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BACKGROUND: We aim to develop a four-tier severity classification system of main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans. METHODS: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n=114), we determined the four-tier cutpoints to maximize sensitivity and specificity, and validated it in a separate cohort (n=114). Cutpoints for mPA were defined with the Framingham sex-specific normative values of ≤27mm(F) and ≤29mm(M) as the normal reference range; mild as >27 to 29 to 34 mm. Cutpoints for ratio PA were defined as normal ≤0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1. RESULTS: Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p1.1 had worse survival than normal values (all p≤0.01). CONCLUSION: Four-tier severity classification of mPA and ratio PA on CT has high accuracy for PH diagnosis with increase mortality in patients with moderate-severe mPA and ratio PA values supporting its use clinically on chest and cardiac CT reports.

This pilot study used acoustic speech analysis to monitor patients with heart failure (HF), which is characterized by increased intracardiac filling pressures and peripheral edema. HF-related edema in the vocal folds and lungs is hypothesized to affect phonation and speech respiration. Acoustic measures of vocal perturbation and speech breathing characteristics were computed from sustained vowels and speech passages recorded daily from ten patients with HF undergoing inpatient diuretic treatment. After treatment, patients displayed a higher proportion of automatically identified creaky voice, increased fundamental frequency, and decreased cepstral peak prominence variation, suggesting that speech biomarkers can be early indicators of HF.

BACKGROUND While abnormal left ventricular (LV) global longitudinal strain (GLS) has been described in patients with heart failure with preserved ejection fraction (HFpEF), its prevalence and clinical significance are poorly understood. METHODS AND RESULTS Patients enrolled in the RELAX trial of sildenafil in HFpEF (LV ejection fraction ≥50%) in whom two-dimensional, speckle-tracking LV GLS was possible (n = 187) were analysed. The distribution of LV GLS and its associations with clinical characteristics, LV structure and function, biomarkers, exercise capacity and quality of life were assessed. Baseline median LV GLS was -14.6% (25th and 75th percentile, -17.0% and -11.9%, respectively) and abnormal (≥ - 16%) in 122/187 (65%) patients. Patients in the tertile with the best LV GLS had lower N-terminal pro-brain natriuretic peptide (NT-proBNP) [median 505 pg/mL (161, 1065) vs. 875 pg/mL (488, 1802), P = 0.008) and lower collagen III N-terminal propeptide (PIIINP) levels [median 6.7 µg/L (5.1, 8.1) vs. 8.1 µg/L (6.5, 10.5), P = 0.001] compared with the tertile with the worst LV GLS. There was also a modest linear relationship with LV GLS and log-transformed NT-proBNP and PIIINP (r = 0.29, P

Objectives This study sought to investigate relationships between insulin-like growth factor–binding protein-7 (IGFBP7) and parameters of diastolic function or functional capacity in patients with heart failure and preserved ejection fraction (HFpEF) who were randomized to receive sildenafil or placebo. Background IGFBP7 was previously found to be associated with diastolic function in heart failure with reduced ejection fraction, but it is unclear whether these associations are present in HFpEF. Methods At baseline and 24 weeks, IGFBP7, imaging studies, and peak oxygen consumption (Vo2max) were obtained and compared in 160 patients with HFpEF who were randomized to receive sildenafil or placebo. Results Patients with supramedian baseline IGFBP7 concentrations were older, had signs of systemic congestion and worse renal function, and had higher concentrations of prognostic heart failure biomarkers including amino-terminal pro-B-type natriuretic peptide (p Conclusions In patients with HFpEF, IGFBP7 may be a novel biomarker of diastolic function and exercise capacity.

After orthotopic heart transplantation (OHT), the allograft undergoes characteristic alterations in myocardial structure, including hypertrophy, increased ventricular stiffness, ischemia, and inflammation, all of which may decrease overall graft survival. Methods to quantify these phenotypes may clarify the pathophysiology of progressive graft dysfunction post-OHT. We performed cardiac magnetic resonance (CMR) with T1 mapping in 26 OHT recipients (mean age 47 ± 7 years, 30 % female, median follow-up post-OHT 6 months) and 30 age-matched healthy volunteers (mean age 50.5 ± 15 years; LVEF 63.5 ± 7 %). OHT recipients had a normal left ventricular ejection fraction (LVEF 65.3 ± 11 %) with higher LV mass relative to age-matched healthy volunteers (114 ± 27 vs. 85.8 ± 18 g; p

Introduction: Obstructive hypertrophic cardiomyopathy (oHCM) consists of a constellation of LV hypercontractility, LV outflow tract obstruction (LVOTO), and impaired relaxation, often resulting in dyspnea and reduced exercise capacity. In healthy dogs, the novel myosin modulator mavacamten (MAVA), decreased LV hypercontractility and improved compliance. In the PIONEER-HCM clinical study, improvements in post-exercise LVOT gradient, exercise capacity, and symptoms were reported. To examine whether MAVA could also limit residual myosin-actin cross-bridges during diastole, and improve LV compliance, its effects on diastolic indices were evaluated. Methods: In PIONEER-HCM, an open-label, multi-site, prospective study, oHCM subjects received MAVA for 12 weeks at either 10-20 mg/d (n = 11, Cohort A; 10 completed) or at 2-5 mg/d (n = 10, Cohort B). Echo-Doppler indices of LV filling and relaxation were compared at baseline to week 12. The p-values are from Wilcoxon signed rank tests, evaluating the distribution of within-subject 12-wk changes from baseline around a null of zero. Results: MAVA reduced hypercontractility in a dose-dependent fashion, with relief of LVOTO in all subjects achieving plasma MAVA concentration >350 ng/ml (data previously reported). There was also an increase in mitral annular velocity during early diastole (e’ lat ). There was a concomitant reduction in E/e’ lat and increase in LV end-diastolic volume (LVEDV) consistent with improved LV compliance (Table). MAVA improved dyspnea score with a trend towards reduction in NT-proBNP. Conclusions: Administration of MAVA is associated with improvement in measures of myocardial relaxation (e’ lat ) and compliance in parallel with reduction in LVOT gradient. These findings are consistent with preclinical findings reported in healthy dogs and support additional evaluation of MAVA in patients with obstructive or non-obstructive HCM.

Heart Failure (HF) and chronic obstructive pulmonary disease (COPD) are morbid diseases that often coexist. In patients with coexisting disease, COPD is an independent risk factor for readmission and mortality. However, spirometry is often inaccurate in those with active heart failure. Therefore, we investigated the association between the presence of emphysema on computed tomography (CT) and readmission rates in smokers admitted with heart failure (HF). The cohort included a consecutive group of smokers discharged with HF from a tertiary center between January 1, 2014 and April 1, 2014 who also had a CT of the chest for dyspnea. The primary endpoint was any readmission for HF before April 1, 2016; secondary endpoints were 30-day readmission for HF, length of stay and all-cause mortality. Over the study period, there were 225 inpatient smokers with HF who had a concurrent chest CT (155 [69%] males, age 69±11 years, ejection fraction [EF] 46±18%, 107 [48%] LVEF of < 50%). Emphysema on CT was present in 103 (46%) and these were older, had a lower BMI, more pack-years, less diabetes and an increased afterload. During a follow-up of 2.1 years, there were 110 (49%) HF readmissions and 55 (24%) deaths. When separated by emphysema on CT, any readmission, 30-day readmission, length of stay and mortality were higher among HF patients with emphysema. In multivariable regression, emphysema by CT was associated with a two-fold higher (adjusted HR 2.11, 95% CI 1.41-3.15, p < 0.001) risk of readmission and a trend toward increased mortality (adjusted HR 1.70 95% CI 0.86-3.34, p = 0.12). In conclusion, emphysema by CT is a frequent finding in smokers hospitalized with HF and is associated with adverse outcomes in HF. This under recognized group of patients with both emphysema and heart failure may benefit from improved recognition and characterization of their co-morbid disease processes and optimization of therapies for their lung disease.

Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Extracorporeal membrane oxygenation (ECMO) is an increasingly used supportive measure for patients with refractory cardiogenic shock (CS). Despite its increasing use, there remain minimal data regarding which patients with refractory CS are most likely to benefit from ECMO. We retrospectively studied all patients (n = 123) who underwent initiation of ECMO for CS from February 2009 to September 2014 at a single center. Baseline patient characteristics, including demographics, co-morbid illness, cause of CS, available laboratory values, and patient outcomes were analyzed. Overall, 69 patients (56%) were weaned from ECMO, with 48 patients (39%) surviving to discharge. Survivors were younger (50 vs 60 years; p ≤0.0001), had a lower rate of previous smoking (27 vs 56%; p = 0.01) and chronic kidney disease (2% vs 13%; p = 0.03), and had lower lactate measured soon after ECMO initiation (3.1 vs 10.2 mmol/l; p = 0.01). Patients with pulmonary embolism (odds ratio 8.0, 95% confidence interval 2.00 to 31.99; p = 0.01) and acute cardiomyopathy (odds ratio 7.5, 95% confidence interval 1.69 to 33.27; p = 0.01) had a higher rate of survival than acute myocardial infarction, chronic cardiomyopathy, and miscellaneous etiologies compared to postcardiotomy CS as a referent. In conclusion, survival after ECMO initiation differs based on underlying cause of CS. Survival may be lower in older patients and those with early evidence of persistent hypoperfusion after initiation of ECMO for CS.

Iron deficiency is associated with reduced functional capacity and increased mortality in patients with heart failure with reduced ejection fraction (HFrEF). Correction of iron deficiency in HFrEF patients with the use of intravenous iron improves symptoms, quality of life, and exercise performance. Whether oral iron improves iron stores in HFrEF patients is unknown. We conducted a retrospective study to assess the efficacy of oral iron supplementation in iron-deficient HFrEF patients.Iron-deficient HFrEF patients with a record of oral iron supplementation and iron studies before and ∼180 days after supplementation were identified. Iron deficiency was defined as ferritin100 ng/mL or as ferritin 100-300 ng/mL with transferrin saturation (Tsat)20%. Spearman correlation was performed to assess for treatment responsiveness. In 105 patients, ferritin (from median 39 ng/mL to 75 ng/mL), Tsat (from 10% to 21%), iron (from 34 μg/dL to 69 μg/dL), and hemoglobin (from 10.4 g/dL to 11.6 g/dL) values increased (P.0001), whereas total iron-binding capacity decreased (from 343 to 313 μg/dL; P = .0007) at 164 days after initiation of oral iron supplementation.In this retrospective study, oral iron supplementation improved iron stores similarly to previously reported results with the use of intravenous iron repletion in HFrEF patients, suggesting that oral iron merits prospective evaluation as an intervention strategy in HFrEF.

Background Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality. Objectives This study sought to prospectively evaluate recovery of the left ventricular ejection fraction (LVEF) and clinical outcomes in the multicenter IPAC (Investigations of Pregnancy Associated Cardiomyopathy) study. Methods We enrolled and followed 100 women with PPCM through 1 year post-partum. The LVEF was assessed by echocardiography at baseline and at 2, 6, and 12 months post-partum. Survival free from major cardiovascular events (death, transplantation, or left ventricular [LV] assist device) was determined. Predictors of outcome, particularly race, parameters of LV dysfunction (LVEF), and remodeling (left ventricular end-diastolic diameter [LVEDD]) at presentation, were assessed by univariate and multivariate analyses. Results The cohort was 30% black, 65% white, 5% other; the mean patient age was 30 ± 6 years; and 88% were receiving beta-blockers and 81% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The LVEF at study entry was 0.35 ± 0.10, 0.51 ± 0.11 at 6 months, and 0.53 ± 0.10 at 12 months. By 1 year, 13% had experienced major events or had persistent severe cardiomyopathy with an LVEF Conclusions In a prospective cohort with PPCM, most women recovered; however, 13% had major events or persistent severe cardiomyopathy. Black women had more LV dysfunction at presentation and at 6 and 12 months post-partum. Severe LV dysfunction and greater remodeling at study entry were associated with less recovery. (Investigations of Pregnancy Associated Cardiomyopathy [IPAC]; NCT01085955 )

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P P =0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P =0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P =0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00987415.

Amyloidosis is a systemic disease characterized by the deposition of misfolded protein fibrils into the extracellular matrix of organs, disrupting their function. Transthyretin (TTR), previously known as prealbumin, is a circulating homotetramer carrier protein that binds either thyroid hormone or

One of the most devastating diagnoses a cardiologist may give a patient is that their heart failure (HF) is due to light-chain (AL) amyloidosis, because their median survival is

Background Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM), traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. This suggests a potential underlying cause for some of the iDCM cases. Objectives This study sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer’s disease. Methods Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence), and the findings were validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro by using pharmacological and genetic gain- and loss-of-function approaches. Results Aggregates in human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease’s morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of “stress-like” fibers and severely impaired cardiomyocyte contractility. Conclusions Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism connecting certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies.

Introduction: Hypertrophic cardiomyopathy (HCM) is a heart muscle disease characterized by left ventricular (LV) hypertrophy without a systemic etiology and is associated with heart failure, stroke and sudden death. Disease prevalence is estimated at 1:500, but ~84% remain undiagnosed. Patients with obstructive HCM (oHCM) have dynamic obstruction of the LV outflow tract and characteristic abnormalities in arterial bloodflow patterns. Hypothesis: Arterial pulsewaves recorded with a wearable biosensor and analyzed with machine learning algorithms could identify a signature of oHCM when compared to unaffected controls. Methods: We compared baseline arterial pulse wave morphology, obtained by photoplethysmography using an investigational wristworn biosensor (Wavelet Health, Mtn. View, CA), from oHCM patients enrolled in a digital health substudy of PIONEER HCM (NCT02842242) to unaffected controls from a Wavelet Health database. Five minute recordings were obtained at rest, and data sets were divided into training and validation cohorts. A beat-by-beat machine learning model was developed using a predefined feature set to calculate an HCM probability score, and an optimal threshold score was determined. The model was evaluated using summary statistics and an ROC area-under-curve metric. Results: Arterial pulsewave recordings were obtained from 14 patients with oHCM at rest and 81 unaffected controls. An oHCM machine learning classifier was developed based on 42 calculated metrics. After training and cross-validation (n=9 oHCM, n=48 control), the model achieved 98% accuracy. Application of this model to a validation cohort (n=5 oHCM, n=33 control) confirmed an increased probability in oHCM patients compared to unaffected controls (0.40 ± 0.13 vs. 0.18 ± 0.10; p=0.006). Analysis of the ROC curve in the pooled cohort shows an area under the curve of 0.88. Conclusion: This first-of-its-kind study suggests that a signature of arterial bloodflow in oHCM can be identified with the combination of a wristworn biosensor and machine learning algorithms. These data raise the possibility of a novel approach to the non-invasive detection of oHCM.

Mechanical circulatory support (MCS) offers a surgical option for advanced heart failure when optimal medical therapy is inadequate. MCS therapy improves prognosis, functional status, and quality of life.1,2 The INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) tracks patient selection and outcomes for all implanted US Food and Drug Administration–approved MCS devices. From June 2006 until December 2014, >15 000 patients received MCS, and >2000 implantations are performed annually. One-year survival with current continuous-flow devices is reported to be 80%, and 2-year survival, 70%.3 In patients awaiting heart transplantation, MCS provides a bridge to transplantation, and for others who are ineligible for heart transplantation, MCS provides permanent support or destination therapy. Indications and absolute and relative contraindications to durable MCS are listed in Table 1. View this table: Table 1. Indications and Contraindications to Durable Mechanical Support As of July 2014, 158 centers in the United States offer long-term MCS.3 Patients often live a substantial distance from the implanting center, necessitating active involvement of local first responders (emergency medical technicians, police, and fire department personnel), emergency department staff, primary care, and referring cardiologists. Because patients with MCS are becoming increasingly mobile, basic knowledge of equipment is necessary for personnel in public areas such as schools, public transportation, and airplanes/airports. Ambulatory patients with MCS can span the entire age spectrum from pediatrics to geriatrics. The aim of this document is to provide guidance for nonexperts in MCS and to facilitate the informed assessment, stabilization, and transport of the patient with MCS back to the MCS center for definitive therapy. In addition, the principles herein provide a foundation for emergency management and a framework to address the management of known MCS-associated complications and expected comorbid medical problems. Currently in the United States, the most frequently used durable devices are continuous-flow devices with …

Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute–sponsored Heart Failure Clinical Research Network. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02742129.

Background The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study was a multicenter, randomized trial of sildenafil versus placebo in heart failure with preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants. Objectives The aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms. Methods The RELAX study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months. Results Compared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p Conclusions HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multimorbidity, impaired chronotropic reserve, left ventricular hypertrophy, and activation of inflammatory, pro-oxidative, vasoconstrictor, and profibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure [The RELAX Study]; NCT00763867 )

Background— Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Methods and Results— Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E / e ′, 16; deceleration time, 185 ms; left atrial volume, 44 mL/m 2 ) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg −1 min −1 , 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P =0.008] and left ventricular mass [1.6%, P =0.008]), resting stroke volume (2.0%, P =0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P =0.03] and E / e ′ [1.4%, P =0.009]), and arterial function (arterial elastance [2.1%, P =0.002] and systemic arterial compliance [1.5%, P =0.007]), each explained only a small additional portion of the variance in peak oxygen consumption. Conclusions— In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867

Hypertrophic cardiomyopathy (HCM) is a heritable disease of heart muscle that increases the risk for heart failure, stroke, and sudden death, even in asymptomatic patients. With only 10–20% of affected people currently diagnosed, there is an unmet need for an effective screening tool outside of the clinical setting. Photoplethysmography uses a noninvasive optical sensor incorporated in commercial smart watches to detect blood volume changes at the skin surface. In this study, we obtained photoplethysmography recordings and echocardiograms from 19 HCM patients with left ventricular outflow tract obstruction (oHCM) and a control cohort of 64 healthy volunteers. Automated analysis showed a significant difference in oHCM patients for 38/42 morphometric pulse wave features, including measures of systolic ejection time, rate of rise during systole, and respiratory variation. We developed a machine learning classifier that achieved a C-statistic for oHCM detection of 0.99 (95% CI: 0.99–1.0). With further development, this approach could provide a noninvasive and widely available screening tool for obstructive HCM.

Background Orthotopic heart transplant (OHT), followed by myeloablative chemotherapy and autologous stem cell transplant (ASCT), has been successful in the treatment of amyloid light-chain (AL) cardiac amyloidosis. The purpose of this study was to identify predictors of survival to OHT in patients with end-stage heart failure due to AL amyloidosis and compare post-OHT survival of cardiac amyloid patients with survival of other cardiomyopathy patients undergoing OHT. Methods From January 2000 to June 2011, 31 patients with end-stage heart failure secondary to AL amyloidosis were listed for OHT at Massachusetts General Hospital. Univariate and multivariate regression analyses identified predictors of survival to OHT. Kaplan-Meier analysis compared survival between the Massachusetts General Hospital amyloidosis patients and non-amyloid cardiomyopathy patients from the Scientific Registry of Transplant Recipients (SRTR). Results Low body mass index was the only predictor of survival to OHT in patients with end-stage heart failure caused by cardiac amyloidosis. Survival of cardiac amyloid patients who died before receiving a donor heart was only 63 ± 45 days after listing. Patients who survived to OHT received a donor organ at 53 ± 48 days after listing. Survival of AL amyloidosis patients on the waiting list was less than patients on the waiting list for all other non-amyloid diagnoses. The long-term survival of amyloid patients who underwent OHT was no different than the survival of non-amyloid, restrictive (p = 0.34), non-amyloid dilated (p = 0.34), or all non-amyloid cardiomyopathy patients (p = 0.22) in the SRTR database. Conclusions Amyloid patients who survive to OHT, followed by ASCT, have a survival rate similar to other cardiomyopathy patients undergoing OHT; however, 35% of the patients died awaiting OHT. The only predictor of survival to OHT in AL amyloidosis patients was a low body mass index, which correlated with a shorter time on the waiting list. To optimize the survival of these patients, access to donor organs must be improved.

Background— Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak V O 2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. Methods and Results— RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak V O 2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and V E /V CO 2 was higher. Conclusions— AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Background: Peripartum cardiomyopathy (PPCM) is a rare condition that carries a high morbidity and mortality among young women. Studies examining the association of modifiable risk factors such as hypertension with outcomes in this population are sparse. Methods: We conducted a multi-center retrospective study across three major centers (BWH, BIDMC, MGH) to identify subjects with PPCM using the following criteria: ejection fraction < 40%, development of heart failure within the last month of pregnancy or within 5 months of delivery and no other identifiable cause of heart failure with reduced ejection fraction. We defined adverse clinical outcome as a composite of heart failure hospitalizations, need for extra-corporeal membrane oxygenation, ejection fraction Results: In all, 237 women met criteria for PPCM across the three centers between April 1995 and November 2015. Participants had a median age of 33.1 years (IQR: 28.6-38.0), gravida 2.0, para 2.0, mean left ventricular ejection fraction at diagnosis of 30%; 25% had chronic hypertension and 14% had preeclampsia. After a median follow-up of 3.2 years (IQR: 1.0-7.8), 59 events occurred. In a logistic regression model adjusting for age, number of prior pregnancies and number of deliveries, women with preeclampsia had an OR of 1.34 (95% CI: 1.05-1.72), p=0.02 as compared to those without preeclampsia. A similar association was observed for hypertension (Table). In sensitivity analysis, the association between preeclampsia and adverse outcomes persisted for blacks and other races, but not for whites. Conclusion: Our study suggests that hypertension or preeclampsia at diagnosis is associated with increased risk of heart failure hospitalizations, need for extra-corporeal membrane oxygenation, poor left ventricular function recovery, cardiac transplantation and death on follow-up in women with PPCM. Clinicians should consider aggressive treatment of hypertension in women of childbearing age.

Right ventricular failure is the subject of renewed attention as the importance of RV function in a variety of disease states has been recognized. The RV is highly compliant, and is able to accommodate a wide range of preload conditions. Yet, it is afterload-sensitive, and normal physiology is dependent on its association with the low resistance of the pulmonary vasculature. Changes in the pulmonary vascular resistance, either acutely or over time, provoke a series of adaptations that are designed to maintain a normal cardiac output, but ultimately lead to decompensation and RV failure. Through ventricular interdependence, RV failure may impair left ventricular diastolic and systolic function, further reducing cardiac performance. Both echocardiography and magnetic resonance imaging can provide detailed information about RV structure, with MRI providing better assessment of ventricular volumes and RV function. Right heart catheterization is often necessary for definitive diagnosis of the etiology of RV failure and for determining the best therapeutic options. The treatment of RV failure is highly dependent on the underlying etiology, which should be corrected if possible. Targeted medical therapy is particularly useful in cases of pulmonary arterial hypertension, and is under investigation for broader use in other causes of pulmonary hypertension.

Aims: Left ventricular apical ballooning syndrome (LVABS) is a clinical condition of unknown etiology, characterized by acute onset of atypical apical wall motion and absence of coronary artery disease. Gadolinium-enhanced cardiac magnetic resonance imaging (Gd-MRI) may be used to identify patients with myocarditis. Using cardiac MRI, we evaluated whether acute myocarditis may be an etiology that underlies LVABS. Methods and Results: Consecutive patients who presented with LVABS during a three-year period were included. Demographic data was recorded and echocardiography, coronary angiography, and hemodynamic assessment performed. Gd-MRI was performed in all patients. The study was deemed consistent with myocarditis when global myocardial to skeletal muscle enhancement ratio was ≥3.5. Regional Gd-MRI analysis was also performed. Patients (n = 11) were female (100%) and of mean age 72 years (72 ± 11). Preceding febrile illness occurred in 4 (36.3%) and leukocytosis in 6 (54.4%) patients. Initial mean left ventricular ejection fraction (41% ± 12%) improved (70.2% ± 8%) upon follow-up (39 ± 43 days). Global MRI analysis was positive in 5/11 (45.5%) (mean relative enhancement ratio 4.8 ± 1.4). Regional MRI analysis was positive in 4/6 further patients (overall: 9/11 (82%)). Conclusions: Gadolinium enhanced MRI imaging in LVABS implicates myocarditis as a possible etiology. Regional MRI analysis adds sensitivity to global cardiac MRI evaluation.

Myotonic dystrophy type 2 (DM2) is an autosomal recessive muscular dystrophy classically affecting skeletal muscle with a latency of 30 to 40 years before the expression of symptoms of skeletal muscle weakness and myalgias. Postmortem studies have identified histopathologic and clinical involvement of the heart,1 and cardiac arrhythmias and sudden death have been observed, including in patients without previous cardiac symptoms.2 Although investigations of other muscular dystrophies have used cardiac magnetic resonance (CMR) assessments of myocardial tissue structure and its relationship with cardiovascular outcomes, no large investigations of DM2 with comprehensive tissue-based structural phenotypes has been reported. In this issue of Circulation: Cardiovascular Imaging , Schmacht et al3 provide detailed CMR characterization of subclinical myocardial phenotypes analogous to peripheral skeletal abnormalities present in DM2. See Article by Schmacht et al In 27 individuals with genetically confirmed DM2, the …

Background— Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity. Methods and Results— Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg, P P 2. PV distensibility also predicted cardiovascular mortality independent of peak VO 2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10–0.93; P =0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility ( P =0.015) in the sildenafil group only. Conclusions— PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00309790.

Iron deficiency is present in ≈50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with heart failure have not been defined. Although results of intravenous iron repletion trials have been promising, regularly treating patients with intravenous iron products is both expensive and poses logistical challenges for outpatients. Herein, we describe the rationale for the Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) trial. This National Institute of Health-sponsored trial will investigate oral iron polysaccharide compared with matching placebo with the primary end point of change in exercise capacity as measured by peak oxygen consumption at baseline and at 16 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02188784.

A B S T R AC T Background Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. Methods We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. Results Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P = 0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was −0.04±0.53 mg per deciliter (−3.5±46.9 μmol per liter) in the pharmacologictherapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P = 0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P = 0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P = 0.03). Conclusions In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.)

AL cardiomyopathy leading to heart failure (HF) represents a significant cause of morbidity and mortality in systemic amyloidosis. However, the paucity of robust in vivo models of AL-induced cardiac dysfunction has limited our ability to probe the mechanisms of AL heart disease. To address this problem, we have developed a model of AL HF in zebrafish embryos by injection of in vitro transcribed mRNA encoding amyloidogenic light chain (aLC) into fertilized oocytes. We demonstrate that expression of aLC causes cardiomyopathy in developing zebrafish without significantly impairing extracardiac development. The cardiac ventricle of embryos expressing aLC exhibit impaired contractility, smaller size, and increased myocardial thickness which result in congestion and edema, features paralleling the clinical manifestations of amyloid cardiomyopathy. Phosphorylated p38, a marker of oxidative stress, was increased in response to aLC expression. No evidence of amyloid fibril deposition was identified. Thus, expression of aLC mRNA in zebrafish results in cardio toxic effects without fibril deposition. This is consistent with prior evidence indicating that aLC oligomers mediate cardiac dysfunction in vitro. This model will allow exploration of amyloid pathophysiology and testing of interventions to reduce and reverse the deleterious effects of amyloidosis on myocardial function.

Heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (HF) accounts for approximately half of HF cases in the community, and the portion of HF with preserved ejection fraction (EF) is increasing.1 Patients with HFpEF have limited functional capacity and poor prognosis. With ongoing shifts in the age distribution of the population, the burden of HFpEF is projected to increase. To date, there is no proven therapy for HFpEF. There is an urgent need for effective therapies for HFpEF. To date, 3 randomized control trials in HFpEF have tested the impact of renin-angiotensin-aldosterone antagonists on clinical outcomes in HFpEF. None of these trials demonstrated benefit individually (Figure 1) or in a pooled analysis (n=8021).2 An aldosterone antagonist trial in HFpEF is ongoing (clinicaltrials.gov NCT00094302). A trial of the β-blocker nebivolol in HF patients with normal or reduced EF was underpowered but suggested a benefit of β-blocker in the relatively small subset of HFpEF patients (Figure 1).3 The digitalis investigation group (DIG) trial showed no reduction in mortality with digoxin in a small ancillary study of HFpEF patients.4 Figure 1. Previous randomized clinical trials in heart failure with preserved ejection fraction (HFpEF): Summary of the hazards ratios (95% CI) for the primary outcome measure of the large randomized placebo-controlled clinical trials in HFpEF to date. CHARM-Preserved indicates Candesartan in Patients With Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction; I-PRESERVE, Irbesartan in Patients With Heart Failure and Preserved Ejection Fraction; PEP-CHF, Perindopril in Elderly People With Chronic Heart Failure; SENIORS, Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure; DIG, Digitalis Investigation Group Trial. Although inadequate power or crossover may have contributed to negative findings in these trials, unique pathophysiology in HFpEF may mediate the differential response to neurohumoral …

Aims Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (PH-sLVD) frequently complicates heart failure (HF), and greatly worsens the prognosis of patients with sLVD, but as yet has no approved treatment. The LEPHT study aims to characterize the haemodynamic profile, safety, tolerability, and pharmacokinetic profile of riociguat (BAY 63-2521), an oral stimulator of soluble guanylate cyclase, in patients with PH-sLVD. Methods and results This 16-week, phase IIb, randomized, placebo-controlled, double-blind study enrols patients with PH-sLVD, defined as left ventricular ejection fraction (LVEF) ≤40% and mean pulmonary arterial pressure (PAPmean) ≥25 mmHg at rest. Patients using optimized HF medication will receive placebo or riociguat 0.5 mg, 1 mg, or up to 2 mg three times daily. The dose will be titrated for 8 weeks, based on systolic blood pressure and well-being, followed by 8 weeks of treatment at a stable dose. The primary efficacy variable is PAPmean, while secondary efficacy endpoints include LVEF, exercise capacity, quality of life, and other haemodynamic and echocardiographic measurements. Safety and pharmacokinetics will also be assessed. After the 16-week study, patients will have the opportunity to be treated with riociguat in a long-term extension phase. Conclusion The LEPHT study will provide valuable information on the haemodynamic, echocardiographic, and preliminary clinical effects of riociguat in patients with PH-sLVD. Trial registration NCT01065454

Background— Risk factors for early mortality after heart transplant (HT) have not been used for quantitative risk prediction. We sought to develop and validate a risk prediction model for posttransplant in-hospital mortality in HT recipients. Methods and Results— We derived the model in subjects aged ≥18 years who underwent primary HT in the United States from January 2007 to June 2009 (n=4248) and validated it internally using a bootstrapping technique (200 random samples, n=4248). We then assessed the model's performance in patients receiving an HT from July 2009 to October 2010 (external validation cohort, n=2346). Posttransplant in-hospital mortality was 4.7% in the model derivation cohort. The best-fitting model based on recipient characteristics at transplant had 6 variables: age, diagnosis, type of mechanical support, ventilator support, estimated glomerular filtration rate, and total serum bilirubin. Model discrimination for survivors versus nonsurvivors was acceptable during derivation and internal validation (C statistic, 0.722 and 0.731, respectively) as was model calibration during derivation (Hosmer Lemeshow [HL] P =0.47). Model performance was reasonable in the external validation cohort (predicted mortality, 4.9%; actual mortality, 4.3%; R 2 =0.95; C statistic, 0.68; HL P =0.48). Adding the donor-related variables of age and ischemic time to the model improved its performance in both the model derivation (C statistic, 0.742; HL P =0.70) and the external validation (C statistic, 0.695; HL P =0.42) cohorts. Conclusions— The proposed model allows risk stratification of HT candidates for early posttransplant mortality and may be useful in counseling patients with regard to their posttransplant prognosis. The model with additional donor-related variables may be useful during donor selection.

Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.The National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF).Treating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.

Aims Current imaging techniques attempt to identify responders to cardiac resynchronization therapy (CRT). However, because CRT response may depend upon several factors, it may be clinically more useful to identify patients for whom CRT would not be beneficial even under optimal conditions. We aimed to determine the negative predictive value of a composite echocardiographic index evaluating atrial-ventricular dyssynchrony (AV-DYS) and intraventricular dyssynchrony. Methods and results Subjects with standard indications for CRT underwent echo before and during the month following device implantation. AV-DYS was defined as a percentage of left ventricular (LV) filling time over the cardiac cycle. AV-DYS, which produces a characteristic rocking of the LV apex, was quantified as the percentage of the cardiac cycle over which tissue Doppler-derived displacement curves of the septal and lateral walls showed discordance. CRT responder status was determined based on the early haemodynamic response to CRT (intra-individual improvement >25% in the Doppler-derived LV d P /d t ). Among 40 patients, optimal cut-points predicting CRT response were 31% for LV apical rocking and 39% for AV-DYS. The presence of either apical rocking >31% or AV-DYS ≤39% had a sensitivity of 95%, specificity of 80%, positive predictive value of 83%, and a negative predictive value of 94% for CRT response. Conclusion After pre-selection of candidates for CRT by QRS duration, application of a simple composite echocardiographic index may exclude patients who would be non-responders to CRT and thus improve the global rate of therapy success.

A panel of experts convened by telephone on April 20, 2011 to discuss their experiences and recommendations regarding diagnosis and management of patients with Group 2 PH. The conversation was facilitated by Myung Park, MD, Associate Professor of Medicine and Director, Pulmonary Vascular Disease Program, Division of Cardiology at University of Maryland School of Medicine and guest editor of this issue. The participants were Rene Alvarez, MD, Associate Professor of Medicine and Director, Advanced Heart Failure/Pulmonary Hypertension Outreach Program, University of Pittsburgh School of Medicine; Teresa De Marco, MD, Professor of Medicine, Director, Heart Failure and Pulmonary Hypertension Program and Director, Heart Transplantation, University of California San Francisco Medical Center; Marc Semigran, MD, Medical Director of the Heart Failure and Cardiac Transplant Program at the Massachusetts General Hospital Center and Associate Professor of Medicine at Harvard Medical School; and Ivan Robbins, MD, Assistant Professor of Medicine and Director, Lung Transplant Program, Vanderbilt University Medical Center.

Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established. Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O(2) for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long-term survival (median follow-up 2.4 years). Five-year survival was 56%. Baseline PVR (mean±SD 850±580 dyne-sec/cm(5)) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO and O(2) was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O(2) had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23-0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O(2) had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22-0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O(2) were independent predictors of survival. Reduction in PVR or mPAP during short-term administration of inhaled NO and O(2) predicts survival in PAH patients.

Granting clinical staff privileges to physicians is a primary mechanism institutions use to uphold quality care. The Joint Commission on Accreditation of Healthcare Organizations requires that medical staff privileges be based on professional criteria specified in medical staff bylaws. Physicians

The purpose of the present study was to assess whether a low socioeconomic (SE) position is associated with outcomes in heart transplant recipients. We used the US Census 2000 database to derive a summary SE score for 520 patients who had undergone underwent a first heart transplant at 1 of 4 Boston hospitals during 1996 to 2005 and compared the outcomes in the lowest quartile SE group (n = 129) to those for the remaining patients (n = 391). The low SE group and controls were similar with respect to cardiac diagnosis, hemodynamic support, listing status, year of transplant, and initial immune suppression. Low SE patients were more likely to be nonwhite. Graft loss occurred in 142 patients (135 deaths and 7 repeat transplants). Hospital mortality after transplantation was not associated with race/ethnicity or low SE position. In patients who survived the transplant hospitalization, nonwhite ethnicity (hazard ratio 1.8, 95% confidence interval 1.1 to 2.9) and low SE group (hazard ratio 1.7, 95% confidence interval 1.1 to 2.5) were associated with a greater risk of subsequent graft loss. In the adjusted analysis, the risk of graft loss remained greater for both nonwhite race/ethnicity (hazard ratio 1.7, 95% confidence interval 1.0 to 2.9) and low SE position (hazard ratio 1.5, 95% confidence interval 1.0 to 2.4). Rejection episodes were more frequent in nonwhite transplant recipients and in those in the low SE group. In conclusion, among heart transplant recipients who survive the transplant hospitalization, nonwhite recipients and those in a low SE position are at greater risk of rejection and graft loss.

Background— Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of β-amyloid impair cell function and lead to cell death. Methods and Results— We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca 2+ homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 ( PSEN1 ) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. Conclusions— On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca 2+ handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of

Indications for implantable cardioverter-defibrillators (ICDs) in heart failure (HF) are expanding and may include more than 1 million patients. This study examined patient expectations from ICDs for primary prevention of sudden death in HF.Study participants (n = 105) had an EF35% and symptomatic HF, without history of ventricular tachycardia/fibrillation or syncope. Subjects completed a written survey about perceived ICD benefits, survival expectations, and circumstances under which they might deactivate defibrillation. Mean age was 58, LVEF 21%, 40% were New York Heart Association Class III-IV, and 65% already had a primary prevention ICD. Most patients anticipated more than10 years survival despite symptomatic HF. Nearly 54% expected an ICD to saveor=50 lives per 100 during 5 years. ICD recipients expressed more confidence that the device would save their own lives compared with those without an ICD (P.001). Despite understanding the ease of deactivation, 70% of ICD recipients indicated they would keep the ICD on even if dying of cancer, 55% even if having daily shocks, and none would inactivate defibrillation even if suffering constant dyspnea at rest.HF patients anticipate long survival, overestimate survival benefits conferred by ICDs, and express reluctance to deactivate their devices even for end-stage disease.

Current implantable left ventricular assist devices (LVAD) improve survival and function for patients with very late stage heart failure (HF) but may also offer benefit before inotrope dependence. Debate continues about selection of HF patients for LVAD therapy. We sought to determine what level of personal risk and disability HF patients thought would warrant LVAD therapy.The study included 105 patients with symptomatic HF and an LV ejection fraction (EF)35% who were given a written paragraph about LVADs and asked about circumstances under which they would consider such a device. New York Heart Association (NYHA) functional class, time trade-off utility, and patient-assessed functional score were determined.Participants (mean age, 58 years) had an LVEF of 21%. The median duration of HF was 5 years, and 65% had a primary prevention implantable cardioverter defibrillator. Presented with a scenario of bed-ridden HF, 81% stated they would definitely or probably want an LVAD; 50% would consider LVAD to prolong survival if HF survival were predicted to be1 year and 75% if6 months. Meanwhile, 44% would consider LVAD if they could only walk1 block and 64% if they could not dress without stopping. Anticipated thresholds did not differ by NYHA class, time trade-off, or functional score.Patient thresholds for LVAD insertion parallel objective survival and functional data. HF patients would be receptive to referral for discussion of LVAD by the time expected mortality is within 6 to 12 months and activity remains limited to less than 1 block.

Apoptosis contributes notably to the pathogenesis of heart failure, but these investigators found that upregulation of endogenous antiapoptotic mechanisms counterbalance the death-receptor and mitochondrial apoptotic pathways. Concurrent activation of antiapoptotic factors can interrupt the apoptotic cascade, prevent cell loss despite the presence of multiple proapoptotic factors, and could offer an opportunity for therapeutic intervention. Background Despite widespread activation of proapoptotic stimuli and mediators, the degree of apoptosis in failing hearts is not very high. Endogenous antiapoptotic mechanisms are thought to be triggered by the heart-failure process. We investigated whether activation of endogenous apoptosis inhibitors plays a part when death receptor and mitochondrial apoptotic pathways have been triggered. Methods We evaluated various proapoptotic and antiapoptotic factors in myocardial tissue specimens obtained from normal and explanted end-stage ischemic and dilated cardiomyopathic hearts. Caspases (CASPs) 3, 8 and 9, total and activated Bcl-2 homology domain 3-interacting domain death agonist, the X-linked inhibitor of apoptosis (XIAP), and DNA fragmentation factor (DFF) proteins were analyzed by western blotting. Expression of messenger RNA was measured by reverse-transcription polymerase chain reaction for the XIAP, DIABLO, CFLAR and DFF genes. We also assessed CASP3, CASP8 and CASP9 and DFF activity. Cytochrome c1 localization in myocytes was analyzed by immunohistochemistry and immunoelectron microscopy. Results We collected myocardial tissue from eight cardiomyopathic hearts and five normal hearts. Cytochrome c1 was released from mitochondria into the cytosol in the cardiomyopathic hearts but CASP9 was not activated. CASP8 activity was increased compared with that in normal myocardium. Although CASP3 was cleaved, activity was not greatly increased because of an increase in XIAP and decrease in DIABLO expression. DFF proteins were conspicuously absent. Conclusions Concurrent upregulation of endogenous antiapoptotic mechanisms can interrupt the apoptotic cascade and prevents cell loss despite the presence of multiple proapoptotic factors. This period might offer a therapeutic window for restoration of myocardial function in heart failure.

Background— Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (V e /V co 2 slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure. Methods and Results— A cohort of patients with systolic heart failure (mean�SD age, 58�13 years; left ventricular ejection fraction, 0.27�0.05; peak oxygen uptake, 11.2�3.2 mL kg −1 min −1 ) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. V e /V co 2 slope was positively related to rest and exercise pulmonary vascular resistance ( R =0.39 and R =0.60, respectively) and rest pulmonary capillary wedge pressure ( R =0.49, P R =−0.29, P =0.03). Over the 12-week study period, V e /V co 2 slope fell 8�3% ( P =0.02) with sildenafil and was unchanged with placebo. Changes in V e /V co 2 slope correlated with changes in exercise pulmonary vascular resistance ( R =0.69, P R =−0.58 and −0.40, respectively, both P Conclusions— In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise.