Ketone bodies in right ventricular failure: A unique therapeutic opportunity.

Background: Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored. Methods: 51 PAH patients were dichotomized into preserved or impaired RV function based on a cardiac index of 2.2 L/min/m2. Impaired RV function patients were further segmented into intermediate or severe RV dysfunction based on a right atrial pressure of 8 mm Hg. Serum ketone bodies acetoacetate (AcAc) and beta-hydroxybutyrate (ßOHB) were quantified using ultra performance liquid chromatography and mass spectrometry. In rodent studies, male Sprague Dawley rats were assigned to three groups: control (saline injection), monocrotaline (MCT) standard chow diet (MCT-Standard), and MCT ketogenic diet (MCT-Keto). Immunoblots and confocal microscopy probed macrophage NLRP3 activation in RV extracts and sections. RV fibrosis was determined by Picrosirus Red. Echocardiography evaluated RV function. Pulmonary arteriole remodeling was assessed from histological specimens. Results: Human RVF patients lacked a compensatory ketosis as serum AcAc and ßOHB levels were not associated with hemodynamic, echocardiographic, or biochemical measures of RV dysfunction. In rodent studies, AcAc and ßOHB levels were also not elevated in MCT-mediated RVF, but the ketogenic diet significantly increased AcAc and ßOHB levels. MCT-Keto exhibited suppressed NLRP3 activation with a reduction in NLRP3, ASC (apoptosis-associated speck-like protein), pro-caspase-1, and interleukin-1 beta on immunoblots. Moreover, the number of ASC-positive macrophage in RV sections was reduced, RV fibrosis was blunted, and RV function was augmented in MCT-Keto rats. Conclusion: The ketogenic response is blunted in pulmonary arterial hypertension (PAH) patients with RVF. In the MCT rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.

Sex differences in right ventricular function between Groups 1 and 3 pulmonary hypertension.

Group 3 pulmonary hypertension (PH) patients have disproportionate right ventricular dysfunction (RVD) compared to pulmonary arterial hypertension. We evaluated how sex and PH etiology modulated RVD. Strain echocardiography showed no intrasex differences between PH types. Heightened RVD in Group 3 PH may be due to a greater male proportion.

Pulmonary tumor thrombotic microangiopathy: Exploration into current diagnostic aids and therapeutics.

Pulmonary tumor thrombotic microangiopathy (PTTM) is an under-recognized cause of pulmonary hypertension and fulminant right ventricle failure. It is associated with a high mortality due to delay in diagnosis. We present two cases of PTTM, both diagnosed postmortem, highlighting the importance of timely identification and initiation of treatment for this near-fatal condition.

Effect of Combination of Balloon Pulmonary Angioplasty and Medical Therapy on Reverse Right Ventricular Remodeling and Hemodynamics in Chronic Thromboembolic Pulmonary Hypertension.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive and debilitating disorder that results from incomplete resolution of vascular obstructions resulting in pulmonary hypertension. Surgical pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH. Unfortunately, many CTEPH patients are ineligible for PTE or do not have access to an expert surgical center. Medical therapy imparts important symptomatic and exercise benefits for CTEPH patients, but it does not extend survival. Balloon pulmonary angioplasty (BPA) is an emerging transcatheter approach that is both safe and efficacious. However, the potential synergy between upfront BPA and medical therapy treatment approaches in patients with inoperable CTEPH is unknown. Here, we evaluated how the combination of BPA and medical therapy compared to medical therapy alone in a newly established BPA program. METHODS: Twenty-one patients with inoperable or residual CTEPH were evaluated in this single-center observational study. Ten patients underwent upfront BPA and medical therapy while 11 patients were treated with medical therapy alone. Hemodynamic and echocardiographic assessments were performed at baseline and at least 1 month after completion of therapy. Continuous variables were compared using t-test or Mann-Whitney U-test. Categorical variables were analyzed with Chi squared and Fisher's exact test where appropriate. RESULTS: Combination therapy significantly reduced mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), but medical therapy only significantly lowered PVR. Comprehensive echocardiographic analysis revealed a more robust reverse right ventricular (RV) remodeling effect and augmentation of RV function with combination therapy. At the end of study, the combination therapy group had lower mPAP and PVR and better RV function. Importantly, there were no significant adverse effects in patients treated with BPA. CONCLUSION: Combination therapy significantly improves hemodynamics and RV function in inoperable CTEPH while carrying an acceptable risk profile, even in a newly developed program. Further studies comparing upfront combination therapy to medical therapy with larger, long-term, and randomized approaches should be considered.

Ketone Bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity.

Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored. Moreover, the cardioprotective properties of ketones in preclinical RVF are unknown. Here, we show a compensatory ketosis is absent in pulmonary arterial hypertension (PAH) patients with RVF. In the monocrotaline (MCT) rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.

Long-term inhaled treprostinil for pulmonary hypertension due to interstitial lung disease: INCREASE open-label extension study.

INTRODUCTION: The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD. METHODS: Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded. RESULTS: At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL-1 at RCT baseline to 359 pg·mL-1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49-0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients. CONCLUSIONS: These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.

Effect of Chronic Digoxin Use on Mortality and Heart Failure Hospitalization in Pulmonary Arterial Hypertension.

Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic digoxin use in PAH are unclear. Methods and Results Data from the Minnesota Pulmonary Hypertension Repository were used. The primary analysis used likelihood of digoxin prescription. The primary end point was a composite of all-cause mortality or heart failure (HF) hospitalization. Secondary end points included all-cause mortality, HF hospitalization, and transplant-free survival. Multivariable Cox proportional hazards analyses determined the hazard ratios (HR) and 95% CIs for the primary and secondary end points. Among 205 patients with PAH in the repository, 32.7% (n=67) were on digoxin. Digoxin was more often prescribed to patients with severe PAH and right ventricular failure. After propensity score-matching, 49 patients were digoxin users, and 70 patients were nonusers; of these 31 (63.3%) in the digoxin group and 41 (58.6%) in nondigoxin group met the primary end point during a median follow-up time of 2.1 (0.6-5.0) years. Digoxin users had a higher combined all-cause mortality or HF hospitalization (HR, 1.82 [95% CI, 1.11-2.99]), all-cause mortality (HR, 1.92 [95% CI, 1.06-3.49]), HF hospitalization (HR, 1.89 [95% CI, 1.07-3.35]), and worse transplant-free survival (HR, 2.00 [95% CI, 1.12-3.58]) even after adjusting for patient characteristics and severity of PAH and right ventricular failure. Conclusions In this retrospective, nonrandomized cohort, digoxin treatment was associated with greater all-cause mortality and HF hospitalization, even after multivariate correction. Future randomized controlled trials should assess the safety and efficacy of chronic digoxin use in PAH.

Pulmonary Arterial Hypertension Patients Have a Proinflammatory Gut Microbiome and Altered Circulating Microbial Metabolites.

Rationale: Inflammation drives pulmonary arterial hypertension (PAH). Gut dysbiosis causes immune dysregulation and systemic inflammation by altering circulating microbial metabolites; however, little is known about gut dysbiosis and microbial metabolites in PAH. Objectives: To characterize the gut microbiome and microbial metabolites in patients with PAH. Methods: We performed 16S ribosomal RNA gene and shotgun metagenomics sequencing on stool from patients with PAH, family control subjects, and healthy control subjects. We measured markers of inflammation, gut permeability, and microbial metabolites in plasma from patients with PAH, family control subjects, and healthy control subjects. Measurements and Main Results: The gut microbiome was less diverse in patients with PAH. Shannon diversity index correlated with measures of pulmonary vascular disease but not with right ventricular function. Patients with PAH had a distinct gut microbial signature at the phylogenetic level, with fewer copies of gut microbial genes that produce antiinflammatory short-chain fatty acids (SCFAs) and secondary bile acids and lower relative abundances of species encoding these genes. Consistent with the gut microbial changes, patients with PAH had relatively lower plasma concentrations of SCFAs and secondary bile acids. Patients with PAH also had enrichment of species with the microbial genes that encoded the proinflammatory microbial metabolite trimethylamine. The changes in the gut microbiome and circulating microbial metabolites between patients with PAH and family control subjects were not as substantial as the differences between patients with PAH and healthy control subjects. Conclusions: Patients with PAH have proinflammatory gut dysbiosis, in which lower circulating SCFAs and secondary bile acids may facilitate pulmonary vascular disease. These findings support investigating modulation of the gut microbiome as a potential treatment for PAH.

Outcomes of Patients Referred for Cardiac Rehabilitation After Left Ventricular Assist Device Implantation.

A single-center continuous-flow left ventricular assist device (LVAD) cohort (n = 503) was reviewed for patients with information on cardiac rehabilitation (CR) participation (n = 273) over a 13-year period. The analysis was then limited LVAD recipients who fit into three main CR categories: those who graduated CR (n = 138), those who were able to but declined participation (n = 61), and those who were too sick to complete or start CR (n = 28). To assess the association between CR categories and mortality and hospitalizations on LVAD support, multivariate cox regression and negative binomial regression analyses were performed, respectively. Among those who started CR and had the opportunity to finish (enough follow-up time, insurance coverage), 79% graduated. Those who graduated CR had a 96% survival at 1 year (95% confidence interval [CI], 91-98). Compared with the graduated group, those in the too sick group had an increased hazards rate of mortality (hazard ratio, 2.85; 95% CI, 1.49-5.44; p < 0.01) and an increase in the incidence rate of hospitalizations (incidence rate ratio, 1.74; 95% CI, 1.14-2.66, p = 0.01). This study is the largest to date to report outcomes of LVAD recipients referred for CR. The lower readmission rates and high survival in the group that graduated CR provides further evidence for the safety of CR in LVAD recipients.

Erratum: Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211020913.].

Riociguat and the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases that can lead to right heart failure and death. Right ventricular dysfunction, hypertrophy and maladaptive remodelling are consequences of increased right ventricular (RV) afterload in PAH and CTEPH and are indicative of long-term outcomes. Because RV failure is the main cause of morbidity and mortality in PAH and CTEPH, successful treatments should lead to improvements in RV parameters. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. This review examines the current evidence showing the effect of riociguat on the right ventricle, with particular focus on remodelling, function and structural parameters in preclinical models and patients with PAH or CTEPH.

Anticoagulation in pulmonary arterial hypertension - association with mortality, healthcare utilization, and quality of life: The Pulmonary Hypertension Association Registry (PHAR).

BACKGROUND: Routine long-term anticoagulation in pulmonary arterial hypertension (PAH) is controversial. To date, anticoagulation has been found to be beneficial or neutral in idiopathic disease (IPAH) and neutral-to-harmful in connective tissue disease (CTD-PAH). We sought to examine the association between anticoagulation and mortality, healthcare utilization, and quality of life (QoL) in PAH. METHODS: The PHAR is a prospective registry of PAH patients referred to 58 pulmonary hypertension care centers in the United States. We compared patients who received anticoagulation during enrollment (questionnaire documented) to those who did not. Cox proportional hazard models were used for mortality, Poisson multivariate regression models for healthcare utilization, and generalized estimating equations for QOL RESULTS: Of 1175 patients included, 316 patients were treated with anticoagulation. IPAH/hereditary PAH (HPAH) comprised 46% of the cohort and CTD-PAH comprised 33%. After adjustment for demographics, clinical characteristics, site and disease severity, anticoagulation was not associated with mortality in the overall population (HR, 1.00; 95% CI, 0.72-1.36), IPAH/HPAH (HR, 1.19; 95% CI, 0.74-1.94), or CTD-PAH (HR 0.87; 95% CI, 0.53-1.42). Anticoagulation was associated with an increased rate of emergency department visits (IRR: 1.41), hospitalizations (IRR: 1.30), and hospital days (IRR 1.33). QOL measured by emPHasis-10 score was worse in patients receiving anticoagulation (mean difference 1.74; 95% CI 0.40-3.09). CONCLUSIONS: Anticoagulation is not associated with higher mortality, but is associated with increased healthcare utilization in the PHAR. PAH-specific QoL may be worse in patients receiving anticoagulation. The risks and benefits surrounding routine prescription of anticoagulation for PAH should be carefully considered.

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

Incidence and Risk Factors of Pulmonary Hypertension After Venous Thromboembolism: An Analysis of a Large Health Care Database.

Background Pulmonary hypertension (PH) is a devastating potential complication of pulmonary embolism, a manifestation of venous thromboembolism (VTE). The incidence of and risk factors for PH in those with prior VTE are poorly characterized. Methods and Results International Classification of Diseases (ICD) codes from inpatient and outpatient medical claims from MarketScan administrative databases for years 2011 to 2018 were used to identify cases of VTE, comorbidities before the VTE event, and PH occurring subsequent to the VTE event. Cumulative incidence and hazard ratios (HR), and their 95% CI, were calculated. The 170 021 VTE cases included in the analysis were on average (±SD) 57.5±15.8 years old and 50.5% were female. A total of 5943 PH cases accrued over an average follow-up of 1.94 years. Two years after incident VTE, the cumulative incidence (95% CI) of PH was 3.5% (3.4%-3.7%) overall. It was higher among older individuals, among women (3.9% [3.8%-4.1%]) than men (3.2% [3.0%-3.3%]), and among patients presenting with pulmonary embolism (6.2% [6.0%-6.5%]) than those presenting with deep vein thrombosis only (1.1% [1.0%-1.2%]). Adjusting for age and sex, risk of PH was higher among patients with VTE with underlying comorbidities. Using the Charlson comorbidity index, there was a dose-response relationship, whereby greater scores were associated with increased PH risk (score ≥5 versus 0: HR, (2.50 [2.30-2.71])). When evaluating individual comorbidities, the strongest associations were observed with concomitant heart failure (HR, 2.17 [2.04-2.31]), chronic pulmonary disease (2.01 [1.90-2.14]), and alcohol abuse (1.66 [1.29-2.13]). Conclusions In this large, real-world population of insured people with VTE, 3.5% developed PH in the 2 years following their initial VTE event. Risk was higher among women, with increasing age, and in those with additional comorbidities at the time of the VTE event. These data provide insights into the burden of PH and risk factors for PH among patients with VTE.

Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association.

This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our goal is to clarify key knowledge gaps in pulmonary hypertension attributable to heart failure with preserved ejection fraction and to suggest specific, actionable scientific directions for addressing such gaps. Areas in need of additional investigation include refined disease definitions and interpretation of hemodynamics, as well as greater insights into noncardiac contributors to pulmonary hypertension risk, optimized animal models, and further molecular studies in patients with combined precapillary and postcapillary pulmonary hypertension. We highlight translational approaches that may provide important biological insight into pathophysiology and reveal new therapeutic targets. Last, we discuss the current and future landscape of potential therapies for patients with heart failure with preserved ejection fraction and pulmonary vascular dysfunction, including considerations of precision medicine, novel trial design, and device-based therapies, among other considerations. This science advisory provides a synthesis of important knowledge gaps, culminating in a collection of specific research priorities that we argue warrant investment from the scientific community.

Hypotension on cardiopulmonary stress test predicts 90 day mortality after LVAD implantation in INTERMACS 3-6 patients.

AIMS: Cardiopulmonary stress test (CPX) is routinely performed when evaluating patient candidacy for left ventricular assist device (LVAD) implantation. The predictive value of hypotensive systolic blood pressure (SBP) response during CPX on clinical outcomes is unknown. This study aims to determine the effect of hypotensive SBP response during to clinical outcomes among patients who underwent LVAD implantation. METHODS AND RESULTS: This was a retrospective single center study enrolling consecutive patients implanted with a continuous flow LVAD between 2011 and 2022. Hypotensive SBP response was defined as peak exercise SBP below the resting value. Multivariable Cox-regression analysis was performed to evaluate the relationship between hypotensive SBP response and all-cause mortality within 30 and 90 days of LVAD implantation. A subgroup analysis was performed for patients implanted with a HeartMate III (HM III) device. Four hundred thirty-two patients underwent LVAD implantation during the pre-defined period and 156 with INTERMACS profiles 3-6 met our inclusion criteria. The median age was 63 years (IQR 54-69), and 52% had ischaemic cardiomyopathy. Hypotensive SBP response was present in 35% of patients and was associated with increased 90 day all-cause mortality (unadjusted HR 9.16, 95% CI 1.98-42; P = 0.0046). Hazard ratio remained significant after adjusting for age, INTERMACS profile, serum creatinine, and total bilirubin. Findings were similar in the HM III subgroup. CONCLUSIONS: Hypotensive SBP response on pre-LVAD CPX is associated with increased perioperative and 90 day mortality after LVAD implantation. Additional studies are needed to determine the mechanism of increased mortality observed.

Association of Right Ventricular Afterload With Atrial Fibrillation Risk in Older Adults: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Atrial fibrillation (AF) is widely perceived to originate from the left atrium (LA). Whether increases in right ventricular (RV) afterload in older adults play an etiological role in AF genesis independent of LA and left ventricular (LV) remodeling is unknown. RESEARCH QUESTION: Is higher RV afterload associated with greater AF risk independent of LA and LV remodeling? STUDY DESIGN AND METHODS: In this observational prospective study, we included 2,246 community-dwelling older adults (mean age, 75 years) without known cardiovascular disease, with LV ejection fraction > 50%, LA volume index < 34 mL/m2, and E/e' ratio < 14 and a measurable functional tricuspid regurgitation jet velocity. From 2D-echocardiograms, we estimated pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR). We ascertained incident AF (through 2018) from hospital discharge codes and death certificates. We estimated hazard ratios (HR) by Cox regression. RESULTS: During follow-up (median, 6.3 years; interquartile interval, 5.5-6.9 years), 215 participants developed AF. AF risk was significantly higher in the third (vs first) tertile of PASP (HR, 1.65; 95% CI, 1.08-2.54) and PVR (HR, 1.38; 95% CI, 1.00-2.08) independent of LA and LV structure and function, heart rate, BMI, prevalent sleep apnea, systemic BP, antihypertensive medications, and lung, kidney, and thyroid function. These associations persisted after further exclusion of participants with tricuspid regurgitation jet velocity > 2.8 m/s and lateral and septal mitral annular velocity above age- and sex-specific reference limits. INTERPRETATION: In older adults, higher RV afterload is associated with greater AF risk independent of LA and LV remodeling. Future research should focus on confirming this novel association and elucidate underlying mechanisms.