J. Cardiovasc. Dev. Dis., Volume 5, Issue 3 (September 2018) – 14 articles

Genetic polymorphisms are variations in DNA sequences which can influence either disease susceptibility, severity, or prognosis. Pulmonary arterial hypertension (PAH) is one of the complications that occurs in certain patients who have atrial septal defect (ASD). This study seeks to determine the association of gene polymorphisms with the pathogenesis of PAH in ASD patients. This study was conducted on 30 ASD patients with PAH, and 50 ASD patients who were not diagnosed with PAH. All respondents were Malay. Patients were selected based on stringent inclusion and exclusion criteria. Molecular analyses were done to detect the genetic polymorphisms of angiotensin converting enzyme (ACE I/D), serotonin transporter (5-HTTLPR), endothelial nitric oxide synthase (eNOS) G894T, and eNOS 4b/4a. The genotypes of these genetic polymorphisms were determined using conventional PCR and PCR-RFLP methods. The PCR products were analysed using agarose gel electrophoresis. Statistical analysis was done using SPSS Version 22. Clinical characteristics, such as the diameter of ASD, mean arterial pressure (MAP), and mean pulmonary artery pressure (mPAP) differed significantly (p < 0.05). Based on the statistical analysis, ACE I/D, eNOS G894T, and eNOS 4b/4a do not contribute to the progression of PAH amongst ASD patients (p > 0.05). However, the L allele of the 5-HTTLPR gene polymorphism may have an affect on the development of PAH in ASD patients (p < 0.05). Full article

Purpose: Fasting or postprandial hypertriglyceridemia is considered an independent cardiovascular disease (CVD) risk factor. The intestinal fatty acid binding protein (FABP2) is involved in the intracellular transport and metabolism of fatty acids. The presence of the Ala54Thr polymorphism of the FABP2 gene appears to be involved in postprandial hypertriglyceridemia. We explored the possible association of the Ala54Thr polymorphism with fat intolerance in apparently healthy, fasting, normolipidemic subjects with normal body-mass index and without diabetes. Methodology: A total of 158 apparently healthy individuals were classified as fat tolerant (n = 123) or intolerant (n = 35) according to their response (plasma triglycerides) to an oral abbreviated tolerance test with blood samples taken at 0, 2 and 4 h. At 0 h, all subjects ingested 26.3 g of fats. Presence of the Ala54Thr polymorphism of the FABP2 gene was evaluated by polymerase chain reaction–restriction fragment length (PCR–RFLP). Results: The group with fat intolerance (postprandial hypertriglyceridemia group) showed an increased frequency of the Thr54Thr genotype when compared with the group with normal fat tolerance (control group) (23% vs. 4%, respectively, OR: 16.53, 95% CI: 4.09–66.82, p: 0.0001, pc: 0.0003). Carriers of at least one Thr54 allele were up to six times more prevalent in the fat intolerant group than in the non-carriers. (OR: 6.35; 95% CI: 1.86–21.59, p: 0.0003, pc: 0.0009). The levels of plasma triglycerides (Tg) at 4 h after the test meal were higher in carriers of at least one 54Thr allele than in carriers of the Ala54 allele (p < 0.05). Conclusions: There is a significant association between postprandial hypertriglyceridemia and the presence of at least one 54Thr allele of the FABP2 gene. In addition, subjects with this genotype showed an increased ratio of Tg/HDL-cholesterol. This parameter is a marker of increased CVD risk and insulin resistance. Full article

That form and function are related is a maxim of anatomy and physiology. Yet, form-function relations can be difficult to prove. Human subjects with excessive trabeculated myocardium in the left ventricle, for example, are diagnosed with non-compaction cardiomyopathy, but the extent of trabeculations may be without relation to ejection fraction. Rather than rejecting a relation between form and function, we may ask whether the salient function is assessed. Is there a relation to electrical propagation, mean arterial blood pressure, or propensity to form blood clots? In addition, how should the extent of trabeculated muscle be assessed? While reviewing literature on trabeculated muscle, we applied Tinbergen’s four types of causation—how does it work, why does it work, how is it made, and why did it evolve—to better parse what is meant by form and function. The paper is structured around cases that highlight advantages and pitfalls of applying Tinbergen’s questions. It further uses the evolution of lunglessness in amphibians to argue that lung reduction impacts on chamber septation and it considers the evolution of an arterial outflow in fishes to argue that reductions in energy consumption may drive structural changes with little consequences to function. Concerning trabeculations, we argue they relate to pumping function in the embryo in the few weeks before the onset of coronary circulation. In human fetal and postnatal stages, a spectrum of trabeculated-to-compact myocardium makes no difference to cardiac function and in this period, form and function may appear unrelated. Full article

Cardiovascular diseases (CVDs) are as menacing as ever and still continue to kill adults worldwide, notwithstanding tremendous efforts to decrease their consequent mortality and morbidity. Lately, a growing body of research indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptors expressed on myeloid cells-1 (TREM-1) was shown to induce and amplify the inflammation in both acute and chronic disease’ pathogenesis and progression, which hence makes it one of the most important complication factors of CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications, and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We critically analyzed and summarized our findings and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management, and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions, such as acute myocardial infarction (AMI) and atherosclerosis. Although most therapeutic approaches are yet to be elucidated, our present research outcome displays a promising future to utilizing the TREM-1 pathway as a potential target for understanding and managing CVDs. Full article

It is now well over 100 years since Sunao Tawara clarified the location of the axis of the specialised myocardium responsible for producing coordinated ventricular activation. Prior to that stellar publication, controversies had raged as to how many bundles crossed the place of the atrioventricular insulation as found in mammalian hearts, as well as the very existence of the bundle initially described by Wilhelm His Junior. It is, perhaps surprising that controversies continue, despite the multiple investigations that have taken place since the publication of Tawara’s monograph. For example, we are still unsure as to the precise substrates for the so-called slow and fast pathways into the atrioventricular node. Much has been done, nonetheless, to characterise the molecular make-up of the specialised pathways, and to clarify their mechanisms of development. Of this work itself, a significant part has emanated from the laboratory coordinated for a quarter of a century by Antoon FM Moorman. In this review, which joins the others in recognising the value of his contributions and collaborations, we review our current understanding of the anatomy, development, and evolution of the atrioventricular conduction axis. Full article

We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long-chain and medium-chain fatty acid metabolites in wild-type hearts. This response was attenuated in mice that lack expression of CHIP (CHIP^−/−). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism pathways that are regulated, in part, by the nuclear receptor PPARα (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP^−/− mice with the PPARα agonist called fenofibrate. We found that treating CHIP^−/− mice with fenofibrate for five weeks under non-pressure overload conditions resulted in decreased skeletal muscle mass, compared to wild-type mice, and a marked increase in cardiac fibrosis accompanied by a decrease in cardiac function. Fenofibrate resulted in decreased mitochondrial cristae density in CHIP^−/− hearts as well as decreased expression of genes involved in the initiation of autophagy and mitophagy, which suggests that a metabolic challenge, in the absence of CHIP expression, impacts pathways that contribute to mitochondrial quality control. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected skeletal muscle and cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism. Full article

Elastic extra-aortic wrapping is a potential non-pharmacological way to improve aortic compliance and treat isolated systolic hypertension associated with a stiffened aorta. We aimed to use computer simulations to re-evaluate whether there is aortic shape distortion in aortic wrapping to achieve greater elasticity of the wrapped aortic segment. Non-linear transient numerical analysis based on an idealized hyper-elastic single-layered aorta model was performed to simulate the force/displacement regimes of external aortic wrapping. Pressure-displacement relationships were used to establish model aortic wall distensibilities of 4.3 and 5.5 (10⁻³ mmHg⁻¹). A physiological pulsatile lumen pressure was employed to estimate the potential improvements in aortic distensibility by compression forces representing elastic aortic wrapping. In the less distensible model of the aortic wall there was increased systolic expansion in the wrapped segment. We found a risk of creasing of the aortic luminal wall with wrapping. Sufficient unloading of a thick and elastic aortic wall to induce increased compliance, as observed in elastic wrapping, is associated with the potential risk of over compression and folding (creasing) inside the lumen. Full article

Background: According to the ventricular myocardial band model, the diastolic isovolumetric period is a contraction phenomenon. Our objective was to employ speckle-tracking echocardiography (STE) to analyze myocardial deformation of the left ventricle (LV) and to confirm if it supports the myocardial band model. Methods: This was a prospective observational study in which 90 healthy volunteers were recruited. We evaluated different types of postsystolic shortening (PSS) from an LV longitudinal strain study. Duration of latest deformation (LD) was calculated as the time from the start of the QRS complex of the ECG to the latest longitudinal deformation peak in the 18 segments of the LV. Results: The mean age of our subjects was 50.3 ± 11.1 years. PSS was observed in 48.4% of the 1620 LV segments studied (19.8%, 13.5%, and 15.1% in the basal, medial, and apical regions, respectively). PSS was more frequent in the basal, medial septal, and apical anteroseptal segments (>50%). LD peaked in the interventricular septum and in the basal segments of the LV. Conclusions: The pattern of PSS and LD revealed by STE suggests there is contraction in the postsystolic phase of the cardiac cycle. The anatomical location of the segments in which this contraction is most frequently observed corresponds to the main path of the ascending component of the myocardial band. This contraction can be attributed to the protodiastolic untwisting of the LV. Full article

Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti-atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies. Full article

Purpose: Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 G > A or Val108 > 158Met or rs4680 G > A influences COMT enzyme activity. The three phenotypes of the COMT enzyme activities include COMT A/A with low enzyme activity, COMT A/G with medium enzyme activity and COMT G/G with high enzyme activity. The Met allele is associated with low enzymatic activity resulting in higher levels of prefrontal dopamine. Conversely, the Val allele is associated with high enzymatic activity and lower levels of prefrontal dopamine. The Met allele has been associated with several psychiatric disorders such as panic disorder. Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and coronary artery diseases risk, but the results are inconclusive. Therefore our study was aimed to explore the association between COMT Val158Met polymorphism and the risk of coronary artery disease in India. Methology: This study was conducted on 100 clinically confirmed cases of coronary artery diseases and 100 healthy controls. COMT Val158Met genotyping was performed by allele-specific polymerase chain reaction (AS-PCR). Results: A significant correlation was observed in the COMT Val158Met genotype distribution between the coronary artery disease cases and healthy controls (p = 0.008). The frequencies of all three genotypes, GG, GA, AA, reported in the CAD patients were 10%, 70%, and 20%, and 30%, 60%, and 10% in the healthy controls respectively. An increased risk of coronary artery disease was observed in the codominant inheritance model for COMT-GA vs. GG genotype with an OR of 3.5, 95% CI (1.58–7.74) p = 0.002) and COMT-AA vs. GG genotype with an OR of 6.0 95% CI (2.11–17.3) p = 0.003). The higher risk of coronary artery disease was observed in the dominant inheritance model for COMT (GA + AA) vs. GG genotype (OR 3.85, 95% CI 1.76–8.4, p < 0.007), whereas a non-significant association was found in recessive model for COMT (GG + GA vs. AA) (OR = 2.01, 95% CI (0.86–4.7) p = 0.72). The results indicated that A allele significantly increased the risk of coronary artery disease compared to the G allele (OR = 1.8, 95% CI (1.20–2.67) p = 0.004). COMT Val158Met polymorphism leads to a 6.0, 3.5 and 1.8-fold increased risk of developing coronary artery disease in the Indian population and providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusions: It is concluded that COMT-AA genotype and A allele are significantly associated with an increased susceptibility to coronary artery disease in Indian population. A larger sample size can be the key to progress in establishing the genetic co-relationship of COMT polymorphism and cardiovascular disease. Full article

The imprinted Dlk1-Dio3 genomic region harbors a noncoding RNA cluster encoding over fifty microRNAs (miRNAs), three long noncoding RNAs (lncRNAs), and a small nucleolar RNA (snoRNA) gene array. These distinct noncoding RNAs (ncRNAs) are thought to arise from a single polycistronic transcript that is subsequently processed into individual ncRNAs, each with important roles in diverse cellular contexts. Considering these ncRNAs are derived from a polycistron, it is possible that some coordinately regulate discrete biological processes in the heart. Here, we provide a comprehensive summary of Dlk1-Dio3 miRNAs and lncRNAs, as they are currently understood in the cellular and organ-level context of the cardiovascular system. Highlighted are expression profiles, mechanistic contributions, and functional roles of these ncRNAs in heart development and disease. Notably, a number of these ncRNAs are implicated in processes often perturbed in heart disease, including proliferation, differentiation, cell death, and fibrosis. However, most literature falls short of characterizing precise mechanisms for many of these ncRNAs, warranting further investigation. Taken together, the Dlk1-Dio3 locus represents a largely unexplored noncoding regulator of cardiac homeostasis, harboring numerous ncRNAs that may serve as therapeutic targets for cardiovascular disease. Full article

Experimental and clinical data indicate that the initiation and progress of atherosclerosis and its clinical manifestations are first caused by circulating apoB-100 lipoproteins that enter and are retained in the arterial intima. Extracellular sulfated proteoglycans (PGs) of the intima are the retention agents. The PGs also initiate physical and biochemical lipoprotein degradation with the production of bioactive, lipid products that trigger an inflammatory response that leads to atherosclerosis. There are many simple methods for measuring abnormalities of circulating lipoproteins and their relation to atherosclerotic cardiovascular disease (ACVD). However, limited research aims to evaluate procedures that could report quantitatively about the contribution of the interaction of apoB-100 lipoprotein-arterial intima PGs to clinical manifestation of ACVD. In the present review we discuss observations indicating that simple ex vivo evaluation of the affinity of apoB-100 lipoproteins for arterial PGs and glycosaminoglycans (GAGs) can give an indication of its association with clinical manifestations of atherosclerosis. In addition, we discuss molecular and cellular aspects of the apoB-100 lipoproteins association with arterial PGs that are related to atherogenesis and that support the experimental framework behind the current “Response-to-Retention” hypothesis of atherosclerosis. Full article

Introduction: Oxidized low-density lipoprotein (ox-LDL) is considered a main biomarker of oxidative stress, a common characteristic in end stage renal disease. We examined the relationship between ox-LDL serum concentrations and cardiovascular disease in permanent hemodiafiltration therapy patients. Methods: Ox-LDL values were measured by ELISA and were corrected for LDL-cholesterol (LDL-C) in 96 participants and in 45 healthy control subjects. We performed chi-square tests and adjusted models for the role of ox-LDL on cardiovascular morbidity including coronary artery disease, left ventricular hypertrophy, systolic, diastolic dysfunction and peripheral arterial disease. Results: ox-LDL/LDL-C values were significantly higher in patients than in control group (p = 0.02), due to increased ox-LDL serum levels rather than to low LDL-C. The unadjusted relationship between high ox-LDL/LDL-C and low ejection fraction was found significant (x² = 9.04, p = 0.003), although the association with the other cardiovascular manifestations was found non-significant. In the adjusted model for the prediction of systolic cardiac dysfunction, high ox-LDL/LDL-C, old age and non-administration of vitamin D supplementation during dialysis session were found to be significant predictors after adjustment to the confounder. Moreover, the association between systolic cardiac dysfunction and non-administration of vitamin D derivatives during dialysis sessions was found significant (x² = 6.9, p = 0.008). Conclusions: This study showed a significant association between high ox-LDL and systolic cardiac dysfunction in permanent hemodiafiltration therapy patients. This relationship seems to be influenced by aging and pharmaceutical therapy during dialysis sessions, including vitamin D derivatives. Full article