [SD = $19,378]) cohorts. The regional and national cohorts had higher mortality (adjusted hazard ratios = 1.52; 95% confidence interval [CI] = 1.31, 1.76; and 1.49; 95% CI = 1.29, 1.73, respectively). Subgroup analysis for dual Medicare-Medicaid eligibility attenuated mortality differences. CONCLUSION JHS-Medicare participants had fewer comorbid conditions, better survival, and lower Medicare costs compared with regional and national cohorts. Observed differences may reflect healthy volunteer bias and higher socioeconomic status.See video abstract at, http://links.lww.com/EDE/B235.

Sacubitril/valsartan was compared to enalapril in the PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure [HF]), which was stopped early after an observed 20% reduction in the composite end point of cardiovascular death or HF hospitalization.1 The US Food and Drug Administration (FDA) approved sacubitril/valsartan for patients with HF with reduced ejection fraction (HFrEF) in July 2015. However, FDA labeling is broader than trial entry criteria, and the scope of potential sacubitril/valsartan use in HFrEF is not well understood. We used the GWTG-HF registry (Get With The Guidelines-Heart Failure) to characterize patients’ eligibility and potential barriers for sacubitril/valsartan initiation according to criteria set forth in FDA labeling and PARADIGM-HF. The GWTG-HF registry was started in 2005 by the American Heart Association to improve adherence to quality of care guidelines for patients hospitalized for HF. Patients were eligible for inclusion in the registry if they were admitted for worsening HF or developed significant HF symptoms during a hospitalization.2 We included GWTG-HF registry participants ≥18 years of age hospitalized with HFrEF (EF ≤40%) between January 1, 2011, and December 31, 2013. Patients were excluded if they had in-hospital death or any missing information for variables needed to determine …

Pulmonary arterial hypertension (PAH) patients have distinct disease courses and responses to treatment, but current diagnostic and treatment schemes provide limited insight. We aimed to see if cluster analysis could distinguish clinical phenotypes in PAH. An unbiased cluster analysis was performed on 17 baseline clinical variables of PAH patients from the FREEDOM-M, FREEDOM-C, and FREEDOM-C2 randomized trials of oral treprostinil versus placebo. Participants were either treatment-naïve (FREEDOM-M) or on background therapy (FREEDOM-C, FREEDOM-C2). We tested for association of clusters with outcomes and interaction with respect to treatment. Primary outcome was 6-minute walking distance (6MWD) change. We included 966 participants with 12-week (FREEDOM-M) or 16-week (FREEDOM-C and FREEDOM-C2) follow-up. Four patient clusters were identified. Compared with Clusters 1 (n = 131) and 2 (n = 496), Clusters 3 (n = 246) and 4 (n = 93) patients were older, heavier, had worse baseline functional class, 6MWD, Borg Dyspnea Index, and fewer years since PAH diagnosis. Clusters also differed by PAH etiology and background therapies, but not gender or race. Mean treatment effect of oral treprostinil differed across Clusters 1-4 increased in a monotonic fashion (Cluster 1: 10.9 m; Cluster 2: 13.0 m; Cluster 3: 25.0 m; Cluster 4: 50.9 m; interaction P value = 0.048). We identified four distinct clusters of PAH patients based on common patient characteristics. Patients who were older, diagnosed with PAH for a shorter period, and had worse baseline symptoms and exercise capacity had the greatest response to oral treprostinil treatment.

BackgroundAs an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xe magnetic resonance imaging (MRI) and spectroscopy to identify patterns of regional gas transfer impairment and haemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH).MethodsHealthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6) and PAH (n=10) underwent 129Xe gas transfer imaging and dynamic spectroscopy. For each patient, three-dimensional maps were generated to depict ventilation, barrier uptake (129Xe dissolved in interstitial tissue) and red blood cell (RBC) transfer (129Xe dissolved in RBCs). Dynamic 129Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift.ResultsCompared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01).ConclusionCOPD, IPF, LHF and PAH each exhibit unique 129Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar–capillary level.

The presence of pulmonary hypertension (PH) significantly worsens outcomes in patients with advanced sarcoidosis, but its optimal management is unknown. We aimed to characterize a large sarcoidosis-associated pulmonary hypertension (SAPH) cohort to better understand patient characteristics, clinical outcomes, and management strategies including treatment with PH therapies. Patients at Duke University Medical Center with biopsy-proven sarcoidosis and SAPH confirmed by right heart catheterization (RHC) were identified from 1990–2010. Subjects were followed for up to 11 years and assessed for differences by treatment strategy for their SAPH, including those who were not treated with PH-specific therapies. Our primary outcomes of interest were change in 6-minute walk distance (6MWD) and change in N-terminal pro-brain natriuretic peptide (NT-proBNP) by after therapy. We included 95 patients (76% women, 86% African American) with SAPH. Overall, 70% of patients had stage IV pulmonary sarcoidosis, and 77% had functional class III/IV symptoms. Median NT-proBNP value was elevated (910 pg/mL), and right ventricular dysfunction was moderate/severe in 55% of patients. Median values for mean pulmonary artery pressure (49 mmHg) and pulmonary vascular resistance (8.5 Woods units) were consistent with severe pulmonary hypertension. The mortality rate over median 3-year follow-up was 32%. Those who experienced a clinical event and those who did not had similar overall echocardiographic findings, hemodynamics, 6MWD and NT-proBNP at baseline, and unadjusted analysis showed that only follow-up NT-proBNP was associated with all-cause hospitalization or mortality. A sign test to evaluate the difference between NT-Pro-BNP before and after PH therapy produced evidence that a significant difference existed between the median pre- and post-NT-Pro-BNP (−387.0 (IQR: −1373.0-109), p = 0.0495). Use of PH-specific therapy may be helpful in selected patients with SAPH and pre-capillary pulmonary vascular disease. Prospective trials are needed to characterize responses to PH-specific therapy in this subset of patients with SAPH.

The clinical characteristics, hemodynamic changes and outcomes of lung disease-associated pulmonary hypertension (LD-PH) are poorly defined.A prospective cohort of PH patients undergoing initial hemodynamic assessment was collected, from which 51 patients with LD-PH were identified. Baseline characteristics and long-term survival were compared with 83 patients with idiopathic pulmonary arterial hypertension (iPAH).Mean age (±standard deviation) of LD-PH patients was 64 ± 10 years, 30% were female and 78% were New York Heart Association class III-IV. The LD-PH group was older than the iPAH group (64 ± 10 vs 56 ± 18 years, respectively, P = 0.003) with a lower percentage of women (30% vs 70%, P = 0.007). LD-PH patients had smaller right ventricular sizes (P = 0.02) and less tricuspid regurgitation (P = 0.03) by echocardiogram, and lower mean pulmonary arterial pressures (mPAP) (P = 0.01) and pulmonary vascular resistance (PVR) (P = 0.001) at catheterization. Despite these findings, mortality was equally high in both groups (P = 0.16). 5-year survival was lower in patients with interstitial lung disease compared to those with obstructive pulmonary disease (P = 0.05). Among the LD-PH population, those with mild to moderately elevated mPAP and those with PVR7 Wood units demonstrated significantly improved survival (P = 0.04 and P = 0.001, respectively). Vasoreactivity was not associated with improved survival (P = 0.64). A PVR ≥7 Wood units was associated with increased risk of mortality (hazard ratio (95% confidence interval), 3.59 (1.27-10.19), P = 0.02).Despite less severe PH and less right heart sequelae, LD-PH has an equally poor clinical outcome when compared to iPAH. A PVR ≥7 Wood units in LD-PH patients was associated with 3-fold higher mortality.

Background: Hospitalizations for acute heart failure (HF) are significant events with downstream implications for patients, as well as healthcare systems and payers. However, from anecdotal experience, both hospitalization and postdischarge courses vary significantly based on severity of presenting decompensation. Methods and Results: We compared patient and hospitalization characteristics, resource utilization, and associated outcomes, among modern era acute HF patients enrolled in the GWTG–HF (Get With the Guidelines–Heart Failure) registry between 2011 and 2016, by varying severity of their acute HF. Among over 165 000 hospitalizations included in our analysis, 2% were considered high-risk and 32% intermediate-risk for in-hospital mortality, similar to findings from 15 years prior. Further, the 1-year mortality rate was 40% among Medicare beneficiaries in GWTG–HF who survived to hospital discharge. Conclusions: The long-term outcomes among acute HF survivors remain poor and, in the context of an increasing HF burden, warrant further study of postdischarge management strategies including inpatient-to-clinic transitions and ambulatory HF systems-based care.

Purpose The prevalence and severity of pulmonary hypertension (PH) in heart-kidney (HK) transplant candidates are not well-characterized. Additional hemodynamic risk factors (i.e. arteriovenous fistula for hemodialysis access, intermittent volume reduction) are present in HK patients. The current study describes PH severity in this patient population to understand its impact on post-transplant outcomes when compared to isolated heart transplant (HT) patients. Methods We searched the UNOS database to identify adult HK and HT recipients who underwent de novo transplantation between 2010-2020. Propensity score matching was used to identify a balanced cohort of HK and HT recipients. Baseline characteristics and invasive hemodynamics were compared between HT and HK. Logistic regression models were constructed to quantify the association of PH with 1-year post-transplant mortality. PH was defined as a mean PA pressure >20 mmHg using the updated hemodynamic classification. Results We identified 1392 HK recipients and propensity-matched them with 1392 HT recipients. Clinical covariates except for wait-list time and creatinine were well-balanced (Table 1A). PH was more frequent in HK recipients than HT although both groups had mean PVR Conclusion HK recipients have greater PH severity and post-transplant mortality risk when compared with matched HT recipients. Further studies are warranted to better understand PH mechanisms and outcomes in the dual-organ populations.

Throughout medical school, residency, and fellowship, most trainees will attend several conferences. These can vary in size, scope, and specialty and can be local, national, or international. Although some trainees attending conferences may be presenting a poster or oral abstract, commonly a

Pulmonary arterial hypertension (PAH) has emerging therapeutic options including prostacyclin analogs. Inhaled therapy offers advantages compared with alternative routes of administration. We aimed to determine the safety and tolerability of inhaled treprostinil (iTRE) titrated to target maintenance dose higher than the labeled dose for PAH. Our study included 80 consecutive patients (69% female, 70% White) followed at the Duke University Medical Center prescribed iTRE at dose >9 breaths (54 μg). Etiology of pulmonary hypertension was most frequently PAH (51%) or secondary to lung disease (35%). Median follow-up was 20.3 months (interquartile range 14.2-33.2). Most patients (91%) had titrated iTRE dose to 12 breaths (72 μg) four times daily. Common side effects reported with drug initiation were cough (41%), headache (28%), and throat irritation (8%); most of the side effects improved at follow-up. Overall, 25% patients discontinued iTRE: 9 transitioned to parenteral therapy, 4 had untolerable side effects, 3 died, and 4 had other reasons. Overall, iTRE taken at a higher dose than approved for use in PAH was safe and well-tolerated in our cohort of pulmonary hypertension patients.

Heart failure continues to be a leading cause of hospitalization worldwide, and acute heart failure (AHF) carries significant risk for short-term morbidity and mortality. Despite many trials of potential new therapies for AHF, there have been very few advances over the recent decades. In this review, we will examine mortality during and after AHF hospitalization, with an emphasis on available data on mode of death (MOD). We will also review data on the timing of different MOD after AHF and the effect of specific therapies, as well as what is known about the contribution of specific pathophysiological mechanisms. Finally, we discuss the potential utility of further study of MOD data for AHF and its application to drug development, risk stratification, and therapeutic tailoring to improve short- and long-term outcomes in AHF.

Background In heart failure (HF) with reduced ejection fraction, 2 clinical trials, the BEST (β-Blocker Evaluation of Survival Trial) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), have reported an effectiveness interaction between the ADRB1 (β-1 adrenergic receptor) Arg389Gly polymorphism and β-blockers (BBs). HF-ACTION additionally reported a dose-related interaction of unclear origin. If confirmed and pharmacogenetically resolved, these findings may have important implications for HF with reduced ejection fraction precision therapy. We used uniform methodology to investigate BB dose-ADRB1 Arg389Gly polymorphism interaction with major clinical end points in BEST/bucindolol and HF-ACTION/other BB databases. Methods This was a retrospective analysis of prospectively designed DNA substudies from BEST (N=1040) and HF-ACTION (N=957). Subjects were genotyped for ADRB1 Arg389Gly and ADRA2C (α2C adrenergic receptor) Ins322-325Del. BB dose was defined as either no/low dose or high dose, according to total daily dose of either bucindolol (BEST subjects) or other BB (HF-ACTION subjects) standardized to carvedilol equivalents. The main outcome of interest was all-cause mortality, and CV mortality/HF hospitalization was a secondary outcome. Results Subjects in each trial had less all-cause mortality with high- versus no/low-dose BB if they had ADRB1 Arg389Arg (BEST: hazard ratio [HR]=0.40, P=0.002; HF-ACTION: HR=0.45, P=0.005) but not Arg389Gly genotype (both P>0.2). Among gene-dose groups, there was a differential favorable treatment effect of 46% for high-dose bucindolol with ADRB1 Arg389Arg versus Gly carrier genotype (HR, 0.54; P=0.018), but not for no/low-dose bucindolol. In contrast, HF-ACTION Arg389Arg genotype subjects taking no/low-dose BB had greater all-cause mortality compared with 389Gly carriers (HR, 1.83; P=0.015), whereas all-cause mortality did not vary by genotype among subjects taking high-dose BB (HR, 0.84; P=0.55). Conclusions The enhanced HF with reduced ejection fraction efficacy of bucindolol in the ADRB1 Arg389Arg versus 389Gly carrier genotypes occurs at high dose. Other BBs taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers, suggesting a greater relative treatment effect at high dose. These data support guideline recommendations to use high, clinical trial target doses of all BBs to treat HF with reduced ejection fraction.

The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in heart failure with preserved ejection fraction. In this study, the authors summarize existing knowledge, persistent controversies, and gaps in evidence with regard to the understanding of heart failure with preserved ejection fraction. Our analysis is based on an expert panel discussion "Think Tank" meeting that included representatives from academia, the National Institutes of Health, the U.S. Food and Drug Administration, the Centers for MedicareMedicaid Services, and industry.

Pulmonary hypertension (PH) associated with sarcoidosis (World Health Organization Group 5) carries a poor prognosis and likely occurs through multiple mechanisms. Routine monitoring and a high clinical suspicion must be maintained to establish early diagnosis. Imaging and other ancillary tests may suggest PH in these patients, but as with all PH groups, right heart catheterization is needed for confirmation and for differentiating contributors to PH. Although there appears to be a role for treatment in select patients with significant concomitant pulmonary arterial hypertension (PAH), pulmonary vasodilator therapy can also risk worsening hypoxia secondary to ventilation/perfusion mismatch. The medical management of patients with sarcoidosis-associated pulmonary hypertension (SAPH) will be better informed with further study in large, randomized trials. At this time, there are no US Food and Drug Administration-approved therapies, including PAH medications, for patients with SAPH.

Pulmonary hypertension portends a poorer prognosis for blacks versus white populations, but the underlying reasons are poorly understood. We investigated associations of disease characteristics, insurance status, and race with clinical outcomes.Retrospective cohort study of patients presenting for initial pulmonary hypertension evaluation at 2 academic referral centers.We recorded insurance status (Medicare, Medicaid, private, self-pay), echocardiographic, and hemodynamics data from 261 patients (79% whites, 17% blacks) with a new diagnosis of pulmonary hypertension. Subjects were followed for 2.3 years for survival. Adjustment for covariates was performed with Cox proportional hazards modeling.Compared with white patients, blacks were younger (50 ± 15 vs 53 ± 12 years; P = .04), with females representing a majority of patients in both groups (80% vs 66%; P = .08) and similar functional class distribution (class 2/3/4: 30%/52%/16% blacks vs 33%/48%/14% whites; P = .69). Blacks diagnosed with incident pulmonary hypertension were more frequently covered by Medicaid (12.5% vs 0.7%) and had less private insurance (50% vs 61%; P = .007) than whites. At presentation, blacks had more right ventricular dysfunction (P = .04), but similar mean pulmonary arterial pressure (46 vs 45 mm Hg, respectively; P = .66). After adjusting for age and functional class, blacks had greater mortality risk (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.18-3.44), which did not differ by race after additional adjustment for insurance status (HR, 1.74; 95% CI, 0.84-3.32; P =.13).In a large cohort of patients with incident pulmonary hypertension, black patients had poorer right-side heart function and survival rates than white patients. However, adjustment for insurance status in our cohort removed differences in survival by race.

Background The safety and efficacy of aerobic exercise in heart failure (HF) patients with atrial fibrillation (AF) has not been well evaluated. Objectives This study examined whether outcomes with exercise training in HF vary according to AF status. Methods HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) randomized 2,331 ambulatory HF patients with ejection fraction ≤35% to exercise training or usual care. We examined clinical characteristics and outcomes (mortality/hospitalization) by baseline AF status (past history of AF or AF on baseline electrocardiogram vs. no AF) using adjusted Cox models and explored an interaction with exercise training. We assessed post-randomization AF events diagnosed via hospitalizations for AF and reports of serious arrhythmia caused by AF. Results Of 2,292 patients with baseline rhythm data, 382 (17%) had AF, 1,602 (70%) had sinus rhythm, and 308 (13%) had “other” rhythm. Patients with AF were older and had lower peak Vo2. Over a median follow-up of 2.6 years, AF was associated with a 24% per year higher rate of mortality/hospitalization (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.34 to 1.74; p 0.10). There was no interaction between AF and exercise training on measures of functional status or clinical outcomes (all p > 0.10). Conclusions AF in patients with chronic HF was associated with older age, reduced exercise capacity at baseline, and a higher overall rate of clinical events, but not a differential response to exercise training for clinical outcomes or changes in exercise capacity. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

Objectives This study sought to assess the effectiveness of a novel percutaneous method to treat left ventricular assist device (LVAD)–associated severe aortic insufficiency (AI) in a series of patients determined to be poor reoperative candidates. Background The increased use of continuous-flow LVAD in advanced heart failure has led to marked changes in the management of patients with this condition. However, secondary AI can become a significant complication. Methods Five patients with continuous-flow LVAD and severe post-LVAD AI underwent percutaneous transcatheter aortic valve closure from September to October 2011 at a single quaternary care academic medical center. All patients had LVAD implanted as destination therapy. LVAD parameters, hemodynamics, and echocardiographic measurements were obtained before and after aortic valve closure. Results All patients underwent successful closure with the Amplatzer cribriform device (AGA Medical, Plymouth, Minnesota) via a percutaneous transcatheter femoral approach with a significant reduction of AI from severe to trivial. Cardiac hemodynamics improved, and the pulmonary capillary wedge pressure was reduced in all patients. There was no change in mitral or tricuspid regurgitation, LVAD power, or pulsatility index. Conclusions Percutaneous transcatheter closure of the aortic valve effectively treats LVAD-associated AI and reduces pulmonary capillary wedge pressure. This procedure should be considered to treat LVAD-associated AI in patients who are poor candidates for repeat operation. Further data are needed to assess long-term results.

Pyruvate dehydrogenase kinase (PDK) is activated in right ventricular hypertrophy (RVH), causing an increase in glycolysis relative to glucose oxidation that impairs right ventricular function. The stimulus for PDK upregulation, its isoform specificity, and the long-term effects of PDK inhibition are unknown. We hypothesize that FOXO1-mediated PDK4 upregulation causes bioenergetic impairment and RV dysfunction, which can be reversed by dichloroacetate. Adult male Fawn-Hooded rats (FHR) with pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH; age 6–12 months) were compared to age-matched controls. Glucose oxidation (GO) and fatty acid oxidation (FAO) were measured at baseline and after acute dichloroacetate (1 mM × 40 min) in isolated working hearts and in freshly dispersed RV myocytes. The effects of chronic dichloroacetate (0.75 g/L drinking water for 6 months) on cardiac output (CO) and exercise capacity were measured in vivo. Expression of PDK4 and its regulatory transcription factor, FOXO1, were also measured in FHR and RV specimens from PAH patients (n = 10). Microarray analysis of 168 genes related to glucose or FA metabolism showed >4-fold upregulation of PDK4, aldolase B, and acyl-coenzyme A oxidase. FOXO1 was increased in FHR RV, whereas HIF-1α was unaltered. PDK4 expression was increased, and the inactivated form of FOXO1 decreased in human PAH RV (P < 0.01). Pyruvate dehydrogenase (PDH) inhibition in RVH increased proton production and reduced GO’s contribution to the tricarboxylic acid (TCA) cycle. Acutely, dichloroacetate reduced RV proton production and increased GO’s contribution (relative to FAO) to the TCA cycle and ATP production in FHR (P < 0.01). Chronically dichloroacetate decreased PDK4 and FOXO1, thereby activating PDH and increasing GO in FHR. These metabolic changes increased CO (84 ± 14 vs. 69 ± 14 ml/min, P < 0.05) and treadmill-walking distance (239 ± 20 vs. 171 ± 22 m, P < 0.05). Chronic dichloroacetate inhibits FOXO1-induced PDK4 upregulation and restores GO, leading to improved bioenergetics and RV function in RVH.

Angina pectoris (AP) is associated with worse outcomes in heart failure (HF). We investigated the association of AP with health-related quality of life (HRQoL), exercise capacity, and clinical outcomes and its interaction with exercise training in an HF population. We grouped 2,331 patients with HF with reduced ejection fraction in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial of usual care ± exercise training according to whether they had self-reported AP by Canadian classification score. HRQoL and clinical outcomes were assessed by AP status. In HF-ACTION, 406 patients (17%) had AP at baseline (44% with Canadian classification score ≥II) with HF severity similar to those without AP. Patients with AP had similar baseline exercise capacity but worse depressive symptoms and HRQoL. AP was associated with 22% greater adjusted risk for all-cause mortality/hospitalizations, driven by hospitalizations. There was significant interaction between baseline AP and exercise training peak VO 2 change (p = 0.019) but not other end points. Exercise training was associated with greater peak VO 2 improvement after 3 months in patients with AP (treatment effect = 1.25 ml/kg/min, 95% CI 0.6 to 1.9). In conclusion, AP was associated with worse HRQoL and depressive symptoms. Despite greater peak VO 2 improvement with exercise training, patients with AP experienced more adverse outcomes.

This study sought to investigate demographic, clinical, and procedural determinants of outcomes in patients treated with percutaneous veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) initiated in the cardiac catheterization laboratory with a portable system.We performed a retrospective review of patients treated with percutaneous VA-ECMO during the study period at our institution. A logistic regression model was applied to investigate the association between sequential organ failure assessment (SOFA) score and survivor status. Fisher's exact test was used to examine the association between survivor status and cannula size (15 Fr vs15 Fr).Percutaneous VA-ECMO was initiated in 25 patients. At 30 days, 10 patients were alive (40%). Fifteen patients had cardiac arrest (CA) prior to ECMO initiation, of which 5 were alive at 30 days (33%). Survivors had a lower baseline median SOFA score (9 vs 16; P=.02; odds ratio, 0.577). Use of a smaller cannula was associated with survival (P=.01). There was an association between the size of the arterial cannula and increased blood transfusions (P.01).Lower presenting SOFA score and smaller cannula size were associated with increased survival in patients with cardiogenic shock (CS) or CA who underwent percutaneous VA-ECMO placed in the cardiac catheterization laboratory using a portable system. Calculation of the SOFA score at presentation may help physicians determine which patients may derive benefit from ECMO. Smaller cannula size, while decreasing the amount of flow, may result in decreased bleeding and increased survival.

Infective endocarditis (IE) affects the pulmonic valve in less than 2% of cases. Not only is pulmonary valve IE rare, it is also challenging to visualise with commonly used imaging modalities. In this vignette, we present a 50-year-old patient with a history of repaired Tetralogy of Fallot who underwent a prolonged hospitalisation and extensive work up for fever of unknown origin. Although we suspected IE as the source of his fevers, he had persistently negative transthoracic and transoesophageal echocardiograms. We were ultimately able to establish the diagnosis with the use of positron emission tomography-CT (PET-CT). Although PET-CT is not part of the traditional work up for IE, it can be a useful imaging modality when there is a high index of suspicion for IE with negative echocardiography findings.

Background— Early repolarization, indicated on the standard 12-lead ECG, has recently been associated with idiopathic ventricular fibrillation in patients without structural heart disease. It is unknown whether there is an association between early repolarization and ventricular arrhythmias in the coronary artery disease (CAD) population. Methods and Results— Patients with CAD with implantable cardioverter-defibrillators in the healed phase of myocardial infarction were analyzed. In a case-control design, 60 patients who had ventricular arrhythmic events were matched for age and sex with 60 control subjects. ECGs were analyzed for early repolarization, defined as notching or slurring morphology of the terminal QRS complex or J-point elevation ≥0.1 mV above baseline in at least 2 lateral or inferior leads. Results were adjusted for left ventricular ejection fraction. Overall, early repolarization in 2 or more leads was more common in cases than control subjects (32% versus 8%, P =0.005). Early repolarization was noted more commonly in inferior leads (23% versus 8%, P =0.03), and a trend was noted in leads V 4 through V 6 (12% versus 3%, P =0.11). Early repolarization was uncommon in leads I and aVL in cases and control subjects (3% versus 0%). Notching was more common in cases than control subjects (28% versus 7%, P =0.008). Slurring and J-point elevation were not associated with ventricular arrhythmias. Conclusions— Early repolarization and, in particular, notching in the inferior leads is associated with increased risk of life-threatening ventricular arrhythmias in patients with CAD, even after adjustment for left ventricular ejection fraction. Our findings suggest early repolarization, and a notching morphology should be considered in a risk prediction model for arrhythmias in patients with CAD.

The clinical characteristics, hemodynamic changes and patient outcomes of lung disease-related pulmonary hypertension (LD-PH) are poorly defined. A prospective two-center cohort of PH patients undergoing initial hemodynamic assessment was designed, from which 64 patients with LD-PH were identified

Background: The population with heart failure (HF) with reduced ejection fraction (HFrEF) is generally older, and presence of comorbid conditions is increasingly relevant to their management. We investigated the relationship between age, comorbidities, and adverse outcomes among subjects in the HF

Importance Increased resting heart rate is associated with worse outcomes in studies of mostly white populations, but its significance is not well established in African Americans persons whose cardiac comorbidities and structural abnormalities differ. Objective To study the prognostic utility of heart rate in a community-based African American cohort in the Jackson Heart Study. Design, Setting, and Participants A total of 5261 participants in the Jackson Heart Study, a prospective, community-based study in Jackson, Mississippi, were evaluated. Baseline heart rate was assessed by quintiles and as a continuous variable. All participants with baseline heart rate documented by a 12-lead electrocardiogram without pacing or atrial fibrillation noted on their baseline Jackson Heart Study examination were included in the study. Follow-up began September 26, 2000, and was completed December 31, 2011. Data analysis was performed from July to October 2015. Main Outcomes and Measures Unadjusted and adjusted associations between heart rate and all-cause mortality and heart failure hospitalization using Cox proportional hazards regression models. Results Of the 5261 individuals included in the analysis, 1921 (36.5%) were men; median (25th-75th percentile) age was 55.7 (45.4-64.8) years. Median (25th-75th percentile) baseline heart rate was 63 beats per minute (bpm) (57-71 bpm). The highest heart rate quintile (73-118 bpm) had higher rates of diabetes (398 [37.4%];P Conclusions and Relevance Higher baseline heart rate was associated with increased mortality and heart failure hospitalizations among African American participants in the Jackson Heart Study. These findings are similar to those seen in white populations, but further study is needed to understand whether African American individuals benefit from interventions targeting heart rate reduction.

The rapid growth of cancer cells is permitted by metabolic changes, notably increased aerobic glycolysis and increased glutaminolysis. Aerobic glycolysis is also evident in the hypertrophying myocytes in right ventricular hypertrophy (RVH), particularly in association with pulmonary arterial hypertension (PAH). It is unknown whether glutaminolysis occurs in the heart. We hypothesized that glutaminolysis occurs in RVH and assessed the precipitating factors, transcriptional mechanisms, and physiological consequences of this metabolic pathway. RVH was induced in two models, one with PAH (Monocrotaline-RVH) and the other without PAH (pulmonary artery banding, PAB-RVH). Despite similar RVH, ischemia as determined by reductions in RV VEGFα, coronary blood flow, and microvascular density was greater in Monocrotaline-RVH versus PAB-RVH. A sixfold increase in (14)C-glutamine metabolism occurred in Monocrotaline-RVH but not in PAB-RVH. In the RV working heart model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) decreased glutaminolysis, caused a reciprocal increase in glucose oxidation, and elevated cardiac output. Consistent with the increased glutaminolysis in RVH, RV expressions of glutamine transporters (SLC1A5 and SLC7A5) and mitochondrial malic enzyme were elevated (Monocrotaline-RVHPAB-RVHcontrol). Capillary rarefaction and glutamine transporter upregulation also occurred in RVH in patients with PAH. cMyc and Max, known to mediate transcriptional upregulation of glutaminolysis, were increased in Monocrotaline-RVH. In vivo, DON (0.5 mg/kg/day × 3 weeks) restored pyruvate dehydrogenase activity, reduced RVH, and increased cardiac output (89 ± 8, vs. 55 ± 13 ml/min, p 0.05) and treadmill distance (194 ± 71, vs. 36 ±7 m, p 0.05) in Monocrotaline-RVH. Glutaminolysis is induced in the RV in PAH by cMyc-Max, likely as a consequence of RV ischemia. Inhibition of glutaminolysis restores glucose oxidation and has a therapeutic benefit in vivo.Patients with pulmonary artery hypertension (PAH) have evidence of cardiac glutaminolysis. Cardiac glutaminolysis is associated with microvascular rarefaction/ischemia. As in cancer, cardiac glutaminolysis results from activation of cMyc-Max. The specific glutaminolysis inhibitor DON regresses right ventricular hypertrophy. DON improves cardiac function and exercise capacity in an animal model of PAH.

Visualization of pulmonic valve vegetations can be challenging with both transthoracic and transesophageal echocardiography (TTE and TEE) due to the anterior position of the pulmonic valve. Recent studies show positron emission tomography-computed tomography (PET-CT) imaging may hold promising

Increased resting heart rate (HR) is associated with worse outcomes in mostly white populations, but its significance is not well established in African Americans whose cardiac comorbidities and structural abnormalities differ. We studied the prognostic utility of HR in a community-based African

Elevated jugular venous pressure (JVP) and peripheral edema predict worse outcomes in chronic heart failure (HF) patients. We studied these findings in acute HF in the ASCEND-HF trial of nesiritide vs. placebo. Of 7,141 ASCEND-HF patients, 7,135 patients had complete data on baseline JVP and

Background— The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein–coupled receptor kinase-2 (GRK2)–mediated uncoupling of β-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ–GRK2 interaction, using gallein, were tested. Methods and Results— Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding–induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular–Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 versus 82.9±4.8 mL/min; P P P Conclusions— GRK2-mediated desensitization-downregulation of adrenergic and dopaminergic receptors impairs inotropic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1–receptor signaling, which is impaired in RVH. Inhibiting Gβγ–GRK2 interactions has therapeutic benefit in RVH.