Is pulmonary vascular disease reversible with PPAR ɣ agonists?

Severe angio-obliterative PAH remains a disease characterized by great morbidity and shortened survival. Unfortunately, the only currently available treatments for angio-obliterative changes are palliative in the form of pulmonary vasodilators evolving from the phosphodiesterase inhibitor sildenafil to endothelin receptor antagonist: Bosentan; while the only definitive treatment is lung transplantation which remains dependent on the availability of donors and the transplant policies which vary widely from a country to another. PPARs, especially the γ isoform, are largely expressed in pulmonary artery endothelial cells and smooth muscle cells. They are also found on endothelial progenitor cells. Several previous studies have highlighted the role of PPAR γ agonists in reversal of vascular remodeling especially in coronary, carotid and peripheral vascular disease atherosclerotic plaques. Experimental studies have also revealed that PPAR γ activation affects many different pathways; thus, the effect of PPAR γ is multifaceted, affecting almost every pathobiological pathway involved in the development of PAH simultaneously. We thereby hypothesize that PPAR γ agonists may play a key role in reversing severe pulmonary angio-obliterative changes and promote microvascular regeneration which may substitute the need for heart-lung transplantation in such patients.

Advanced Echocardiography Techniques: The Future Stethoscope of Systemic Diseases.

Cardiovascular disease (CVD) has been showing patterns of extensive rise in prevalence in the contemporary era, affecting the quality of life of millions of people and leading the causes of death worldwide. It has been a provocative challenge for modern medicine to diagnose CVD in its crib, owing to its etiological factors being attributed to a large array of systemic diseases, as well as its non-binary hideous nature that gradually leads to functional disability. Novel echocardiography techniques have enabled the cardiac ultrasound to provide a comprehensive analysis of the heart in an objective, feasible, time- and cost-effective manner. Speckle tracking echocardiography, contrast echocardiography, and 3D echocardiography have shown the highest potential for widespread use. The uses of novel modalities have been elaborately demonstrated in this study as a proof of concept that echocardiography has a place in routine general practice with supportive evidence being as recent as its role in the concurrent COVID-19 pandemic. Despite such evidence, many uses remain off-label and unexploited in practice. Generalization of echocardiography at the point of care can become a much-needed turning point in the clinical approach to case management. To actualize such aspirations, we recommend further prospective and interventional studies to examine the effect of implementing advanced techniques at the point of care on the decision-making process and evaluate their effectiveness in prevention of cardiovascular morbidities and mortalities.

Peroxisome proliferator-activated receptor agonists and reversal of vascular degeneration through DNA repair, a step toward drug-induced regenerative medicine.

Endothelial dysfunction with subsequent degeneration and vasoocclusive remodeling is the hallmark of many cardiovascular disorders including pulmonary vascular disease (PVD). To date, the available treatments slows disease progression but does not prevent deterioration. Reversing such pathologies would spare many patients risky surgeries and long waiting lists for a possible organ donor. Peroxisome proliferator-activated receptor agonists were first introduced as sole insulin sensitizers, however, there is increasing body of evidence that they have different actions on DNA which might help reverse vascular degeneration. This effect appears to be mainly achieved through enhancement of DNA damage responses (DDR). The aforementioned effect could offer new insights about repurposing drugs for achieving organ or tissue regeneration, an understudied field named drug-induced regenerative medicine.

Revisiting the pathogenic role of insulin resistance in Duchenne muscular dystrophy cardiomyopathy subphenotypes.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is known to impact the subepicardial layer of the myocardium through chronic inflammation. Recent animal studies have shown predominant subendocardial involvement in rats with DMD. The primary outcome parameter was to determine by cardiovascular MRI (CMR) if two differential patterns of myocardial involvements exist in DMD; the secondary outcome parameters were to correlate the observed pattern with metabolic markers such as insulin resistance measures. METHODS: Forty patients with DMD were screened using CMR to determine which of them had predominantly subendocardial dysfunction (SENDO group), or subepicardial/midmyocardial involvement (SEPMI group). Patients were subjected to body mass index measurement, serum creatinine kinase, serum lactate dehydrogenase enzyme, fasting glucose-insulin ratio (FGIR), full lipid profile, left ventricular ejection fraction (LVEF), left ventricle E/E´ ratio (the ratio of early mitral inflow velocity to average early diastolic velocities of the basal septum and mitral annulus) for left ventricle diastolic function, and myocardial layer strain discriminating echocardiography (MLSD-STE). Results: 26 patients displayed SENDO while 34 displayed SEPMI. SENDO group displayed overt insulin resistance; (FGIR (SENDO: 7 ± 1 vs. SEPMI: 5 ± 1, P < 0.001). FGIR was negatively correlated with Subendocardial Global Longitudinal Strain (ENDO-LS) with r = -0.75. CONCLUSION: DMD does not seem to influence the heart uniformly; DMD cardiomyopathy probably has two separate phenotypes with different mechanisms. Insulin resistance might be implicated in its pathogenesis and its reversal may help to slow disease progression.

Is it infection or rather vascular inflammation? Game-changer insights and recommendations from patterns of multi-organ involvement and affected subgroups in COVID-19.

Coronavirus disease 2019 (COVID-19) is a serious illness that has rapidly spread throughout the globe. The seriousness of complications puts significant pressures on hospital resources, especially the availability of ICU and ventilators. Current evidence suggests that COVID-19 pathogenesis majorly involves microvascular injury induced by hypercytokinemia, namely interleukin 6 (IL-6). We recount the suggested inflammatory pathway for COVID-19 and its effects on various organ systems, including respiratory, cardiac, hematologic, reproductive, and nervous organ systems, as well examine the role of hypercytokinemia in the at-risk geriatric and obesity subgroups with upregulated cytokines' profile. In view of these findings, we strongly encourage the conduction of prospective studies to determine the baseline levels of IL-6 in infected patients, which can predict a negative outcome in COVID-19 cases, with subsequent early administration of IL-6 inhibitors, to decrease the need for ICU admission and the pressure on healthcare systems. Video abstract: http://links.lww.com/CAEN/A24.

A multicenter consensus: A role of furin in the endothelial tropism in obese patients with COVID-19 infection.

Furin, a cleavage enzyme, is increasingly recognized in the pathogenesis of metabolic syndrome. Its cleavage action is an essential activation step for the endothelial pathogenicity of several viruses including SARS-CoV-2. This Furin-mediated endothelial tropism seems to underlie the multi-organ system involvement of COVID-19; which is a feature that was not recognized in the older versions of coronaviridae. Obese and diabetic patients, males, and the elderly, have increased serum levels of Furin, with its increased cellular activity; this might explain why these subgroups are at an increased risk of COVID-19 related complications and deaths. In contrast, smoking decreases cellular levels of Furin, this finding may be at the origin of the decreased severity of COVID-19 in smokers. Chinese herbal derived luteolin is suggested to be putative Furin inhibitor, with previous success against Dengue Fever. Additionally, Furin intracellular levels are largely dependent on concentration of intracellular ions, notably sodium, potassium, and magnesium. Consequently, the use of ion channel inhibitors, such as Calcium Channel blockers or Potassium Channel blockers, can prevent cellular transfection early in the course of the illness. Nicotine patches and Colchicine have also been suggested as potential therapies due to Furin mediated inhibition of COVID-19.

Single cell sequencing unraveling genetic basis of severe COVID19 in obesity.

COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one.

The potential use of ABO blood group system for risk stratification of COVID-19.

ABO blood groups is a cheap and affordable test that can be immediately retrieved from COVID-19 patients at the diagnosis. There is increasing evidence that non-O blood groups have both higher susceptibility and higher severity of COVID-19 infections. The reason behind such relationship seems elusive. Regarding susceptibility, Non-O individuals have Anti-A antibodies which can prevent viral entry across ACE-2 receptors, moreover, Non-O individuals are at higher risk of autoimmunity, hypercoagulable state, and dysbiosis resulting in an augmented tendency for vascular inflammatory sequelae of COVID-19. We can conclude, on the diagnostic level, that ABO blood groups can be potentially used for risk stratification of affected COVID-19 patients, to anticipate the deterioration of patients at higher risk for complications. On a therapeutic level, plasma from normal O blood group individuals might potentially replace the use of convalescent serum for the treatment of COVID-19.

Left ventricular mass index and subendocardial myocardial function in children with chronic kidney disease, a transmural strain and three-dimensional echocardiographic study.

Introduction: Left ventricular hypertrophy (LVH) is the commonest myocardial response to chronic kidney disease (CKD); this response has been regarded detrimental as it impairs the blood flow to the deepest layers of the myocardium causing progressive myocardial dysfunction. The aim of these series is to assess the determinants of LVH in CKD patients and its impact on subendocardial function in such patients. Methods: This study has been conducted on 40 CKD patients (Group 1) and 40 age-matched controls, both groups were assessed by transmural echocardiography to determine the subepicardial and subendocardial global longitudinal strain (GLS) as an expression of the systolic function of each of those layers. LVH was assessed by calculation of left ventricle mass index (LVMI). Both groups underwent ambulatory blood pressure monitoring. Group 1 was assessed as regards lipid profile and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR). Results: HOMA-IR proved to be a more important determinant of LV hypertrophy than SBP and DBP with a P of 0.01. Moreover subendocardial GLS was negatively correlated with LVMI with r = 0.69 and P < 0.01 denoting the negative effect. LVH plays on subendocardial function probably by impairing myocardial perfusion. Conclusion: This study points toward the importance of insulin resistance in aggravation of myocardial remodeling in CKD patients; more studies are warranted to examine the role of insulin Sensitizers in reversing such remodeling and restoring subendocardial function in such important systemic disorder.