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Background Established prognostic factors for pulmonary hypertension (PH) include brain natriuretic peptide, troponins and hemodynamic measures such as central venous pressure and cardiac output. The prognostic role of thrombocytopenia, however, has yet to be determined in patients with PH. The aim of this study was to evaluate effect of thrombocytopenia on mortality in patients with PH. Methods 521 patients with severe PH, defined by a pulmonary artery systolic pressure >60 mm Hg on transthoracic echocardiography and a platelet count measured within one month after diagnosis were enrolled from three hospitals of Montefiore Medical Center. The cohort was divided into two groups: mild thrombocytopenia to a normal platelet count (platelet count 100,000–450,000 per uL); and moderate to severe thrombocytopenia (platelet count <100,000 per uL). Inpatient and social security death records were used to determine 1-year all-cause mortality. Results Mean age was 70.3 ± 15.6 with 40% of patients being male. Overall mortality at 1 year was 30.7%, with increased mortality in PH patients with mild thrombocytopenia compared to those with moderate to severe thrombocytopenia (46.5% vs. 27.0%, p < 0.001). In multivariate analysis, moderate to severe thrombocytopenia remained an independent predictor of mortality (HR 1.798, 95% CI 1.240–2.607, p = 0.002). Conclusions Moderate to severe thrombocytopenia is an independent predictor of higher mortality in patients with severe PH. These findings may support the use of thrombocytopenia as a useful prognostic indicator in patients with severe PH. [ABSTRACT FROM AUTHOR]

Since its discovery in 1988, the endothelin system has been employed in multiple physiological and pathological roles. Endothelin-1 (ET-1) is not only a major regulator of vascular tone and cardiac contractility but also exerts mitogenic effects and is involved in inflammatory responses. ET-1 acts via two endothelin receptors located mainly on smooth muscle and endothelial cells through complex intracellular pathways differing between receptors and cell types. Polymorphisms of the endothelin receptor A have been associated not only with the risk in pulmonary arterial hypertension (PAH), systolic heart failure and systemic hypertension but are also of prognostic significance in dilated cardiomyopathy. Polymorphisms of endothelin receptors might lead to altered endothelin signaling and influence the response to endothelin receptor antagonist therapy in PAH in light of pharmacogenetics. This review will summarize the role of ET-1 within major cardiovascular pathologies and discuss endothelin receptor polymorphisms with special emphasis on potential therapeutic and screening implications. [ABSTRACT FROM AUTHOR]

Background Heart failure with preserved ejection fraction (HFpEF) has been increasingly recognized as a leading cause of pulmonary hypertension (HFpEF-PH). It remains unknown how HFpEF-PH fares in relation to systolic HF (reduced ejection fraction)-induced PH (HFrEF-PH). Therefore, we sought to determine the long-term morbidity and mortality of HFpEF-PH and HFrEF-PH. Methods and Results We studied all patients over a 6-year period with symptomatic HF and severe PH (PASP ≥65 mm Hg) in The Bronx, New York. We classified patients as having either preserved (≥50%) or reduced (≤35%) left ventricular ejection fraction. Trends in mortality and HF readmission rates were defined in 650 patients (HFrEF-PH: n = 277; HFpEF-PH: n = 373). HFpEF-PH patients were older and more often female and white. HFrEF-PH patients were more often black, had ischemic cardiomyopathy, and were on typical HF drug regimens. Patients with HFpEF-PH had a significantly increased all-cause 5-year mortality (52% vs 42%; P = .024). HFpEF-PH was a significant predictor of mortality (adjusted hazard ratio 1.70; P = .012). Patients with HFrEF-PH had more HF readmissions (≥1) than patients with HFpEF-PH (28.6% vs 15%; P = .003), especially within the 1st year (9.1% vs 1.7%; P = .005). Conclusions Patients with HFrEF-PH and HFpEF-PH have a significantly elevated long-term mortality, with HFpEF-PH having a higher 5-year mortality rate. These findings testify to the overall poor prognosis of World Health Organization Group II PH, especially HFpEF-PH. [ABSTRACT FROM AUTHOR]

Right-to-left shunting (RLS), usually through a patent foramen ovale (PFO), has been associated with migraine, cryptogenic stroke and hypoxemia. With emerging observational studies and clinical trials on the subject of PFO, there is a need for accurate diagnosis of PFO in patients being considered for transcatheter closure. While transesophageal echo (TEE) bubble study is the current standard reference for diagnosing PFO, transthoracic echo with second harmonic imaging (TTE-HI) may be a preferable screening test for RLS due to its high accuracy and non-invasiveness. The aim of this meta-analysis was to determine the accuracy of TTE-HI compared to TEE as the reference. A systematic review of Medline, Cochrane and Embase was done for all the prospective studies assessing for intracardiac RLS using TTE-HI compared to TEE as the reference; both TTE-HI and TEE were performed with a contrast agent and a maneuver to provoke RLS in all studies. A total of 15 studies with 1995 patients fulfilled the inclusion criteria. The weighted mean sensitivity and specificity for TTE-HI were 91 and 93 % respectively. Likewise, the positive and negative likelihood ratios were 13.52 and 0.13 respectively. TTE-HI is a reliable, non-invasive test with proficient diagnostic accuracies. The high sensitivity and specificity of TTE-HI make it a useful initial screening test for RLS. If the precise anatomy is required, then TEE can be obtained before scheduling a patient for transcatheter PFO closure. [ABSTRACT FROM AUTHOR]

Adult-onset Still's Disease ( AOSD), often though as the adult variant of systemic juvenile idiopathic arthritis ( JIA), has an incidence of 1-3 cases per 1 million. Cardinal manifestations include fever, arthritis, skin rash, sore throat, hepatosplenomegaly and lymphadenopathy. Prolongation in diagnosing this disease results from its similarity to infectious, malignant and rheumatic diseases and lack of biomarkers. Pulmonary arterial hypertension ( PAH) is a rare pulmonary complication of AOSD, and we are aware of only six cases reported in literature to date. Here we present a patient with AOSD who has developed pulmonary hypertension as a complication. We report a case of AOSD complicated by PAH treated successfully with tocilizumab, a humanized monoclonal antibody to human interleukin ( IL)-6 receptor. A Pubmed and Medline search for evidence of pulmonary hypertension in AOSD and use of IL-6 inhibition in management was performed. Data for this study was collected from the patient's chart records. No infectious or neoplastic cause of her disease was identified and after extensive diagnostic workup, the patient was diagnosed with AOSD fulfilling Yamaguchi criteria. After initiation of IL-6 therapy the patient was followed over time to monitor the hemodynamic changes in pulmonary vasculature. Following treatment with Tocilizumab, the patient showed dramatic improvement in her clinical symptoms and remains in remission, through combination of tocilizumab (8 mg/kg), methotrexate and prednisone. Improvement of systemic symptoms, right heart catheterization ( RHC) findings and the VECTRA-DA score served as a measure of treatment response. Tocilizumab has been effective in demonstrating marked improvement in both the clinical and laboratory parameters. Tocilizumab is an effective novel treatment for AOSD with PAH. This is the first documented report of successful use of tocilizumab in AOSD patients presenting with PAH. Prospective comparative studies could help validate its efficacy and safety. [ABSTRACT FROM AUTHOR]

Aim Acute decompensated heart failure (ADHF) is associated with significant morbidity and mortality but the relationship between LVEF and outcomes is unclear. We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. Methods and results We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. LVEF was analysed both as a continuous variable and according to three categories: < 40% (LowEF), 40-50% [intermediate EF (IntEF)], and > 50% [preserved ejection fraction (PresEF)]. Of the patients in the trial, 4474 (78.7%) had LowEF, 674 (11.9%) had IntEF, and 539 (9.5%) had PresEF. The unadjusted 30 and 180 day mortality was similar for LowEF (3.7%, 12.3%), IntEF (3.4%, 13.1%), and PresEF (4.3%, 14.1%), respectively ( P > 0.05). After multivariable adjustment, the hazard ratio (HR) for 180 day mortality remained similar for the LowEF [HR 0.96, 95% confidence interval (CI) 0.75-1.24; P = 0.77] and IntEF (0.91, 95% CI 0.66-1.3; P = 0.58) compared to PresEF patients. By contrast, when LVEF was evaluated as a continuous measure, it exhibited a U-shaped pattern with mortality. After matching for age and sex, the mortality risk attributed to LVEF was attenuated, as the LVEF increased as a continuous variable over 35%. However, in patients with EF < 35%, the mortality risk continue to increase as the LVEF declined. Conclusions Among patients with ADHF, the unadjusted mortality rates are similar across LVEF strata. However, after accounting for key patient variables, the mortality risk increases as EF falls below 35%. These data will be useful in planning future studies of ADHF. Clinical Trial Registration identifier: NCT00475852 [ABSTRACT FROM AUTHOR]

Background : Although beta blockers (BBs) are established therapy in heart failure, some patients whose left ventricular ejection fraction (LVEF) initially increases on BB therapy experience a subsequent LVEF decline. This study aimed to evaluate the proportion of patients with non-ischemic cardiomyopathy (NICM) whose LVEF declines while on BB therapy and determine important predictors of LVEF decline. Methods: A retrospective analysis of 238 patients receiving a BB (carvedilol, metoprolol succinate, or tartrate), with an ejection fraction of ≤40 % and NICM, whose LVEF initially rose ≥5 % after 1 year of BB therapy, was conducted. Post-response LVEF decline ≥5 % to a final LVEF of ≤35 % was evaluated within 4 years of BB initiation. Results: In our study, we had 52 Caucasians (22 %), 78 Hispanics (33 %), and 108 African Americans (45 %). Overall, 32 patients (13.44 %) had post-response LVEF decline. The nadir LVEF of patients with post-response LVEF decline was 25 % (interquartile range 20-27). Compared with others, Hispanics had lower nadir LVEF (22 %, p < 0.001). Important predictors of LVEF decline were Hispanic race (odds ratio (OR) 6.094, p < 0.001), New York Heart Association (NYHA) class (OR 2.287, p < 0.05), baseline LVEF (OR 1.075, p < 0.05), and age (OR 0.933, p < 0.001). Conclusion: A significant proportion (13.44 %) of NICM patients with LVEF increase over 1 year of BB therapy experienced subsequent LVEF decline. Race, NYHA class, baseline LVEF, and age are important predictors of this decline. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hyponatremia is known to be an important marker and prognosticator in left-sided heart failure. However, less is known about the significance of hyponatremia in pulmonary hypertension, particularly in the absence of left ventricular dysfunction. Methods and Results: We identified 635 patients with pulmonary hypertension and preserved ejection fraction who were normonatremic (n = 493) or hyponatremic (n = 142). End points were mortality and readmission at 1 year. Overall, 27% of all of the patients died within 1 year. Hyponatremia was significantly associated with an increased rate of 1-year mortality (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.27–2.61; P = .001) and trended toward an association with the composite of mortality and readmission (HR 1.25, 95% CI 0.97–1.62; P = .08). Additionally, the severity of hyponatremia was directly related to the rate of 1-year mortality (P < .001). Conclusions: Hyponatremia is an indicator of poor prognosis in patients with echocardiographic evidence of pulmonary hypertension. [Copyright &y& Elsevier]

Abstract: Background: Relative effectiveness of carvedilol and metoprolol succinate has never been compared in patients with heart failure (HF). Methods and Results: From January 1998 to December 2008, 3,716 consecutive patients with ejection fraction (EF) ≤40%, initiated and maintained on carvedilol or metoprolol succinate, were enrolled and followed until June 2010. The primary end point was all-cause mortality, and the secondary end points were readmissions from HF and follow up EFs at 1, 3, and 5 years. HF etiology (ischemic or nonischemic) was a significant effect modifier, and separate analysis was performed for these subcohorts. Compared with those on carvedilol, patients on metoprolol succinate were less likely to experience mortality in the ischemic HF cohort (adjusted hazard ratio [aHR] 0.54, 95% confidence interval [CI] 0.43–0.66) but were more likely to die in the nonischemic HF cohort (aHR 1.18, 95% CI 1.10–1.28). Follow-up EF was similar by type of beta-blocker used in both ischemic and nonischemic HF cohorts. Furthermore, no significant difference was noted in the incidence of HF hospitalizations by beta-blocker type used in both ischemic and nonischemic HF cohorts. Conclusions: Metoprolol succinate was associated with an improved survival in patients with ischemic HF, and carvedilol was associated with an improved survival in patients with nonischemic HF. [Copyright &y& Elsevier]

The role of nesiritide in patients with decompensated heart failure with preserved ejection fraction (dHFpEF) has not been previously studied. In this investigation, the authors retrospectively analyzed the effect of nesiritide on renal function and clinical outcomes in patients admitted with dHFpEF. Of the 658 patients included, 328 were treated with nesiritide while 330 patients were treated with standard diuretic therapy. In both the nesiritide and no nesiritide groups, there was a significant change in mean glomerular filtration rate (GFR) and creatinine at 72 hours as well as at day of discharge ( P<.001). This trend did not progress at 1 month in the nesiritide group, although it did in the no nesiritide group. At 1 month after therapy, however, there was a significant difference between the two groups in the mean change of GFR and creatinine ( P<.001). There was no significant difference in >25% decrease of GFR anytime through day 30 (25% vs 29.69%, P=.236) between the two groups. On multivariate analysis, nesiritide was an important predictor of renal function at 1 month ( P<.05). Thus, nesiritide can be administered safely without negatively impacting long-term renal function in patients admitted with dHFpEF. ©2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Treatment of right ventricular failure (RVF) can be challenging due to the correlation between RVF and worsening renal function with diuretic therapy. Nesiritide has been studied in patients with left ventricular failure but has not been evaluated in isolated RVF. The authors retrospectively analyzed 140 patients admitted with RVF, pulmonary hypertension (PH), and preserved left ventricular systolic function. Seventy patients were treated with nesiritide while the remaining patients received only furosemide (no nesiritide group). Serum creatinine and GFR at baseline, 72 hours, discharge, and 1 month post-treatment, as well as hemodynamic data were compared between the groups. In the nesiritide group, there was a significant decrease in mean GFR (42.77±25.33, P<.001) at day of discharge and 1 month post-nesiritide infusion (41.17±24.94, P<.001) but not in the no nesiritide group. There was a significant difference in >25% decrease in GFR anytime through day 30 (47.14% vs 25.71%, P=.036) between the two groups. On multivariate analysis, nesiritide remained an important predictor of renal function at discharge and at 1 month ( P<.01) as well as a predictor of >25% decrease in GFR anytime through day 30 ( P=.007). Thus, nesiritide is associated with worsening kidney function in patients with RVF in the setting of PH. Congest Heart Fail. 2012;18:18-24. ©2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective: Impairment of flow-mediated, endothelium-dependent vasodilatation (FMD) of the brachial artery identifies peripheral endothelial dysfunction in subjects with chronic congestive heart failure (CHF) and is associated with increased morbidity and mortality. To further elucidate the interaction of peripheral and central mechanisms in the syndrome of CHF, we examined the association between endothelial function and chronotropic incompetence, an emerging prognostic marker in CHF. Methods: Thirty subjects with stable New York Heart Association (NYHA) functional class II–III CHF were studied. A vascular ultrasound study was performed to measure brachial artery FMD. The percentage of age-adjusted maximal predicted heart rate (MPHR) reached during cardiopulmonary exercise tolerance testing (CPETT) was used to assess the degree of chronotropic competence. All patients received ACE inhibitors and β-adrenoceptor blockers. Results: Brachial artery FMD averaged 1.3 ± 2.4% and age-adjusted % MPHR 74.1 ± 11.7%. FMD correlated with % MPHR among all patients (r = 0.60, P = 0.01). FMD and resting heart rate (RHR) did not significantly correlate (r = 0.13, P = 0.55). Conclusions: FMD, a measure of peripheral endothelial dysfunction, and % MPHR, a central determinant of cardiac output, are moderately correlated in heart failure patients receiving optimal medical therapy. Whether a cause-effect relationship underlies this association remains to be investigated. [ABSTRACT FROM AUTHOR]

The article presents a study which examined baseline and peak exercise heart rates and norepinephrine levels in subjects with chronic heart failure treated with carvedilol or metoprolol. The methodology of the study is described, as well as cardiopulmonary exercise tolerance testing. Charts are presented that show baseline characteristics of subjects and hemodynamic data.

Background: Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1α (HIF-1α), a transcriptional factor in hypoxic signaling. Methods: Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unused hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1α was measured by Western blotting with commercially available antibodies. Results: Heart failure was associated with a decrease in α-myosin heavy chain and sarcoplasmic reticulum-Ca2+ adenosine triphosphatase messenger RNA expression along with an increase in skeletal tropomyosin. This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including glucose transporter 1 (GLUT1). These patterns also persisted after assist device therapy despite a reduction in atrial natriuretic peptide expression and normalization of HIF-1α. Conclusions: Failure of assist devices to produce sustained recovery of myocardial contractile function may be due in part to persistent fetal transcriptional patterns of contractile and metabolic genes. [Copyright &y& Elsevier]

Abstract: Background: Quality of life (QOL) was a prespecified secondary end point in the Beta-Blocker Evaluation of Survival Trial. The Beta-Blocker Evaluation of Survival Trial used four QOL questionnaires to evaluate patient health status over time in response to treatment with placebo or bucindolol. The goal of the current study was to determine the relationship between the different questionnaires, assess the effect of treatment on health status, and evaluate the association between changes in health status and prognosis. Methods: The San Diego Heart Failure (SDHF), Minnesota Living with Heart Failure (MLHF), Patient Global Assessment (PGA), and Physician Global Assessment (PhyGA) questionnaires were measured at baseline through 48 months of follow-up. For SDHF and MLHF, changes from baseline were calculated. Spearman correlation was used to assess relationships, and Cox Proportional Hazards regression was used to predict time to all-cause mortality, and mortality or heart failure hospitalization, bivariately and multivariately. To determine whether beta-blocker treatment affected QOL, the Wilcoxon rank-sum test was used to compare treatment groups. Results: At 12 months, SDHF (r = +0.56, P = .0001), PGA (r = +0.36, P = .0001), and PhyGA (r = +0.37, P = .0001) correlated with MLHF. SDHF (P = .0001), MLHF (P = .0004), PGA (P = .0001), and PhyGA (P = .0001) were all strongly associated with all-cause mortality, with low values of each associated with a lower hazard. For the combined end point of all-cause mortality or heart failure hospitalization, change in QOL with each instrument had a P value of .0001. At 12 months, bucindolol-treated patients had improvement in both PhyGA and PGA compared with placebo; neither the SDHF nor the MLWF instrument distinguished between the two treatment groups unless a worst-rank assignment was used for patients who died. Conclusion: The four instruments correlate with each other and predict clinical end points, suggesting that each is a valid measure of health status. According to the PGA and the PhyGA, bucindolol improves QOL. [Copyright &y& Elsevier]