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Journal of the American Heart... Jun 2024The aim of this study was to evaluate the association between obesity and risk of incident left ventricular hypertrophy (LVH) in community-dwelling populations with... (Observational Study)
Observational Study
BACKGROUND
The aim of this study was to evaluate the association between obesity and risk of incident left ventricular hypertrophy (LVH) in community-dwelling populations with hypertension and investigate whether this association would be attenuated by a lower achieved systolic blood pressure (SBP).
METHODS AND RESULTS
We used the EMINCA (Echocardiographic Measurements in Normal Chinese Adults) criteria, which were derived from healthy Chinese populations to define LVH. A total of 2069 participants with hypertension and without LVH (obesity 20.4%) were included. The association between obesity and risk of incident LVH was evaluated using Cox proportional hazard models and stratified by achieved follow-up SBP levels (≥140, 130-139, and <130 mm Hg). These analyses were also assessed using the American Society of Echocardiography/European Association of Cardiovascular Imaging criteria, which were derived from European populations to define LVH. After a median follow-up of 2.90 years, the rates of incident LVH in the normal-weight, overweight, and obese groups were 13.5%, 20.3%, and 27.8%, respectively (<0.001). In reference to normal weight, obesity was associated with increased risk of incident LVH (adjusted hazard ratio [aHR], 2.51 [95% CI, 1.91-3.29]), which was attenuated when achieved SBP was <130 mm Hg (aHR, 1.78 [95% CI, 0.99-3.19]). This association remained significant when achieved SBP was ≥140 mm Hg (aHR, 3.45 [95% CI, 2.13-5.58]) or at 130 to 139 mm Hg (aHR, 2.32 [95% CI, 1.23-4.36]). Differences in these findings were noted when LVH was defined by the American Society of Echocardiography/European Association of Cardiovascular Imaging criteria.
CONCLUSIONS
Obesity was associated with incident LVH and an SBP target <130 mm Hg might be needed to attenuate this risk in patients with hypertension and obesity.
Topics: Humans; Hypertrophy, Left Ventricular; Male; Hypertension; Obesity; Female; Middle Aged; Incidence; Blood Pressure; China; Risk Factors; Independent Living; Aged; Echocardiography; Risk Assessment; Adult
PubMed: 38842284
DOI: 10.1161/JAHA.123.033521 -
Journal of the American Heart... Jun 2024The aim of this study was to assess how early-adulthood body mass index (BMI) and waist circumference (WC) relate to long-term cardiovascular structure, function, and...
BACKGROUND
The aim of this study was to assess how early-adulthood body mass index (BMI) and waist circumference (WC) relate to long-term cardiovascular structure, function, and prognosis in individuals without obesity and with low cardiovascular risk factor (CVRF) burden.
METHODS AND RESULTS
A total of 2024 participants aged 18 to 30 from the CARDIA (Coronary Artery Risk Development in Young Adults) study, without obesity and with low CVRFs defined as the absence of cardiovascular disease (CVD), diabetes, hypertension, current smoking, and dyslipidemia were included. A CVRF-optimal subgroup was also defined, with blood pressure<120/80 mm Hg, fasting glucose <100 mg/dL, total cholesterol <200, low-density lipoprotein cholesterol <130, and women with high-density lipoprotein cholesterol ≥50 mg/dL. Coronary artery calcification, carotid intima-media thickness, left ventricular mass, left ventricular ejection fraction, longitudinal peak systolic strain, and diastolic function were assessed in midlife. Cox regression was used to calculate hazard ratios of BMI and WC for all-cause death and CVD events. Logistic regression was used to estimate odds ratios for subclinical CVD. Over 33.9 years (median follow-up), 5.2% (n=105) died, and 2.6% (n=52) had CVD events. Each 1-SD BMI increase was associated with 27% (95% CI, 1.10-1.47), 24% (1.08-1.43), 42% (1.20-1.68), 28% (1.05-1.57), 51% (1.20-1.90), and 49% (1.10-2.02) higher odds of coronary artery calcification presence, increased carotid intima-media thickness, left ventricular hypertrophy, reduced left ventricular ejection fraction, low longitudinal peak systolic strain, and diastolic dysfunction, respectively, in the CVRF-low group. Generally, similar associations were found for WC and in the CVRF-optimal subgroup. No significant associations between BMI and WC with CVD and death were found.
CONCLUSIONS
Elevations in BMI and WC among young low-risk individuals, even within the nonobesity range, are associated with midlife cardiovascular health.
PubMed: 38842274
DOI: 10.1161/JAHA.123.033355 -
Journal of the American Heart... Jun 2024The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal...
BACKGROUND
The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes.
METHODS AND RESULTS
We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity.
CONCLUSIONS
We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.
Topics: Animals; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Naphthyridines; Ventricular Dysfunction, Left; Male; Disease Models, Animal; Fibrosis; Nitric Oxide Synthase Type III; Glomerular Filtration Rate; Ventricular Function, Left; Diastole; Kidney; Phosphorylation; Myocardium; Rats, Sprague-Dawley; Rats; Nephrectomy
PubMed: 38842271
DOI: 10.1161/JAHA.123.032971 -
Frontiers in Veterinary Science 2024Studies on aberrant bronchoesophageal arteries are limited. Herein, we report a case of a multi-origin systemic-to-pulmonary shunt with suspected bronchoesophageal...
INTRODUCTION
Studies on aberrant bronchoesophageal arteries are limited. Herein, we report a case of a multi-origin systemic-to-pulmonary shunt with suspected bronchoesophageal artery hypertrophy and fistula in a dog.
CASE REPORT
A 4-year-old castrated male beagle weighing 11 kg underwent routine medical screening. Physical examination revealed a right-sided continuous murmur of grades 1-2. Thoracic radiography revealed a mild cardiomegaly. Echocardiography revealed a continuous turbulent shunt flow distal to the right pulmonary artery (RPA) branch from the right parasternal short axis pulmonary artery view. Computed tomography demonstrated systemic-to-pulmonary shunts originating from the descending aorta at the level of T7-8, the right 5th and 6th dorsal intercostal arteries, and the right brachiocephalic trunk, which formed anomalous networks around the trachea and esophagus that anastomosed into a large tortuous vessel at the level of T6-7 and entered the RPA. Surgical ligation of multiple shunting vessels was performed. Postoperative echocardiography and computed tomography showed decreased left ventricular volume overload and markedly decreased size of the varices. Additionally, most of the shunting vessels were without residual shunt flow.
CONCLUSION
The present study provides information regarding imaging features and the successful surgical management of multiple systemic-to-pulmonary shunts originating from the descending aorta, right brachiocephalic trunk, and intercostal arteries and terminating at the RPA. Multimodal imaging features after surgical ligation have also been described.
PubMed: 38840636
DOI: 10.3389/fvets.2024.1400076 -
Drug Metabolism and Disposition: the... Jun 2024This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450...
This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450 1B1 (CYP1B1) and arachidonic acid (AA) metabolites. Currently there is no evidence to suggest that cannflavin-C; a prenylated flavonoid, has any significant effects on the heart or cardiac hypertrophy. The metabolism of arachidonic acid (AA) into midchain hydroxyeicosatetraenoic acids (HETEs), facilitated by CYP1B1 enzyme, plays a role in the development of cardiac hypertrophy which is marked by enlarged cardiac cells. Adult human ventricular cardiomyocytes cell line (AC16) were cultured and exposed to cannflavin-C in the presence and absence of Ang II. The assessment of mRNA expression pertaining to cardiac hypertrophic markers and CYPs was conducted via real-time polymerase chain reaction (PCR) while the quantification of CYPs protein levels was carried out through western blot analysis. Ang II induced hypertrophic markers myosin heavy chain (β/α-MHC), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) and increased cell surface area, while cannflavin-C mitigated these effects. Gene and protein expression analysis revealed that cannflavin-C downregulated CYP1B1 gene expression, protein level as well as the enzyme activity assessed by 7-methoxyresorufin O-deethylase (MROD). Arachidonic acid metabolites analysis, using LC-MS/MS, demonstrated that Ang II increased midchain (R/S)-HETEs concentrations, which were attenuated by cannflavin-C. This study provides novel insights into the potential of cannflavin-C in modulating arachidonic acid metabolites and attenuating Ang II-induced cardiac hypertrophy, highlighting the importance of this compound as potential therapeutic agents for cardiac hypertrophy. This study demonstrates that cannflavin-C offers protection against cellular hypertrophy induced by Ang II. The significance of this research lies in its novel discovery, which elucidates a mechanistic pathway involving the inhibition of CYP 1B1 by cannflavin-C. This discovery opens up new avenues for leveraging this compound in the treatment of heart failure.
PubMed: 38839111
DOI: 10.1124/dmd.124.001705 -
Annals of Vascular Surgery Jun 2024This study's objective is to describe outcomes of adult patients who underwent thoracic stent graft placement treatment for primary or recurrent aortic coarctation.
OBJECTIVE
This study's objective is to describe outcomes of adult patients who underwent thoracic stent graft placement treatment for primary or recurrent aortic coarctation.
METHODS
This is a retrospective study of 30 adult patients who underwent thoracic stent graft placement for aortic coarctation at our institution. Average age was 46.5 years, with 53.3% of patients presented with no prior treatment or repair for coarctation. Indications for repair included gradient ≥20 mm Hg with anatomic evidence of coarctation on imaging with left ventricular hypertrophy, pseudoaneurysm, aneurysm, refractory hypertension, or claudication. Stent grafts used for repair included MDT (Medtronic, Santa Rosa, CA) and GORE TAG (W. L. Gore & Associates, Flagstaff, AZ).
RESULTS
Patients were observed for a median of 979 days, with one death during the study. All patients had complete resolution of symptoms with no recurrences. TEVAR significantly reduced the gradient across the coarctation (p <0.0001). Aortic coarctation diameter significantly increased at 30-days postoperatively and continued to increase up to 5 years post-treatment. At 3+ years, aortic remodeling was observed at the coarctation site and surrounding regions. At 30 days, systolic, diastolic, and mean arterial pressure were all reduced. Systolic and diastolic blood pressure as well as MAP continued to significantly improve 1-year post-treatment.
CONCLUSIONS
Stent grafts are a safe and effective treatment for aortic coarctation. We observed a clinically significant improvement in blood pressure, and longitudinal aortic remodeling of the coarctation segment and the entire aorta that persisted over more than 3 years.
PubMed: 38838987
DOI: 10.1016/j.avsg.2024.03.009 -
Circulation Jun 2024Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown.
BACKGROUND
Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown.
METHODS
We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and NO consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system.
RESULTS
In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb and plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress.
CONCLUSIONS
AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT05603520. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01805739.
PubMed: 38836358
DOI: 10.1161/CIRCULATIONAHA.123.064747 -
Circulation Jun 2024Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the...
BACKGROUND
Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms.
METHODS
Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control.
RESULTS
We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo.
CONCLUSIONS
These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.
PubMed: 38836349
DOI: 10.1161/CIRCULATIONAHA.123.067606 -
Channels (Austin, Tex.) Dec 2024Alterations in ion channel expression and function known as "electrical remodeling" contribute to the development of hypertrophy and to the emergence of arrhythmias and...
Alterations in ion channel expression and function known as "electrical remodeling" contribute to the development of hypertrophy and to the emergence of arrhythmias and sudden cardiac death. However, comparing current density values - an electrophysiological parameter commonly utilized to assess ion channel function - between normal and hypertrophied cells may be flawed when current amplitude does not scale with cell size. Even more, common routines to study equally sized cells or to discard measurements when large currents do not allow proper voltage-clamp control may introduce a selection bias and thereby confound direct comparison. To test a possible dependence of current density on cell size and shape, we employed whole-cell patch-clamp recording of voltage-gated sodium and calcium currents in Langendorff-isolated ventricular cardiomyocytes and Purkinje myocytes, as well as in cardiomyocytes derived from trans-aortic constriction operated mice. Here, we describe a distinct inverse relationship between voltage-gated sodium and calcium current densities and cell capacitance both in normal and hypertrophied cells. This inverse relationship was well fit by an exponential function and may be due to physiological adaptations that do not scale proportionally with cell size or may be explained by a selection bias. Our study emphasizes the need to consider cell size bias when comparing current densities in cardiomyocytes of different sizes, particularly in hypertrophic cells. Conventional comparisons based solely on mean current density may be inadequate for groups with unequal cell size or non-proportional current amplitude and cell size scaling.
Topics: Myocytes, Cardiac; Animals; Cell Size; Cardiomegaly; Mice; Male; Patch-Clamp Techniques
PubMed: 38836323
DOI: 10.1080/19336950.2024.2361416 -
Frontiers in Genetics 2024Variants in the gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be...
BACKGROUND
Variants in the gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers.
METHODS
Probands with HCM caused by a pathogenic deletion of exon 23-26 of were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding , was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach.
RESULTS
We identified 24 probands with HCM harbouring the exon 23-26 deletion. Probands were on average 51 ± 16 years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19 Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8 Mb haplotype. The founder event was estimated to have happened five generations, or 175-200 years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19 years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21 years; < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; = 0.002), arrhythmia (41.7% vs. 12.9%, = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50 years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5 years with an average age of 50 (±21) years.
CONCLUSION
A Belgian founder variant, an exon 23-26 deletion in , was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50 years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up.
PubMed: 38836037
DOI: 10.3389/fgene.2024.1392527