Efficacy and safety of the Aria pulmonary endovascular device in pulmonary hypertension.

AIMS: A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (CPA), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and haemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH-LHD) and chronic lung disease (PH-CLD). METHODS AND RESULTS: Eight patients with PH-LHD and 10 patients with PH-CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas-filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Haemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. No complications or investigational device-related serious adverse events occurred. Device activation in PH-LHD and PH-CLD patients decreased pulmonary arterial pulse pressure by 5.6 ± 4.2 mmHg (-12%; p = 0.003) and 4.2 ± 2.2 mmHg (-11%; p < 0.001), increased CPA by 0.4 ± 0.2 ml/mmHg (+23%; p = 0.004) and 0.4 ± 0.3 ml/mmHg (+25%; p = 0.001), and increased right ventricular-to-pulmonary vascular (RV-PV) coupling by 0.24 ± 0.18 (+40%; p = 0.012) and 0.11 ± 0.07 (+21%; p = 0.001), respectively. CONCLUSIONS: Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of CPA and RV-PV coupling.

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.

Intermittent Fasting Enhances Right Ventricular Function in Preclinical Pulmonary Arterial Hypertension.

Background Intermittent fasting (IF) confers pleiotropic cardiovascular benefits including restructuring of the gut microbiome and augmentation of cellular metabolism. Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by right ventricular (RV) mitochondrial dysfunction and resultant lipotoxicity and microbiome dysbiosis. However, the effects of IF on RV function in PAH are unexplored. Therefore, we investigated how IF altered gut microbiota composition, RV function, and survival in the monocrotaline model of PAH. Methods and Results Male Sprague Dawley rats were randomly allocated into 3 groups: control, monocrotaline-ad libitum feeding, and monocrotaline-IF (every other day feeding). Echocardiography and invasive hemodynamics showed IF improved RV systolic and diastolic function despite no significant change in PAH severity. IF prevented premature mortality (30% mortality rate in monocrotaline-ad libitum versus 0% in monocrotaline-IF rats, P=0.04). IF decreased RV cardiomyocyte hypertrophy and reduced RV fibrosis. IF prevented RV lipid accrual on Oil Red O staining and ceramide accumulation as determined by metabolomics. IF mitigated the reduction in jejunum villi length and goblet cell abundance when compared with monocrotaline-ad libitum. The 16S ribosomal RNA gene sequencing demonstrated IF changed the gut microbiome. In particular, there was increased abundance of Lactobacillus in monocrotaline-IF rats. Metabolomics profiling revealed IF decreased RV levels of microbiome metabolites including bile acids, aromatic amino acid metabolites, and gamma-glutamylated amino acids. Conclusions IF directly enhanced RV function and restructured the gut microbiome. These results suggest IF may be a non-pharmacological approach to combat RV dysfunction, a currently untreatable and lethal consequence of PAH.

RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury.

The regulator of G protein signaling (RGS) represents a widespread system of controllers of cellular responses. The activities of the R4 subfamily of RGSs have been elucidated in allergic pulmonary diseases. However, the R4 signaling in other inflammatory lung diseases, with a strong cellular immune response, remained unexplored. Thus, our study aimed to discern the functional relevance of the R4 family member, RGS5, as a potential modulating element in this context. Gene profiling of the R4 subfamily showed increased RGS5 expression in human fibrosing lung disease samples. In line with this, RGS5 was markedly increased in murine lungs following bleomycin injury. RGS knock-out mice (RGS-/-) had preserved lung function while control mice showed significant combined ventilatory disorders three days after bleomycin application as compared to untreated control mice. Loss of RGS5 was associated with a significantly reduced neutrophil influx and tissue myeloperoxidase expression. In the LPS lung injury model, RGS5-/- mice also failed to recruit neutrophils into the lung, which was accompanied by reduced tissue myeloperoxidase levels after 24 h. Our in-vitro assays showed impaired migration of RGS5-/- neutrophils towards chemokines despite preserved Ca2+ signaling. ERK dephosphorylation might play a role in reduced neutrophil migration in our model. As a conclusion, loss of RGS5 preserves lung function and attenuates hyperinflammation in the acute phase of bleomycin-induced pulmonary fibrosis and LPS-induced lung injury. Targeting RGS5 might alleviate the severity of exacerbations in interstitial lung diseases.

Hemodynamic Characteristics and Outcomes of Pulmonary Hypertension in Patients Undergoing Tricuspid Valve Repair or Replacement.

BACKGROUND: The impact of pulmonary hypertension (PH) on outcomes after surgical tricuspid valve replacement (TVR) and repair (TVr) is unclear. We sought to characterize PH in patients undergoing TVR/TVr, based on invasive hemodynamics and evaluate the effect of PH on mortality. METHODS: We identified 86 consecutive patients who underwent TVR/TVr with invasive hemodynamic measurements within 3 months before surgery. We used Kaplan-Meier survival and restricted mean survival time (RMST) analyses to quantify the effects of PH on survival. RESULTS: The mean age was 63 ± 13 years, 59% were female, 45% had TVR, 55% had TVr, 39.5% had isolated TVR/TVr, and 60.5% had TVR/TVr concomitant with other cardiac surgeries). Eighty-six percent of these patients had PH with a mean pulmonary artery pressure of 30 ± 10 mm Hg, pulmonary vascular resistance (PVR) of 2.5 (interquartile range: 1.5-3.9) Wood units (WU), pulmonary arterial compliance of 2.3 (1.6-3.6) mL/mm Hg, and pulmonary arterial elastance of 0.8 (0.6-1.2) mm Hg/mL. Cardiac output was mildly reduced at 4.0 ± 1.4 L/min, with elevated right-atrial pressure (14 ± 12 mm Hg) and pulmonary capillary wedge pressure (19 ± 7 mm Hg). Over a median follow-up of 6.3 years, 22% of patients died. Patients with PVR ≥ 2.5 WU had lower RMST over 5 years compared with patients with PVR < 2.5 WU. CONCLUSION: PH is common in patients undergoing TVR/TVr, with combined pre- and postcapillary being the most common type. PVR ≥ 2.5 WU is associated with lower survival at 5-year follow-up.

CONTEXTE: On connaît mal les répercussions de l'hypertension pulmonaire (HP) chez les patients qui ont subi une intervention chirurgicale de remplacement de la valve tricuspide (RVT) ou de réparation de la valve tricuspide (rVT). Nous avons tenté de caractériser l'HP chez les patients ayant subi un RVT ou une rVT en fonction des paramètres de surveillance hémodynamique effractive et d'évaluer l'effet de l'HP sur la mortalité. MÉTHODOLOGIE: Nous avons relevé 86 patients consécutifs ayant subi un RVT ou une rVT qui avaient fait l'objet de mesures hémodynamiques effractives dans les trois mois précédant l'intervention chirurgicale. Pour quantifier les effets de l'HP sur la survie, nous avons analysé la survie au moyen de la méthode de Kaplan-Meier et de la survie moyenne restreinte. RÉSULTATS: Les patients avaient en moyenne 63 ± 13 ans; 59 % d'entre eux étaient des femmes; 45 % avaient subi un RVT et 55 %, une rVT; 39,5 % avaient subi seulement un RVT ou une rVT lors de l'intervention chirurgicale; 60,5 % avaient subi un RVT ou une rVT en même temps qu'une autre intervention cardiaque. Quatre-vingt-six pour cent de ces patients présentaient une HP avec une pression artérielle pulmonaire moyenne de 30 ± 10 mmHg, une résistance vasculaire pulmonaire (RVP) de 2,5 (intervalle interquartile : 1,5 à 3,9) unités de Wood (UW), une compliance artérielle pulmonaire de 2,3 (1,6 à 3,6) ml/mmHg et une élastance artérielle pulmonaire de 0,8 (0,6 à 1,2) mmHg/ml. On a observé une légère baisse du débit cardiaque à 4,0 ± 1,4 L/min, ainsi qu'une augmentation de la pression auriculaire droite (14 ± 12 mmHg) et de la pression artérielle pulmonaire d'occlusion (19 ± 7 mmHg). Sur une période médiane de suivi de 6,3 ans, 22 % des patients sont décédés. Le taux de survie moyenne restreinte à 5 ans était plus faible chez les patients présentant une RVP ≥ 2,5 UW que chez les patients présentant une RVP < 2,5 UW. CONCLUSION: L'HP est fréquente chez les patients subissant un RVT ou une rVT, le type le plus courant étant l'HP mixte (pré-capillaire et post-capillaire). Une RVP ≥ 2,5 UW est associée à un taux de survie à 5 ans plus faible.

A Case Report of Portopulmonary Hypertension Precipitated by Transjugular Intrahepatic Portosystemic Shunt.

We report here a case of portopulmonary hypertension following transjugular intrahepatic portosystemic shunt.

Does vitamin D deficiency increase the severity of COVID-19?

The severity of coronavirus 2019 infection (COVID-19) is determined by the presence of pneumonia, severe acute respiratory distress syndrome (SARS-CoV-2), myocarditis, microvascular thrombosis and/or cytokine storms, all of which involve underlying inflammation. A principal defence against uncontrolled inflammation, and against viral infection in general, is provided by T regulatory lymphocytes (Tregs). Treg levels have been reported to be low in many COVID-19 patients and can be increased by vitamin D supplementation. Low vitamin D levels have been associated with an increase in inflammatory cytokines and a significantly increased risk of pneumonia and viral upper respiratory tract infections. Vitamin D deficiency is associated with an increase in thrombotic episodes, which are frequently observed in COVID-19. Vitamin D deficiency has been found to occur more frequently in patients with obesity and diabetes. These conditions are reported to carry a higher mortality in COVID-19. If vitamin D does in fact reduce the severity of COVID-19 in regard to pneumonia/ARDS, inflammation, inflammatory cytokines and thrombosis, it is our opinion that supplements would offer a relatively easy option to decrease the impact of the pandemic.

Hypochloremia Is a Noninvasive Predictor of Mortality in Pulmonary Arterial Hypertension.

Background Pulmonary arterial hypertension (PAH) is a lethal disease. In resource-limited countries PAH outcomes are worse because therapy costs are prohibitive. To improve global outcomes, noninvasive and widely available biomarkers that identify high-risk patients should be defined. Serum chloride is widely available and predicts mortality in left heart failure, but its prognostic utility in PAH requires further investigation. Methods and Results In this study 475 consecutive PAH patients evaluated at the University of Minnesota and Vanderbilt University PAH clinics were examined. Clinical characteristics were compared by tertiles of serum chloride. Both the Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. Categorical net reclassification improvement and relative integrated discrimination improvement compared prediction models. PAH patients in the lowest serum chloride tertile (≤101 mmol/L: hypochloremia) had the lowest 6-minute walk distance and highest right atrial pressure despite exhibiting no differences in pulmonary vascular disease severity. The 1-, 3-, and 5-year survival was reduced in hypochloremic patients when compared with the middle- and highest-tertile patients (86%/64%/44%, 95%/78%/59%, and, 91%/79%/66%). After adjustment for age, sex, diuretic use, serum sodium, bicarbonate, and creatinine, the hypochloremic patients had increased mortality when compared with the middle-tertile and highest-tertile patients. The Minnesota noninvasive model (functional class, 6-minute walk distance, and hypochloremia) was as effective as the French noninvasive model (functional class, 6-minute walk distance, and elevated brain natriuretic peptide or N-terminal pro-brain natriuretic peptide) for predicting mortality. Conclusions Hypochloremia (≤101 mmol/L) identifies high-risk PAH patients independent of serum sodium, renal function, and diuretic use.

Can intestinal microbiota and circulating microbial products contribute to pulmonary arterial hypertension?

Pulmonary arterial hypertension (PAH) is a fatal disease with a median survival of only 5-7 yr. PAH is characterized by remodeling of the pulmonary vasculature causing reduced pulmonary arterial compliance (PAC) and increased pulmonary vascular resistance (PVR), ultimately resulting in right ventricular failure and death. Better therapies for PAH will require a paradigm shift in our understanding of the early pathophysiology. PAC decreases before there is an increase in the PVR. Unfortunately, present treatment has little effect on PAC. The loss of compliance correlates with extracellular matrix remodeling and fibrosis in the pulmonary vessels, which have been linked to chronic perivascular inflammation and immune dysregulation. However, what initiates the perivascular inflammation and immune dysregulation in PAH is unclear. Alteration of the gut microbiota composition and function underlies the level of immunopathogenic involvement in several diseases, including atherosclerosis, obesity, diabetes mellitus, and depression, among others. In this review, we discuss evidence that raises the possibility of an etiologic role for changes in the gut and circulating microbiome in the initiation of perivascular inflammation in the early pathogenesis of PAH.

Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats.

Patients with pulmonary arterial hypertension (PAH) and right ventricular (RV) failure have a poor clinical outcome, but the mechanisms of PAH and RV failure development are not totally clear. PAH is associated with reduced NO bioavailability and increased endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). Dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays a critical role in ADMA degradation. Here we generated a novel DDAH1 deficiency rat strain using the CRISPR-Cas9 technique, and studied the effect of DDAH1 dysfunction on monocrotaline-induced PAH, lung vascular remodeling and RV hypertrophy. DDAH1 knockout resulted in abolished DDAH1 expression in various tissues, and significant increases of plasma and lung ADMA content. DDAH1 knockout has no detectable effect on cardiac and lung structure, and LV function under control conditions in rats. However, DDAH1 knockout significantly aggravated monocrotaline-induced lung and RV oxidative stress, lung vascular remodeling and fibrosis, pulmonary hypertension and RV hypertrophy in rats. DDAH1 KO resulted in significantly greater increases of plasma and lung ADMA content under control conditions. In the wild type rats monocrotaline resulted in significant increases of plasma and lung ADMA contents and reduction of lung eNOS protein content and these changes were more marked in DDAH1 KO rats. Together, our results demonstrated that DDAH1 plays an important role in attenuating monocrotaline-induced lung oxidative stress, pulmonary hypertension and RV hypertrophy in rats.

Isolevuglandin scavenger attenuates pressure overload-induced cardiac oxidative stress, cardiac hypertrophy, heart failure and lung remodeling.

Increased levels of reactive isolevuglandins (IsoLGs) are associated with vascular inflammation and hypertension, two important factors affect heart failure (HF) development. The role of IsoLGs in HF development is unknown. Here we studied the role of IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) in transverse aortic constriction (TAC) induced heart failure. We observed that TAC caused a significant increase of IsoLG protein adducts in cardiac and lung tissues in mice. Both IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) and its less reactive isomer 4-hydroxybenzylamine (4-HOBA) significantly attenuated the left ventricular (LV) and lung IsoLGs in mice after TAC. 2-HOBA and 4-HOBA attenuated TAC-induced LV hypertrophy, heart failure, and the increase of lung weight in mice, and also improved TAC-induced LV dysfunction. Moreover, both 2-HOBA and 4-HOBA effectively attenuated LV cardiomyocyte hypertrophy, lung inflammation, lung fibrosis. These findings suggest that methods to reduce IsoLGs may be useful for HF therapy.

Short term Pm2.5 exposure caused a robust lung inflammation, vascular remodeling, and exacerbated transition from left ventricular failure to right ventricular hypertrophy.

Heart failure (HF) is the single largest cause for increased hospitalization after fine particulate matter (PM2.5) exposure. Patients with left HF often progress to right ventricular (RV) failure even with optimal medical care. An increase of PM2.5 of 10 µg per cubic meter was associated with a 76% increase in the risk of death from cardiovascular disease in 4 years' period. However, the role and mechanism of PM2.5 in HF progression are not known. Here we investigated the role of PM2.5 exposure in mice with existing HF mice produced by transverse aortic constriction (TAC). TAC-induced HF caused lung inflammation, vascular remodeling and RV hypertrophy. We found increased PM2.5 profoundly exacerbated lung oxidative stress in mice with existing left HF. To our surprise, PM2.5 exposure had no effect on LV hypertrophy and function, but profoundly exacerbated lung inflammation, vascular remodeling, and RV hypertrophy in mice with existing left HF. These striking findings demonstrate that PM2.5 and/or air pollution is a critical factor for overall HF progression by regulating lung oxidative stress, inflammation and remodeling as well as RV hypertrophy. Improving air quality may save HF patients from a dismal fate.

Clinical Determinants and Prognostic Implications of Right Ventricular Dysfunction in Pulmonary Hypertension Caused by Chronic Lung Disease.

Background Patients with pulmonary hypertension caused by chronic lung disease (Group 3 PH ) have disproportionate right ventricle ( RV ) dysfunction, but the correlates and clinical implications of RV dysfunction in Group 3 PH are not well defined. Methods and Results We performed a cohort study of 147 Group 3 PH patients evaluated at the University of Minnesota. RV systolic function was quantified using right ventricular fractional area change ( RVFAC ) and + dP /dtmax/instantaneous pressure. Tau and RV diastolic stiffness characterized RV diastolic function. Multivariate linear regression was used to define correlates of RVFAC . Kaplan-Meier and Cox proportional hazards analyses were used to examine freedom from heart failure hospitalization and death. Positive correlates of RVFAC on univariate analysis were pulmonary arterial compliance, cardiac index, and left ventricular diastolic dimension. Conversely, male sex, N-terminal pro-brain natriuretic peptide, heart rate, right atrial enlargement, mean pulmonary arterial pressure, and pulmonary vascular resistance were negative correlates. Male sex was the strongest predictor of lower RVFAC , after adjusting for pulmonary vascular resistance and pulmonary arterial compliance. When comparing sexes, males had lower RVFAC (26% versus 31%, P=0.03) both overall and for any given mean pulmonary arterial pressure and pulmonary vascular resistance value. Males exhibited a reduction in + dP /dtmax/instantaneous pressure as pulmonary vascular resistance increased, whereas females did not. There were no sex differences in RV diastolic function. RV dysfunction ( RVFAC <28%) was associated with increased risk of heart failure hospitalization or death (hazard ratio: 1.84, 95% CI : 1.04-3.10, P=0.035). Conclusions Male sex is associated with RV dysfunction in Group 3 PH , even after adjusting for RV afterload. RV dysfunction ( RVFAC <28%) identifies Group 3 PH patients at risk for poor outcomes.

Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusion capacity of the lungs for carbon monoxide.

BACKGROUND: Patients with pulmonary hypertension (PH) due to chronic lung disease (Group 3 PH) have poor long-term outcomes. However, predictors of survival in Group 3 PH are not well described. METHODS: We performed a cohort study of Group 3 PH patients (n = 143; mean age 65 ± 12 years, 52% female) evaluated at the University of Minnesota. The Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. The clinical characteristics and survival were compared in patients categorized by PH severity based on the World Health Organization (WHO) classification and lung disease etiology. RESULTS: After a median follow-up of 1.4 years, there were 69 (48%) deaths. The 1-, 3-, and 5-year survival rates were 79%, 48%, and 31%. Age, coronary artery disease, atrial fibrillation, Charlson comorbidity index, serum N-terminal pro‒brain natriuretic peptide (NT-proBNP), creatinine, diffusion capacity of carbon monoxide (DLCO), total lung capacity, left ventricular ejection fraction, right atrial and right ventricular enlargement on echocardiography, cardiac index, and pulmonary vascular resistance (PVR) were univariate predictors of survival. On multivariable analysis, DLCO was the only predictor of mortality (adjusted hazard ratio [HR] for every 10% decrease in predicted value: 1.31 [95% confidence interval 1.12 to 1.47]; p = 0.003). The 1-/5-year survival by tertiles of DLCO was 84%/56%, 82%/44%, and 63%/14% (p = 0.01), respectively. On receiver-operating characteristic curve analysis, DLCO <32% of predicted had the highest sensitivity and specificity for predicting survival. The 1- and 5-year survival in patients with a DLCO ≥32% predicted was 84% and 60% vs 68% and 13% in patients with a DLCO <32% predicted (adjusted HR: 2.5 [95% confidence interval 1.3 to 5.0]; p = 0.007). Lung volumes and DLCO were not related, but higher PVR was strongly associated with reduced DLCO. There was increased mortality in interstitial lung disease‒PH as compared with chronic obstructive pulmonary disease‒PH, but PH severity based on the WHO classification did not alter survival. CONCLUSIONS: Low DLCO is a predictor of mortality and should be used to risk-stratify Group 3 PH patients.

Application of a novel in vivo imaging approach to measure pulmonary vascular responses in mice.

Noninvasive imaging of the murine pulmonary vasculature is challenging due to the small size of the animal, limits of resolution of the imaging technology, terminal nature of the procedure, or the need for intravenous contrast. We report the application of laboratory-based high-speed, high-resolution x-ray imaging, and image analysis to detect quantitative changes in the pulmonary vascular tree over time in the same animal without the need for intravenous contrast. Using this approach, we detected an increased number of vessels in the pulmonary vascular tree of animals after 30 min of recovery from a brief exposure to inspired gas with 10% oxygen plus 5% carbon dioxide (mean ± standard deviation: 2193 ± 382 at baseline vs. 6177 ± 1171 at 30 min of recovery; P < 0.0001). In a separate set of animals, we showed that the total pulmonary blood volume increased (P = 0.0412) while median vascular diameter decreased from 0.20 mm (IQR: 0.15-0.28 mm) to 0.18 mm (IQR: 0.14-0.26 mm; P = 0.0436) over the respiratory cycle from end-expiration to end-inspiration. These findings suggest that the noninvasive, nonintravenous contrast imaging approach reported here can detect dynamic responses of the murine pulmonary vasculature and may be a useful tool in studying these responses in models of disease.