Current Vascular Pharmacology - Volume 23, Issue 1, 2025

Cardiovascular disorders (CVDs) are reported to occur with very high rates of incidence and exhibit high morbidity and mortality rates across the globe. Therefore, research is focused on searching for novel therapeutic targets involving multiple pathophysiological mechanisms. Oxidative stress plays a critical role in the development and progression of various CVDs, such as hypertension, pulmonary hypertension, heart failure, arrhythmia, atherosclerosis, ischemia-reperfusion injury, and myocardial infarction. Among multiple pathways generating reactive oxygen species (ROS), Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases of the NOX family as the major source of ROS generation and plays an intricate role in the development and progression of CVDs. Therefore, exploring the role of different NADPH oxidase isoforms in various cardiovascular pathologies has attracted attention to current cardiovascular research. Focusing on NADPH oxidases to reduce oxidative stress in managing diverse CVDs may offer unique therapeutic approaches to prevent and treat various heart conditions. The current review article highlights the role of different NADPH oxidase isoforms in the pathophysiology of various CVDs. Moreover, the focus is also to emphasize different experimental studies that utilized various NADPH oxidase isoform modulators to manage other disorders. The present review article considers new avenues for researchers/scientists working in the field of cardiovascular pharmacology utilizing NADPH oxidase isoform modulators.

Atrial fibrillation (AF) is the commonest cardiac arrhythmia, constituting a major cause of morbidity and mortality, with an age-dependent incidence and prevalence ranging from 1-2% in the general population to ~10% in persons aged >60 years. The global prevalence of AF is rapidly increasing, mostly due to the aging population. If not properly and timely managed, this arrhythmia adversely affects left ventricular function, increases the risk of stroke five-fold, impairs quality of life, and shortens longevity. There is a genetic, hence non-modifiable, predisposition to the arrhythmia, while several life-style and cardiometabolic inciting factors, such as hypertension, heart failure, coronary disease, metabolic syndrome, alcohol use, and thyroid disorders, can be addressed, attesting to the importance of a holistic approach to its management. Thromboembolism is a serious consequence of AF, which could lead to a disabling stroke or have a lethal outcome. The risk of a thromboembolic complication can be estimated as based on a scoring system that takes into consideration the patient’s age, previous thromboembolic events, and clinical comorbidities. In addition, rapid AF could affect cardiac performance, leading to an elusive type of arrhythmia-induced cardiomyopathy and heart failure with grave consequences if undetected and untreated. Furthermore, AF may cause silent brain infarcts and/or its hemodynamic perturbations can account for a type of dementia that needs to be taken into account, emphasizing the need for AF screening and prevention strategies. All these issues are herein detailed, the causes of the arrhythmia are tabulated, and an algorithm illustrates our current approach to its management.

Mendelian Randomization (MR) studies have emerged as a powerful tool for investigating causal relationships between modifiable risk factors and clinical outcomes, using genetic variants as instrumental variables. In the context of vitamin D research, MR is a promising approach to elucidate the effects of vitamin D on various health outcomes, including adverse cardiovascular events. However, the validity of MR analyses relies heavily on the strength of the genetic associations found. “Weak instrument bias”, arising from instruments with low explanatory power for the exposure of interest, can lead to biased estimates and compromise causal inference. We have, herein, briefly reviewed the challenges posed by weak instrument bias in a large MR study on vitamin D [25(OH)D] and stroke, exploring implications for the study's validity and reliability of findings. We have then added an original meta-analysis stratified by 25(OH)D levels. By using aggregated data from a recent MR study, an original meta-analysis stratified by population mean levels of 25(OH)D has indicated that interventions based on vitamin D supplementations in population mean levels ranging from 50 to 70 nmol/L are likely to translate into a 13% reduction of stroke risk (pooled odds ratio=0.873, 95% CI: 0.764-0.997, p-value=0.04). MR studies are a valuable approach for discerning causal relationships between exposures, such as vitamin D, and health outcomes. However, the effectiveness of MR analyses depends on the robustness of the genetic instruments employed. By recognizing and addressing weak instrument bias in MR studies of vitamin D, researchers can enhance the credibility and utility of causal inference in understanding the health effects of this essential nutrient. A meta-analysis stratified by population mean levels of 25(OH)D has revealed the potential benefits of targeted interventions with vitamin D supplementations for stroke.