Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease.

BACKGROUND: Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology. OBJECTIVE: We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. METHODS: Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. RESULTS: Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-ß-induced ASM cell proliferation and CXCL8 release. CONCLUSIONS: Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.

Long-term effects of pulmonary endarterectomy on pulmonary hemodynamics, cardiac function, and exercise capacity in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Long-term changes in exercise capacity and cardiopulmonary hemodynamics after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been poorly described. METHODS: We analyzed the data from 2 prospective surgical CTEPH cohorts in Hammersmith Hospital, London, and Amsterdam UMC. A structured multimodal follow-up was adopted, consisting of right heart catheterization, cardiac magnetic resonance imaging, and cardiopulmonary exercise testing before and after PEA. Preoperative predictors of residual pulmonary hypertension (PH; mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥2 WU) and long-term exercise intolerance (VO2max <80%) at 18 months were analyzed. RESULTS: A total of 118 patients (61 from London and 57 from Amsterdam) were included in the analysis. Both cohorts displayed a significant improvement of pulmonary hemodynamics, right ventricular (RV) function, and exercise capacity 6 months after PEA. Between 6 and 18 months after PEA, there were no further improvements in hemodynamics and RV function, but the proportion of patients with impaired exercise capacity was high and slightly increased over time (52%-59% from 6 to 18 months). Long-term exercise intolerance was common and associated with preoperative diffusion capacity for carbon monoxide (DLCO), preoperative mixed venous oxygen saturation, and postoperative PH and right ventricular ejection fraction (RVEF). Clinically significant RV deterioration (RVEF decline >3%; 5 [9%] of 57 patients) and recurrent PH (5 [14%] of 36 patients) rarely occurred beyond 6 months after PEA. Age and preoperative DLCO were predictors of residual PH post-PEA. CONCLUSIONS: Restoration in exercise tolerance, cardiopulmonary hemodynamics, and RV function occurs within 6 months. No substantial changes occurred between 6 and 18 months after PEA in the Amsterdam cohort. Nevertheless, long-term exercise intolerance is common and associated with postoperative RV function.

Utility of cardiac magnetic resonance feature tracking strain assessment in chronic thromboembolic pulmonary hypertension for prediction of REVEAL 2.0 high risk status.

Chronic thromboembolic pulmonary hypertension may be cured by pulmonary endarterectomy (PEA). Thromboembolic disease distribution/PEA success primarily determines prognosis but risk scoring criteria may be adjunctive. Right ventriculoarterial (RV-PA) and ventriculoatrial (RV-right atrium [RA]) coupling may be evaluated by cardiac MRI (CMR) feature tracking deformation/strain assessment. We characterized biatrial and biventricular CMR feature tracking (FT) strain parameters following PEA and tested the ability of CMR FT to identify REVEAL 2.0 high-risk status. We undertook a retrospective single-center cross-sectional study of patients (n = 57) who underwent PEA (2015-2020). All underwent pre and postoperative catheterization and CMR. Pulmonary arterial hypertension validated risk scores were calculated. Significant postoperative improvements were observed in mean pulmonary artery pressure (mPAP) (pre-op 45 ± 11 mmHg vs. post-op 26 ± 11 mmHg; p < 0.001) and PVR however a large proportion had residual pulmonary hypertension (45%; mPAP ≥25 mmHg). PEA augmented left heart filling with left ventricular end diastolic volume index and left atrial volume index increment. Left ventricular ejection fraction was unchanged postoperatively but LV global longitudinal strain improved (pre-op median -14.2% vs. post-op -16.0%; p < 0.001). Right ventricular (RV) geometry and function also improved with reduction in RV mass. Most had uncoupled RV-PA relationships which recovered (pre-op right ventricular free wall longitudinal strain -13.2 ± 4.8%, RV stroke volume/right ventricular end systolic volume ratio 0.78 ± 0.53 vs. post-op -16.8 ± 4.2%, 1.32 ± 0.55; both p < 0.001). Postoperatively, there were six REVEAL 2.0 high-risk patients, best predicted by impaired RA strain which was superior to traditional volumetric parameters (area under the curve [AUC] 0.99 vs. RVEF AUC 0.88). CMR deformation/strain evaluation can offer insights into coupling recovery; RA strain may be an expeditious surrogate for the more laborious REVEAL 2.0 score.

MRI Feature Tracking Strain in Pulmonary Hypertension: Utility of Combined Left Atrial Volumetric and Deformation Assessment in Distinguishing Post- From Pre-capillary Physiology.

Aims: Pulmonary hypertension (PH) is dichotomized into pre- and post-capillary physiology by invasive catheterization. Imaging, particularly strain assessment, may aid in classification and be helpful with ambiguous hemodynamics. We sought to define cardiac MRI (CMR) feature tracking biatrial peak reservoir and biventricular peak systolic strain in pre- and post-capillary PH and examine the performance of peak left atrial strain in distinguishing the 2 groups compared to TTE. Methods and Results: Retrospective cross-sectional study from 1 Jan 2015 to 31 Dec 2020; 48 patients (22 pre- and 26 post-capillary) were included with contemporaneous TTE, CMR and catheterization. Mean pulmonary artery pressures were higher in the pre-capillary cohort (55 ± 14 vs. 42 ± 9 mmHg; p < 0.001) as was pulmonary vascular resistance (median 11.7 vs. 3.7 WU; p < 0.001). Post-capillary patients had significantly larger left atria (60 ± 22 vs. 25 ± 9 ml/m2; p < 0.001). There was no difference in right atrial volumes between groups (60 ± 21 vs. 61 ± 29 ml/m2; p = 0.694), however peak RA strain was lower in post-capillary PH patients (8.9 ± 5.5 vs. 18.8 ± 7.0%; p < 0.001). In the post-capillary group, there was commensurately severe peak strain impairment in both atria (LA strain 9.0 ± 5.8%, RA strain 8.9 ± 5.5%). CMR LAVi and peak LA strain had a multivariate AUC of 0.98 (95% CI 0.89-1.00; p < 0.001) for post-capillary PH diagnosis which was superior to TTE. Conclusion: CMR volumetric and deformation assessment of the left atrium can highly accurately distinguish post- from pre-capillary PH.

COVID-19 and its impact on the cardiovascular system.

OBJECTIVES: The clinical impact of SARS-CoV-2 has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare National Health Service Trust, UK. METHODS: We retrospectively analysed 498 COVID-19 positive adult admissions to our institute from 7 March to 7 April 2020. Patient data were collected for baseline demographics, comorbidities and in-hospital outcomes, especially relating to cardiovascular intervention. RESULTS: Mean age was 67.4±16.1 years and 62.2% (n=310) were male. 64.1% (n=319) of our cohort had underlying cardiovascular disease (CVD) with 53.4% (n=266) having hypertension. 43.2%(n=215) developed acute myocardial injury. Mortality was significantly increased in those patients with myocardial injury (47.4% vs 18.4%, p<0.001). Only four COVID-19 patients had invasive coronary angiography, two underwent percutaneous coronary intervention and one required a permanent pacemaker implantation. 7.0% (n=35) of patients had an inpatient echocardiogram. Acute myocardial injury (OR 2.39, 95% CI 1.31 to 4.40, p=0.005) and history of hypertension (OR 1.88, 95% CI 1.01 to 3.55, p=0.049) approximately doubled the odds of in-hospital mortality in patients admitted with COVID-19 after other variables had been controlled for. CONCLUSION: Hypertension, pre-existing CVD and acute myocardial injury were associated with increased in-hospital mortality in our cohort of COVID-19 patients. However, only a low number of patients required invasive cardiac intervention.