Correction: Noureddine et al. Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives. Int. J. Mol. Sci. 2020, 21, 4268.

The authors would like to make the following correction to the publication dealing with Reference #3 [...].

Potential Alternative Receptors for SARS-CoV-2-Induced Kidney Damage: TLR-4, KIM-1/TIM-1, and CD147.

Kidney damage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can occur even in patients with no underlying kidney disease. Signs of kidney problems can progress to a state that demands dialysis and hampering recovery. Although not without controversy, emerging evidence implicates direct infectivity of SARS-CoV-2 in the kidney. At the early stage of the pandemic, consideration was mainly on the well-recognized angiotensin-converting enzyme 2 (ACE2) receptor as being the site for viral interaction and subsequent cellular internalization. Despite the abundance of ACE2 receptors in the kidneys, researchers have expanded beyond ACE2 and identified novel viral entry pathways that could be advantageously explored as therapeutic targets. This review presents the potential involvement of toll-like receptor 4 (TLR-4), kidney injury molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1), and cluster of differentiation 147 (CD147) in SARS-CoV-2-associated renal damage. In this context, we address the unresolved issues surrounding SARS-CoV-2 renal infectivity.

Nicotinamide Riboside Supplementation Restores Myocardial Nicotinamide Adenine Dinucleotide Levels, Improves Survival, and Promotes Protective Environment Post Myocardial Infarction.

AIMS: Myocardial infarction (MI) is a major cause of death. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme in oxidative phosphorylation and substrate of sirtuins and poly-ADP ribose polymerases, enzymes critical for cardiac remodeling post-MI. Decreased NAD+ is reported in several heart failure models with paradoxically an upregulation of nicotinamide riboside kinase 2, which uses nicotinamide riboside (NR) as substrate in an NAD+ biosynthetic pathway. We hypothesized that stimulating nicotinamide riboside kinase 2 pathway by NR supplementation exerts cardioprotective effects. METHODS AND RESULTS: MI was induced by LAD ligation in 2-3-month-old male mice. NR was administered daily (1 µmole/g body weight) over 7 days. RT-PCR showed a 60-fold increase in nicotinamide riboside kinase 2 expression 4 days post-MI with a 60% drop in myocardial NAD+ and overall survival of 61%. NR restored NAD+ levels and improved survival to 92%. Assessment of respiration in cardiac fibers revealed mitochondrial dysfunction post-MI, and NR improved complexes II and IV activities and citrate synthase activity, a measure of mitochondrial content. Additionally, NR reduced elevated PARP1 levels and activated a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. CONCLUSION: Our data show that nicotinamide riboside could be useful for MI management.

Assessing the outcomes of prescribing angiotensin converting enzyme inhibitors and angiotensin receptor blockers for COVID-19 patients.

Background: Patients with heart failure were affected severely by COVID-19. Most heart failure patients are on guideline directed medical therapy, which includes ACE inhibitors (ACEI) and ARBs. These medications were controversial at the beginning of the pandemic due to their interplay with the receptor that SARS-CoV-2 binds in the lungs. We investigated the effect that ACEI and ARB had on patients with hypertension, coronary artery disease, and heart failure. Methods: We recruited 176 patients with COVID-19 infection and cardiovascular comorbidities at the American University of Beirut Medical Center in Lebanon. Of these, 110 patients were taking ACEI or ARB and 66 were not. We collected clinical data and looked at inflammatory markers such as CRP and IL-6 and cardiac markers such as troponin T. We also reported the incidence of ARDS, sepsis, and death of each patient, and compared the 2 groups. Results: We found that patients taking ACEI and ARB had a statistically significant decrease in levels of troponin T, IL-6, and CRP compared to patients not taking these medications (p < 0.05). We found no difference in rates of ARDS, sepsis, or death between the 2 groups. Conclusion: Inhibition of the renin-angiotensin-aldosterone-system had no effect on the mortality of patients with COVID-19 and on their overall disease progression. However, it may be beneficial not to stop these medications as they decrease inflammation in the body and the levels of troponin, which are related to increased stress on the heart.

Cooling Down Inflammation in the Cardiovascular System via the Nicotinic Acetylcholine Receptor.

ABSTRACT: Inflammation is a major player in many cardiovascular diseases including hypertension, atherosclerosis, myocardial infarction, and heart failure. In many individuals, these conditions coexist and mutually exacerbate each other's progression. The pathophysiology of these diseases entails the active involvement of both innate and adaptive immune cells. Immune cells that possess the α7 subunit of the nicotinic acetylcholine receptor on their surface have the potential to be targeted through both pharmacological and electrical stimulation of the cholinergic system. The cholinergic system regulates the inflammatory response to various stressors in different organ systems by systematically suppressing spleen-derived monocytes and chemokines and locally improving immune cell function. Research on the cardiovascular system has demonstrated the potential for atheroma plaque stabilization and regression as favorable outcomes. Smaller infarct size and reduced fibrosis have been associated with improved cardiac function and a decrease in adverse cardiac remodeling. Furthermore, enhanced electrical stability of the myocardium can lead to a reduction in the incidence of ventricular tachyarrhythmia. In addition, improving mitochondrial dysfunction and decreasing oxidative stress can result in less myocardial tissue damage caused by reperfusion injury. Restoring baroreflex activity and reduction in renal damage can promote blood pressure regulation and help counteract hypertension. Thus, the present review highlights the potential of nicotinic acetylcholine receptor activation as a natural approach to alleviate the adverse consequences of inflammation in the cardiovascular system.

Risk of thromboembolic events in non-hospitalized COVID-19 patients: A systematic review.

The risk of thromboembolism in non-hospitalized COVID-19 patients remains uncertain and was assessed in this review to better weigh benefits vs. risks of prophylactic anticoagulation in this population. A search was performed through three databases: Medline, Embase, and Cochrane Library until 2022. Self-controlled case series, case-control and cohort studies were included, and findings summarized narratively. Meta-analyses for risk of thromboembolism including deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) between COVID-19 and non-COVID-19 non-hospitalized patients were conducted. Frequency, incidence rate ratio (IRR), and risk ratio (RR) of stroke were used to assess risk in non-hospitalized COVID-19 patients considering the lack of studies to conduct a meta-analysis. Ten studies met inclusion criteria characterized by adult non-hospitalized COVID-19 patients. Risk of bias was relatively low. Risk of DVT (RR: 1.98 with 95% CI: 1.03-3.83) and PE (OR: 6.72 with 95% CI: 4.81-9.39 and RR: 4.44 with 95% CI: 1.98-9.99) increased in non-hospitalized COVID-19 patients compared to controls. Risk of MI (OR: 1.91 with 95% CI: 0.89-4.09) is possibly increased in non-hospitalized COVID-19 patients with moderate certainty when compared to controls. A trend in favor of stroke was documented in the first week following infection. Our meta-analyses support the increase in risk of DVT and PE, and likely increase of MI, in non-hospitalized COVID-19 patients. The risk of stroke appears significant in the first week following infection but drops to insignificance two weeks later. More studies are needed to establish evidence-based recommendations for prophylactic anticoagulation therapy in non-hospitalized COVID-19 patients.

Sexual dimorphism in acute myocardial infarction-induced acute kidney injury: cardiorenal deteriorating effects of ovariectomy in premenopausal female mice.

Acute kidney injury (AKI) is a common complication of cardiovascular diseases (CVDs) in both males and females, increasing mortality rate substantially. Premenopausal females appear to be more protected, suggesting a potential protective role of female sex hormones. Here, we tested the hypothesis that ovariectomy (OVX) eliminates the beneficial effect of female sex on renal protection following acute myocardial infarction (MI). Seven days post-MI, both sexes exhibited worsened kidney function and a substantial decrease in total kidney NAD levels. Unlike MI female mice, MI males showed exacerbated morphological alterations with increased proinflammatory, proapoptotic, and profibrotic biomarkers. The expression of NAD+ biosynthetic enzymes NAMPT and NMRK-1 was increased in MI females only, while males showed a substantial increase in NAD+ consuming enzyme PARP-1. OVX did not eliminate the female-sex protection of glomerular morphology but was associated with swelling of proximal convoluted tubules with MI as in males. With OVX, MI females had enhanced proinflammatory cytokine release, and a further decrease in creatinine clearance and urine output was observed. Our findings suggest that MI induced AKI in both sexes with pre-menopausal female mice being more protected. Ovariectomy worsens aspects of AKI in females after MI, which may portend increased risk for development of chronic kidney disease.

Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats.

Heart failure with preserved ejection fraction (HFpEF) remains a medical anomaly that baffles researchers and physicians alike. The overall phenotypical changes of diastolic function and left ventricular hypertrophy observed in HFpEF are definable; however, the metabolic and molecular alterations that ultimately produce these changes are not well established. Comorbidities such as obesity, hypertension, and diabetes, as well as general aging, play crucial roles in its development and progression. Various animal models have recently been developed to better understand the pathophysiological and metabolic developments in HFpEF and to illuminate novel avenues for pharmacotherapy. These models include multi-hit rodents and feline aortic constriction animals. Recently, genomic, proteomic, and metabolomic approaches have been used to define altered signaling pathways in the heart associated with HFpEF, including those involved in inflammation, cGMP-related, Ca2+ handling, mitochondrial respiration, and the unfolded protein response in endoplasmic reticulum stress. This article aims to present an overview of what has been learnt by these studies, focusing mainly on the findings in common while highlighting unresolved issues. The knowledge gained from these research models will not simply be of benefit for treating HFpEF but will undoubtedly provide new insights into the mechanisms by which the heart deals with external stresses and how the processes involved can fail.

Sex differences in cardiac remodeling post myocardial infarction with acute cigarette smoking.

BACKGROUND: Whether cigarette smoking affects the heart post-myocardial infarction (MI) in a sex-dependent way remains controversial. Using a mouse model, we investigated cardiac remodeling under the influence of acute cigarette smoke (CS) exposure following ischemic injury in both sexes. METHODS: Ten cigarettes were smoked twice daily for 2 weeks followed by MI and then 1 additional week post permanent LAD ligation. Cardiac function, histology, and infarct size were assessed, and inflammatory markers quantified by RT-PCR. Statistical comparisons were performed using an unpaired t test or ANOVA followed by Tukey post hoc test. RESULTS: We observed that cigarette smoking exacerbated both left and right ventricular remodeling only in males at an early stage of post-MI. Females did not display a significant structural and/or functional alteration within 7 days of cardiac remodeling post-MI upon CS exposure. Worsened right ventricular remodeling in males was independent of pulmonary congestion. CS-exposed males exhibited enhanced increases in left ventricular end systolic and diastolic volumes, as well as reductions in ejection fraction and fractional area changes of left ventricular base. At day 7, infarct size was increased by cigarette smoking in males only, which was accompanied by enhanced collagen deposition in both the infarcted and peri-infarcted areas. Both IL-6 and TNF-α mRNA expression significantly increased in CS-exposed MI male group only at day 7 post-MI suggestive of prolonged inflammation. CONCLUSIONS: These findings indicate that CS exposure worsens the progression of cardiac remodeling post-MI in male sex in a significant manner compared to female sex at least at early stages.

Urinary Biomarkers of Oxidative Stress in Aging: Implications for Prediction of Accelerated Biological Age in Prospective Cohort Studies.

Background: Aging is a major risk factor for a range of chronic diseases. Oxidative stress theory of aging has been previously proposed as one of the mechanisms responsible for the age-related decline in organ/tissue function and the development of age-related diseases. Urine contains rich biological information on the health status of every major organ system and can be an important noninvasive source for biomarkers of systemic oxidative stress in aging. Aims: The objective of this cross-sectional study was to validate a novel panel of urinary oxidative stress biomarkers. Methods: Nucleic acid oxidation adducts and oxidative damage markers of lipids and proteins were assessed in urine samples from nondiabetic and currently nonsmoking subjects (n = 198) across different ages (20 to 89 years old). Urinary parameters and chronological age were correlated then the biological age of enrolled individuals was determined from the urinary oxidative stress markers using the algorithm of Klemera and Doubal. Results: Our findings showed that 8-oxo-7,8-deoxyguanosine (8-oxoG), 8-oxo-7,8-dihydroguanosine (8-OHdG), and dityrosine (DTyr) positively correlated with chronological age, while the level of an F2-isoprostane (iPF2 α-VI) correlated negatively with age. We found that 8-oxoG, DTyr, and iPF2 α-VI were significantly higher among accelerated agers compared to nonaccelerated agers and that a decision tree model could successfully identify accelerated agers with an accuracy of >92%. Discussion. Our results indicate that 8-oxoG and iPF2 α-VI levels in the urine reveal biological aging. Conclusion: Assessing urinary biomarkers of oxidative stress may be an important approach for the evaluation of biological age by identifying individuals at accelerated risk for the development of age-related diseases.

Early cardiac-chamber-specific fingerprints in heart failure with preserved ejection fraction detected by FTIR and Raman spectroscopic techniques.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is a matter of investigation and its diagnosis remains challenging. Although the mechanisms that are responsible for the development of HFpEF are not fully understood, it is well known that nearly 80% of patients with HFpEF have concomitant hypertension. We investigated whether early biochemical alterations were detectable during HFpEF progression in salt-induced hypertensive rats, using Fourier-transformed infrared (FTIR) and Raman spectroscopic techniques as a new diagnostic approach. Greater protein content and, specifically, greater collagen deposition were observed in the left atrium and right ventricle of hypertensive rats, together with altered metabolism of myocytes. Additionally, Raman spectra indicated a conformational change, or different degree of phosphorylation/methylation, in tyrosine-rich proteins. A correlation was found between tyrosine content and cardiac fibrosis of both right and left ventricles. Microcalcifications were detected in the left and right atria of control animals, with a progressive augmentation from six to 22 weeks. A further increase occurred in the left ventricle and right atrium of 22-week salt-fed animals, and a positive correlation was shown between the mineral deposits and the cardiac size of the left ventricle. Overall, FTIR and Raman techniques proved to be sensitive to early biochemical changes in HFpEF and preceded clinical humoral and imaging markers.

Role of ranolazine in heart failure: From cellular to clinic perspective.

Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review.

Cannabinoids and Myocardial Ischemia: Novel insights, Updated Mechanisms, and Implications for Myocardial Infarction.

Cannabis is the most widely trafficked and abused illicit drug due to its calming psychoactive properties. It has been increasingly recognized as having potential health benefits and relatively less adverse health effects as compared to other illicit drugs; however, growing evidence clearly indicates that cannabis is associated with considerable adverse cardiovascular events. Recent studies have linked cannabis use to myocardial infarction (MI); yet, very little is known about the underlying mechanisms. A MI is a cardiovascular disease characterized by a mismatch in the oxygen supply and demand of the heart, resulting in ischemia and subsequent necrosis of the myocardium. Since cannabis is increasingly being considered a risk factor for MI, there is a growing need for better appreciating its potential health benefits and consequences. Here, we discuss the cellular mechanisms of cannabis that lead to an increased risk of MI. We provide a thorough and critical analysis of cannabinoids' actions, which include modulation of adipocyte biology, regional fat distribution, and atherosclerosis, as well as precipitation of hemodynamic stressors relevant in the setting of a MI. By critically dissecting the modulation of signaling pathways in multiple cell types, this paper highlights the mechanisms through which cannabis may trigger life-threatening cardiovascular events. This then provides a framework for future pharmacological studies which can identify targets or develop drugs that modulate cannabis' effects on the cardiovascular system as well as other organ systems. Cannabis' impact on the autonomic outflow, vascular smooth muscle cells, myocardium, cortisol levels and other hemodynamic changes are also mechanistically reviewed.

Insights into the modulation of the interferon response and NAD+ in the context of COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in dramatic worldwide mortality. Along with developing vaccines, the medical profession is exploring new strategies to curb this pandemic. A better understanding of the molecular consequences of SARS-CoV-2 cellular infection could lead to more effective and safer treatments. This review discusses the potential underlying impact of SARS-CoV-2 in modulating interferon (IFN) secretion and in causing mitochondrial NAD+ depletion that could be directly linked to COVID-19's deadly manifestations. What is known or surmised about an imbalanced innate immune response and mitochondrial dysfunction post-SARS-CoV-2 infection, and the potential benefits of well-timed IFN treatments and NAD+ boosting therapies in the context of the COVID-19 pandemic are discussed.

Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate.

Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei-mitochondria crosstalk with in utero stress awaits further investigation.

Distorted assessment of left atrial size by echocardiography in patients with increased aortic root diameter.

BACKGROUND: Left atrial (LA) size is frequently assessed by posterior-anterior linear measurement of LA (LAD P-A) in the parasternal long axis to expedite examination. Aging, changes in body surface area, and several cardiovascular pathologies can affect aortic root (AoR) size, thereby affecting LA anatomical shape. We hypothesized that AoR dilatation influences LAD P-A and consequently correct assessment of LA size. RESULTS: We tested our hypothesis in a study of 70 patients with AoR diameter ranging from 2.7 to 4.8 cm. LA size assessed in parasternal long axis view as LAD P-A was compared to that with LA width and length acquired in the apical two and four chamber view. Simpson's method of discs was used as standard measurement to assess LA volume. We observed that LAD P-A in the parasternal long axis decreases when AoR diameter increases. Thus, the increase in LA size assessed in parasternal long axis did not correlate with the increase of LA volume. Further analysis revealed that a significant positive correlation was observed when LAV was plotted as a function of LAD P-A only for those with a normal size AoR. In contrast, LA volume increase correlated with LA diameters assessed in the apical two and four chamber view regardless of AoR size. CONCLUSIONS: Our study documents that increases in AoR impact on the linear measurement of LA, resulting in an underestimated LAD P-A. LA size ought to be calculated from the apical two and four chambers view parameters, especially in patients with AoR dilatation.