ResearchPad - pathophysiology-of-cardiometabolic-disease Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SUN-574 A1AT: Novel Inhibitor of Active PCSK9]]> Heart disease is the principal cause of death and disability for both men and women in the US, accounting for 40% of all annual deaths. African American populations are disproportionately burdened with metabolic diseases, due in part to cholesterol metabolism deficiencies. Elevated low density lipoprotein (LDL) cholesterol levels and inflammation promote atherogenic conditions which lead to heart disease. Proprotein convertase subtilisin/kexin-9 (PCSK9) is a biomarker which enhances athrogenic progression by controlling the number of LDL receptor molecules expressed at the plasma membrane. PCSK9 indirectly regulates LDL-cholesterol levels. Previous reports show some patients do not respond well to general anti-cholesterolemic treatments. We believe this is due to altered PCSK9 activity, which is currently not being evaluated. We have developed a novel assay to detect active PCSK9. A1AT is a SERPIN family member whose primary objective is inhibition of proteases. Specific levels of A1AT are required to maintain metabolic homeostasis. Based on this, we hypothesized that a specific ratio between A1AT serum levels and PCSK9 activity levels would eliminate statin intolerance/resistance, regulating LDL-cholesterol metabolism congruently. Using this novel active PCSK9 detection assay, we provide evidence that A1AT interacts with PCSK9 in the medium of C3A hepatic-like cells, preventing the formation of PCSK9/LDL receptor complexes in vitro. There was an approximate 20% inhibition in PCSK9-LDL receptor complex formation when liver cells were treated with recombinant A1AT (rA1AT). A dose dependent response analysis proved 200ng/ml of rA1AT had an 46% reduction in PCSK9 activity. We determined PCSK9 activty and A1AT levels correlate with key diabetic factors in humans, suggesting that A1AT could effect diabetes progression.

<![CDATA[SUN-565 The Effect of Leptin Treatment on Blood Pressure and Autonomic Nervous System Function in Patients with Lipodystrophy]]> Leptin is an adipokine that reflects energy storage levels. Patients with obesity have high leptin, hypertension, and increased cardiovascular disease (CVD) risk. In rodents, leptin increases blood pressure (BP), by increasing sympathetic nervous system (SNS) activity, suggesting high leptin may cause hypertension and CVD. Studies of leptin administration in 2 human models of leptin deficiency (weight reduced and congenital leptin deficiency) showed decreased SNS activity in the leptin-deficient state, which increased after leptin replacement. This has clinical relevance as high SNS and low parasympathetic nervous system (PNS) activity correlate with increased risk of hypertension and CVD. In lipodystrophy syndromes adipose tissue is deficient thus leptin is low. We hypothesized that leptin treatment in patients with lipodystrophy would increase SNS activity and BP. SNS and PNS activity in the heart can be assessed using heart rate variability (HRV). The high frequency (HF) component of HRV is directly related to PNS activity whereas the low frequency (LF) component reflects both SNS and PNS. The LF/HF ratio reflects sympathetic-vagal balance. Lower standard deviation of the beat to beat interval (SDNN) inversely correlates with CVD risk. Leptin-naïve patients with lipodystrophy (N=17, 5 generalized, 12 partial) were housed on an inpatient unit for 19 days. Patients were studied without leptin for the first five days. Leptin was administered for the next 14 days. At the end of the OFF-leptin and ON-leptin periods, 24-hr EKG recordings were used to derive HRV parameters and an automated BP monitor measured BP every 30 minutes during the day and every 60 minutes at night. 5 patients had generalized lipodystrophy (median 25th,75th percentile] endogenous leptin [0.5 [0.4, 0.6] ng/mL); 12 had partial lipodystrophy (leptin 7.5 [3.9, 20.3]). In the combined cohort with generalized and partial lipodystrophy, leptin treatment did not alter BP or any measure of autonomic nervous system function after 24 hours, 2 weeks, or 6 months. In exploratory subgroup analyses of generalized vs partial lipodystrophy, those with generalized lipodystrophy had an increase in LF after 2 weeks of leptin and a 4.5 mm Hg increase in systolic BP after 6 months; no changes were observed in those with partial lipodystrophy. Unlike previous human and rodent studies, we did not see increased SNS tone or BP after leptin treatment in patients with lipodystrophy. However, exploratory analyses in patients with generalized lipodystrophy and very low endogenous leptin levels showed small increases in systolic BP and increased LF component of HRV after 2 weeks, which is regulated by both SNS and PNS. This suggests that leptin may alter autonomic function in the transition from very low to normal plasma leptin levels.

<![CDATA[SUN-573 Use of PCSK9 Inhibitors Post-Transplant]]> Background:

Dyslipidemia is common in patients after transplant. While statins are the mainstay of therapy, interactions with immunosuppressants such as calcineurin inhibitors (CNIs) can limit dose titration or lead to intolerance of this important drug class. Withdrawal of statin therapy can precipitate hyperlipidemia and potentially accelerate cardiovascular disease in transplant recipients, including coronary allograft vasculopathy (CAV) in heart transplant (HT) patients. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) may provide a safe, effective option for such patients. PCSK9i profoundly reduce low-density lipoprotein (LDL) and subsequently the risk of cardiovascular events in nontransplant patients. Further, these novel agents have no known interactions with CNIs. There is a paucity of data describing PSCK9i use post-transplant, with only a few small case series reported in HT recipients. Here, we summarize our experience along with available literature on this topic.


In this retrospective case series we investigated adult recipients of heart transplant who were treated with PCSK9 inhibitors from July 2015 to 2019 because of statin intolerance or refractory hyperlipidemia. We compared the data of patients at baseline and after various durations of therapy with the PSCK9i evolocumab and alirocumab using the median and interquartile range (IQR). Specifically, we evaluated PCSK9i efficacy, effect on immunosuppressant levels, cardiac function and adverse events.


Five patients (4 men; median age 54, IQR 52-60) underwent heart transplant an average of 7.4 years ago. Median treatment duration of evolocumab or alirocumab was 12 months (IQR 7-17). This led to a reduction of total cholesterol by 94 mg/dl (p=0.04) (47% decrease) and LDL cholesterol by 83 mg/dl (p=0.04) (69% decrease). No statistically significant difference in HDL cholesterol, triglycerides or liver function tests (LFTs) were observed. There were no episodes of rejection. Immunosuppressant levels remained at goal. One patient noted a few days of fatigue after alirocumab injections but otherwise no side effects were reported.


The PCSK9 inhibitors evolocumab and alirocumab are promising alternatives to statin therapy in transplant recipients with statin intolerance or refractory hyperlipidemia. Our study showed their potential to significantly reduce LDL cholesterol in heart transplant patients without altering IST levels. No episodes of transplant rejection were noted. Further long-term studies to establish the safety and efficacy of PSCK9 inhibitors post-transplant are needed.

<![CDATA[SUN-550 CARF Through Its Lipid Lowering Effect May Play a Pivotal Role in the Development of Non-Alcoholic Fatty Liver Diseases]]> CARF (Collaborator of ARF), a member of ARF-MDM2-p53 pathway and an emerging multifunctional protein, regulates cellular fate in response to various stresses including oxidative DNA damage and replicative stresses. However, its role in metabolic syndrome (MS) and associated diseases has not been studied. This study, using our well established in vivo and in vitro model systems, examines the role of CARF in the development of non-alcoholic fatty liver disease (NAFLD). Indeed, we have found that, compared to control, CARF expression along with Sirt1, pAMPK and pACC (common biological markers of NAFLD) was significantly decreased in the nicotine and high-fat-diet (HFD) in combination or HFD alone induced fatty livers. Additionally, CARF expression was down regulated in palmitate (PA)-treated HepG2 cells, an in vitro model of steatosis, suggesting that CARF expression is negatively regulated in MS, such as NAFLD. Our study further revealed that shRNA mediated knockdown or lentiviral mediated over expression of CARF induced or reduced endogenous fat accumulation, respectively, in HepG2 cells. We also found that overexpression of CARF lowered the exogenous fat accumulation in PA treated HepG2 cells. RNA seq analysis after CARF knockdown in HEK-293T cells further revealed that genes associated with lipid metabolism and triglyceride (TG) synthesis such as diacylglycerol O-acyltransferase2 (DGAT2), acyl-CoA synthetase long-chain family member 4 and 6 (ACSL4, ACSL6) were upregulated in CARF-depleted cells. Likewise, we also found increased expression of DGAT2 in CARF-depleted HepG2 cells, which enhanced TG synthesis. Intriguingly, consistent with the lipid lowering effects of metformin, an antidiabetic drug, we further found that CARF expression along with pAMPK and Sirt1 were significantly increased in metformin-treated HepG2 cells. However, we also found increased pACC levels in CARF over-expressing cells which was further enhanced in metformin-treated cells, suggesting, for the first time, that CARF may contribute to lipid lowering effect of metformin by inhibiting lipogenesis. We conclude that CARF has a lipid lowering effect in hepatocytes and its down regulation in response to MS perturbs lipid metabolism that may lead to the development of NAFLD.

<![CDATA[SUN-551 Impaired Vascular Relaxation and Altered eNOS Regulation in Boys with Hypospadias]]> Background: Sex hormones influence vascular function. Whether boys with hypospadias who have insufficient androgen exposure during the masculinisation programming window have altered vascular function is unknown. Objective: To investigate whether vascular function is impaired in boys with hypospadias and to explore the putative role of eNOS. Methods: Peripheral arteries from excess foreskin tissue obtained from boys undergoing hypospadias repair (cases) or circumcision (controls) were used. Vascular function was assessed by myography. mRNA expression was measured by qPCR in vascular smooth muscle cells (VSMCs). Nitric oxide (NO) was measured by DAF fluorescence assay and peroxynitrite levels measured via ELISA. Results: 23 boys with hypospadias and 34 age-matched controls were studied. There were 18 (52%) cases of distal, 7 (22%) of midshaft and 9 (26%) of proximal hypospadias and none of them had biochemical evidence of hypogonadism or a variant in AR. Clinical cardiometabolic parameters were similar between groups. Endothelium-dependent relaxation to acetylcholine (ACh) and endothelium-independent relaxation to sodium nitroprusside (SNP) were reduced in arteries from cases vs controls (Emax %U46619: 72.4 vs 1.2, p<0.0001 and Emax %U46619: (42.7 vs 11.8, p<0.01 respectively). Incubation with the NO synthase inhibitor, L-NAME (1x10-5 M) worsened endothelial-dependent relaxation in controls (Emax % U46619: 76.8 vs 1.2, p<0.0001) but had no effect in cases (Emax % U46619:60.6 vs 72.4, p=0.3). Testosterone (1x10-7 M) ameliorated vascular relaxation (p<0.05), whereas17[[Unsupported Character - Symbol Font 𝝱]];-estradiol stimulation (1x10-9 M) did not. In cultured VSMCs, mRNA expression of eNOS and iNOS was reduced whereas that of nNOS was increased in cases versus controls. Nitric oxide production was reduced in cases (5 fold, p<0.01), as was peroxynitrite production (0.5 fold, p<0.05). Testosterone increased expression of eNOS in VSMCs. There was no difference in mRNA expression of the AR and GPRC6A but cases had increased expression of ESR1 (2.71 fold), ESR2 (2.63 fold) and GPR30 (2.86 fold) (p<0.05). Conclusion: Arteries in eugonadal boys with hypospadias show vascular dysfunction which involves impaired NOS/NO regulation effects that are ameliorated with testosterone but not oestrogen. These processes may predispose to long-term cardiovascular disease.

<![CDATA[SUN-562 Long-Term Mental Stress Implications to Cardiovascular Disease in an Aged Mouse Model]]> While clinical evidence indicates that exposure to mental stress is a linked to a two-fold increased risk for coronary heart disease, even independently from traditional risk factors, the underlying direct mechanisms between psychological stress and cardiovascular health status has not been determined. A growing aging population of adults 65 and older represents a particular patient population vulnerable to chronic mental stressors due to a decline in normal physiologic functions. The decrease in function of the cardiovascular system that occurs during aging leads to the activation of pathological processes associated with an increased risk for heart disease. Using a mouse model of mental stress induced by restraint, we mimic the biochemical and physiologic changes observed in chronically stressed humans, which is characterized by an increase in circulating glucocorticoids, such as cortisol. Middle-aged mice (6 months old) as well as old-aged mice (18 months old) were used to differentiate the effects of aging on the burden of mental stress associated cardiovascular disease. Genes implicated in cardiomyopathy and CVD were found to be significantly up-regulated, not only immediately after a two-week stress period, but remained significantly up-regulated after the mice were allowed to recover stress-free for 5 weeks. Gene expression of the glucocorticoid receptor was down-regulated following exposure to chronic stress, suggesting an involvement of the hypothalamic-pituitary axis negative feedback loop. Gene expression of markers for hypertrophy (MHY7, ACTA1, NPPB) were upregulated and persisted in upregulation after mice were allowed to recover. Hypertrophy was further indicated by heart weight to tibia length ratios. Significant changes in aortic samples also implicate an involvement of the vasculature. Chronic stress in humans and mice leads to an increase in inflammatory and pro-coagulant markers. In our study, inflammatory markers (LCN, IL-6, IL-17c, PTGS2) were shown to be significantly increased immediately after the period of chronic stress, however the markers return to non-significant levels when mice were allowed a recovery period. Chronic mental stress has a lasting and direct deleterious effect on the cardiovascular system and it is essential to understand these implications in an aging population.

<![CDATA[SUN-580 PCSK9 and Lp(a): Association Between PCSK9 Level and Larger Apo(a) Isoform Size in African-Americans and Caucasians]]> Introduction: An elevated level of lipoprotein(a) [Lp(a)] is an independent causal risk factor for cardiovascular disease. Non-genetic factors do not appreciably influence Lp(a) levels due to a strong genetic control. However, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to reduce Lp(a) levels. The association of PCSK9 with Lp(a) level and its major genetic determinant—apolipoprotein(a) [apo(a)] size—is not fully understood. In this study, we assessed the relationship between PCSK9, Lp(a) level, apo(a) size, age, and race/ethnicity.

Methods: Healthy Caucasian and African-American families were recruited from the general population (age range: 6–74 years, N=267). PCSK9 and Lp(a) levels were assayed enzymatically; apo(a) isoform and LPA allele sizes and isoform-specific Lp(a) levels were determined.

Results: In all participants, PCSK9 levels differed significantly by race/ethnicity, age, and sex. Thus, the mean PCSK9 levels were significantly higher in African-Americans vs. Caucasians (104 ± 29 vs. 95 ± 30 ng/mL, respectively, p=0.020), in adults vs. children (102 ± 29 vs. 92 ± 31 ng/mL, respectively, p=0.001) and in females vs. males (103 ± 30 vs. 94 ± 29 ng/mL, respectively, p=0.007). PCSK9 levels were not associated with total plasma Lp(a) levels neither in all participants nor in ethnicity-specific analyses. However, PCSK9 levels were significantly and positively associated with isoform-specific Lp(a) levels carried by the larger apo(a) size in all subjects (r=0.139, p=0.0361). In race/ethnicity analyses, a significant association was seen for African-Americans (r=0.268, p=0.0199), but not for Caucasians. In contrast, there were no significant associations of PCSK9 with isoform-specific Lp(a) levels for the smaller apo(a) sizes in all participants nor in ethnic-specific analyses. Of note, PCSK9 levels were significantly negatively associated with the larger apo(a) isoform sizes in all participants (r=-0.139, p=0.0366). Although significant in both groups, heritability of PCSK9 level was higher in Caucasians than in African-Americans (47% vs. 22%, respectively).

Conclusions: Among African-Americans, but not Caucasians, PCSK9 levels were associated with isoform-specific Lp(a) levels carried on larger, but not smaller, apo(a) sizes. The findings illustrate a diverging relationship of PCSK9 with isoform-specific Lp(a) levels.

<![CDATA[SUN-569 The Normalization of Sleep Duratioin as a Factor of Glyhemoglobin Reducing]]> Sleep deprivation is an important risk factor of the metabolic disorder. According to the systematic review published in the Circulation there are a lot of data from epidemiological, clinical and experimental researches which confirm this fact. The goal of our research was to assess the level of glycohemoglibin after the normalization of sleep duration. 24 patients with diabetes mellitus type2 (19 females and 7 males, average age 58.7 ±1.3 yer) were included in the research. Diabetes mellitus type 2 duration was 9.5 years. Criteria excluded were myocardial infarction, stroke, sleep apnea, oncological diseases and depression. To exclude depression we used the questionnaires: Center for Epidemiological Studies Depression Scale and The Hospital Anxiety And Depression Scale. To exclude sleep apnea we used questionnaire STOP-Bang score. The sleep duration was assessed by the patients self-reports. Glycohemoglibin was determined by Immunoinhibition Method Cobas 6000, Roche Diagnostics. The sleep duration was corrected by cognitive behavioral therapy. For statistic assess of the results we used the method Wilcoxon F. Results: At the beginning of the treatment the level of glyhemoglobin was 7.8% and the sleep duration was 6.4 hours.The included patients were treated by cognitive behavioral therapy for 6 months without changing other kinds of therapy. The sleep duration significantly(P=-0.35) enlarged until 7.5±0.2 hours and the level of glyhemoglobin was lowered by 0.4% significantly (P=0.47). The improving of sleep duration can successfully reduce the level of glyhemoglobin in diabetes mellitus type 2 without any intervention at glycemia and could contribute to the prevention of diabetes complications.

<![CDATA[SUN-575 Levels of Nesfatin-1 in Adolescents, and Its Association with Body Mass Index and Risk of Cardiovascular Disease]]> <![CDATA[SUN-571 The Associations Between p,p’-DDE Levels and Serum Levels of Lipoproteins and Their Subclasses in an Elderly Population Determined by Lipidomics Analysis]]> VLDL > LDL > HDL) and within total serum (p<0.005). DDE levels were positively associated with cholesterol and cholesterol ester levels only in VLDL and LDL (p<0.05) and with apolipoprotein B (p<0.0009). The positive associations observed between each lipoprotein class and elevated DDE support previous data suggesting that DDE interacts with lipoproteins within plasma. We speculate that both physio-chemical and biological mechanisms may explain why DDE does not uniformly associate with lipids across lipoproteins. ]]> <![CDATA[SUN-556 Cardiac Phenotype in Familial Partial Lipodystrophy]]>


Pathogenic variants in Lamin A/C (

) gene are the most common monogenic etiology in Familial Partial Lipodystrophy (FPLD) causing FPLD2.

pathogenic variants have been previously associated with cardiomyopathy, familial arrhythmias or conduction system abnormalities independent of lipodystrophy. We aimed to assess cardiac impacts of FPLD, and to explore the extent of overlap between cardiolaminopathies and FPLD.

We conducted a retrospective review of an established cohort of 122 patients (age range: 13-77, M/F 21/101) with FPLD from Michigan (n = 83) and Turkey (n = 39) with an accessible cardiac evaluation. Also, functional syncytia of mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a FLPD2 patient was studied for assessment of autonomous rhythm and action potential duration with optical mapping using a voltage sensitive dye.

In the whole study cohort, 95 (78%) patients had cardiac alterations (25% ischemic heart disease, 36% arrhythmia, 16% conduction abnormality, 20% prolonged QT interval, 11% cardiomyopathy, and 15% congestive heart failure). The likelihood of having an arrhythmia (OR; 3.95, 95% CI: 1.49-10.49) and conduction disease (OR: 3.324, 95% CI: 1.33-8.31) was significantly higher in patients with

pathogenic variants. Patients with

pathogenic variants were at high risk for atrial fibrillation/flutter (OR: 6.77, 95% CI: 1.27- 39.18). The time to first arrhythmia was significantly shorter in the

group with a higher hazard rate of 3.04 (95% CI: 1.29-7.17, p = 0.032). Non-482

pathogenic variants were more likely to be associated with cardiac events (vs. 482

: OR: 4.74, 95% CI: 1.41- 15.98 for arrhythmia; OR: 17.67, 95% CI: 2.44- 127.68 for atrial fibrillation/flutter; OR: 5.71, 95% CI: 1.37- 23.76 for conduction disease. hiPSC-CMs from a FPLD2 patient had higher frequency of autonomous activity, and shorter Fridericia corrected action potential duration at 80% repolarization compared to control cardiomyocytes. Furthermore, FPLD2 functional syncytia of mature hiPSC-CMs presented several rhythm alterations such as early after-depolarizations, spontaneous quiescence and spontaneous tachyarrhythmia; none of those were observed in the control cell lines. Finally, FPLD2 hiPSC-CMs presented significantly slower recovery in chronotropic changes induced by isoproterenol exposure; which indicates disrupted beta-adrenergic response.

Our results suggest the need for vigilant cardiac monitoring in FPLD, especially in patients with FPLD2 who have an increased risk to develop cardiac arrhythmias and conduction system diseases. In addition, study of human induced pluripotent stem cell-derived cardiomyocytes may prove useful to understand the mechanism of cardiac disease and arrhythmias and to create precision therapy opportunities in the future.

<![CDATA[SUN-555 Vitamin E Sequestration by Liver Fat in Vitro and in Women with Hepato-Steatosis]]> <![CDATA[SUN-582 Effect of the Combination of Conjugated Estrogens and Bazedoxifene on Muscle and Serum Lipidome in Obese Postmenopausal Women: A Placebo-Controlled Randomized Pilot Trial]]> <![CDATA[SUN-559 Involvement of Sarco/Endoplasmic Reticulum Ca- ATPase (SERCA) in Membrane Progesterone Receptor Alpha (PAQR7)-Mediated Progesterone Induction of Vascular Smooth Muscle Relaxation]]> <![CDATA[SUN-570 The Crosstalk Between Central Leptin and PPARbeta/delta Protects the Heart Against Oxidative Stress Damage and the Development of Hypertrophy]]> <![CDATA[SUN-557 Hypertriglyceridemia-Induced Pancreatitis: Experience from a Quaternary Care Center]]> <![CDATA[SUN-566 Metabolic Effects of Cross-Hormone Treatments in Transgender Individuals in Taiwan]]> <![CDATA[SUN-LB90 Taurine Reverses Protein Malnutrition-Induced Endothelial Dysfunction of Pancreatic Vasculature]]> <![CDATA[SUN-552 Follistatin-Like 3 (FSTL3), a Transforming Growth Factor β (TGFβ) Ligand Inhibitor, Regulates Placental Development in Mice]]> <![CDATA[SUN-577 Effect of Growth Hormone Replacement on Metabolic Profile and Vascular System in Adult Patients with Congenital Hypopituitarism]]>