Pulmonary Hypertension Is Associated With Systemic Arterial Hypertension Among Patients With Normal Left Ventricular Diastolic Function

Background The association of pulmonary and systemic arterial hypertension is believed to be mediated through hypertensive left heart disease. The purpose of the current study was to investigate whether pulmonary hypertension (PHT) is associated with systemic arterial hypertension among patients with apparently normal left ventricular diastolic function. Methods and Results Consecutive patients who had echocardiographic evaluation between 2007 and 2019 were enrolled. Patients with disease states that are known to be associated with PHT, including diastolic dysfunction, were excluded from the analysis. Estimated right ventricular systolic pressure was extracted for all patients from the echocardiographic reports. PHT was defined as estimated right ventricular systolic pressure >40 mm Hg. Multivariate logistic regression models were applied. Final study population included 25 916 patients with a median age of 59 (interquartile range, 44–69) years, of whom 12 501 (48%) were men and 13 265 (51%) had systemic arterial hypertension. Compared with normotensive patients, hypertensive patients were 3.2 times more likely to have PHT (95% CI, 2.91–3.53; P <0.001). A multivariate model adjusted for clinical and echocardiographic parameters that are known to be associated with PHT demonstrated that hypertensive patients are almost 3 times more likely to have PHT (95% CI, 2.45–3.15; P <0.001). The association was significant in multiple subgroups but was more significant among women compared with men (odds ratio, 3.1 versus 2.4; P for interaction <0.001). Conclusions PHT is associated with systemic arterial hypertension irrespective of left heart disease. The association is more pronounced among women.

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

Prevalence, Incidence and Associates of Pulmonary Hypertension Complicating Type 2 Diabetes: Insights from the Fremantle Diabetes Study Phase 2 and National Echocardiographic Database of Australia

There is a paucity of epidemiologic data examining the relationship between pulmonary hypertension (PH) and diabetes. The aim of this study was to determine prevalence, incidence and associates of PH complicating type 2 diabetes. Data from 1430 participants (mean age 65.5 years, 51.5% males) in the Fremantle Diabetes Study Phase 2 (FDS2) were linked with the National Echocardiographic Database of Australia (NEDA) to ascertain the prevalence and incidence of PH (estimated right ventricular systolic pressure (eRVSP) >30 mmHg as a new suggested threshold or the conventional >40 mmHg) over a 12-year period. PH prevalence in FDS2 was compared with that in NEDA overall and a geographically close sub-population. Multivariable analyses identified associates of prevalent/incident PH in the FDS2 cohort. Of 275 FDS2 patients (19.2%) with pre-entry echocardiography, 90 had eRVSP >30 mmHg and 35 had eRVSP >40 mmHg (prevalences 32.7% (95% CI 27.3–38.7%) and 12.7% (9.1–17.4%), respectively), rates that are 35–50% greater than national/local NEDA general population estimates. Moreover, 70 (5.0%) and 123 (9.2%) FDS2 participants were identified with incident PH at the respective eRVSP thresholds (incidence (95% CI) 7.6 (6.0–9.7) and 14.2 (11.8–17.0)/1000 person-years), paralleling data from recognised high-risk conditions such as systemic sclerosis. The baseline plasma N-terminal pro-brain natriuretic peptide concentration was the strongest independent associate of prevalent/incident PH. Approximately 1 in 8 people with type 2 diabetes have PH using the eRVSP >40 mmHg threshold. Its presence should be considered as part of regular clinical assessment of individuals with type 2 diabetes.

Athlete's Heart in Asian Military Males: The CHIEF Heart Study

Background: Elite athlete's heart is characterized by a greater left ventricular mass indexed by body surface area (LVMI) and diastolic function; however previous studies are mainly conducted in non-Asian athletes compared to sedentary controls.Methods: This study included 1,388 male adults, aged 18–34 years, enrolled in the same unified 6-month physical training program in Taiwan. During the midterm exams of 2020, all trainees completed a 3-km run (endurance) test, and 577 were randomly selected to attend a 2-min push-up (muscular strength) test. Elite athletes were defined as the performance of each exercise falling one standard deviation above the mean (16%). Cardiac structure and function were measured by echocardiography and compared between elite and non-elite athletes. Multiple logistic regression analysis was used to determine the independent predictors of elite athlete status at each exercise modality.Results: As compared to non-elite controls, elite endurance athletes had greater LVMI (84.4 ± 13.6 vs. 80.5 ± 12.9 g/m2, p &lt; 0.001) and lateral mitral E'/A' ratio (2.37 ± 0.73 vs. 2.22 ± 0.76, p &lt; 0.01) with lower late diastolic A' (7.77 ± 2.16 vs. 8.30 ± 3.69 cm/s, p = 0.03). Elite strength athletes had greater LVMI (81.8 ± 11.4 vs. 77.5 ± 12.1, p = 0.004) and lateral mitral E'/A' ratio (2.36 ± 0.70 vs. 2.11 ± 0.71, p &lt; 0.01) with a greater early diastolic E' (19.30 ± 4.06 vs. 18.18 ± 4.05 cm/s, p = 0.02). Greater LVMI and lower heart rate were independent predictors of elite endurance athletes [odds ratio (OR) and 95% confidence intervals: 1.03 (1.02, 1.04) and 0.96 (0.95, 0.98), respectively]. Greater LVMI, lateral mitral E'/A' ratio and right ventricular systolic pressure were independent predictors of elite strength athletes [OR: 1.03 (1.01, 1.05), 1.50 (1.06, 2.12), and 1.12 (1.05, 1.19), respectively].Conclusions: Cardiac structural and functional characteristics differ between endurance and strength elite athletes. While greater LVMI predicts elite status in both groups of Asian athletes, consistent with findings from Western elite athletes, greater diastolic function, and right ventricular systolic pressure characterize strength elite athletes, while lower heart rate at rest predicts endurance elite athletic status.

Inhibition of HDAC1 alleviates monocrotaline-induced pulmonary arterial remodeling through up-regulation of miR-34a

Background It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether inhibition of HDAC1 suppresses the development of PAH via restoring miR-34a level in monocrotaline (MCT)-induced PAH rats. Methods PAH rat models were induced by intraperitoneal injection of MCT. HDAC1 was suppressed by intraperitoneal injection of the class I HDAC inhibitor MS-275, and miR-34a was over-expressed via tail vein injection of miR-34a agomiR. Results HDAC1 protein was significantly increased in MCT-induced PAH rats; this was accompanied with down-regulation of miR-34a and subsequent up-regulation of matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2/TIMP-2. Administration of PAH rats with MS-275 or miR-34a agomiR dramatically abolished MCT-induced reduction of miR-34a and subsequent up-regulation of MMP-9/TIMP-1 and MMP-2/TIMP-2, finally reduced extracellular matrix (ECM) accumulation, pulmonary arterial remodeling, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) in PAH rats. Conclusions HDAC1 contributes to the development of MCT-induced rat PAH by suppressing miR-34a level and subsequently up-regulating the ratio of MMP-9/TIMP-1 and MMP-2/TIMP-2. Inhibition of HDAC1 alleviates pulmonary arterial remodeling and PAH through up-regulation of miR-34a level and subsequent reduction of MMP-9/TIMP-1 and MMP-2/TIMP-2, suggesting that inhibition of HDAC1 might have potential value in the management of PAH.

Cardiac involvement in a child post COVID-19: a case from Lebanon

We report on an 8-year-old boy, who presented to the emergency department at our institution with fever, generalised oedema and hypotension. Investigations revealed anaemia, thrombocytopenia in addition to elevated serum inflammatory markers, a negative COVID-19 PCR test and a positive COVID-19 IgG. His echocardiography was consistent with carditis in otherwise morphologically normal heart with depressed cardiac function, moderate-to-severe mitral valve regurgitation, moderate tricuspid regurgitation with an estimated right ventricular systolic pressure half systemic, trace aortic regurgitation, bilateral small pleural effusions, distended inferior vena cava and normal coronaries. He was started on inotropic support, intravenous immunoglobulin and methylprednisolone, and was transferred to the paediatric intensive care unit. To the best of our knowledge, this was the first case of multisystem inflammatory syndrome in children encountered in Lebanon. The presentation and management were thoroughly described in this article aiming to share our experience and to contribute to the rapidly emerging literature on this syndrome.

EXPRESS: SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

Introduction: SU5416 plus chronic hypoxia causes pulmonary arterial hypertension (PAH) in rats and is assumed to occur through VEGFR2 inhibition. Cabozantinib is a far more potent VEGFR2 inhibitor than SU5416. Therefore, we hypothesized that cabozantinib plus hypoxia would induce severe PAH in rats. Methods: Cell proliferation and pharmacokinetic studies were performed. Rats were given SU5416 or cabozantinib SC or via osmotic pump and kept hypoxic for 3 weeks. Right ventricular systolic pressure (RVSP) and hypertrophy (RVH) were evaluated at day 14 and 28 following removal from hypoxia. RV fibrosis was evaluated with Picro-Sirius Red staining. Kinome inhibition profiles of SU5416 and cabozantinib were performed. Inhibitor binding constants of SU5416 and cabozantinib for BMPR2 were determined and Nanostring analyses of lung mRNA were performed. Results: Cabozantinib was a more potent VEGFR inhibitor than SU5416 and had a longer half-life in rats. Cabozantinib SC plus hypoxia did not induce severe PAH. RVSP at 14 and 28d post-hypoxia was 36.8 ± 2.3 mmHg and 36.2 ± 3.4 mmHg, respectively, versus 27.5 ± 1.5 mmHg in normal controls. For cabozantinib given by osmotic pump during hypoxia, RVSP was 40.0 ± 3.1 mmHg at 14d and 27.9 ± 1.9 mmHg at 28d post-hypoxia. SU5416 plus hypoxia induced severe PAH (RVSP 61.9 ± 6.1 mmHg and 64.9 ± 8.4 mmHg at 14d and 28d post-hypoxia, respectively). Cabozantinib induced less RVH (RV/(LV+IVS) at 14d post-hypoxia compared to SU5416. RV fibrosis was more extensive in the SU5416 groups compared to the Cabozantinib groups. SU5416 (but not cabozantinib) inhibited BMPR2. Nanostring analyses showed effects on pulmonary gene expression of BMP10 and VEGFR1 in the SU5416 28 day post hypoxia group. Conclusion: Selective VEGFR2 inhibition using cabozantinib plus hypoxia did not induce severe PAH. Severe PAH due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.

Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling

Pulmonary arterial hypertension (PAH) is a rare, progressive pulmonary vascular disease with limited therapeutic options. Pulmonary circulation resistance, pulmonary vascular remodeling, and over-activated NMDARs (N-methyl-d-aspartate receptors) play vital roles in the pathogenesis of PAH. In the present study, we aimed to evaluate the efficacy and molecular mechanism of MN-08, a dual-functional memantine nitrate derivative, in experimental animal models of PAH. MN-08 showed a high degree of accumulation in the lungs and dilated pulmonary arterial rings ex vivo by releasing nitric oxide. MN-08 did not lower systemic blood pressure. MN-08 attenuated right ventricular systolic pressure and right ventricular hypertrophy, inhibited pulmonary arterial remodeling, alleviated glutamate-NMDARs dysregulation, and improved survival rates in monocrotaline-induced PAH rats. More importantly, the therapeutic benefit of MN-08 for PAH was greater than that of sildenafil. Moreover, MN-08 can reduce right ventricular systolic pressure in U46619-induced acute PAH rats. Mechanistically, MN-08 suppressed proliferation of pulmonary arterial smooth muscle cells exposed to human platelet-derived growth factor-BB by regulating the cell cycle and expression of NMDAR1, AKT (serine/threonine kinase Akt), and ERK (extracellular signal-regulated kinase) 1/2. In conclusion, our studies demonstrated that MN-08 may be a promising therapeutic agent for PAH.