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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.

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— 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

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.

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 …

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.

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.

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.

Retrospectively investigate potential associations between rosiglitazone and congestive heart failure (CHF) and, separately, events of myocardial ischemia.Data from 14 237 individuals in 42 short-term, double-blind, randomized studies of rosiglitazone versus placebo or active diabetes medications were analyzed across seven treatment comparisons using an exact logistic regression model, adjusted for number of major cardiovascular risk factors and duration of exposure.CHF incidence ranged 0-1.27% (SAEs) and 0.12-2.42% (all AEs) with rosiglitazone versus 0.07-0.75% (SAEs) and 0.25-1.36% (all AEs) with control. Higher odds ratios (95%CI) were observed for CHF SAEs with sulfonylurea- and insulin-containing combinations: rosiglitazone monotherapy versus placebo, 0.25 (0.01-4.75); rosiglitazone monotherapy versus sulfonylurea/metformin monotherapy, 0.23 (0.01-2.14); sulfonylurea + rosiglitazone versus sulfonylurea monotherapy, 0.95 (0.01-75.20); metformin + rosiglitazone versus metformin monotherapy, 0.60 (0.00-8.28); metformin + rosiglitazone versus metformin + sulfonylurea, 1.04 (0.39-2.86); sulfonylurea + metformin + rosiglitazone versus sulfonylurea + metformin, 3.15 (0.35-150.52); insulin + rosiglitazone versus insulin monotherapy, 1.63 (0.52-6.01). Myocardial ischemia incidence ranged 0.75-1.40% (SAEs) and 1.49-2.77% (all AEs) with rosiglitazone versus 0.21-2.04% (SAEs) and 0.56-2.38% (all AEs) with control. Each comparison had an OR1, with wide confidence intervals generally including unity. With data pooling, more events of myocardial ischemia were observed with rosiglitazone (2.00%) versus control (1.53%) (HR 1.30, 95%CI 1.004-1.69).CHF incidence may be greater when rosiglitazone is combined with sulfonylureas or insulin. When data were pooled, more events of myocardial ischemia were observed with rosiglitazone versus control. Final results from RECORD will allow a more rigorous evaluation of the cardiovascular safety profile.

Background: Excessive alcohol consumption is recognized as a cause of left ventricular dysfunction and leads often to alcohol-induced heart failure. It is thought that 36% of all cases of dilated cardiomyopathy are due to excessive alcohol intake. In addition, since chronic alcohol-consumption is a social behavior that is not always clearly self-reported clinically, it has been difficult to diagnose alcohol-induced heart failure versus heart failure due to idiopathic dilated cardiomyopathy (IDCM). Interestingly, both diseases are associated with left ventricular dysfunction and congestive heart failure. Methods: We have created a human heart failure cDNA array for IDCM from nonfailing and failing human hearts. The array contains 1,143 heart specific oligonucleotide probes. This array was used to screen RNA samples from transplant recipients and organ donors with alcohol-related heart failure. Results: Our study shows that alcohol-induced heart failure has a “specific fingerprint” profile of de-regulated genes. This profile can differentiate patients with pure alcohol-induced heart failure from patients with heart failure from IDCM with alcohol as a complicating or contributing factor. Furthermore, the pattern of gene de-regulation suggests a pivotal role for changes in matrix, cytoskeletal, and structural proteins in the development of clinical heart failure resulting from excessive alcohol consumption. Conclusions: We report for the first time a genomic “fingerprint” profile of de-regulated genes associated with human alcohol-induced heart failure. We conclude that the pathogenesis of alcohol-induced heart failure in humans is likely related to changes in architectural (e.g. cytoskeletal), matrix, and/or structural proteins. The reversibility of the disease upon cessation of alcohol consumption makes this a likely pathogenetic mechanism. Nevertheless, there is a point at which extracellular as well as cellular changes result in irreversible heart failure.

A man was admitted 1 month after heart transplantation because of left ventricular dysfunction. Systemic amyloidosis with cardiomyopathy had been diagnosed 19 months earlier; cardiac function declined rapidly, and he underwent sequential cardiac and bone marrow transplantation. His cardiac function was then normal, and biopsy specimens showed no rejection. When an echocardiogram showed left ventricular dysfunction, a diagnostic procedure was performed.

Background:A substantial percentage of patients with heart failure remain nonresponsive to cardiac resynchronization therapy (CRT). There is a paucity of information on the impact of baseline elevated pulmonary artery pressure on clinical outcome and on left ventricular reverse remodeling (LV-RR) after CRT. We sought to investigate the impact of elevated estimated pulmonary artery systolic pressure (ePASP) on clinical outcome and LV-RR after CRT. Methods:This study retrospectively analyzed data from 68 subjects with standard indications for CRT over a 12-month period. Subjects were stratified into two groups based on the echocardiographic estimation of pulmonary artery pressure i.e., ePASP ≥ 50 mmHg (n = 27) and ePASP < 50 mmHg (n = 41). Long-term response was measured as a combined endpoint of heart failure hospitalizations and all cause mortality at 12 months, and compared within the two groups using the Kaplan-Meier method. Follow up echocardiograms to assess for LV-RR were available in 51 subjects (mean duration 7.1 months). LV-RR was defined as any improvement in global systolic function with reduction in left ventricular internal diameter. Results:The study population was composed of 24 women and 44 men (age, mean ± SD; 70 ± 11 years), with a decreased left ventricular ejection fraction ([25 ± 9]%) and a wide QRS (171 ± 54 ms). There were no significant differences in the clinical features between the high and low ePASP group. Subjects with ePASP ≥ 50 mmHg had a significantly worse clinical outcome (Hazard ratio (95% CI), 2.0 (1.2–5.5), P = 0.02). Baseline ePASP was not predictive of LV-RR (P = 0.32). Conclusion:In patients receiving CRT, although elevated estimated pulmonary artery systolic pressure (ePASP ≥ 50 mmHg) does not significantly impact LV reverse remodeling, it is associated with an adverse long-term outcome.

Heart transplant recipients present a challenge to cardiac multi-detector computed tomography (MDCT) imaging due to high resting heart rates and body mass indices. Previous studies demonstrated the feasibility of coronary allograft vasculopathy detection by MDCT in heart transplant recipients. However, its performance in assessing cardiac structure and function in these patients has not been evaluated. The aim of this study was to compare 64-slice MDCT analysis of cardiac structure and function to 2-dimensional echocardiography in heart transplant recipients.Two independent observers used both semi-automated and automated software to measure chamber dimensions and left ventricular ejection fraction and mass in 20 heart transplant recipients by 64-slice MDCT. Inter-observer variability was determined. The results were compared with echocardiographic measurements provided by another blinded observer.There was moderate agreement between MDCT and echocardiography for chamber dimension measurements, except for left atrial diameter. Ejection fraction by MDCT was slightly lower (mean difference: -2 +/- 9%, p = 0.29) than that obtained by echocardiography and the correlation was moderate (R = 0.49 to 0.54). Left ventricular mass measurements were significantly lower by MDCT (mean difference: -87 +/- 44 g, p0.001). Inter-observer agreement for MDCT analysis of left ventricular function (R = 0.90) and mass (R = 0.83) were excellent.These findings demonstrate moderate agreement between 64-slice MDCT and echocardiography in the assessment of chamber dimensions as well as left ventricular mass and function in heart transplant recipients with low inter-observer variability. Also, the addition of cardiac structural and functional analysis to MDCT coronary angiography requires no additional scan time, contrast administration or radiation exposure.

Coronary allograft vasculopathy (CAV) is the most important limitation to long-term survival in adult heart transplant recipients and is difficult to detect without intravascular ultrasound (IVUS). We systematically evaluated the image quality of 64-slice multidetector computed tomographic (MDCT) coronary angiography in heart transplant recipients and tested the hypothesis that this modality is comparable to invasive coronary angiography with IVUS for the detection of CAV. Heart transplant recipients (n = 20) underwent invasive coronary angiography with IVUS and MDCT coronary angiography with a 64-slice scanner. Images were systematically analyzed for image quality and the presence of CAV. In addition, multidetector computed tomography and quantitative coronary angiography were used to measure lumen diameters at prespecified locations. Image quality analysis showed that, despite high mean heart rates (77 +/- 7 beats/min) and body mass index (29.5 +/- 5.3 kg/m(2)), 83% of coronary segments were graded as of excellent or good image quality. On average, 95 +/- 9% of the overall visualized length of the coronary arteries was imaged without motion artifacts, and the mean contrast-to-noise ratio was 11.3 +/- 4.6. Compared with IVUS, multidetector computed tomography had a sensitivity of 70%, specificity of 92%, positive predictive value of 89%, and negative predictive value of 77% for the detection of CAV. MDCT vessel diameter measurements correlated well with those obtained from quantitative coronary angiography (R(2) = 0.89). In conclusion, 64-slice multidetector computed tomography provides good to excellent image quality in heart transplant recipients and has moderate to excellent test characteristics for the detection of CAV. Further, MDCT measurements of lumen diameters correlated well with quantitative coronary angiography.

Study objectives: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH. Design: Single center, case series, pharmacohemodynamic study. Setting: Cardiac catheterization laboratory of a tertiary care academic teaching hospital. Patients: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH. Interventions: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization. Measurements and results: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 5%, PVR by 12 5%, systemic vascular resistance (SVR) by 13 6%, and pulmonary capillary wedge pressure by 12 7%, and increased CI by 14 5% (all p < 0.05) [ SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 4%, decreased SVR by 24 3%, and increased CI by 30 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function. Conclusions: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH. (CHEST 2005; 127:1647–1653) Abbreviations: cGMP cyclic guanosine monophosphate; CI cardiac index; dP/dtmax maximal rate of rise in LV pressure; dP/dtmax/DT maximal rate of rise in LV pressure normalized for developed pressure; dP/ dtmax maximal rate of LV pressure decline; LV left ventricular; NO nitric oxide; NYHA New York Heart Association; PCWP pulmonary capillary wedge pressure; PDE5 type 5 isoform of phosphodiesterase; PH pulmonary hypertension; PVR pulmonary vascular resistance; RV right ventricular; SVR systemic vascular resistance; Td time constant of isovolumic relaxation, derivative method; Tl time constant of isovolumic relaxation, logarithmic method

The availability of selective inhibitors of the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE5) has created increasing interest in unlocking the therapeutic potential of PDE5 inhibition in cardiovascular diseases that are marked by dysfunction of nitric oxide (NO)-cGMP signaling. Pulmonary arterial hypertension (PAH) and heart failure (HF) are characterized by pulmonary arterial vasoconstriction that is thought to be caused by relative deficiencies of vasodilators such as NO and exaggerated production of vasoconstrictors such as endothelin. PDE5 is abundant in the pulmonary vasculature where it catabolizes cGMP, the second messenger of NO. Inhibition of PDE5 has been shown to lower pulmonary vascular resistance in PAH and HF by augmenting local cGMP. This review outlines the therapeutic potential of PDE5 inhibition for the treatment of PAH and HF.

Objectives: To assess left ventricular systolic and diastolic function in adult patients with cystic fibrosis using radionuclide ventriculography. Background: Although myocardial fibrosis has been described in autopsy specimens of patients with cystic fibrosis, the possibility that myocardial dysfunction may occur during life in adult patients with cystic fibrosis has not been explored. Methods: To assess the possibility of cardiac dysfunction occurring in cystic fibrosis, we studied 40 patients with advanced cystic fibrosis with first-pass radionuclide ventriculography and compared them to 9 patients with advanced bronchiectasis and 18 normal control subjects. Results: Indexes of right ventricular systolic function were similarly impaired in patients with cystic fibrosis and patients with bronchiectasis. Left ventricular ejection fraction of patients with cystic fibrosis, patients with bronchiectasis, and normal control subjects did not differ. Fractional left ventricular filling at 50% of diastole, an index of diastolic function, was significantly lower in patients with cystic fibrosis (54 ± 13%, mean ± SD) in comparison to patients with bronchiectasis (66 ± 4%, p=0.009) or normal control subjects (69 ± 14, p=0.0002). The contribution of atrial systole to total diastolic left ventricular filling was greater in patients with cystic fibrosis (38 ± 18%) than in patients with bronchiectasis (21 ± 4%, p=0.01) or normal control subjects (25 ± 12%, p=0.01). Conclusions: Patients with advanced cystic fibrosis demonstrate impaired left ventricular distensibility when compared to normal control subjects and patients with bronchiectasis. Patients with cystic fibrosis may be at risk of heart failure due to right ventricular dysfunction or left ventricular diastolic dysfunction.

In obstructive hypertrophic cardiomyopathy (oHCM) LV hypertrophy, reduced compliance, and hyperdynamic function result in dyspnea, fatigue, and limited exercise capacity. Mavacamten is an oral, allosteric modulator of cardiac myosin that targets an underlying biomechanical abnormality in HCM and was

s S95 to compare 1-year survival in patients (pts) receiving a left ventricular assist device (LVAD) as a bridge to transplantation (BTT) or to candidacy (BTC), or HTx from donors ≥ 55 years Methods: Pts receiving a continuous-flow LVAD as BTT/BTC (n= 61) were compared to those undergoing HTx from donors ≥ 55 years (HTx≥ 55y, n= 44 out of 212 adult HTx without prior bridging, 21%) between January 2006 and September 2014. Pts transplanted after LVAD were included in LVAD group only; survival lwas evaluated 1) according to first operation, with pts censored at the time of death or HTx or last follow-up visit, and 2) as overall survival, including postHTx outcome. Results: LVAD and HTx≥ 55y pts differ with respect to gender (Females 9.8 vs 41%, p> 0.005), prior cardiac surgery (11 vs 34%, p= 0.005), hemodynamic (PAPm 38±11 vs 22±8, p> 0.05; PCW 27±8 vs 16±7, p> 0.05). According to first operation, there were 8 deaths in LVAD (13%) and 13 in HTx≥ 55y (32%). Kaplan Meier survival curves estimated a 1-years survival of 87% in LVAD vs 70.5% in HTx≥ 55y pts, (hazard ratio 0.40; 95% confidence interval 0.17-0.97; p= 0.04 for LVAD vs HTx). Early (30 days) mortality was 4.9% in LVAD vs 20.5% in HTx≥ 55y, p0.005) in LVAD than in HTx pts. Nine LVAD pts (14.8%) were transplanted within 1 year, and 7 later; overall survival including post-Htx outcome was 76 % at 1-years. Conclusion: In possible HTx candidates, 1-y survival appears better with LVAD than with HTx from donors≥ 55y, but LVAD complications may require emergency, high risk HTx. Advantages and risks of LVAD or HTx with older donors should be carefully evaluated on an individual basis. Much efforts should be directed to reduce post-LVAD complications, in order to reduce readmissions, and increase the probability of success of subsequent HTx.

Tricuspid regurgitation is common immediately after cardiac transplantation, but its course over long-term follow-up is not known. This study was performed to determine the prevalence of valvular regurgitation and to evaluate if pulmonary hypertension or right ventricular enlargement were associated with the severity of tricuspid regurgitation at early and late follow-up after cardiac transplantation. Fifty-five patients had hemodynamic and echocardiographic studies performed at 1 week and 2.4 +/- 1.3 years after cardiac transplantation. Right ventricular dimensions were measured and related to the severity of tricuspid regurgitation as assessed by Doppler color flow. There was a fall in right heart filling pressures with decreases in the systolic pulmonary artery pressure (31 mmHg +/- 7 mmHg vs 27 mmHg +/- 7 mmHg, P = 0.0001) and right atrial pressure (8 +/- 5 mmHg vs 6 +/- 4 mmHg, P < 0.01). Sixty-three percent of patients had mild or higher grade tricuspid regurgitation initially and 71% at follow-up (P = NS). The major determinant of tricuspid regurgitation severity at late follow-up was the presence of flail tricuspid leaflets (P < 0.0001). There was an association between the change in grade of tricuspid regurgitation and the change in right ventricular diastolic area (P = 0.002) and the change in tricuspid annulus diameter (P < 0.0001). The prevalence of tricuspid regurgitation remains high at late follow-up after cardiac transplantation and neither pulmonary hypertension nor right ventricular dilatation are prerequisites for tricuspid regurgitation, which can persist in their absence. Flail tricuspid leaflets are the most important predictors of the severity of tricuspid regurgitation following cardiac transplantation.

Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested.To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction.Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America.Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119).Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point).Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes.In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy.clinicaltrials.gov Identifier: NCT01132846.

Importance Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). Objective To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Design Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Interventions Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Main Outcome Measures Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Results Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e′ (16), left atrial volume index (44 mL/m 2 ), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (−0.20 [IQR, −0.70 to 1.00]) or sildenafil (−0.20 [IQR, −1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, −0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, −26.0 to 45.0]) or sildenafil (5.0 m [IQR, −37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Conclusion and Relevance Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. Trial Registration clinicaltrials.gov Identifier: NCT00763867

ObjectivesThis study aimed to evaluate the role of gene expression for predicting myocardial recovery in recent-onset cardiomyopathy.BackgroundApoptosis may limit ventricular recovery. We examined the myocardial expression of Fas, Fas ligand (FasL), tumor necrosis factor (TNF)-alpha, and TNF receptor 1 (TNFR1), and myocardial recovery in patients from the multicenter Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) study.MethodsEndomyocardial biopsy samples were obtained in 20 patients with recent-onset (

While abnormal resting 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. Patients enrolled in the RELAX trial of sildenafil in HFpEF (EF

Acute decompensated heart failure (ADHF) occurs with preserved (heart failure with preserved ejection fraction [HFpEF] ≥50%) or reduced (heart failure with reduced ejection fraction [HFrEF]50%) ejection fraction. Natriuretic peptide (NP) levels are lower in HFpEF than HFrEF. We hypothesized that lower NP levels in HFpEF may be associated with other differences in biomarkers, specifically, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, and a biomarker that reflects collagen synthesis.In this prespecified ancillary analysis of patients with ADHF enrolled in the Diuretic Optimization Strategies Evaluation study, clinical features and N-terminal pro-B-type NP, cystatin C, plasma renin activity, aldosterone, oxidative stress (uric acid), and procollagen type III N-terminal peptide were compared in HFpEF and HFrEF at enrollment and 60-day follow-up.Compared with HFrEF (n = 219), HFpEF (n = 81) patients were older, heavier, more commonly female, less treated with RAAS antagonists, but with similar New York Heart Association class, jugular venous pressure, and edema severity. N-terminal pro-B-type NP was lower, and systolic blood pressure and cystatin C were higher in HFpEF. Despite higher systolic blood pressure and less RAAS antagonist use in HFpEF, plasma renin activity and aldosterone levels were similar in HFpEF and HFrEF as were uric acid and procollagen type III N-terminal peptide levels. Changes in biomarker levels from enrollment to 60 days were similar between HFrEF (n = 149) and HFpEF (n = 50).Lower NP levels in decompensated HFpEF occur in association with similar ADHF severity, more impaired vascular and renal function but similar elevation of biomarkers that reflect RAAS activation, oxidative stress, and collagen synthesis as in HFrEF.

BackgroundPeripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality.ObjectivesThis 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.MethodsWe 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.ResultsThe 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

ObjectivesWe sought to assess the effect of sildenafil, a highly-specific type 5 phosphodiesterase (PDE5) inhibitor, on platelet-mediated cyclic coronary flow reductions occurring in a canine model of coronary thrombosis despite aspirin therapy.BackgroundThe PDE5 inhibitors augment the antithrombotic effects of nitric oxide in vitro and in vivo, but it has been proposed that the PDE5 inhibitor sildenafil is prothrombotic.MethodsCyclic coronary flow reductions were induced in the left anterior descending coronary artery by creation of a stenosis, endothelial injury, and thrombus formation followed by treatment with aspirin, heparin, and tissue plasminogen activator. After an initial observation period, dogs were treated with or without sildenafil (100 μg/kg bolus followed by 4 μg/kg/min infusion).ResultsCyclic coronary flow reductions ceased in five of six animals 18 ± 5 min after initiation of sildenafil but continued in all six control animals. The portion of the observation period during which the coronary artery was patent increased from 52 ± 9% to 83 ± 5% after sildenafil administration (p = 0.008) but did not differ between the first and second observation periods in untreated dogs (49 ± 11% vs. 44 ± 11%, respectively). Among animals with plasma free sildenafil levels ≥20 nmol/l, cyclic coronary flow reductions were 73 ± 12% less frequent and the time to cessation of cycling 72 ± 14% shorter than in animals with levels

Objectives The aim of this study was to evaluate whether chronic heart failure (HF) therapy guided by concentrations of amino-terminal pro–B-type natriuretic peptide (NT-proBNP) is superior to standard of care (SOC) management. Background It is unclear whether standard HF treatment plus a goal of reducing NT-proBNP concentrations improves outcomes compared with standard management alone. Methods In a prospective single-center trial, 151 subjects with HF due to left ventricular (LV) systolic dysfunction were randomized to receive either standard HF care plus a goal to reduce NT-proBNP concentrations ≤1,000 pg/ml or SOC management. The primary endpoint was total cardiovascular events between groups compared using generalized estimating equations. Secondary endpoints included effects of NT-proBNP–guided care on patient quality of life as well as cardiac structure and function, assessed with echocardiography. Results Through a mean follow-up period of 10 ± 3 months, a significant reduction in the primary endpoint of total cardiovascular events was seen in the NT-proBNP arm compared with SOC (58 events vs. 100 events, p = 0.009; logistic odds for events 0.44, p = 0.02); Kaplan-Meier curves demonstrated significant differences in time to first event, favoring NT-proBNP–guided care (p = 0.03). No age interaction was found, with elderly patients benefitting similarly from NT-proBNP–guided care as younger subjects. Compared with SOC, NT-proBNP–guided patients had greater improvements in quality of life, demonstrated greater relative improvements in LV ejection fraction, and had more significant improvements in both LV end-systolic and -diastolic volume indexes. Conclusions In patients with HF due to LV systolic dysfunction, NT-proBNP–guided therapy was superior to SOC, with reduced event rates, improved quality of life, and favorable effects on cardiac remodeling. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting; NCT00351390 )

Exercise Capacity is similarly impaired in patients with heart failure with preserved LV ejection fraction (HFpEF) and HF with reduced LVEF (HFrEF). However, relative contributions of cardiac output (CO) and arterio-mixed venous oxygen content difference (C(a-v)O2) to VO2 during exercise in HFpEF vs

Background Heart failure (HF) is frequently associated with dysregulation of nitric oxide-mediated vascular tone. In HF patients with left ventricular systolic dysfunction (LVSD), right ventricular (RV) performance is an important determinant of exercise capacity and prognosis. Abnormal regulation of pulmonary vascular tone in these patients can lead to an increase in RV afterload and diminished function at rest and with exercise. The increased pulmonary vasomotor tone in HF patients is responsive to nitric oxide (NO), as administration of inhaled NO to patients with LVSD reduces pulmonary vascular resistance (PVR) and increases cardiac index (CI). As these beneficial effects of inhaled NO persist only briefly after cessation of its administration technically challenging to administercontinuously to ambulatory patients, the hydrolysis of its second messenger in vascular smooth muscle cells, cGMP, is an alternative target for pharmacologic augmentation through inhibition of phosphodiesterases (PDEs) responsible for its catabolism. Selective inhibition of Type 5 PDE, the predominant PDE isoform responsible for hydrolysis of cGMP in the lungs has been shown to lower resting PVR and pulmonary capillary wedge pressure (PCWP) and increase CI without causing systemichypotension in LVSD patients

Modified body mass index (mBMI), (BMI × serum albumin) predicts clinical outcomes after liver-transplant for transthyretin-related amyloidosis (ATTR). We sought to evaluate the utility of mBMI to predict outcomes in patients with cardiac amyloidosis undergoing orthotopic heart transplantation (OHT