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BACKGROUND Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. METHODS AND RESULTS ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression , participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1–0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%–5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors. CONCLUSIONS These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown.The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) 25 mm Hg and ≥ 25 mm Hg. Exploratory univariable analysis was undertaken to identify candidate risk factors associated with 30-day and 1-year survival (conditional on 30-day survival) in recipients with mPAP 25 mm Hg, and subsequently, parsimonious multivariable Cox proportional hazards models were constructed to assess the independent association with PVR.Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP 25 mm Hg. The median age was 55 years (interquartile range, 47-62) and the median PVR was 1.5 Wood units (WU) (interquartile range, 1-2.2) in recipients with mPAP 25 mm Hg. After controlling for confounders, PVR was independently associated with increased risk for 30-day mortality (hazard ratio, 1.16; 95% CI, 1.05-1.27; P .01), but not conditional 1-year mortality (hazard ratio, 1.03; 95% CI, 0.94-1.12; P = .55). PVR ≥ 3 WU was associated with an absolute 1.9% increase in 30-day mortality in those with mPAP 25 mm Hg, a similar risk to recipients with PVR ≥ 3 WU and mPAP ≥ 25 mm Hg.Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.

Rationale: Air pollution may influence sleep through airway inflammation or autonomic nervous system pathway alterations. Epidemiological studies may provide evidence of relationships between chronic air pollution exposure and sleep apnea. Objectives: To determine whether ambient-derived pollution exposure is associated with obstructive sleep apnea and objective sleep disruption. Methods: We analyzed data from a sample of participants in MESA (Multi-Ethnic Study of Atherosclerosis) who participated in both the Sleep and Air studies. Mean annual and 5-year exposure levels to nitrogen dioxide (NO(2)) and particulate matter ≤ 2.5 μm in aerodynamic diameter (PM(2.5)) were estimated at participants’ homes using spatiotemporal models based on cohort-specific monitoring. Participants completed in-home full polysomnography and 7 days of wrist actigraphy. We used multivariate models, adjusted for demographics, comorbidities, socioeconomic factors, and site, to assess whether air pollution was associated with sleep apnea (apnea–hypopnea index ≥ 15) and actigraphy-measured sleep efficiency. Results: The participants (n = 1,974) were an average age of 68 (±9) years, 46% male, 36% white, 24% Hispanic, 28% black, and 12% Asian; 48% had sleep apnea and 25% had a sleep efficiency of ≤88%. A 10 ppb annual increase in NO(2) exposure was associated with 39% greater adjusted odds of sleep apnea (95% confidence interval [CI], 1.03–1.87). A 5 μg/m(3) greater annual PM(2.5) exposure was also associated with 60% greater odds of sleep apnea (95% CI, 0.98–2.62). Sleep efficiency was not associated with air pollution levels in fully adjusted models. Conclusions: Individuals with higher annual NO(2) and PM(2.5) exposure levels had a greater odds of sleep apnea. These data suggest that in addition to individual risk factors, environmental factors also contribute to the variation of sleep disorders across groups, possibly contributing to health disparities.

Background: Myocardial H2 receptor activation may promote cardiac fibrosis and apoptosis in pre-clinical models and histamine H2 receptor antagonist (H2RA) use may improve symptoms in parti...

IntroductionWhile the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States.MethodsUsing the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score.ResultsWe analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of −6.0 points (range −5.0–−7.6 points).ConclusionsThe e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.

Background: Acute right heart failure (RHF) after left ventricular assist device implantation remains a major source of morbidity and mortality, yet the definition of RHF and the preimplant variables that predict RHF remain controversial. This study evaluated the ability of (1) INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) RHF classification to predict post-left ventricular assist device survival and (2) preoperative characteristics and hemodynamic parameters to predict severe and severe acute RHF. Methods and Results: An international, multicenter study at 4 large academic centers was conducted between 2008 and 2016. All subjects with hemodynamics measured by right heart catheterization within 30 days before left ventricular assist device implantation were included. RHF was defined using the INTERMACS definition for RHF. In total, 375 subjects were included (mean age, 57.4±13.2 years, 54% bridge-to-transplant). Mild RHF was most common (34%), followed by moderate RHF (16%), severe RHF (13%), and severe acute RHF (9%). Estimated on-device survival rates at 2 years were 72%, 71%, and 55% in the patients with none, mild-to-moderate, and severe-to-severe acute RHF, respectively ( P =0.004). In addition, the independent hazard ratio for mortality was only increased in the patients with severe-to-severe acute RHF (hazard ratio, 3.95; 95% CI, 2.16–7.23; P Conclusions: The INTERMACS RHF classification correctly identifies patients at risk for mortality, though this risk is only increased in patients with severe-to-severe acute RHF. Several predictors for RHF were identified, of which ratio of systolic pulmonary artery pressure to stroke volume was the strongest hemodynamic predictor. Coupling ratio of systolic pulmonary artery pressure to stroke volume with right atrial pressure may be most helpful in identifying patients at risk for severe-to-severe acute RHF.

Disease-specific metabolomic signatures have been associated with mortality in pulmonary arterial hypertension (PAH). We explore whether this reflects right ventricular (RV) dysfunction. We analyzed quantitative targeted profiling of over 300 metabolites from a prospective cohort of PAH patients.

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension. Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters. Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

Patients with adult congenital heart disease have an increased risk of developing pulmonary hypertension. There are several mechanisms of pulmonary hypertension in patients with adult congenital heart disease, and understanding them requires a systematic approach to define the patient's hemodynamics and physiology. This article reviews the updated classification of pulmonary hypertension in patients with adult congenital heart disease with a focus on pathophysiology, diagnostics, and the evaluation of pulmonary hypertension in special adult congenital heart disease populations.

Objectives: This study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD).Background: P...

Proton pump inhibitor use is associated with a reduction in subclinical interstitial lung disease http://ow.ly/dbFN30aoRPf

Exercise-induced PH defined by the mPAP-CO relationship may lack sensitivity for detecting pulmonary vascular disease http://ow.ly/v0r330dVzxr

Right heart failure is a cause of morbidity and mortality in common and rare heart and lung diseases. Exposure to traffic-related air pollution is linked to left ventricular hypertrophy, heart failure, and death. Relationships between traffic-related air pollution and right ventricular (RV) structure and function have not been studied.To characterize the relationship between traffic-related air pollutants and RV structure and function.We included men and women with magnetic resonance imaging assessment of RV structure and function and estimated residential outdoor nitrogen dioxide (NO2) concentrations from the Multi-ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease at baseline. Multivariable linear regression estimated associations between NO2 exposure (averaged over the year prior to magnetic resonance imaging) and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Adjustment for corresponding left ventricular parameters, traffic-related noise, markers of inflammation, and lung disease were considered in separate models. Secondary analyses considered oxides of nitrogen (NOx) as the exposure.The study sample included 3,896 participants. In fully adjusted models, higher NO2 was associated with greater RV mass and larger RV end-diastolic volume with or without further adjustment for corresponding left ventricular parameters, traffic-related noise, inflammatory markers, or lung disease (all P0.05). There was no association between NO2 and RV ejection fraction. Relationships between NOx and RV morphology were similar.Higher levels of NO2 exposure were associated with greater RV mass and larger RV end-diastolic volume.

Although the transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are commonly used to differentiate heart failure patients with pulmonary vascular disease from those with passive pulmonary hypertension (PH), elevations in TPG and PVR may not always reflect pre-capillary PH. Recently, it has been suggested an elevated diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient (DPG) may be a better indicator of pulmonary vascular remodeling, and therefore, may be of added prognostic value in patients with PH being considered for cardiac transplantation.Using the United Network for Organ Sharing (UNOS) database, we retrospectively reviewed all primary adult (age17 years) orthotropic heart transplant recipients between 1998 and 2011. All patients with available pre-transplant hemodynamic data and PH (mean pulmonary artery pressure ≥ 25 mm Hg) were included (n = 16,811). We assessed the prognostic value of DPG on post-transplant survival in patients with PH and an elevated TPG and PVR.In patients with PH and a TPG12 mm Hg (n = 5,827), there was no difference in survival at up to 5 years post-transplant between high DPG (defined as ≥3, ≥5, ≥7, or ≥10 mm Hg) and low DPG (3,5,7, or10 mm Hg) groups. Similarly, there was no difference in survival between high and low DPG groups in those with a PVR3 Wood units (n = 6,270). Defining an elevated TPG as15 mm Hg (n = 3,065) or an elevated PVR5 (n = 1,783) yielded similar results.This large analysis investigating the prognostic value of DPG found an elevated DPG had no effect on post-transplant survival in patients with PH and an elevated TPG and PVR.

Pulmonary artery compliance (PAC) contributes to right ventricular (RV) afterload, is decreased in the setting of increased left ventricular (LV) filling pressures, and may be an important component of World Health Organization (WHO) group II pulmonary hypertension (PH). Left ventricular assist device (LVAD) implantation can rapidly change LV filling, but its relationship with PAC is unknown. Right heart catheterization was performed preoperatively, postoperatively (between 48 and 72 hours), and30 days post-LVAD implantation in a cohort of 64 patients with end-stage systolic heart failure. Within 72 hours, LVAD implantation was associated with an increase in PAC (2.0-3.7 ml/mm Hg, p0.0001), a decrease in pulmonary vascular resistance (3.5-1.7 Wood units, p0.0001). Pulmonary arterial compliance did not increase further at the30 post-LVAD time point (3.7 ± 1.7 to 3.6 ± 0.44 ml/mm Hg, p = 0.44). Pulmonary artery compliance improves rapidly after LVAD implantation. This suggests that more permanent changes in the pulmonary vascular bed may not be responsible for the abnormal PAC observed in WHO group II PH.

The dangers of cigarette smoking are not disputed and yet it remains a multibillion dollar industry.1 Despite their first-hand experience with complications of cigarette smoking, even the occasional physician continues to smoke.2 Furthermore, alternatives to traditional cigarette smoking, such as e-cigarette use, are on the rise.3 This illustrates the ongoing public appetite for smoking and reinforces the strong public interest in continuing to better understand relationships between smoking and disease. See Article by Nadruz et al Cigarette smoking can cause disease directly, but smoking is also associated with a suite of health behaviors and socioeconomic determinants of health.4 If we knew definitively that cigarettes caused heart failure, a public health campaign to reduce heart failure could have a precise and targeted mandate. On the contrary, if we knew definitively that cigarette smoking was merely a marker of a man or woman’s exposure to outdoor air pollution, access to healthcare, a healthy diet, or medication adherence then the public health approach might be much different. This is not meant to diminish the importance of smoking cessation. Smoking is known to cause many diseases, and cessation remains a vitally important pillar of public health, but it is important to try and understand where it fits into a complex, multifaceted, and nuanced understanding of disease causation.1 The importance of trying to understand causality is a core principle in epidemiology and can be complex. At a time when the world was convinced that improved life expectancy was a direct result of germ theory, antibiotics, and medical science, the microbiologist Rene Dubos demonstrated that mortality had been falling for several decades before these medical advances. …

Screening for disease before the arrival of symptoms is an intuitive cornerstone of preventive medicine and good clinical practice in many cases. However, screening is not appropriate for all conditions. Disease, test, and treatment should all be considered when developing a rational approach to screening.1–4 Specifically, screening may be warranted if the target disease has significant morbidity and mortality. Testing in specific populations should be able to detect early disease, have relatively low risk, and a low rate of pseudo-disease detection (including both false positive results and true disease which naturally regresses). Lastly, treatments should be more effective if employed early.56 This article reviews the available literature addressing these key aspects of screening for pulmonary arterial hypertension (PAH).

Right ventricular (RV) failure is a key determinant of morbidity and mortality in pulmonary hypertension (PH). The present study aims to add to existing descriptions of RV structural and functional changes in PH through a comprehensive three-dimensional (3D) shape analysis. We performed 3D echocardiography on 53 subjects with PH and 19 normal subjects. Twenty short-axis slices from apex to tricuspid centroid were measured to characterize regional shape: apical angle, basal bulge, eccentricity, and area. Transverse shortening was assessed by fractional area change (FAC) in each short-axis slice, longitudinal contraction was assessed by tricuspid annular plane systolic excursion (TAPSE) and global function by RV ejection fraction. Multivariate logistic analysis was used to compare the association of RV parameters with New York Heart Association (NYHA) class. Compared to normal, RV function in PH is characterized by decreased stroke volume index (SVi), fractional area change and ejection fraction. Increased eccentricity, apical rounding and bulging at the base characterize the shape of the RV in PH. Increased SVi, ejection fraction and mid-ventricular FAC were associated with less severe NYHA class in adjusted analyses. The RV in idiopathic PH (iPAH) was observed to have a larger end-diastolic volume and decreased function compared with connective tissue disease associated PH (ctd-PH). This work describes increased eccentricity and decreased systolic function in subjects with PH. Functional parameters were associated with NYHA class and heterogeneity in the phenotype was noted between subjects with iPAH and ctd-PH.

Invasive cardiopulmonary exercise testing (iCPET) combines full central hemodynamic assessment with continuous measurements of pulmonary gas exchange and ventilation to help in understanding the pathophysiology underpinning unexplained exertional intolerance. There is increasing evidence to support the use of iCPET as a key methodology for diagnosing heart failure with preserved ejection fraction and exercise-induced pulmonary hypertension as occult causes of exercise limitation, but there is little information available outlining the methodology to use this diagnostic test in clinical practice. To bridge this knowledge gap, the operational protocol for iCPET at our institution is discussed in detail. In turn, a standardized iCPET protocol may provide a common framework to describe the evolving understanding of mechanism(s) that limit exercise capacity and to facilitate research efforts to define novel treatments in these patients.

Survivors of septic shock have impaired functional status. Volume overload is associated with poor outcomes in patients with septic shock, but the impact of volume overload on functional outcome and discharge destination of survivors is unknown.This study describes patterns of fluid management both during and after septic shock. We examined factors associated with volume overload upon intensive care unit (ICU) discharge. We then examined associations between volume overload upon ICU discharge, mobility limitation, and discharge to a healthcare facility in septic shock survivors, with the hypothesis that volume overload is associated with increased odds of these outcomes.We retrospectively reviewed the medical records of 247 patients admitted with septic shock to an academic county hospital between June 2009 and April 2012 who survived to ICU discharge. We defined volume overload as a fluid balance expected to increase the subject's admission weight by 10%. Statistical methods included unadjusted analyses and multivariable logistic regression.Eighty-six percent of patients had a positive fluid balance, and 35% had volume overload upon ICU discharge. Factors associated with volume overload in unadjusted analyses included more severe illness, cirrhosis, blood transfusion during shock, and higher volumes of fluid administration both during and after shock. Blood transfusion during shock was independently associated with increased odds of volume overload (odds ratio [OR], 2.65; 95% confidence interval [CI], 1.33-5.27; P = 0.01) after adjusting for preexisting conditions and severity of illness. Only 42% of patients received at least one dose of a diuretic during their hospitalization. Volume overload upon ICU discharge was independently associated with inability to ambulate upon hospital discharge (OR, 2.29; 95% CI, 1.24-4.25; P = 0.01) and, in patients admitted from home, upon discharge to a healthcare facility (OR, 2.34; 95% CI, 1.1-4.98; P = 0.03).Volume overload is independently associated with impaired mobility and discharge to a healthcare facility in survivors of septic shock. Prevention and treatment of volume overload in patients with septic shock warrants further investigation.

Patients with adult congenital heart disease have an increased risk of developing pulmonary hypertension. There are several mechanisms of pulmonary hypertension in patients with adult congenital heart disease, and understanding them requires a systematic approach to define the patient's hemodynamics and physiology. This article reviews the updated classification of pulmonary hypertension in patients with adult congenital heart disease with a focus on pathophysiology, diagnostics, and the evaluation of pulmonary hypertension in special adult congenital heart disease populations.

Right ventricular (RV) failure is a source of morbidity and mortality after left ventricular assist device (LVAD) implantation. In this study we sought to define hemodynamic changes in afterload and RV adaptation to afterload both early after implantation and with prolonged LVAD support.We reviewed right heart catheterization (RHC) data from participants who underwent continuous-flow LVAD implantation at our institutions (n = 244), excluding those on inotropic or vasopressor agents, pulmonary vasodilators or additional mechanical support at any RHC assessment. Hemodynamic data were assessed at 5 time intervals: (1) pre-LVAD (within 6 months); (2) early post-LVAD (0 to 6 months); (3) 7 to 12 months; (4) 13 to 18 months; and (5) very late post-LVAD (18 to 36 months).Sixty participants met the inclusion criteria. All measures of right ventricular load (effective arterial elastance, pulmonary vascular compliance and pulmonary vascular resistance) improved between the pre- and early post-LVAD time periods. Despite decreasing load and pulmonary artery wedge pressure (PAWP), RAP remained unchanged and the RAP:PAWP ratio worsened early post-LVAD (0.44 [0.38, 0.63] vs 0.77 [0.59, 1.0], p0.001), suggesting a worsening of RV adaptation to load. With continued LVAD support, both RV load and RAP:PAWP decreased in a steep, linear and dependent manner.Despite reducing RV load, LVAD implantation leads to worsened RV adaptation. With continued LVAD support, both RV afterload and RV adaptation improve, and their relationship remains constant over time post-LVAD. These findings suggest the RV afterload sensitivity increases after LVAD implantation, which has major clinical implications for patients struggling with RV failure.

We appreciate the thoughtful review of our work [(1)][1] by Dr. He and colleagues. Although salient, the lack of subgroup analyses by specific H2-receptor antagonists (H2RAs) is a limitation of our work imposed by the data structure and limited number of participants in individual drug subgroups in

We appreciate the thoughtful review of our work by Dr. Patane. We unreservedly agree that our observations just scratch the surface regarding histamine and/or histamine receptor activation in heart failure pathogenesis. Our work was intended to explore whether a biologically relevant association

H2 receptor antagonist (H2RA) use is common and may act directly on the heart through myocardial H2 receptors or indirectly through changes in pulmonary vascular resistance.To determine the relationship between histamine H2RA use and right ventricular (RV) morphology.We studied 4,122 participants in the Multi-Ethnic Study of Atherosclerosis without clinical cardiovascular disease who had magnetic resonance imaging assessment of RV morphology and ascertainment of medication use. Multivariable linear regression estimated cross-sectional associations between H2RA use and RV morphology after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Further adjustments for co-medication use, left ventricular parameters, lung structure and function, renal function, or inflammatory markers were considered in separate models. Analyses in a subcohort restricted to H2RA or proton pump inhibitor users accounted for confounding by the indication of gastroesophageal reflux disease.H2RA use was associated with lower RV mass (-0.7 g; 95% confidence interval, -1.2 to -0.2 g; P = 0.004) and smaller RV end-diastolic volume (-4.2 ml; 95% confidence interval, -7.2 to -1.2 ml; P = 0.006). This relationship was unchanged with adjustment for co-medication use, lung structure and function, renal function, and inflammation. The relationship with RV mass was independent of left ventricular mass. Results were similar in the smaller cohort restricted to proton pump inhibitor and H2RA users.H2RA use was associated with lower RV mass and smaller RV end-diastolic volume. Additional study of histamine and H2 receptors in cardiopulmonary diseases affecting the RV may have direct clinical relevance.

To the Editor: CKD is associated with cardiovascular disease including myocardial infarction, heart failure, and cardiovascular mortality. Altered mineral metabolism, often seen in CKD, may contribute to cardiovascular disease by promoting adverse cardiac remodeling. Specifically, excess PTH and FGF-23 and insufficient 1,25-dihydroxyvitamin D have direct effects on left ventricle (LV)1-3 growth in experimental models. Right heart failure also contributes to morbidity and mortality across a broad range of cardiopulmonary diseases. Increased right ventricle (RV) mass has been associated with incident heart failure and cardiovascular mortality4. Compared to the LV, the RV has a distinct geometry, fiber orientation, embryologic origin, and is upstream of the low-pressure pulmonary circulation. As a result, lessons learned in the LV cannot be directly translated to the RV. The impact of disturbed mineral metabolism on the RV is unknown. We hypothesized that elevated serum concentrations of PTH and FGF-23 and lower serum concentrations of 25(OH)D are associated with increased RV mass and volumes and lower RV systolic function in MESA, a longitudinal cohort study of risk factors for subclinical atherosclerosis5. Ancillary studies have measured serum biomarkers of mineral metabolism (PTH, FGF-23, 25(OH)D, phosphorus, and calcium) and RV morphology (mass, end-diastolic volume (EDV), and ejection fraction (EF)) by cardiac magnetic resonance imaging at the baseline visit (details in Item S1). For this study, we examined 3777 of 6814 MESA participants with measurements of mineral metabolism biomarkers and RV dimensions. Cross-sectional associations of mineral metabolism biomarkers with RV measures were tested using multivariable linear regression. Study participants were racially and ethnically diverse with a normal eGFR (Table 1). Compared to those excluded, included participants had a lower prevalence of diabetes mellitus and hypertension and lower UACR and BMI (Table 1). Table 1 Characteristics of the participants in MESA PTH, FGF-23, calcium, and phosphorus were not associated with RV mass, RVEF, or RVEDV (Table 2, Table S1). Lower 25(OH)D was associated with a slightly greater RV mass in unadjusted, but not adjusted, analyses. Unadjusted associations are likely limited given confounding by body size. In adjusted analyses, lower 25(OH)D was associated with higher RVEF and lower RVEDV. Limited models adjusting for body size alone were similar to fully adjusted models (Table S1). Table 2 Associations of PTH, 25(OH)D, FGF-23, and RV structure and function. The lack of association between mineral metabolism biomarkers and RV mass in our large, community-based cohort was surprising and contrary to our hypothesis. These results contrast with published studies, including MESA data, suggesting that disturbed mineral metabolism may promote LV hypertrophy1-3, 6. Given our large cohort and precise RV mass measurements, insufficient power and misclassification seem unlikely to explain our null results. The ranges of PTH and FGF-23 were limited in this cohort with predominantly normal eGFR, however, and results might differ with more advanced kidney disease. Our null associations may suggest differential relationships of abnormal mineral metabolism on the LV relative to the RV. The ventricles are distinct7: the LV originates from the primary heart field whereas the RV arises from the anterior heart field. The LV is elliptical whereas the RV is triangular or crescentic. The LV is thicker and has more mass than the RV and as such, is better suited to handle pressure overload. The more compliant RV is better equipped to handle volume overload. Given their inherent differences and unique responses to physiologic insults, it is conceivable that mineral metabolism alterations affect each ventricle differently. Unexpectedly, lower 25(OH)D concentrations were associated with lower RVEDV and higher RVEF. This observation is counterintuitive because higher RVEF is associated with better outcomes in heart failure8 and pulmonary arterial hypertension9, but low 25(OH)D is typically associated with poor outcomes. One potential explanation is that lower 25(OH)D concentrations could lead to decreased RV compliance, such as that seen with mild fibrosis or diastolic dysfunction. This would be expected to result in a decreased RVEDV, 10 as was observed. In this relatively healthy population, compensation to maintain cardiac output would require increases in heart rate or RVEF. Unfortunately methods to identify fibrosis and diastolic dysfunction in the RV are not widely agreed on and these data were not available in MESA. Our study strengths include large size, a community-based multiethnic cohort free of baseline cardiovascular disease (reducing the likelihood of reverse causality), a comprehensive assessment of mineral metabolism markers, and precise RV measurements. Limitations include cross-sectional design; limited ranges of eGFR, PTH, and FGF-23; and lack of clinical outcomes. In conclusion, unlike associations established for the LV, mineral metabolism biomarkers were not associated with RV mass in a diverse, community-based population. Associations of 25(OH)D with RVEDV and RVEF were small, but hypothesis generating.

Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.

Background Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Proposed mechanisms may be relevant in right heart failure, but relationships between pericardial fat and right ventricular (RV) morphology have not been explored. Methods The Multi-Ethnic Study of Atherosclerosis is a prospective cohort that enrolled participants without clinical cardiovascular disease. Pericardial fat was measured using computed tomography and RV parameters using cardiac MRI. Linear regression estimated associations of pericardial fat with RV mass, RV end diastolic volume (RV-EDV), RV end systolic volume (RV-ESV), RV stroke volume (RV-SV), and RV ejection fraction (RV-EF). Limited models adjusted for age, gender, race, height, and study site with and without weight. Fully adjusted models also accounted for socioeconomic parameters and health behaviors. Adjustment for left ventricular morphology, metabolic syndrome, and systemic inflammation was also performed. Results The study sample included 3988 participants with complete assessment of RV morphology, pericardial fat and all covariates. Greater pericardial fat volume was associated with reduced RV mass (-0.3g per 40 cm3 increase in pericardial fat, p

OBJECTIVE To explore the association between the presence of maternal heart disease and maternal, perinatal, and infant outcomes. METHODS We conducted a population-based retrospective cohort study using Washington State birth certificates linked with hospital discharge records of mothers noted to have maternal congenital heart disease, ischemic heart disease, heart failure, or pulmonary hypertension. Women who gave birth between 1987 and 2009 (n=2,171) were compared with a sample of mothers without these conditions (n=21,710). We described characteristics of pregnant women with heart disease over time. Logistic regression estimated the association between chronic maternal heart disease and small-for-gestational-age (SGA) neonates as well as perinatal, postneonatal, and maternal death. RESULTS The proportion of births to women with reported heart disease increased 224% between the 1987 and 1994 and 2002 and 2009 calendar periods. Chronic maternal heart disease was associated with increased risk of SGA (62 additional SGA newborns per 1,000 births, 95% confidence interval [CI] 46-78; P

Elevation in plasma activity of von Willebrand factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension. Higher vWF activity is also associated with a lower right ventricular (RV) ejection fraction in pulmonary arterial hypertension. Little is known about the relation between vWF and RV structure and function in adults without cardiovascular disease. The present investigation included 1,976 participants with magnetic resonance imaging assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension, and the corresponding left ventricular parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume, and RV stroke volume in models with and without adjustment for the corresponding left ventricular parameter (all p values0.05). There was no association observed between vWF activity and the RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume, and RV stroke volume. These associations are independent of common cardiovascular risk factors and left ventricular morphologic changes.

Lung transplant patients commonly undergo transbronchial biopsy to evaluate for rejection. Post-biopsy radiographs are used to exclude pneumothorax, one of the most common major complications. We report a lung transplant patient who developed a pneumothorax 5 months after transbronchial biopsy, with multiple intervening chest computed tomograms documenting that the pneumothorax developed from the biopsy site. This case illustrates that in transplant patients transbronchial biopsy can evolve to pneumothorax several months later, despite normal post-biopsy radiographs.

Controversy exists as to whether platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, can actually protect the heart from postischemic injury. To determine whether endogenous activation of the PAF receptor is cardioprotective, we examined postischemic functional recovery in isolated hearts from wild-type and PAF receptor-knockout mice. Postischemic function was reduced in hearts with targeted deletion of the PAF receptor and in wild-type hearts treated with a PAF receptor antagonist. Furthermore, perfusion with picomolar concentrations of PAF improved postischemic function in hearts from wild-type mice. To elucidate the mechanism of a PAF-mediated cardioprotective effect, we employed a model of intracellular Ca2+ overload and loss of function in nonischemic ventricular myocytes. We found that PAF receptor activation attenuates the time-dependent loss of shortening and increases in intracellular Ca2+ transients in Ca2+-overloaded myocytes. These protective effects of PAF depend on nitric oxide, but not activation of cGMP. In addition, we found that reversible S-nitrosylation of myocardial proteins must occur in order for PAF to moderate Ca2+ overload and loss of myocyte function. Thus our data are consistent with the hypothesis that low-level PAF receptor activation initiates nitric oxide-induced S-nitrosylation of Ca2+-handling proteins, e.g., L-type Ca2+ channels, to attenuate Ca2+ overload during ischemia-reperfusion in the heart. Since inhibition of the PAF protective pathway reduces myocardial postischemic function, our results raise concern that clinical therapies for inflammatory diseases that lead to complete blockade of the PAF receptor may eliminate a significant, endogenous cardioprotective pathway.