Update in genetic and epigenetic causes of hypertension.

Hypertension is a heritable disease that affects one-fourth of the population and accounts for about 50% of cardiovascular deaths. The genetic basis of hypertension is multifaceted, involving both monogenic and most commonly complex polygenic forms. With the advent of the human genome project, genome-wide association studies (GWAS) have identified a plethora of loci linked to hypertension by examining common genetic variations. It's notable, however, that the majority of these genetic variants do not affect the protein-coding sequences, posing a considerable obstacle in pinpointing the actual genes responsible for hypertension. Despite these challenges, precise mapping of GWAS-identified loci is emerging as a promising strategy to reveal novel genes and potential targets for the pharmacological management of blood pressure. This review provides insight into the monogenic and polygenic causes of hypertension. Special attention is given to PRDM6, among the earliest functionally characterized GWAS-identified genes. Moreover, this review delves into the roles of genes contributing to renal and vascular forms of hypertension, offering insights into their genetic and epigenetic mechanisms of action.

ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging.

ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) in vivo are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific ZFVYE21-/- reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from ZFYVE21 EC-/- mice showed interstitial edema and glomerular EC injury. ZFYVE21-mediated phenotypes were not programmed developmentally as loss of ZFYVE21 in ECs during adulthood phenocopied its loss prenatally, and a nitric oxide donor normalized kidney function in adult hosts. Using live cell imaging and human kidney organ cultures, we found that in a GTPase Rab5- and protein kinase Akt-dependent manner, ZFYVE21 reduced vesicular levels of inhibitory caveolin-1 and promoted transfer of Golgi-derived ENOS to a perinuclear Rab5+ vesicular population to functionally sustain ENOS activity. Thus, our work defines a ZFYVE21- mediated trafficking mechanism sustaining ENOS activity and demonstrates the relevance of this pathway for maintaining kidney function with aging.

Anticoagulation in Patients with Premature Peripheral Artery Disease Undergoing Lower Extremity Revascularization.

BACKGROUND: Premature peripheral artery disease (PAD), defined by lower extremity revascularization (LER) at age ≤ 50 years, is associated with poor major adverse limb events. The early onset of disease is thought to be influenced by genetic factors that regulate homeostasis of the vascular wall and coagulation. The aim of this study is to investigate the effect of anticoagulation as an adjunct to antiplatelet therapy on the outcomes of LER in patients with premature PAD. METHODS: There were 8,804 patients with premature PAD on preoperative and postoperative antiplatelet therapy only and 1,236 patients on preoperative and postoperative anticoagulation plus antiplatelet therapy in the Vascular Quality Initiative peripheral vascular intervention, infrainguinal, and suprainguinal files. Propensity score matching (2:1) was performed between patients with premature PAD who were on antiplatelet therapy and those on anticoagulation plus antiplatelet therapy. Perioperative and 1-year outcomes were analyzed including reintervention, major amputation, and mortality. RESULTS: Patients on anticoagulation were more likely to have coronary artery disease (48.7% vs. 41.2%, P < 0.001), congestive heart failure (20.2% vs. 13.1%, P < 0.001), and have undergone prior LER (73.9% vs. 49.2%, P < 0.001) compared to patients on antiplatelet therapy only. They were also less likely to be independently ambulatory (74.2% vs. 81.8%, P < 0.001) and be on a statin medication (66.8% vs. 74.3%, P < 0.001) compared to patients on antiplatelet therapy only. Patients on anticoagulation were also less likely to be treated for claudication (38.1% vs. 48.6%, P < 0.001), and less likely to be treated with an endovascular procedure (64.8% vs. 73.8%, P < 0.001). After matching for baseline characteristics, there were 1,256 patients on antiplatelet therapy only and 628 patients on anticoagulation. Patients on anticoagulation were more likely to require a return to the operating room (3.7% vs. 1.6%, P < 0.001) and had higher perioperative mortality (1.1% vs. 0.3%, P = 0.032), but major amputation was not significantly different (1.8% vs. 1.6%, P = 0.798) compared to patients on antiplatelet therapy alone. At 1 year, amputation-free survival was higher in patients on antiplatelets only compared to patients on anticoagulation and antiplatelet medications (87.5% vs. 80.9%, log-rank P = 0.001). CONCLUSIONS: Anticoagulation in addition to antiplatelet therapy in patients with premature PAD undergoing LER is associated with increased reintervention and mortality at 1 year.

From mouse to human.

A deep analysis of multiple genomic datasets reveals which genetic pathways associated with atherosclerosis and coronary artery disease are shared between mice and humans.

A Form of Metabolic-Associated Fatty Liver Disease Associated with a Novel LIPA Variant.

BACKGROUND: The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. METHODS: A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels. Fatty liver disease was found in six of her family members using vibration-controlled transient elastography (VCTE). Baseline routine laboratory tests were performed and whole-exome sequencing and confirmation by Sanger sequencing were done. RESULTS: The index case had severe dyslipidemia and cirrhosis despite a body mass index of 21.09 kg/m2 . Six other family members had dyslipidemia and fatty liver or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA which caused LAL-D was found to be associated with fatty liver disease and/or cirrhosis. CONCLUSION: A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of the LIPA gene which caused LAL-D was found to be associated with dyslipidemia, fatty liver disease and/or cirrhosis in six members of an Iranian family. These results should be confirmed by functional studies and extending the study to at least three families.

FKBP14 kyphoscoliotic Ehlers-Danlos syndrome misdiagnosed as Larsen syndrome: a case report.

Hereditary connective tissue disorders have overlapping phenotypes, particularly in regard to musculoskeletal features. This contributes to the challenge of phenotype-based clinical diagnoses. However, some hereditary connective tissue disorders have distinct cardiovascular manifestations that require early intervention and specific management. Molecular testing has increased the ability to categorize and diagnose distinct hereditary connective tissue disorders. A 42-yr-old female with a clinical diagnosis of Larsen syndrome from birth presented for genetic testing based on her recent diagnosis of premenopausal breast cancer. She had a past medical history of multiple carotid dissections. As she never had confirmatory molecular genetic testing for Larsen syndrome, whole-exome sequencing was utilized to assess both hereditary cancer predisposition syndromes and connective tissue disorders. A homozygous pathogenic variant in the FKBP14 gene was identified associated with FKBP14 kyphoscoliotic Ehlers-Danlos syndrome. We recommend that patients with a clinical diagnosis of Larsen syndrome undergo broad-based molecular sequencing for multiple hereditary connective tissue disorders. Molecular diagnosis is particularly crucial for all individuals who have a history of significant vascular events in the setting of a clinical diagnosis only. Early diagnosis of a hereditary connective tissue disorder with vascular features allows for screening and subsequent prevention of cardiovascular events.

Shared Lifestyle-Related Risk Factors of Cardiovascular Disease and Cancer: Evidence for Joint Prevention.

Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide and are the major focus of the World Health Organization's joint prevention programs. While, diverse diseases, CVD and cancer, have many similarities. These include common lifestyle-related risk factors and shared environmental, metabolic, cellular, inflammatory, and genetic pathways. In this review, we will discuss the shared lifestyle-related and environmental risk factors central to both diseases and how the strategies commonly used to prevent atherosclerotic vascular disease can be applied to cancer prevention.

Dysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent condition affecting approximately a quarter of the global population. It is associated with increased morbidity, mortality, economic burden, and healthcare costs. The disease is characterized by the accumulation of lipids in the liver, known as steatosis, which can progress to more severe stages such as steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). This review focuses on the mechanisms that contribute to the development of diet-induced steatosis in an insulin-resistant liver. Specifically, it discusses the existing literature on carbon flux through glycolysis, ketogenesis, TCA (Tricarboxylic Acid Cycle), and fatty acid synthesis pathways in NAFLD, as well as the altered canonical insulin signaling and genetic predispositions that lead to the accumulation of diet-induced hepatic fat. Finally, the review discusses the current therapeutic efforts that aim to ameliorate various pathologies associated with NAFLD.

A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension.

Genetic variants in the third intron of the PRDM6 gene have been associated with BP traits in multiple GWAS. By combining fine mapping, massively parallel reporter assays, and gene editing, we identified super enhancers that drive the expression of PRDM6 and are partly regulated by STAT1 as the causal variants for hypertension. The heterozygous disruption of Prdm6 in mice expressing Cre recombinase under the control of mouse smooth muscle cell protein 22-α promoter (Prdm6fl/+ SM22-Cre) exhibited a markedly higher number of renin-producing cells in the kidneys at E18.5 compared with WT littermates and developed salt-induced systemic hypertension that was completely responsive to the renin inhibitor aliskiren. Strikingly, RNA-Seq analysis of the mouse aortas identified a network of PRDM6-regulated genes that are located in GWAS-associated loci for blood pressure, most notably Sox6, which modulates renin expression in the kidney. Accordingly, the smooth muscle cell-specific disruption of Sox6 in Prdm6fl/+ SM22-Cre mice resulted in a dramatic reduction of renin. Fate mapping and histological studies also showed increased numbers of neural crest-derived cells accompanied by increased collagen deposition in the kidneys of Prdm6fl/+ Wnt1Cre-ZsGreen1Cre mice compared with WT mice. These findings establish the role of PRDM6 as a regulator of renin-producing cell differentiation into smooth muscle cells and as an attractive target for the development of antihypertensive drugs.

Association of vitamins, minerals, and lead with lipoprotein(a) in a cross-sectional cohort of US adults.

Lipoprotein(a)(Lp[a]) is a low-density lipoprotein-cholesterol (LDL-C)-like particle with potent pro-atherothrombotic properties. The association of Lp(a) with several circulating factors, including vitamins, remains unresolved. We performed an observational analysis using the National Health and Nutrition Examination Survey III cohort, a cohort used to monitor the nutrition status of US-citizens. We used multivariable linear regression to test associations of Lp(a) and LDL-C with levels of serum vitamins and minerals and whole-blood lead. Analyses controlled for factors known to associate with Lp(a) (age, sex, race/ethnicity, statin use, hemoglobin A1c, body mass index, hypertension, diabetes, glomerular filtration rate, alcohol intake, and saturated fat intake). LDL-C was corrected for Lp(a) mass. Multiple sensitivity tests were performed, including considering factors as categorical variables (deficient, normal, elevated). Among 7,662 subjects, Lp(a) correlated (ß-coefficient) positively (change per 1 conventional unit increase) with carotenoids (lycopene (0.17(0.06,0.28), p=0.005), lutein (0.19(0.07,0.30), p=0.002), ß-cryptoxanthin (0.21(0.05,0.37), p=0.01), ß-carotene (0.05(0.02,0.09), p=0.003), and α-carotene (0.15(0.01,0.30), p=0.04)) and lead (0.54(0.03,1.05), p=0.04) levels when tested as continuous variables. LDL-C had similar associations. Lp(a) did not associate with vitamins A, B12, C, or E retinyl esters, folate, RBC-folate, selenium, ferritin, transferrin saturation, or calcium. With factors as categorical variables, Lp(a) but not LDL-C negatively associated with elevated vitamin B12 (-5.41(-9.50, -1.53), p=0.01) and folate (-2.86(-5.09, -0.63), p=0.01). In conclusion, Lp(a) associated similarly to LDL-C when vitamins, minerals, and lead were tested as continuous variables, while only Lp(a) correlated with vitamin B12 and folate when tested as categorical variables. These observations are hypotheses generating and require further studies to determine causality.

Major Adverse Limb Events Among Patients with Premature Peripheral Artery Disease Compared with Those at the Common Age Undergoing Revascularization in the Vascular Quality Initiative.

BACKGROUND: Premature peripheral artery disease (PAD), defined as ≤ 50 years of age, is associated with poor outcomes following lower extremity revascularization (LER). However, the specific characteristics and outcomes of this group of patients compared to those at the common age undergoing revascularization have not been examined. The aim of this study is to compare patients with early versus late onset premature PAD undergoing LER focusing on major adverse limb events (MALEs). METHODS: All LER procedures (open and endovascular) in the Vascular Quality Initiative (VQI) were reviewed. A histogram of patient age at the time of initial LER (no prior LER) was used to define the common age, which included all patients within one standard deviation of the mean. Characteristics and outcomes of patients with premature PAD were compared to patients treated at the common age of presentation undergoing LER. RESULTS: A histogram of all patients undergoing LER was used to define 60 to 80 years as the common age. Patients with premature PAD were more likely to be female, African American, and Hispanic compared to patients at the common age. Patients with premature PAD were also more likely to have insulin-dependent diabetes, be current smokers, on dialysis, and be treated for claudication. Patients with premature PAD were less likely to have Transatlantic Intersociety Consensus (TASC II) C or D disease and were less likely to be on antiplatelets and statins. These differences were more pronounced in patients with chronic limb-threatening ischemia (CLTI). Cox proportional hazards regression demonstrated that premature PAD was independently associated with major adverse limb events (MALEs) at 1-year for patients with claudication (HR:1.7, 95% CI:1.4-2.0) and CLTI (HR:1.3, 95% CI:1.2-1.5) compared to patients 60 to 80 years of age. CONCLUSIONS: Patients with premature PAD have significant differences in characteristics compared to patients treated at the common age. Vascular providers should emphasize medical therapy prior to LER given the lower rates of medical optimization and worse 1-year MALEs in patients with premature PAD.

Complex regulation of fatty liver disease.

Hepatic lipogenesis is fine-tuned by mechanistic target of rapamycin (mTOR) signaling.

PDE4DIP in health and diseases.

Cyclic-AMP (cAMP), the first second messenger to be identified, is synthesized, and is universally utilized as a second messenger, and plays important roles in integrity, and function of organs, including heart. Through its coupling with other intracellular messengers, cAMP facilitates excitation-contraction coupling, increases heart rate and conduction velocity. It is degraded by a class of enzymes called cAMP-dependent phosphodiesterase (PDE), with PDE3 and PDE4 being the predominant isoforms in the heart. This highly diverse class of enzymes degrade cAMP and through anchoring proteins generates dynamic microdomains to target specific proteins and control specific cell functions in response to various stimuli. The impaired function of the anchoring protein either by inherited genetic mutations or acquired injuries results in altered intracellular targeting, and blunted responsiveness to stimulating pathways and contributes to pathological cardiac remodeling, cardiac arrhythmias and reduced cell survival. Recent genetic studies provide compelling evidence for an association between the variants in the anchoring protein PDE4DIP and atrial fibrillation, stroke, and heart failure.

Echocardiography fails to detect an extensive aortic root abscess in a patient with infective endocarditis: a case report.

Background: Echocardiography plays a central role in the diagnosis of infective endocarditis (IE). In recent years, additional imaging techniques have begun to challenge the conventional approach. We present a case where the use of transthoracic/transoesophageal echocardiography (TTE/TOE) in suspected IE failed to identify an extensive periannular abscess, later identified by 18F-flurodeoxyglucose-positron emission tomography (FDG-PET), requiring urgent intervention. Case summary: A 69-year-old man with symptomatic Streptococcus sanguinis bacteraemia and a bicuspid aortic valve was found to have new-onset left bundle branch block that progressed to complete heart block. After starting on IV Penicillin G and having a temporary pacemaker inserted, his clinical condition improved. Transthoracic echocardiography and TOE showed no evidence of abscess. However, persistent first-degree atrioventricular block raised clinical suspicion of a possible extended infection. Subsequent FDG-PET revealed focal activity around the aortic root that extended inferiorly into the interatrial septum, consistent with active infection and possible abscess. Composite aortic root replacement with insertion of a mechanical prosthesis was carried out, revealing extensive IE and multiple periannular abscesses. Discussion: As guidelines grapple with evolving understandings of how best to define the optimal imaging approach for the management of complicated IE, the results of this case clearly show the importance of heightened clinical suspicion and need for prompt operative intervention when faced with patients who present with predisposing conditions and concern for advanced conduction disease. Clinicians and researchers are encouraged to learn from the potential near-miss of an extensive periannular abscess to help guide guideline-development of imaging in complicated IE and prevent adverse outcomes in patients with similar presentations.

Does Opium Consumption Have Shared Impact on Atherosclerotic Cardiovascular Disease and Cancer?

Although atherosclerotic cardiovascular disease (ASCVD) and cancer are seemingly different types of disease, they have multiple shared underlying mechanisms and lifestyle-related risk factors like smoking, unhealthy diet, excessive alcohol consumption, and inadequate physical activity. Opium abuse is prevalent in developing countries, especially the Middle East region and many Asian countries. Besides recreational purposes, many people use opium based on a traditional belief that opium consumption may confer protection against heart attack and improve the control of the risk factors of ASCVD such as diabetes mellitus, hypertension, and dyslipidemia. However, scientific reports indicate an increased risk of ASCVD and poor control of ASCVD risk factors among opium abusers compared with nonusers. Moreover, there is accumulating evidence that opium consumption exerts potential carcinogenic effects and increases the risk of developing various types of cancer. We conducted a review of the literature to review the current evidence on the relationship between opium consumption and ASCVD as well as various kinds of cancer. In addition, we will discuss the potential shared pathophysiologic mechanisms underlying the association between opium abuse and both ASCVD and cancer.

TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.

FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2+/- mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, VilinCreert2 ; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6R611C substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.

Prdm6 controls heart development by regulating neural crest cell differentiation and migration.

The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs). Using transcriptomic analysis and genetic and fate mapping approaches in transgenic mice, we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction. Bulk and single-cell RNA-Seq analyses of the DA and CNCCs identified Prdm6 as a regulator of a network of CNCC specification genes, including Wnt1, Tfap2b, and Sox9. Loss of Prdm6 in CNCCs diminished its expression in the pre-epithelial-mesenchymal transition (pre-EMT) cluster, resulting in the retention of NCCs in the dorsal neural tube. This defect was associated with diminished H4K20 monomethylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we showed was the major driver of the impaired CNCC migration. Altogether, these findings revealed Prdm6 as a key regulator of CNCC differentiation and migration and identified Prdm6 and its regulated network as potential targets for the treatment of congenital heart diseases.

Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice.

Mutations in Dyrk1b are associated with metabolic syndrome and nonalcoholic fatty liver disease in humans. Our investigations showed that DYRK1B levels are increased in the liver of patients with nonalcoholic steatohepatitis (NASH) and in mice fed with a high-fat, high-sucrose diet. Increasing Dyrk1b levels in the mouse liver enhanced de novo lipogenesis (DNL), fatty acid uptake, and triacylglycerol secretion and caused NASH and hyperlipidemia. Conversely, knockdown of Dyrk1b was protective against high-calorie-induced hepatic steatosis and fibrosis and hyperlipidemia. Mechanistically, Dyrk1b increased DNL by activating mTORC2 in a kinase-independent fashion. Accordingly, the Dyrk1b-induced NASH was fully rescued when mTORC2 was genetically disrupted. The elevated DNL was associated with increased plasma membrane sn-1,2-diacylglyerol levels and increased PKCε-mediated IRKT1150 phosphorylation, which resulted in impaired activation of hepatic insulin signaling and reduced hepatic glycogen storage. These findings provide insights into the mechanisms that underlie Dyrk1b-induced hepatic lipogenesis and hepatic insulin resistance and identify Dyrk1b as a therapeutic target for NASH and insulin resistance in the liver.

Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1.

Rare gain of function mutations in the gene encoding Dyrk1b, a key regulator of skeletal muscle differentiation, have been associated with sarcopenic obesity (SO) and metabolic syndrome (MetS) in humans. So far, the global gene networks regulated by Dyrk1b during myofiber differentiation have remained elusive. Here, we have performed untargeted proteomics to determine Dyrk1b-dependent gene-network in differentiated C2C12 myofibers. This analysis led to identification of translational inhibitor, 4e-bp1 as a post-transcriptional target of Dyrk1b in C2C12 cells. Accordingly, CRISPR/Cas9 mediated knockout of Dyrk1b in zebrafish identified 4e-bp1 as a downstream target of Dyrk1b in-vivo. The Dyrk1b knockout zebrafish embryos exhibited markedly reduced myosin heavy chain 1 expression in poorly developed myotomes and were embryonic lethal. Using knockdown and overexpression approaches in C2C12 cells, we found that 4e-bp1 enhances autophagy and mediates the effects of Dyrk1b on skeletal muscle differentiation. Dyrk1bR102C, the human sarcopenic obesity-associated mutation impaired muscle differentiation via excessive activation of 4e-bp1/autophagy axis in C2C12 cells. Strikingly, the defective muscle differentiation in Dyrk1bR102C cells was rescued by reduction of autophagic flux. The identification of Dyrk1b-4e-bp1-autophagy axis provides significant insight into pathways that are relevant to human skeletal muscle development and disorders.