Cardiovascular-associated Mortality Research Articles

Genetics, Safety, Cost-Effectiveness, and Accessibility of Injectable Lipid-Lowering Agents: A Narrative Review.

Cardiovascular disease causes significant personal, financial, and societal burden and is a major cause of mortality and morbidity globally. Dyslipidemia has proven to be a major factor that contributes to its increased incidence; thus, since a long time, low-density lipoprotein cholesterol-lowering therapies have been employed to reduce coronary artery disease-associated mortality. The first-line therapy for hyperlipidemia and dyslipidemia is statins. Evidence showed that statins decrease the level of LDL-C resulting in a lower risk of CVD (20-25% for every decrease of 1 mmol/L). However, due to statin intolerance in some patients and despite using maximal doses, they have not been successful in lowering cardiovascular-associated mortality. Moreover, bococizumab was recently suspended due to its higher immunogenicity with time, resulting in less efficacy with long-term use. Alternatives to statins are PCSK9 inhibitors which are administered subcutaneously every two or four weeks. They are injectables with considerable lipid-lowering properties. This narrative review discusses their genetics, safety, tolerability, and cost-effectiveness. It also quantifies their benefit in certain subgroups by analyzing the findings from recent randomized clinical trials. Current data from phase 2 and 3 trials (ORION, ODYSSEY, and FOURIER) suggest a favorable profile for evolocumab, alirocumab, and inclisiran with minimal tolerable side effects and superior efficacy in statin-intolerant patients. Their cost-effectiveness has not yet been established clearly, but future outcomes seem promising.

Chronic Chagas Disease-the Potential Role of Reinfections in Cardiomyopathy Pathogenesis.

Chagas disease is a neglected anthropozoonosis of global importance with significant cardiovascular-associated mortality. This review focuses on the Trypanosoma cruzi reinfections' role in chronic Chagas cardiomyopathy pathogenesis. We discuss and summarize the available data related to pathology, pathogenesis, diagnosis, and treatment of reinfections. Reinfections influence the genetic and regional diversity of T. cruzi, tissue tropism, modulation of the host's immune system response, clinical manifestations, the risk for congenital infections, differences in diagnostics performances, response to antiparasitic therapy, and the natural history of the disease. Animal models suggest that reinfections lead to worse outcomes and increased mortality, while other studies showed an association between reinfections and lower parasitemia levels and subsequent infection protection. In some regions, the human risk of reinfections is 14% at 5years. Evidence has shown that higher anti-T. cruzi antibodies are correlated with an increased rate of cardiomyopathy and death, suggesting that a higher parasite exposure related to reinfections may lead to worse outcomes. Based on the existing literature, reinfections may play a role in developing and exacerbating chronic Chagas cardiomyopathy and are linked to worse outcomes. Control efforts should be redirected to interventions that address structural poverty for the successful and sustainable prevention of Chagas disease.

Glucose-6-phosphatase catalytic subunit 2 negatively regulates glucose oxidation and insulin secretion in pancreatic β-cells

Elevated fasting blood glucose (FBG) is associated with increased risks of developing type 2 diabetes (T2D) and cardiovascular-associated mortality. G6PC2 is predominantly expressed in islets, encodes a glucose-6-phosphatase catalytic subunit that converts glucose-6-phosphate (G6P) to glucose, and has been linked with variations in FBG in genome-wide association studies. Deletion of G6pc2 in mice has been shown to lower FBG without affecting fasting plasma insulin levels in vivo. At 5 mM glucose, pancreatic islets from G6pc2 knockout (KO) mice exhibit no glucose cycling, increased glycolytic flux, and enhanced glucose-stimulated insulin secretion (GSIS). However, the broader effects of G6pc2 KO on β-cell metabolism and redox regulation are unknown. Here we used CRISPR/Cas9 gene editing and metabolic flux analysis in βTC3 cells, a murine pancreatic β-cell line, to examine the role of G6pc2 in regulating glycolytic and mitochondrial fluxes. We found that deletion of G6pc2 led to ∼60% increases in glycolytic and citric acid cycle (CAC) fluxes at both 5 and 11 mM glucose concentrations. Furthermore, intracellular insulin content and GSIS were enhanced by approximately two-fold, along with increased cytosolic redox potential and reductive carboxylation flux. Normalization of fluxes relative to net glucose uptake revealed upregulation in two NADPH-producing pathways in the CAC. These results demonstrate that G6pc2 regulates GSIS by modulating not only glycolysis but also, independently, citric acid cycle activity in β-cells. Overall, our findings implicate G6PC2 as a potential therapeutic target for enhancing insulin secretion and lowering FBG, which could benefit individuals with prediabetes, T2D, and obesity.

Mutations in G6PC2 gene with increased risk for development of type 2 diabetes: Understanding via computational approach.

An increase in the fast blood glucose (FBG) levels has been linked to an increased risk of developing a chronic condition, type 2 diabetes (T2D). The mutation in the G6PC2 gene was identified to have a lead role in the modulation of FBG levels. The abnormal regulation of this enzyme influences glucose-stimulated insulin secretion (GSIS), which controls the insulin levels corresponding to the system's glucose level. This study focuses on the mutations at the G6PC2 gene, which cause the variation from normal expression levels and increase the risk of T2D. We examined the non-synonymous single nucleotide polymorphisms (nsSNPs) present in the G6PC2 and subjected them to pathogenicity, stability, residue conservation, and membrane simulation. The individual representation of surrounding amino acids in the mutant (I63T) model showed the loss of hydrophobic interactions compared to the native G6PC2. In addition, the trajectory results from the membrane simulation exhibited reduced stability, and the least compactness was identified for the I63T mutant model. Our study shed light on the structural and conformational changes at the transmembrane region due to the I63T mutation in G6PC2. Additionally, the Gibbs free energy landscape analysis against the two principal components showed structural differences and decreased the conformational stability of the I63T mutant model compared to the native. Like those presented in this study, dynamical simulations may indeed be crucial to comprehending the structural insights of G6PC2 mutations in cardiovascular-associated mortality and T2D.

Bedtime administration of antihypertensive medication can reduce morning blood pressure surges in hypertensive patients: a systematic review and meta-analysis.

The risk of cardiovascular and cerebrovascular events is the highest during the first several hours post-awakening in patients with hypertension. This is largely due to surges in morning blood pressure (BP). The current meta-analysis explored whether morning BP is affected by the timing of antihypertensive drug administration. Four medical databases were searched for clinical trials that examined the relationship between the timing of antihypertensive drug administration and morning BP levels. This meta-analysis compared morning BP surges in patients administered medication at bedtime versus patients administered medication during the day. The random effects model demonstrated that bedtime administration of antihypertensive drugs reduced morning systolic blood pressure (SBP) by 1.17 mmHg [with 95% confidence interval (CI): -2.47 to 0.37; P=0.08), and reduced morning diastolic blood pressure (DBP) by 0.95 mmHg (95% CI: -2.03 to 0.13; P=0.08), compared with patients who were administered medication during the daytime hours. However, the results did not demonstrate statistical significance. There was strong heterogeneity in both morning SBP (I2 =77.9% >50%, and Q test >0.1) and morning DBP results (I2 =77.9% >50%, and Q test >0.1). The funnel plots showed no publication bias in this study. Studies have shown that a 1 mmHg change was sufficient to reduce the risk of cardiovascular-related deaths by 2.1%. Therefore, changing the time of taking antihypertensive medications may significantly reduce cardiovascular-associated mortality. There were certain limitations to this meta-analysis. First, the heterogeneity of the meta-analysis was strong, with undefined reasons. Second, the sample size was relatively small, and future studies involving larger cohorts are warranted to further assess the effects of bedtime antihypertensive medication on minimizing morning BP surges.

Hidradenitis suppurativa and major adverse cardiac events: A systematic review and meta-analysis

To the Editor: Hidradenitis suppurativa (HS) is a chronic inflammatory disorder that results in significant morbidity. There is conflicting evidence on whether HS is associated with major adverse cardiac events (MACEs), including cerebrovascular accident (CVA), myocardial infarction (MI), and cardiovascular-associated mortality.1,2 Here, we aim to resolve these discrepancies through a systematic review and meta-analysis of the literature.

G6PC2 confers protection against hypoglycemia upon ketogenic diet feeding and prolonged fasting

ObjectiveG6PC2 is predominantly expressed in pancreatic islet beta cells. G6PC2 hydrolyzes glucose-6-phosphate to glucose and inorganic phosphate, thereby creating a futile substrate cycle that opposes the action of glucokinase. This substrate cycle determines the sensitivity of glucose-stimulated insulin secretion to glucose and hence regulates fasting blood glucose (FBG) but not fasting plasma insulin (FPI) levels. Our objective was to explore the physiological benefit this cycle confers. MethodsWe investigated the response of wild type (WT) and G6pc2 knockout (KO) mice to changes in nutrition. ResultsPancreatic G6pc2 expression was little changed by ketogenic diet feeding but was inhibited by 24 hr fasting and strongly induced by high fat feeding. When challenged with either a ketogenic diet or 24 hr fasting, blood glucose fell to 70 mg/dl or less in G6pc2 KO but not WT mice, suggesting that G6PC2 may have evolved, in part, to prevent hypoglycemia. Prolonged ketogenic diet feeding reduced the effect of G6pc2 deletion on FBG. The hyperglycemia associated with high fat feeding was partially blunted in G6pc2 KO mice, suggesting that under these conditions the presence of G6PC2 is detrimental. As expected, FPI changed but did not differ between WT and KO mice in response to fasting, ketogenic and high fat feeding. ConclusionsSince elevated FBG levels are associated with increased risk for cardiovascular-associated mortality (CAM), these studies suggest that, while G6PC2 inhibitors would be useful for lowering FBG and the risk of CAM, partial inhibition will be important to avoid the risk of hypoglycemia.

Coenzyme Q10 Supplementation in Fibrosis and Aging.

Coenzyme Q10 (CoQ10) is a vitamin-like substance which functions as an electron carrier within the mitochondrial respiratory chain, as well as serving as an important intracellular antioxidant. Most of the body's CoQ10 requirements are met by endogenous synthesis, although the capacity for CoQ10 production decreases substantially with increasing age. In this article we have reviewed the potential role of CoQ10 supplementation in the treatment of tissue fibrosis, which has been implicated in the age-related loss of function of various organs including the heart. Clinical studies have indicated that CoQ10 supplementation may decrease the level of cardiovascular fibrosis to which older individuals are subjected, and thereby improve cardiovascular function and reduce the risk of cardiovascular associated mortality. Although the factors responsible for the anti-fibrotic action of CoQ10 have yet to be fully elucidated, its antioxidant and anti-inflammatory functions are thought to be major contributors to its clinical efficacy in the treatment of this age-related disorder.

PMD41 - Economic Impact of the use of Rapid Deployment Valve Replacements in Brazil and Colombia

To compare the economic impact of rapid deployment valve (RDV) versus using conventional valve, a third-party payer perspective in Brazil and Colombia. A model was done to compare each valve replacement treatment during inpatient of 30-day and the complication rates such as: intensive care (ICU) and ward length of stay, vascular complications, cardiovascular-attributed mortality, myocardial infarction, stroke, need for pacemaker obtained from best evidence review of the published literature and cost from Health System in Brazil (Private System) and Colombia (Entidades Promotoras de Salud [Health Promoting Entities] EPS) and outputs consists of local currencies (BRL/Brazil, COP/Colombia). In the current scenario with RDV, the economic benefit associated per patient were BRL 21,935 and COP 31,038.048 for Brazil and Colombia, respectively. It was found a 1.8% reduction on cardiovascular-associated mortality when using RDV. Other benefits associated with RDV included reduction in ICU length of stay (-38.7%) and time to recover in surgical room (-2 days). For this preliminary analyze RDV has the potential to promote better resources allocation, by reducing mortality at reasonable costs in patients who need aortic valve replacement.

Antihypertensive nano-ceuticales based on chitosan biopolymer: Physico-chemical evaluation and release kinetics

Prime risk factor behind cardiovascular associated mortality and morbidity is hypertension. The main challenge with antihypertensive (AHT) drug therapy is their extreme hydrophobic nature and very low oral bio-availability; which result into higher dosage/frequency and associated side effects of drugs. The main objective of this study was to fabricate AHT nano-ceuticals in hydrophilic carriers of natural origin to improve drugs′ solubility, protection and sustained release. AHT nano-carrier systems (NCS) encapsulating captopril, amlodipine and valsartan were fabricated using chitosan (CS) polymer by ionic gelation assisted ultra-sonication method. Drug encapsulation efficiencies of 92±1.6%, 91±0.9% and 87±0.5% were observed for captopril, valsartan and amlodipine respectively. Scanning electron microscopy (SEM) based analysis had revealed that captopril loaded polymeric NCS were regular, smooth and without any agglomeration. FTIR analyses of drug loaded and empty NCS demonstrated that drugs were molecularly dispersed inside the nanoparticles via week hydrogen bonding. Captopril and valsartan have demonstrated grafting reaction with NH group of chitosan. Zeta sizer results had confirmed that average size of chitosan nanoparticles was below 100nm. Encapsulation of captopril had reduced the surface charge value from +52.6±4.8 to +46.5±5.2mV. Controlled release evaluation of highly encapsulated drug captopril had revealed a slow release in vitro from NCS in physiological buffer. Thus, here reported innovative AHT nano-ceuticals of polymeric origin can improve the oral administration of currently available hydrophobic drugs while providing the extended-release function.

Association between depression and inflammatory/anti-inflammatory cytokines in chronic kidney disease and end-stage renal disease patients: a review of literature.

Depression is a common psychiatric disorder in patients with advanced chronic kidney diseases (CKDs). Strong correlation has been reported between depression and patients' morbidity and mortality among dialysis patients. On the contrary, chronic inflammation may be a major contributor to morbidity and mortality in these patients. Elevated plasma levels of proinflammatory cytokines, especially C-reactive protein and interleukin (IL)-6, have been correlated with cardiovascular events, hospitalization, and all-cause and cardiovascular-associated mortality in dialysis patients. Studies suggested that inflammation-mediated atherosclerotic cardiovascular diseases are the possible reasons for depression-induced mortality among patients without renal diseases. Several studies found significant elevations in circulating levels of proinflammatory cytokines, particularly IL-6 and tumor necrosis factor-α, in patients with major depression. Furthermore, depressive mood and behaviors, including sadness and suicidal ideation, were observed in patients who received repeated injections of recombinant cytokines. A thorough literature review indicates that while depressive symptoms and elevated inflammatory cytokine levels coexist in CKD and dialysis patients, their association is uncertain. Depression seems to be more associated with elevated serum levels of IL-6 than other cytokines in these patients. Further studies are needed to clarify the possibility of a causal relationship between inflammation and depressive symptoms in CKD and dialysis patients.

Moving on from GWAS: Functional Studies on the G6PC2 Gene Implicated in the Regulation of Fasting Blood Glucose

Genome-wide association studies (GWAS) have shown that single-nucleotide polymorphisms (SNPs) in G6PC2 are the most important common determinants of variations in fasting blood glucose (FBG) levels. Molecular studies examining the functional impact of these SNPs on G6PC2 gene transcription and splicing suggest that they affect FBG by directly modulating G6PC2 expression. This conclusion is supported by studies on G6pc2 knockout (KO) mice showing that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux and opposing the action of glucokinase. Suppression of G6PC2 activity might, therefore, represent a novel therapy for lowering FBG and the risk of cardiovascular-associated mortality. GWAS and G6pc2 KO mouse studies also suggest that G6PC2 affects other aspects of beta cell function. The evolutionary benefit conferred by G6PC2 remains unclear, but it is unlikely to be related to its ability to modulate FBG.

We Are What We Eat, Or Are We?

We Are What We Eat, Or Are We?

G6PC2: A Negative Regulator of Basal Glucose-Stimulated Insulin Secretion

Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum–resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux.

Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey

IntroductionIncreased rates of cardiovascular disease are implicated in several rheumatologic diseases. Our aim was to characterize dermatomyositis hospitalizations and evaluate cardiovascular-associated mortality in this patient population.MethodsWe examined the frequency and mortality rates of several atherosclerotic cardiovascular diagnoses and procedures among hospitalized adult patients with dermatomyositis using data from the US Nationwide Inpatient Sample (NIS) from 1993 to 2007. We compared the odds of death among hospitalized dermatomyositis patients with each cardiovascular diagnosis or procedure to those without, as well as to controls with cardiovascular diagnoses, using logistic regression.ResultsA total of 50,322 hospitalizations of dermatomyositis patients occurred between 1993 and 2007 (mean age 58 years, and 73% female). Of all dermatomyositis hospitalizations, 20% were associated with a concurrent atherosclerotic cardiovascular diagnosis or procedure. The overall in-hospital mortality was 5.7%. Dermatomyositis patients with any associated atherosclerotic cardiovascular diagnosis or procedure were twice as likely to die during the inpatient stay compared to dermatomyositis patients who did not have atherosclerotic cardiovascular disease (OR = 2.0 95% CI 1.7-2.5, p < 0.0001). The odds ratio for death in patients with both dermatomyositis and cardiovascular disease compared to controls with cardiovascular disease alone was 1.98 (95% CI 1.57-2.48) in multivariate adjusted models.ConclusionsApproximately one fifth of dermatomyositis hospitalizations in the US were associated with an atherosclerotic cardiovascular diagnosis or procedure. These patients have double the risk of in-hospital death in comparison with controls and dermatomyositis patients without a cardiovascular diagnosis, making identification of these groups important for both prognostic purposes and clinical care.

Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet beta cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in betaTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in betaTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a approximately 50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.

Video rate electrical impedance tomography of vascular changes: preclinical development

Peripheral vasculature disease is strongly correlated with cardiovascular-associated mortality. Monitoring circulation health, especially in the peripheral limbs, is vital to detecting clinically significant disease at a stage when it can still be addressed through medical intervention. Electrical impedance tomography (EIT) maps the electrical properties of tissues within the body and has been used to image dynamically varying physiology, including blood flow. Here, we suggest that peripheral vasculature health can be monitored with EIT by imaging the hemodynamics of peripheral vessels and the surrounding tissues during reactive hyperemia testing. An analysis based on distinguishability theory is presented that indicates that an EIT system capable of making measurements with a precision of 50 µV may be able to detect small changes in vessel size associated with variations in blood flow. An EIT system with these precision capabilities is presented that is able to collect data at frame rates exceeding 30 fps over a broad frequency range up to 10 MHz. The system's high speed imaging performance is verified through high contrast phantom experiments and through physiological imaging of induced ischemia with a human forearm. Region of interest analysis of the induced ischemia images shows a marked decrease in conductivity over time, changing at a rate of approximately −3 × 10−7 S m−1 s−1, which is the same order of magnitude as reported in the literature. The distinguishability analysis suggests that a system such as the one developed here may provide a means to characterize the hemodynamics associated with blood flow through the peripheral vasculature.