Gut Microbial Metabolite Trimethylamine N-Oxide Aggravates Pulmonary Hypertension.

Trimethylamine N-oxide (TMAO), a metabolite derived from intestine microbial flora, enhances vascular inflammation in a variety of cardiovascular diseases, and the bacterial communities associated with TMAO metabolism are higher in pulmonary hypertension (PH) patients. The effects of TMAO on PH, however, have not been elucidated. In the present study, circulating TMAO was found to be elevated in intermediate to high-risk PH patients when compared with healthy control or low-risk PH patients. In monocrotaline-induced rat PH models, circulating TMAO was elevated; and reduction of TMAO using 3,3-dimethyl-1-butanol (DMB) significantly decreased right ventricle systolic pressure and pulmonary vascular muscularization in both monocrotaline-induced rat PH and hypoxia-induced mouse PH models. RNA sequencing of rat lungs revealed that DMB treatment significantly suppressed the pathways involved in cytokine-cytokine receptor interaction and in cytokine and chemokine signaling. Protein-protein interaction analysis of the differentially expressed transcripts regulated by DMB showed five hub genes with a strong connectivity of proinflammatory cytokines and chemokines, including Kng1, Cxcl1, Cxcl2, Cxcl6, and Il6. In vitro, TMAO significantly increased the expression of Kng1, Cxcl1, Cxcl2, Cxcl6, and Il6 in bone-marrow-derived macrophage. Also, TMAO-treated conditioned medium from macrophage increased the proliferation and migration of pulmonary artery smooth muscle cells, but TMAO treatment did not change the proliferation or migration of pulmonary artery smooth muscle cells. In conclusion, our study demonstrates that TMAO is increased in severe PH, and the reduction of TMAO decreases pulmonary vascular muscularization and alleviates PH by suppressing the macrophage production of chemokines and cytokines.

Clinical Features of Coronavirus Disease 2019 Patients With Mechanical Ventilation: A Nationwide Study in China.

OBJECTIVES: The outbreak of coronavirus disease 2019 is becoming a worldwide pandemic. Mechanical ventilation is lifesaving for respiratory distress, this study was designed to delineate the clinical features of the coronavirus disease 2019 patients with mechanical ventilation from a national cohort in China. DESIGN: Prospective observational study. SETTING: The rapid spread of severe acute respiratory syndrome coronavirus 2 has infected more than 7.7 million people and caused more than 423,000 deaths. PATIENTS: Adult hospitalized coronavirus disease 2019 patients with mechanical ventilation from 557 hospitals from China. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From a nationwide cohort, 141 coronavirus disease 2019 cases with mechanical ventilation were extracted from 1,590 cases. Cigarette smoke, advanced age, coexisting chronic illness, elevated systolic blood pressure, high body temperature, and abnormal laboratory findings are common in these ventilated cases. Multivariate regression analysis showed that higher odds of in-hospital death was associated with invasive mechanical ventilation requirement (hazard ratio: 2.95; 95% CI, 1.40-6.23; p = 0.005), and coexisting chronic obstructive pulmonary disease (hazard ratio, 4.57; 95% CI, 1.65-12.69; p = 0.004) and chronic renal disease (hazard ratio, 5.45; 95% CI, 1.85-16.12; p = 0.002). Compared with patients with noninvasive mechanical ventilation, patients who needs invasive mechanical ventilation showed higher rate of elevated D-dimer (> 1.5 mg/L) at admission (hazard ratio, 3.28, 95% CI, 1.07-10.10; p = 0.039). CONCLUSIONS: The potential risk factors of elevated D-dimer level could help clinicians to identify invasive mechanical ventilation requirement at an early stage, and coexisting chronic obstructive pulmonary disease or chronic renal disease are independent risk factors associated with fatal outcome in coronavirus disease 2019 patients with mechanical ventilation.

Predictors of fatal outcomes among hospitalized COVID-19 patients with pre-existing hypertension in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving pandemic, hypertension is one of the most common co-existing chronic conditions and a risk factor for mortality. Nearly one-third of the adult population is hypertensive worldwide, it is urgent to identify the factors that determine the clinical course and outcomes of COVID-19 patients with hypertension. METHODS AND RESULTS: 148 COVID-19 patients with pre-existing hypertension with clarified outcomes (discharge or deceased) from a national cohort in China were included in this study, of whom 103 were discharged and 45 died in hospital. Multivariate regression showed higher odds of in-hospital death associated with high-sensitivity cardiac troponin (hs-cTn) > 28 pg/ml (hazard ratio [HR]: 3.27, 95% confidence interval [CI]: 1.55-6.91) and interleukin-6 (IL-6) > 7 pg/ml (HR: 3.63, 95% CI:1.54-8.55) at admission. Patients with uncontrolled blood pressure (BP) (n = 52) which were defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg for more than once (≥2 times) during hospitalization, were more likely to have ICU admission (p = 0.037), invasive mechanical ventilation (p = 0.028), and renal injury (p = 0.005). A stricter BP control with the threshold of 130/80 mm Hg was associated with lower mortality. Treatment with renin-angiotensin-aldosterone system (RAAS) suppressors, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and spironolactone, was associated with a lower rate of ICU admission compared to other types of anti-hypertensive medications (8 (22.9%) vs. 25 (43.1%), p = 0.048). CONCLUSION: Among COVID-19 patients with pre-existing hypertension, elevated hs-cTn and IL-6 could help clinicians to identify patients with fatal outcomes at an early stage, blood pressure control is associated with better clinical outcomes, and RAAS suppressors do not increase mortality and may decrease the need for ICU admission.