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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.

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.

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 …

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.

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.

Background: Orthotopic heart transplant (OHT) is an accepted treatment option for transthyretin amyloidosis (ATTR) patients with end-stage heart failure. The incremental survival benefit of adjunctive liver transplant remains poorly defined. Methods: We aim to describe the clinical profiles/prognoses of patients undergoing OHT/liver transplant compared with OHT alone. From January 1998 to May 2015, 42 of 48 ATTR patients being evaluated for OHT at 10 institutions underwent transplant and were included in the final analysis. Data were entered into an encrypted online database, Research Electronic Data Capture. The primary endpoint of post-OHT all-cause mortality was compared between 3 cohorts defined by transplant and mutation status using Kaplan-Meier survival analysis: OHT alone-wild type (WT) (n=12; Cohort A); OHT alone-ATTR mutation (n=21; Cohort B); and combined OHT/liver transplant (n=9; Cohort C). Results: Of those undergoing OHT, 12 (28.6%) were WT, 15 (32.5%) had a V122I mutation, 3 (7.1%) had a T60A mutation, 8 had other mutations, and 4 had unknown mutations. For the subset of 9 patients who underwent combined OHT/liver transplant (4 concurrently, 5 sequentially), the mutations were as follows: V122I (n=3), T60A (n=3), S23A (n=2), and Tyr77 (n=1). Baseline characteristics did not differ significantly across the 3 cohorts for age, sex, LV ejection fraction, and other demographic, clinical, and hemodynamic characteristics. Peripheral neuropathy was present in 2 (17%) of Cohort A, 7 (33%) of Cohort B, and 4 (44%) of Cohort C (p=0.08). Post-OHT all-cause mortality was similar across cohorts (log-rank P=0.218; Figure). Conclusions: This is the largest analysis of ATTR cardiac amyloidosis patients receiving heart and liver transplantation. ATTR patients receiving OHT/liver transplant versus OHT alone have similar median-term survival. The added survival benefit of liver transplantation to OHT in ATTR mutant patients should be investigated further.

Background: Cardiac amyloidosis is characterized by progressive ventricular thickening and diastolic heart failure. The left ventricular ejection fraction (EF) often remains normal even in advanced disease. The myocardial contraction fraction (MCF, the ratio of left ventricular stroke volume to myocardial volume) is a novel measure of myocardial shortening and may be superior to EF for predicting survival in cardiac amyloidosis. Methods: We measured MCF and EF from two-dimensional echocardiograms obtained in 86 subjects undergoing heart transplant evaluation for AL cardiac amyloidosis. Cox proportional hazards models and Kaplan-Meier survival analysis were used to compare MCF and EF as predictors of all-cause mortality. Subjects were censored at the time of heart transplant. Results: The mean age was 54.6 ± 7.9 years. The mean EF was 49.3 ± 12.7% and the mean MCF was 13.0 ± 5.5%. Over a median follow-up of 59 days (IQR 29-110 days), 38 subjects (44.2%) died and 48 (55.8%) underwent heart transplant. In unadjusted analyses, both MCF (HR 0.89, 95% CI 0.82-0.96, p = 0.002) and EF (HR 0.96, 95% CI 0.94-0.99, p = 0.015) predicted overall survival. In multivariate analyses adjusted for serum free light chain difference, the hazard ratio associated with each 5% absolute decrease in MCF was 2.11 (95% CI 1.32-3.38, p= 0.002). The hazard ratio associated with each 5% absolute decrease in EF was not statistically significant (HR 1.16, 95% CI 0.97-1.39, p=0.09). Conclusions: Myocardial contraction fraction is superior to EF for predicting survival in patients undergoing heart transplant evaluation for AL cardiac amyloidosis.

Introduction: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an emerging therapy for refractory cardiogenic shock (CS); however, characteristics of patients most likely to benefit from this therapy remain to be determined. We hypothesized that the underlying etiology of CS and patient specific characteristics predict survival to discharge. Methods: We compared outcomes in patients supported with VA-ECMO for refractory CS resulting from (1) acute myocardial infarction (AMI; with or without revascularization); (2) acute pulmonary embolism (PE); (3) acute cardiomyopathy; (4) chronic cardiomyopathy; (5) post-cardiotomy; and (6) other etiologies of shock. Chi-square analysis was used to identify predictors of survival to discharge after VA-ECMO. Results: From 2009-2013, 102 patients were initiated on VA-ECMO for refractory CS. The average age was 52 ±15 (mean ± SD) years old with 71 (70%) males. Overall, 39 (38%) patients survived to discharge. In the cohort, 22 patients were post-cardiotomy and 5 (23%) of those survived to discharge. Of the 80 patients without prior cardiotomy, survival to discharge was 27% (8/30) after AMI, 64% (9/14) after PE, 75% (6/8) with acute cardiomyopathy, 50% (5/10) with chronic cardiomyopathy, and 39% (7/18) with other CS etiologies. Survivors were younger (45 ±13 vs 56 ±14, p = 0.0002) and none of the 24 patients over the age of 64 years old survived to discharge. There was a significant difference in survival when comparing etiologies of shock (p = 0.012 by Chi-square comparison among etiologies). There was no significant difference in survival by gender. Conclusions: Survival in patients with refractory CS requiring VA-ECMO may depend on age and underlying etiology of shock. Further research into predictors of survival after institution of VA-ECMO is warranted.

Of the molecules that transmit an extracellular message to alter cardiomyocyte physiology, the cyclic nucleotides are among the better understood as regulators of cell function. The relatively recent identification of nitric oxide (NO) as a stimulus of cGMP production by soluble guanyl cyclase,1 as well as of the natriuretic peptides as a stimulating membrane-bound guanylate cyclase,2 has led to increasing interest in the study of the effects of modulating intracellular cGMP, with most interest being in the area of vascular biology. Studies of the myocardial effects of altering intracellular cGMP have been less extensive, perhaps because systemic agents that affect cGMP levels are often vasodilatory, and their administration is accompanied by changes in blood pressure that can limit the ability to observe myocardial effects. Both cAMP, the second messenger of the β-adrenergic signaling system, and cGMP have a rapid intracellular turnover as a result of the balance between their formation by cyclases and their degradation by phosphodiesterases (PDEs). In this issue of Circulation , Borlaug and colleagues use load-independent measures of contractility to assess the myocardial effects of an agent (sildenafil) that increases intracellular cGMP levels by inhibiting its degradation.3 Article p 2642 In myocardial cells, cGMP has a several intracellular targets that may alter contractility and diastolic function. cGMP can activate a cGMP-dependent cAMP PDE, decreasing myocardial cAMP levels and thereby leading to a reduction of cAMP-dependent phosphorylation of the L-type calcium channels and of calcium influx.4 cGMP can also depress cAMP production by inhibiting adenylate cyclase.5 Furthermore, a cGMP-dependent protein kinase can also directly decrease the magnitude of calcium influx through the L-type channels.6 In addition, a separate cGMP-dependent protein kinase can phosphorylate troponin I, which results in a decreased sensitivity of the contractile apparatus to calcium.7 The phosphorylation of troponin …

Background— Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Methods and Results— Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (−6.1±1.3 mm Hg; P P =0.10), cardiac index (0.4 L·min −1 ·m −2 ; 95% confidence interval, 0.2–0.5; P =0.0001) and stroke volume index (5.2 mL·m −2 ; 95% confidence interval, 2.0–8.4; P =0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (−46.6 dynes·s −1 ·cm −5 ; 95% confidence interval, –89.4 to –3.8; P =0.03) and systemic vascular resistance (−239.3 dynes·s −1 ·cm −5 ; 95% confidence interval, –363.4 to –115.3; P =0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score ( P =0.0002). Discontinuation of treatment was similar between treatment groups. Conclusions— Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01065454.

Background Nitric oxide (NO) and nitrosovasodilators that release NO inhibit platelet aggregation. The antithrombotic effect of intravenously infused nitrosovasodilators is usually accompanied by systemic vasodilation. Inhaled NO is a pulmonary vasodilator that does not produce systemic hemodynamic effects. This study examines the antithrombotic effect of inhaled NO in a canine model of platelet-mediated coronary artery reocclusion after thrombolysis. Methods and Results In 25 anesthetized dogs, a segment of the left anterior descending coronary artery was traumatized and a high-grade stenosis created. Thrombus was injected at this site, and tissue plasminogen activator was administered, producing cyclic flow variations (CFVs) in 24 of 25 dogs. CFV frequency was unchanged in dogs not breathing NO but decreased by 35±9% ( P P P P P 2 agonist U-46619. In vitro ADP-induced platelet aggregation was inhibited by NO gas. Conclusions Inhaled NO at concentrations of 20 and 80 ppm increases coronary patency and decreases CFV frequency in a canine model of platelet-mediated coronary reocclusion after thrombolysis without producing systemic hemodynamic effects.

The era of mechanical circulatory support (MCS) began in 1953 with the development of cardiopulmonary bypass to facilitate open heart surgery.1 In 1964, the National Heart Institute (now the National Heart, Lung, and Blood Institute) funded the Artificial Heart Program and became actively involved in MCS development. This led to requests for Proposals issued in 1977 and 1980, which laid the foundation for the development of implantable MCS for long-term use, including devices capable of hospital discharge, in the 1990s. Although heart transplantation is now commonplace at many hospitals, the inadequate supply of donor hearts and patient contraindications to transplantation continue to severely restrict its application. As the demand for long-term replacement of diseased hearts increases, there is a clear need for innovative, safe, and durable MCS to treat the growing population of patients with advanced heart failure (HF). Many exciting changes in the field of MCS have occurred in the past few years, including the development of smaller portable pumps and the concept of destination therapy (DT), or permanent pump placement as an alternative to heart transplantation. Currently, there are no published guidelines for the use of MCS. Thus, it is our intent that this statement will provide the contemporary cardiologist and other HF providers with an understanding of general considerations when determining the appropriateness of MCS. There is little hope that complete consensus will ever be reached on the definition of advanced HF, but most physicians caring for such patients on a regular basis readily identify the characteristics of these patients. Advanced HF patients are those with clinically significant circulatory compromise who require special care, including consideration for heart transplantation, continuous intravenous inotropic therapy, MCS, or hospice.2,3 Typically, such patients have symptoms at rest or with minimal exertion and cannot perform many activities of …

Secondary pulmonary hypertension (PH) is an important prognostic indicator in patients with systolic heart failure (HF), but the pattern of increase in pulmonary arterial pressure (PAP) during exercise and its relationship to exercise capacity and pulmonary capillary wedge pressure (PCWP) have not been comprehensively investigated. We hypothesized that HF patients would develop an increase in PAP out of proportion to the increase in PCWP during exercise and that the rate of PAP increase during exercise would predict exercise capacity in HF. Thirty-three patients with systolic HF (mean±SD, age 58 ± 7 years, left ventricular ejection fraction 0.27 ± 0.05, peak oxygen uptake 11.2 ± 3.2 ml/kg/min) and 10 normal subjects (age 53±9, sex, VO2) underwent cardiopulmonary exercise testing with simultaneous hemodynamic monitoring. There was a linear relationship between PAP and work rate in watts (R>0.85 for all subjects) whereas no consistent relationship between PCWP and work rate was present (R=0.02– 0.93). HF patients had a 3-fold greater rate of increase in PAP per watt than normals (slope=0.23±0.02 vs. 0.07±0.002 mmHg/W respectively, p2 (R=−0.41, p=0.04 and R=−0.12, p=0.56, respectively). Fifteen of the HF subjects underwent repeated exercise testing after 12-weeks of treatment with the pulmonary vasodilator sildenafil, with a resultant decrease in slope of the PAP-PCWP gradient from 0.11±0.02 to 0.07±0.01 mmHg, P This research has received full or partial funding support from the American Heart Association, AHA National Center.

Introduction : Ventilatory efficiency (V E /V CO2 ) is a prognostic marker in heart failure (HF). The relationship between V E /V CO2 and cardiovascular function in systolic HF remains unclear. We used cardiopulmonary exercise testing with continuous hemodynamic monitoring to clarify the relationship between V E /V CO2 and rest and exercise hemodynamics in patients with HF due to LV systolic dysfunction. Methods : Breath-by-breath ventilation, pulmonary gas exchange, and right heart hemodynamics were measured during incremental cycle ergometry in 15 subjects (62±11 years old, 14 male, 53% ischemic HF, LVEF 0.28±0.05) with NYHA class II-IV HF at baseline and after 12 weeks. Ventilatory efficiency was determined by linear regression of V E versus V CO2 throughout exercise with R 2 >0.95 in all cases. Pearson correlation and paired Student’s t -test (for baseline versus 12 week testing) were used for analysis. Results : Baseline V E /V CO2 was 40.6±10.5. Higher V E /V CO2 (reduced ventilatory efficiency) trended with higher resting mean pulmonary arterial (PA) pressure (r=0.49, p=0.06) and had a positive correlation with exercise PA pressure (r=0.57, p=0.03). Although pulmonary vascular resistance (PVR) at rest was not significantly related to V E /V CO2 (r=0.30, p=0.28), exercise PVR correlated with V E /V CO2 (r=0.62, p=0.01). There was no significant correlation between V E /V CO2 and rest (r=0.29) or exercise (r=0.27) pulmonary capillary wedge pressure; rest (r=−0.15) or exercise (r=−0.27) cardiac index; and rest (r=−0.17) or exercise (r=0.05) right atrial pressure. At 12 weeks, repeat exercise testing revealed no significant change in V E /V CO2 relative to baseline (41.4±15.4, p=0.70) or in any other measured hemodynamic parameters at rest or exercise. Conclusions : V E /V CO2 can be measured reproducibly in HF patients with LV systolic dysfunction. Impaired ventilatory efficiency is associated with higher exercise PA pressure and PVR, and is not related to rest or exercise ventricular filling pressures in this small patient cohort. In systolic HF, ventilatory efficiency may be intrinsically related to dynamic changes in pulmonary vasomotor tone occurring with exercise.

Background— Heart failure (HF) is frequently associated with dysregulation of nitric oxide–mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation. Methods and Results— Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index ( P o 2 increased (15±9%) and ventilatory response to CO 2 output (V̇ e /V̇ co 2 slope) decreased (16±5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure >25 mm Hg). Conclusions— The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak V̇ o 2 , reduces V̇ e /V̇ co 2 slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

Background Implantable cardioverter/defibrillators (ICDs) may reduce sudden tachyarrhythmic death in patients with severe left ventricular dysfunction. It is uncertain whether this improves survival, particularly in patients awaiting cardiac transplantation. Methods and Results The effect of treatment for spontaneous ventricular arrhythmias (ICD [n=59], antiarrhythmic drugs [n=53], or no antiarrhythmic treatment [n=179]) on total mortality and mode of cardiac death was analyzed in 291 consecutive patients evaluated for cardiac transplantation between January 1986 and January 1995. There were 109 deaths (37.4%) (63 [21.6%] sudden, 40 [13.7%] nonsudden, and 6 [2.1%] noncardiac) during mean follow-up of 15 months (range, 1 to 118 months). Baseline clinical variables, medical therapies for heart failure, and actuarial rates of transplantation were similar between treatment groups. Kaplan-Meier sudden death rates were lowest in the ICD group, intermediate in the no antiarrhythmic treatment group, and highest in the drug treatment group throughout follow-up (12-month sudden death rates, 9.2%, 16.0%, and 34.7%, respectively; P =.004). Total mortality and nonsudden death rates did not differ. Cox proportional-hazards model revealed that antiarrhythmic drug treatment was associated with sudden death (relative risk, 2.1; 95% CI, 1.04 to 3.39; P =.04) and ICD was associated with nonsudden death (relative risk, 2.26; 95% CI, 1.12 to 4.62; P =.02). Conclusions Sudden death rates were lowest in patients treated with ICDs compared with drug treatment or no antiarrhythmic treatment. However, although ICDs reduced sudden death in selected high-risk patients with severe left ventricular dysfunction, the effect on long-term survival was limited, principally by high nonsudden death rates.

A 57-year-old cardiac transplant recipient was admitted for the management of heart failure. He had severe graft coronary arteriosclerosis and normal left ventricular systolic function. In addition, the patient had hypertension and diabetes mellitus. During the hospitalization, enalapril was initiated for the control of hypertension. A progressive increase in the serum …