Targeting Mitochondrial Metabolic Dysfunction in Pulmonary Hypertension: Toward New Therapeutic Approaches?

Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling leading to right heart failure and death. To date, despite the three therapeutic approaches targeting the three major endothelial dysfunction pathways based on the prostacyclin, nitric oxide/cyclic guanosine monophosphate, and endothelin pathways, PAH remains a serious disease. As such, new targets and therapeutic agents are needed. Mitochondrial metabolic dysfunction is one of the mechanisms involved in PAH pathogenesis in part through the induction of a Warburg metabolic state of enhanced glycolysis but also through the upregulation of glutaminolysis, tricarboxylic cycle and electron transport chain dysfunction, dysregulation of fatty acid oxidation or mitochondrial dynamics alterations. The aim of this review is to shed light on the main mitochondrial metabolic pathways involved in PAH and to provide an update on the resulting interesting potential therapeutic perspectives.

Peripheral Blood Mononuclear Cells Mitochondrial Respiration and Superoxide Anion after Heart Transplantation.

INTRODUCTION: The mitochondrial function of circulating peripheral blood mononuclear cells (PBMCs) is an interesting new approach to cardiac diseases. Thus, PBMC's mitochondrial respiration decreases in relation to heart failure severity. However, no data are available on heart-transplanted patients (Htx). POPULATION AND METHODS: We determined PBMCs mitochondrial respiration by high-resolution respirometry (Oroboros Instruments) and superoxide anion production using electron paramagnetic resonance (Bruker-Biospin) in 20 healthy subjects and 20 matched Htx and investigated clinical, biological, echocardiographic, coronarography and biopsy characteristics. RESULTS: PBMCs mitochondrial respiratory chain complex II respiration was decreased in Htx (4.69 ± 0.84 vs. 7.69 ± 1.00 pmol/s/million cell in controls and Htx patients, respectively; p = 0.007) and complex IV respiration was increased (24.58 ± 2.57 vs. 15.68 ± 1.67 pmol/s/million cell; p = 0.0035). Superoxide anion production was also increased in Htx (1.47 ± 0.10 vs. 1.15 ± 0.10 µmol/min; p = 0.041). The leucocyte-to-lymphocyte ratio was increased in Htx, whom complex II correlated with leucocyte number (r = 0.51, p = 0.02) and with the left ventricular posterior wall peak early diastolic myocardial velocity (r = -0.62, p = 0.005). Complex IV was increased in the two patients with acute rejection and correlated negatively with Htx's isovolumetric relation time (r = -0.45, p = 0.045). DISCUSSION: Although presenting with normal systolic function, Htx demonstrated abnormal PBMC's mitochondrial respiration. Unlike immunosuppressive therapies, subclinical diastolic dysfunction might be involved in these changes. Additionally, lymphopenia might reduce complex II, and acute rejection enhances complex IV respirations. CONCLUSION: PBMC's mitochondrial respiration appears modified in Htx, potentially linked to cellular shift, mild diastolic dysfunction and/or acute rejection.

Pathophysiology of Heart Failure: A Role for Peripheral Blood Mononuclear Cells Mitochondrial Dysfunction?

Heart failure (HF) is a leading cause of hospitalization in patients aged more than 65 years and is associated with high mortality rates. A better comprehension of its physiopathology is still needed, and, in addition to neurohormonal systems and sodium glucose co-transporter 2 modulations, recent studies focus on the mitochondrial respiration of peripheral blood circulating cells (PBMCs). Thus, cardiovascular metabolic risk factors and cellular switch with an increased neutrophil/lymphocytes ratio might favor the decreased PBMC mitochondrial respiration observed in relation with HF severity. PBMCs are implicated in the immune system function and mitochondrial dysfunction of PBMC, potentially induced by their passage through a damaged heart and by circulating mitoDAMPs, which can lead to a vicious circle, thus sustaining negative cardiac remodeling during HF. This new approach of HF complex pathophysiology appears to be a promising field of research, and further studies on acute and chronic HF with reduced or preserved LVEF are warranted to better understand whether circulating PBMC mitochondrial function and mitoDAMPs follow-ups in HF patients might show diagnosis, prognosis or therapeutic usefulness.

The Effect of Transoesophageal Echocardiography on Treatment Change in a High-Volume Stroke Unit.

Background and purpose-current guidelines recommend the use of transesophageal echocardiography (TEE) in relation to cardio-embolic sources of stroke. Methods-by using an hospital-based cohort, we retrospectively analyzed consecutive patients with acute ischemic stroke (AIS), acute hemorrhagic stroke (AHS) and transient ischemic attack (TIA) who were admitted in Strasbourg Stroke Center, France between November 2017 to December 2018. TEE reports were screened for detection of potential cardiac sources of embolism and the subsequent change in medical management. We performed univariate and multivariate analyses to identify predictors of relevant TEE findings. Results-out of the 990 patients admitted with confirmed stroke, 432 patients (42.6%) underwent TEE. Patients with TEE were younger (62.8 ± 14.8 vs. 73.8, p < 0.001), presented less comorbidities and lower stroke severity assessed by lower NIHSS (2 IQR (0-4) vs. 3 IQR (0-10), p < 0.01) and Modified Rankin Scale (1 IQR (0-1) vs. 1 (0-3), p < 0.01). A total of 227 examinations (52.5%) demonstrated abnormal findings considered as potential cardiac sources of embolism and 31 examinations (7.1%) were followed by subsequent change in medical management. Age (HR: 0.948, 95% CI 0.923 to 0.974; p < 0.001), previous AIS (HR: 3.542, 95% CI 1.290 to 9.722; p = 0.01), previous TIA (HR: 7.830, CI 95% 2214 to 27,689; p = 0.001) and superficial middle cerebral artery territory infarction (HR: 2.774, CI 95% 1.168-6.589; p = 0.021) were strong independent predictors with change in medical management following TEE. Conclusions-additional TEE changed the medical course of stroke patients in 7.1% in a French high-volume stroke unit.

Life-threatening arrhythmias in anterior ST-segment elevation myocardial infarction patients treated by percutaneous coronary intervention: adverse impact of morphine.

AIMS: Important controversies remain concerning the determinants of life-threatening arrhythmias during ST-segment elevation myocardial infarction (STEMI) and their impact on late adverse events. This study sought to investigate which factors might facilitate ventricular tachycardia (VT) and ventricular fibrillation (VF), in a homogeneous population of anterior STEMI patients defined by abrupt left anterior descending coronary artery (LAD) occlusion and no collateral flow. METHODS AND RESULTS: The 967 patients, who entered into the CIRCUS (Does Cyclosporine ImpRove Clinical oUtcome in ST elevation myocardial infarction patients) study, were assessed for further analysis. Acute VT/VF was defined as VT (run of tachycardia >30 s either self-terminated or requiring electrical/pharmacological cardioversion) or VF documented by electrocardiogram or cardiac monitoring, during transportation to the cathlab or initial hospitalization. VT/VF was documented in 136 patients (14.1%). Patients with VT/VF were younger and had shorter time from symptom onset to hospital arrival. Site of LAD occlusion, thrombus burden, area at risk, pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction flow, and ST-segment resolution were similar to that of patients without VT/VF. There was no impact of VT/VF on left ventricular remodelling or clinical outcomes. By multivariate analysis, the use of morphine (odds ratio 1.71; 95% confidence interval (1.13-2.60); P = 0.012) was the sole independent predictor of VT/VF occurrence. CONCLUSIONS: In STEMI patients with LAD occlusion, our findings support the view that morphine could favour severe ventricular arrhythmias.

Pericardial effusion in patients with COVID-19: case series.

BACKGROUND: SARS-coronavirus-2 [coronavirus disease 2019 (COVID-19)] infection is a public health issue affecting millions of people. It started in Wuhan in China in December 2019 spreading rapidly worldwide. CASE SUMMARY: Three patients aged 51-84 developed a pericarditis related to COVID-19, associated for two of them with a myocarditis. Case 1 was a COVID-19 cardiac tamponade without myocarditis, confirmed by a positive chest computed tomography (CT) scan. Case 2 showed a COVID-19 myopericarditis, confirmed by a positive chest CT scan and a SARS-coronavirus-2 positive swab. Case 3 was a cardiac tamponade due to COVID-19 pericarditis, with a positive polymerase chain reaction on pericardial fluid. They were all treated by colchicine and their condition improved rapidly. DISCUSSION: Presumably rare, we reported three cases of pericardial effusions (PEs) occurring in a single cardiology centre. There is a higher incidence of COVID-19-related cardiac diseases such as pericarditis that can manifest as a minimal PE to a cardiac tamponade, which should result in a higher awareness of cardiologists. A systematic measure of the high-sensitivity troponin kinetic in patients affected by COVID-19 could be interesting in order to screen for potential myocarditis. Any unexplained haemodynamic failure or increased cardiac biomarkers should make the medical team search for myopericarditis by a transthoracic echocardiography.