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

ABSTRACT: 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.

SUBMITTER: Prisco SZ

PROVIDER: S-EPMC8751945 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Prisco Sasha Z SZ Eklund Megan M Moutsoglou Daphne M DM Prisco Anthony R AR Khoruts Alexander A Weir E Kenneth EK Thenappan Thenappan T Prins Kurt W KW

Journal of the American Heart Association 20211108 22

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 ...[more]

PMID: 34747187

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Project description:BackgroundMultiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.Research questionDoes RV adaptation predict therapeutic response over time?Study design and methodsWe evaluated 52 incident treatment-naive patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 months), and follow-up 2 (∼18 months). All patients received goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I or II was not achieved. On the basis of their therapeutic response, patients were evaluated at follow-up 1 as nonresponders (died) or as responders, and again at follow-up 2 as super-responders (low risk) or partial responders (high/intermediate risk). Multiparametric risk was based on a simplified European Respiratory Society/European Society of Cardiology guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean ± SD or as OR (95% CI).ResultsNine patients (17%) were nonresponders. PAH-directed therapy improved the European Respiratory Society low-risk score from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was nonsignificantly higher in responders (0.9 ± 0.4) vs nonresponders (0.6 ± 0.4; P = .09) but could not be used to predict super-responder status at follow-up 2 (OR, 1.40 [95% CI, 0.28-7.0]; P = .84). Baseline RV ejection fraction and change in Eed were successfully used to predict super-responder status at follow-up 2 (OR, 1.15 [95% CI, 1.0-1.27]; P = .009 and OR, 0.29 [95% CI, 0.86-0.96]; P = .04, respectively).InterpretationIn patients with advanced PAH, RV-pulmonary arterial coupling could not discriminate irreversible RV failure (nonresponders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RV ejection fraction were the best predictors of therapeutic response.

Project description:To evaluate the relationships of right ventricular (RV) and left ventricular (LV) myocardial perfusion reserves with ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) by using adenosine stress perfusion cardiac magnetic resonance (MR) imaging.This HIPAA-compliant study was institutional review board approved. Twenty-five patients known or suspected to have PAH underwent right heart catheterization and adenosine stress MR imaging on the same day. Sixteen matched healthy control subjects underwent cardiac MR imaging only. RV and LV perfusion values at rest and at adenosine-induced stress were calculated by using the Fermi function model. The MR imaging-derived RV and LV functional data were calculated by using dedicated software. Statistical testing included Kruskal-Wallis tests for continuous data, Spearman rank correlation tests, and multiple linear regression analyses.Seventeen of the 25 patients had PAH: 11 with scleroderma-associated PAH, and six with idiopathic PAH. The remaining eight patients had scleroderma without PAH. The myocardial perfusion reserve indexes (MPRIs) in the PAH group (median RV MPRI, 1.7 [25th-75th percentile range, 1.3-2.0]; median LV MPRI, 1.8 [25th-75th percentile range, 1.6-2.1]) were significantly lower than those in the scleroderma non-PAH (median RV MPRI, 2.5 [25th-75th percentile range, 1.8-3.9] [P = .03]; median LV MPRI, 4.1 [25th-75th percentile range, 2.6-4.8] [P = .0003]) and control (median RV MPRI, 2.9 [25th-75th percentile range, 2.6-3.6] [P < .01]; median LV MPRI, 3.6 [25th-75th percentile range, 2.7-4.1] [P < .01]) groups. There were significant correlations between biventricular MPRI and both mean pulmonary arterial pressure (mPAP) (RV MPRI: ρ = -0.59, Bonferroni P = .036; LV MPRI: ρ = -0.79, Bonferroni P < .002) and RV stroke work index (RV MPRI: ρ = -0.63, Bonferroni P = .01; LV MPRI: ρ = -0.75, Bonferroni P < .002). In linear regression analysis, mPAP and RV ejection fraction were independent predictors of RV MPRI. mPAP was an independent predictor of LV MPRI.Biventricular vasoreactivity is significantly reduced with PAH and inversely correlated with RV workload and ejection fraction, suggesting that reduced myocardial perfusion reserve may contribute to RV dysfunction in patients with PAH.

Project description:BACKGROUND:An elevated serum level of interleukin-6 (IL-6) in pulmonary arterial hypertension (PAH) patients results in a greater symptom burden and increased mortality; however, the mechanisms underlying these observations remain unclear. Because both pre-clinical and clinical data associate elevated IL-6 levels with impaired cardiac function, we hypothesized that the adverse effects of IL-6 in PAH result, in part, from right ventricular (RV) dysfunction. METHODS:We analyzed the relationship between IL-6 and RV function in 40 patients with PAH identified in our institutional PAH registry. Serum IL-6 levels was quantified by enzyme-linked immunoassay. RESULTS:PAH patients had higher IL-6 levels than age- and gender-matched controls. Circulating IL-6 levels correlated inversely with echocardiography-based measures of RV function and RV-pulmonary artery (RV-PA) coupling. When dividing PAH patients by median IL-6 level, patients with higher IL-6 had significantly worse RV function (fractional area change [FAC] 23 ± 12% vs 38 ± 11%, tricuspid annular plane systolic excursion [TAPSE] 1.3 ± 0.3 cm vs 2.1 ± 0.5 cm), impaired RV-PA coupling (0.6 ± 0.5%/mm Hg vs 0.9 ± 0.5%/mm Hg), higher right atrial pressure (13 ± 7 mm Hg vs 9 ± 5 mm Hg), reduced cardiac index (2.0 ± 0.5 liters/min/m2 vs 2.8 ± 1.0 liters/min/m2) and lower stroke volume (48 ± 20 ml vs 70 ± 28 ml). In contrast, the relationships between IL-6 and mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) were not significant. Finally, IL-6 was independently associated with RV function and RV-PA coupling after adjusting for static (PVR) and pulsatile (PAC) after-load on the RV. CONCLUSIONS:Serum IL-6 levels are independently associated with RV function and RV-PA coupling in PAH. Patients with higher IL-6 levels have more severe RV dysfunction and diminished RV-PA coupling despite a comparable severity of pulmonary vascular disease.

Dataset Information

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

Publications

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

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