Long-term outcomes of phenoclusters in severe tricuspid regurgitation.

AIMS: Severe tricuspid regurgitation (TR) exhibits high 1-year morbidity and mortality, yet long-term cardiovascular risk overall and by subgroups remains unknown. This study characterizes 5-year outcomes and identifies distinct clinical risk profiles of severe TR. METHODS AND RESULTS: Patients were included from a large US tertiary referral center with new severe TR by echocardiography based on four-category American Society of Echocardiography grading scale between 2007 and 2018. Patients were categorized by TR etiology (with lead present, primary, and secondary) and by supervised recursive partitioning (survival trees) for outcomes of death and the composite of death or heart failure hospitalization. The Kaplan-Meier estimates and Cox regression models were used to evaluate any association by (i) TR etiology and (ii) groups identified by survival trees and outcomes over 5 years. Among 2379 consecutive patients with new severe TR, median age was 70 years, 61% were female, and 40% were black. Event rates (95% confidence interval) were 30.9 (29.0-32.8) events/100 patient-years for death and 49.0 (45.9-52.2) events/100 patient-years for the composite endpoint, with no significant difference by TR etiology. After applying supervised survival tree modeling, two separate groups of four phenoclusters with distinct clinical prognoses were separately identified for death and the composite endpoint. Variables discriminating both outcomes were age, albumin, blood urea nitrogen, right ventricular function, and systolic blood pressure (all P < 0.05). CONCLUSION: Patients with newly identified severe TR have high 5-year risk for death and death or heart failure hospitalization. Partitioning patients using supervised survival tree models, but not TR etiology, discriminated clinical risk. These data aid in identifying relevant subgroups in clinical trials of TR and clinical risk/benefit analysis for TR therapies.

Pulmonary Hypertension Subtypes and Mortality in CKD.

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.

Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.

Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 µg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.

Representativeness of Medicare Participants in the Jackson Heart Study for African American Medicare Beneficiaries.

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.

Pharmacogenomics of Bucindolol in Atrial Fibrillation and Heart Failure.

PURPOSE OF REVIEW: We explore the pharmacogenomics of the beta-blocker bucindolol by discussing relevant beta-1 adrenergic receptor (ADRB1) polymorphisms and recent beta-blocker studies. Through this, we will understand how bucindolol may help patients with atrial fibrillation and heart failure with reduced ejection fraction (AF-HFrEF), which carries poor prognosis. RECENT FINDINGS: Retrospective study of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial revealed the interaction between the optimal beta-blocker dose and the ADRB1 Arg389 genotype for HFrEF clinical outcomes. Further, a combinatorial genotype analysis in the Beta-Blocker Evaluation of Survival Trial showed that the Arg389Arg genotype, but not the Gly carrier, was associated with 40% lower mortality risk with bucindolol. Finally, the AF-HFrEF subgroup with the ADRB1 Arg389Arg genotype had greater heart rate reduction and suggestion for mortality benefit. Therapeutic response to beta-blockers varies by beta-blocker mechanism, ADRB1 Arg389 genotype, and clinical setting (AF, HFrEF, AF-HFrEF). The ongoing trial A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure prospectively identifies AF-HFrEF patients with favorable genotype for bucindolol to prevent AF recurrence.

Safety and Tolerability of High-dose Inhaled Treprostinil in Pulmonary Hypertension.

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.

Mode of Death After Acute Heart Failure Hospitalization　- A Clue to Possible Mechanisms.

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.

Use of outcome measures in pulmonary hypertension clinical trials.

OBJECTIVES: To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice. BACKGROUND: Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined. METHODS: We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014. RESULTS: Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients). CONCLUSIONS: The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures.

Potential applications of pharmacogenomics to heart failure therapies.

Pharmacogenomics explores one drug's varying effects on different patient genotypes. A better understanding of genomic variation's contribution to drug response can impact 4 arenas in heart failure (HF): (1) identification of patients most likely to receive benefit from therapy, (2) risk stratify patients for risk of adverse events, (3) optimize dosing of drugs, and (4) steer future clinical trial design and drug development. In this review, the authors explore the potential applications of pharmacogenomics in patients with HF in the context of these categories.

GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.

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 ß-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gßγ-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<0.001) and treadmill distance (41.5±11.6 versus 244.1±12.4 m; P<0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of ß1-, α1- and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (P<0.01). ß1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo. 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 Gßγ-GRK2 interactions has therapeutic benefit in RVH.

Wellens syndrome: a life-saving diagnosis.

The diagnosis of acute coronary syndrome relies on clinical history, electrocardiographic (ECG) changes, and cardiac biomarkers; but within the spectrum of acute coronary syndrome, there exist subtle presentations that cannot afford to be overlooked. Wellens syndrome is one such example, in which a patient can present with both ECG changes that are not classic for myocardial ischemia and negative cardiac biomarkers. The characteristic ECG findings associated with Wellens syndrome consist of deep, symmetric T-wave inversions in the anterior precordial leads. However, Wellens syndrome can also present as biphasic T-wave inversions in those same ECG leads. The associated critical stenosis of the proximal left anterior descending artery carries an immediately life-threatening prognosis if not recognized promptly (Am Heart J. 1982;103[4 Pt 2]:730-736). We describe a case of a less common manifestation of Wellens syndrome (type 1) followed by a discussion of its implications and management.

Relationship of Nonalcoholic Fatty Liver Disease and Heart Failure With Preserved Ejection Fraction.

Although there is an established bidirectional relationship between heart failure with reduced ejection fraction and liver disease, the association between heart failure with preserved ejection fraction (HFpEF) and liver diseases, such as nonalcoholic fatty liver disease (NAFLD), has not been well explored. In this paper, the authors provide an in-depth review of the relationship between HFpEF and NAFLD and propose 3 NAFLD-related HFpEF phenotypes (obstructive HFpEF, metabolic HFpEF, and advanced liver fibrosis HFpEF). The authors also discuss diagnostic challenges related to the concurrent presence of NAFLD and HFpEF and offer several treatment options for NAFLD-related HFpEF phenotypes. The authors propose that NAFLD-related HFpEF should be recognized as a distinct HFpEF phenotype.

Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension.

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.

Outcomes of lung disease-associated pulmonary hypertension and impact of elevated pulmonary vascular resistance.

BACKGROUND: The clinical characteristics, hemodynamic changes and outcomes of lung disease-associated pulmonary hypertension (LD-PH) are poorly defined. METHODS: 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). RESULTS: Mean age (±standard deviation) of LD-PH patients was 64 ±â€¯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 ±â€¯10 vs 56 ±â€¯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 PVR <7 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). CONCLUSIONS: 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.

Characteristics of Acute Heart Failure Hospitalizations Based on Presenting Severity.

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.

Echocardiographic Assessment of Right Ventricular Function and Response to Therapy in Pulmonary Arterial Hypertension.

Echocardiography is a key tool in the management of patients with pulmonary arterial hypertension (PAH), but many potential parameters could be used to assess response to therapy. In this retrospective study of 48 patients with severe PAH at baseline, we examined echocardiographic variables before and after initiation of PAH-specific therapy to evaluate which measures of right ventricular (RV) function best correlated with clinical response to therapy as assessed by 6-minute walk distance (6MWD) and 3-year all-cause mortality. Tricuspid annular plane systolic excursion (TAPSE), mid-RV and basal-RV diameters, RV systolic pressure, and RV global longitudinal strain were all found to significantly improve after initiation of a PAH therapy. Decreases in right atrial area (r = -0.50, p = 0.002) and mid-RV diameter (r = -0.36, p = 0.03) were most strongly correlated with improvement in 6MWD. Pretreatment values of RA area (hazard ratio [HR] per 1 SD: 2.72; 95% confidence interval [CI] 1.58, 4.69), mid-RV diameter (HR 2.03; 1.20, 3.45), basal-RV diameter (HR 2.27; 1.40, 3.70), and RV global longitudinal strain (HR 2.36; 1.22, 4.56) were all associated with mortality risk. 6MWD and TAPSE were the 2 variables for which pretreatment measures (6MWD - HR 0.35; 0.17, 0.72; TAPSE - HR 0.41; 0.21, 0.82) and change with treatment (6MWD - HR 0.26; 0.10, 0.64; TAPSE - HR 0.40; 0.21, 0.77) were both significantly associated with 3-year mortality. Change in RV systolic pressure with treatment was significantly associated with mortality (HR 2.55; 1.23, 5.28,) but pretreatment baseline had no association (HR 1.48; 0.72, 3.06). Although many echocardiographic parameters change with initiation of PAH treatment, the strong association of both baseline TAPSE and change in TAPSE with mortality supports the ongoing use of TAPSE as an important measure in the assessment of disease severity and treatment response in PAH.

Monitoring Pulmonary Arterial Hypertension Using an Implantable Hemodynamic Sensor.

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.

Dose Response of ß-Blockers in Adrenergic Receptor Polymorphism Genotypes.

Background In heart failure (HF) with reduced ejection fraction, 2 clinical trials, the BEST (ß-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 (ß-1 adrenergic receptor) Arg389Gly polymorphism and ß-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.

Relation of Volume Overload to Clinical Outcomes in Acute Heart Failure (From ASCEND-HF).

We aimed to study whether jugular venous distension (JVD) and peripheral edema were associated with worse outcomes in patients with acute heart failure in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial. Of 7,141 patients in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure, 7,135 had complete data on baseline JVD and peripheral edema status. Patients were grouped according to baseline examination findings: (1) no JVD or peripheral edema; (2) JVD only; (3) peripheral edema only; (4) JVD and peripheral edema. We used unadjusted and adjusted logistic or Cox regression analyses to assess associations between groups and the outcomes of index length of stay (LOS), in-hospital mortality, 30- and 180-day all-cause mortality. Patients with peripheral edema (Groups 3 and 4) had higher body mass index, NT-proBNP and BNP values, and more co-morbid disease, and reduced left ventricular ejection fraction compared with patients in Groups 1-2. The median (25th-75th) LOS for Groups 1-4 was 6 (4-9), 5 (4-8), 7 (4-11), and 6 days (4-10), respectively. For the 30-day and 180-day outcomes, adjusted analyses found no significant difference in risk for patients presenting with JVD only or peripheral edema only as compared with patients without evidence of JVD or peripheral edema (p >0.05 for all). The presence of both JVD and peripheral edema was associated with an adjusted 24% increase in risk for all-cause mortality at 30 days, but no risk difference at 180 days. In conclusion, in patients with heart failure presenting to the hospital with dyspnea, the presence of peripheral edema is associated with a longer hospital LOS, but no difference in short- and long-term clinical outcomes when compared with patients wihout peripheral edema. The combination of peripheral edema and JVD identifies the highest risk cohort for poor clinical outcomes.