Association of Mitochondrial Genetic Variation with Carotid Atherosclerosis

Peer reviewe

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and white matter microstructure in UK Biobank

Background: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. Methods: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). Results: We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, p =.029) and significantly higher MD in a global measure of thalamic radiations (β =.029, p =.021), as well as higher MD in the superior (β =.034, p =.039) and inferior (β =.029, p =.043) longitudinal fasciculus and in the anterior (β =.025, p =.046) and superior (β =.027, p =.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. Conclusions: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts

Creation of Cybrid Cultures Containing mtDNA Mutations m.12315G&gt;A and m.1555G&gt;A, Associated with Atherosclerosis

In the present work, a pilot creation of four cybrid cultures with high heteroplasmy level was performed using mitochondrial genome mutations m.12315G&gt;A and m.1555G&gt;A. According to data of our preliminary studies, the threshold heteroplasmy level of mutation m.12315G&gt;A is associated with atherosclerosis. At the same time, for a mutation m.1555G&gt;A, such a heteroplasmy level is associated with the absence of atherosclerosis. Cybrid cultures were created by fusion of rho0-cells and mitochondria from platelets with a high heteroplasmy level of the investigated mutations. To create rho0-cells, THP-1 culture of monocytic origin was taken. According to the results of the study, two cybrid cell lines containing mutation m.12315G&gt;A with the heteroplasmy level above the threshold value (25% and 44%, respectively) were obtained. In addition, two cybrid cell lines containing mutation m.1555G&gt;A with a high heteroplasmy level (24%) were obtained. Cybrid cultures with mtDNA mutation m.12315G&gt;A can be used to model both the occurrence and development of atherosclerosis in cells and the titration of drug therapy for patients with atherosclerosis. With the help of cybrid cultures containing single nucleotide replacement of mitochondrial genome m.1555G&gt;A, it is possible to develop approaches to the gene therapy of atherosclerosis

MtDNA mutations linked with left ventricular hypertrophy

Aim: In left ventricular hypertrophy (LVH), the heart muscle thickens. One third of individuals with LVH never complain of heart problems. However, such patients have a high risk of sudden death. LVH can be caused by arterial atherosclerotic lesions. The linkage of mtDNA mutations 652insG, m.5178C&gt;A, m.3336T&gt;C, m.14459G&gt;A, 652delG, m.14846G&gt;A, m.1555A&gt;G, m.15059G&gt;A, m.3256C&gt;T, m.12315G&gt;A and m.13513G&gt;A with atherosclerosis was described earlier by our laboratory. The aim of the study was to analyze the linkage of these mtDNA mutations with LVH.Methods: DNA from white blood cells was isolated using a phenol-chloroform method. PCR-fragments of DNA contained the region of the investigated mutations. The heteroplasmy level of mtDNA mutations was analyzed using a pyrosequencing-based method developed by our laboratory.Results: We investigated two groups of individuals. One hundred and ninety-four patients with LVH. Two hundred and ten were conventionally healthy. It was found that mtDNA mutation m.5178C&gt;A was significantly associated with LVH. Single nucleotide replacement m.1555A&gt;G was associated with LVH at the level of significance P ≤ 0.1. At the same time m.12315G&gt;A and m.3336T&gt;C were significantly associated with the absence of this pathology. Single nucleotide replacement m.14459G&gt;A was associated with the absence of LVH at the significance level P ≤ 0.1.Conclusion: MtDNA mutations m.5178C&gt;A and m.1555A&gt;G can be used for molecular genetic assessment of the predisposition of individuals to the occurrence of left ventricular hypertrophy. They can also be used for the family analysis of this pathology. Mutations m.12315G&gt;A, m.3336T&gt;C and m.14459G&gt;A can be used in the development of LVH gene therapy methods

Significance of Mitochondrial Dysfunction in the Progression of Multiple Sclerosis

The prevalence of multiple sclerosis and the complexity of its etiology and pathogenesis require further study of the factors underlying the progression of this disease. The prominent role of mitochondria in neurons makes this organelle a vulnerable target for CNS diseases. The purpose of this review is to consider the role of mitochondrial dysfunction in the pathogenesis of multiple sclerosis, as well as to propose new promising therapeutic strategies aimed at restoring mitochondrial function in multiple sclerosis

Mitochondrial mutations associated with cardiac angina

Aim: Cardiac angina is a disease in which discomfort or retrosternal pain may occur. Atherosclerosis of coronary arteries is one of the main risk factors for cardiac angina. The aim of the investigation was to analyze the association of 11 mitochondrial genome mutations with cardiac angina. In our preliminary studies an association of these mutations with atherosclerosis, a risk factor for cardiac angina, was found.Methods: We used samples of white blood cells collected from 192 patients with cardiac angina and 201 conventionally healthy study participants. DNA from blood leukocyte samples was isolated using a phenol-chloroform method. DNA amplicons containing the investigated regions of 11 mitochondrial genome mutations (m.12315G&gt;A, m.652delG, m.5178C&gt;A, m.14459G&gt;A, m.3336T&gt;C, 652insG, m.3256C&gt;T, m.1555A&gt;G, m.15059G&gt;A, m.13513G&gt;A, m.14846G&gt;A) were pyrosequenced. The heteroplasmy level of mitochondrial DNA (mtDNA) mutations was analyzed using a method developed by our laboratory on the basis of pyrosequencing technology.Results: According to the obtained data, three mitochondrial mutations of human genome correlated with cardiac angina. A positive correlation was observed for mutation m.14459G&gt;A (P ≤ 0.05). One single nucleotide substitution m.5178C&gt;A (P ≤ 0.1) had a trend for positive correlation. A negative correlation for mutation m.15059G&gt;A with cardiac angina (P ≤ 0.05) was found.Conclusion: MtDNA mutations m.14459G&gt;A and m.5178C&gt;A can be used for evaluation the predisposition of individuals to atherosclerotic lesions. At the same time, mitochondrial genome mutation m.15059G&gt;A may be used for gene therapy of atherosclerosis

Changes of mitochondria in atherosclerosis : possible determinant in the pathogenesis of the disease

Electron-microscopic analysis of atherosclerotic lesions demonstrated a high variability in the ultra-structural appearance of mitochondria in human aortic atherosclerotic lesions compared with the appearance of mitochondria in the normal parts of the aortic intima. This prompted us to suggest that the structural variations in the appearance of mitochondria might reflect the existence of somatic mutations in the human mitochondrial genome which could be a determinant of atherosclerosis. To test this hypothesis, we have compared the levels of heteroplasmy for several mitochondrial mutations previously proposed to be associated with different types of atherosclerotic lesions. The homogenates of unaffected aortic intimae and lipofibrous plaques of 12 male aortas were compared to reveal the average level of heteroplasmy for A1555G, C3256T, T3336T, G12315A, G14459A, and G15059A mutations of human mitochondrial genome. It has been shown at least four mutations of mitochondrial genome, namely, A1555G in MT-RNR1 gene, C3256T in MT-TL1 gene, G12315A in MT-TL2 gene, and G15059A in MT-CYB gene have significantly higher prevalence and mean value in lipofibrous plaques as compared to non-atherosclerotic intima, and therefore are associated with atherosclerosis. Somatic mutations in the human mitochondrial genome might play a role in the development of atherosclerosis. The mitochondrial mutations observed in our study should encourage further exploration of the concept that mitochondrial DNA heteroplasmy might be used as a biomarker of atherogenesis

Mitochondrial mutations are associated with atherosclerotic lesions in the human aorta

Somatic mutations of the human mitochondrial genome can be a possible determinant of atherosclerosis. To test this possibility, forty mitochondrial mutations were analyzed in the present study in order to see which of these mutations might be associated with atherosclerosis. Ten mitochondrial mutations belonging to mitochondrial genes MT-RNR1 (rRNA 12S); MT-TL1 (tRNA-Leu, recognizes UUR); MT-TL2 (tRNA-Leu, recognizes CUN); MT-ND1, MT-ND2, MT-ND5, and MT-ND6 (subunits 1, 2, 5, and 6, respectively, of NADH dehydrogenase); and MT-CYB (cytochrome b) were potentially associated with atherosclerosis. From 29% (2 of 7 aortic samples) upto 86% (6 of 7 aortic samples) of aortic samples had a significant difference between atherosclerotic plaques and unaffected tissue, with the respect to the level of heteroplasmy for each mutation. Further, the homogenates of affected and normal intimae of 22 aortas were compared to reveal the average level of heteroplasmy for the above-mentioned 10 mutations. For five mutations, the mean level of heteroplasmy was significantly different in atherosclerotic intimal homogenates in comparison with the unaffected tissue. These mutations were A1555G, C3256T, T3336C, G13513A, and G15059A. Thus, it was demonstrated that at least five mitochondrial mutations occurring in MT-RNR1, MT-TL1, MT-ND2, MT-ND5, and MT-CYB genes are associated with atherosclerosis