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Objective: By incorporating myocardial deformation and afterload, novel echocardiographic myocardial work indices appear to be advantageous compared to load-dependent left ventricular (LV) deformation analyses. As such, these indices may provide a more accurate and, above all, load-independent estimation of LV function in patients with chronically increased afterload. To date however, data on the relation of these indices to clinical and conventional echocardiographic parameters are scarce., Purpose: Our aim was to evaluate the relationship between myocardial work indices and age, body mass index (BMI), NTproBNP, the clinical history of arterial hypertension and diastolic dysfunction as well as selected conventional echocardiographic parameters in women., Methods: We analyzed echocardiographic data of women included in the Berlin Female Risk Evaluation (BEFRI) trial. Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW) and Global Work Efficiency (GWE) were calculated using commercially available software based on noninvasive pressure-strain loops. The impact of selected clinical and echocardiographic characteristics on myocardial work parameters was investigated by uni- and multivariate regression analyses., Results: A total of 224 women were included in the final analysis. 155 of them were normotensive and 69 had a history of arterial hypertension. Diastolic dysfunction was more prevalent in subjects with arterial hypertension. Study participants with arterial hypertension showed higher GWI and GCW whereas GWW and GWE did not significantly differ between groups. GCW and GWW were lower and GWE higher in the presence of normal diastolic function. In multivariate regression analyses, arterial hypertension, LV GLS, and interventricular septal thickness were significantly associated with GWI. GCW showed significant associations with the clinical history of arterial hypertension, LV GLS, age and IVRT. Similarly, LV GLS, IVRT and mitral inflow E wave deceleration time were identified to be significant determinants of GWW and GWE., Conclusion: Our data confirm that, in a randomly selected sample of the general urban female population, myocardial work parameters are predominantly determined by LV GLS. In addition, the presence of arterial hypertension was identified to be a significant determinant of GWI and GCW, but not for GWW and GWE. Finally, a prolonged LV relaxation time was significantly associated with GWW and GWE, suggesting more wasted myocardial work and lower GWE values with increasing LV relaxation time., (© 2023 Wiley Periodicals LLC.)

Genetic variants in UMOD associate with kidney function and hypertension. These phenotypes are also linked to sex-related differences and impairment in cognitive and physical function in older age. Here we evaluate longitudinal associations between a common UMOD rs4293393-A>G variant and changes in estimated glomerular filtration rate (eGFR), blood pressure (BP), cognitive and physical function parameters in older participants in the BASE-II after long-term follow-up as part of the GendAge study. Overall, 1010 older participants (mean age 75.7 ± 3.7 years, 51.6% women) were analyzed after follow-up (mean 7.4 years) both in cross-sectional analysis and in longitudinal analysis as compared to baseline. In cross-sectional analysis, heterozygous G-allele carriers exhibited significantly higher eGFR values (AA, 71.3 ml/min/1.73 m 2 , 95% CI, 70.3-72.3 vs. AG, 73.5 ml/min/1.73 m 2 , 95% CI, 72.1-74.9, P = 0.033). Male heterozygous G-allele carriers had lower odds of eGFR < 60 mL/min/1.73 m 2 (OR 0.51, 95% CI, 0.28-0.95, P = 0.032) and in Timed Up and Go-Test ≥ 10 s (OR 0.50, 95% CI, 0.29-0.85, P = 0.011) whereas women were less likely to have hypertension (OR 0.58, CI, 0.37-0.91, P = 0.018). UMOD genotypes were not significantly associated with longitudinal changes in any investigated phenotype. Thus, while the impact of UMOD rs4293393 on kidney function is maintained in aging individuals, this variant has overall no impact on longitudinal changes in BP, kidney, cognitive or functional phenotypes. However, our results suggest a possible sex-specific modifying effect of UMOD on eGFR and physical function in men and hypertension prevalence in women., (© 2022. The Author(s).)

Background: Melusin is a muscle specific signaling protein, required for compensatory hypertrophy response in pressure-overloaded heart. The role of Melusin in heart function has been established both by loss and gain of function experiments in murine models. With the aim of verifying the hypothesis of a potential role of the Melusin encoding gene, ITGB1BP2, in the modification of the clinical phenotype of human cardiomyopathies, we screened the ITGB1BP2 gene looking for genetic variations possibly associated to the pathological phenotype in three selected groups of patients affected by hypertension and dilated or hypertrophic cardiomyopathy, Methods: We analyzed ITGB1BP2 by direct sequencing of the 11 coding exons and intron flanking sequences in 928 subjects, including 656 hypertensive or cardiopathic patients and 272 healthy individuals., Results: Only three nucleotide variations were found in patients of three distinct families: a C>T missense substitution at position 37 of exon 1 causing an amino acid change from His-13 to Tyr in the protein primary sequence, a duplication (IVS6+12&#95;18dupTTTTGAG) near the 5'donor splice site of intron 6, and a silent 843C>T substitution in exon 11., Conclusions: The three variations of the ITGB1BP2 gene have been detected in families of patients affected either by hypertension or primary hypertrophic cardiomyopathy; however, a clear genotype/phenotype correlation was not evident. Preliminary functional results and bioinformatic analysis seem to exclude a role for IVS6+12&#95;18dupTTTTGAG and 843C>T in affecting splicing mechanism.Our analysis revealed an extremely low number of variations in the ITGB1BP2 gene in nearly 1000 hypertensive/cardiopathic and healthy individuals, thus suggesting a high degree of conservation of the melusin gene within the populations analyzed.

We tested the hypothesis that female and male mice differ in terms of cardiac hypertrophy after deoxycorticosterone acetate (DOCA)+salt hypertension (uninephrectomy and 1% saline in drinking water) and focused on calcineurin signaling. We excluded confounding effects of blood pressure elevation or sex-related blood pressure differences by treating DOCA-salt mice with hydralazine (250 mg/L in drinking water). We found that directly measured mean arterial blood pressure was lowered to control values with hydralazine and corroborated this finding in separate mouse groups with radiotelemetry. Male mice were more responsive to DOCA-salt-related effects. They developed more left ventricular hypertrophy and more renal hypertrophy after 6 weeks of DOCA-salt+hydralazine compared with female mice. In hearts, transcripts for calcineurin Abeta and for myocyte-enriched calcineurin interacting protein 1 were upregulated in male but not in female mice. Enhanced activity of calcineurin Abeta, as indicated by diminished phosphorylation of NFATc2 in male mice, accounted for this sex-specific difference. Stretch-related, inflammatory, and profibrotic responses were also accentuated in male mice, as shown by higher transcript levels of atrial natriuretic peptide, monocyte chemoattractant protein-1, and transforming growth factor-beta. Our results support sex-specific regulation of the calcineurin pathway in response to largely blood pressure-independent mineralocorticoid action. We suggest that sex-specific calcineurin activation determines the maladaptive cardiac and renal hypertrophic responses and accompanying organ injury in male mice.

Large differences exist between women and men in the syndrome of heart failure (HF). In contrast to men, hypertension and diabetes represent the major risk factors for development of HF in women and hypertension is also the major cause of left ventricular hypertrophy and stroke. Left ventricular hypertrophy in women increases the risk for mortality to a higher degree than it does in men. The clinical course of HF is generally more benign and more frequently characterized by HF with preserved systolic function. Estrogen receptors are present in the human heart. Based on data from rodent models, they are believed to modulate hypertrophy and the progression of HF. Some of the signaling pathways have been described and involve phosphorylation of intracellular kinases and production of nitric oxide. Interestingly, estrogen receptors are upregulated in human hypertrophy and HF. The clinical course of HF in women is characterized by the more frequent occurrence of diastolic HF. Myocardial remodeling with age and, as a consequence, of mechanical load is different in both genders. Adherence to guidelines in the diagnosis and treatment of HF is less strict in women than in men, leading to undertreatment with inhibitors of the renin-angiotensin system. Women are generally underrepresented in clinical trials in HF and gender-specific analyses have been neglected in most older large survival trials. In some of the large survival studies angiotensin-converting enzyme inhibitors or beta-receptor blockers did not reach significant endpoints in women. However, meta-analyses show overall positive effects for these groups of substances. Angiotensin receptor blockers were effective in large studies including high percentages of women.

Background: The angiotensin II type 2 (AT2) receptor is thought to play a role in cardiovascular disorders such as neointima formation after vascular injury, cardiac hypertrophy and myocardial infarction (MI). Recently, the biallelic polymorphism G + 1675A in intron 1 of the AT2 receptor gene has been associated with left ventricular posterior, septal and relative wall thickness, as well as left ventricular mass index in young hypertensive males., Methods: To investigate its potential role in left ventricular hypertrophy (LVH) and other cardiovascular traits, 1968 individuals from two population samples (the Glasgow Heart Scan, GLAECO and Glasgow Heart Scan Old, GLAOLD studies) with echocardiographically and electrocardiographically assessed phenotypes, were genotyped for G + 1675A using allele-specific oligonucleotide hybridization. Both studies had a similar design, only the age-ranges differed, being 25-74 years in the GLAECO study and 55-74 years in the GLAOLD study, so that internal consistency of results could also be assessed. Since the AT2 gene is located on the X chromosome, males and females were analysed separately., Results: The + 1675A allele frequency was 0.49 and 0.51, in the GLAECO and GLAOLD studies, respectively. In both studies, the genotype frequencies were similar in hypertensive and non-hypertensive individuals. In the GLAOLD study, in females with episodes of coronary ischemia and MI, the AT2 + 1675A allele was more common than in females with no episode (86.5% vs. 73.5%, respectively; P < 0.007). This effect was not observed in males. In the same study, AT2 + 1675A allele carriers were more common in males with LVH, than in those without LVH (60.3% vs. 46.0%, respectively; P = 0.047). This result was unchanged after exclusion of subjects taking antihypertensive drugs (including ACE inhibitors) (64.4% vs. 47.4%, P = 0.038). However, in the GLAECO study, these results could not be replicated, even when subjects > 55 years of age were considered separately., Conclusions: Our study gives rise to a potential implication of the AT2 G + 1675A polymorphism in LVH and coronary ischemia subgroups. Since these results were not consistent in both studies, but are partially in agreement with two independent investigations, further efforts should be made to elucidate the specific nature of these genotype/phenotype interactions., (Copyright 2002 European Society of Cardiology)

Objectives: This study examined the association between the -344 C/T polymorphism of the human aldosterone synthase promoter and left ventricular structure in arterial hypertension., Background: Because of conflicting results from different studies, the mechanism of such an association, if any, has not been determined., Methods: We examined the aldosterone synthase promoter genotype in 120 young (age: 26 +/- 3 years) male, white subjects with normal or mildly elevated blood pressure. Left ventricular structural parameters and urinary sodium excretion over 24 h before and after additional oral sodium load (6 g/day over 1 week) were determined., Results: Hypertensive subjects with the CC genotype had a greater left ventricular end-diastolic diameter but smaller relative wall thickness than those with the TT genotype (54 +/- 2 vs. 50 +/- 4 mm, and 0.37 +/- 0.07 vs. 0.44 +/- 0.06 mm, respectively; p < 0.05). Hypertensive subjects with the TT genotype (n = 15) had a greater increase in urinary sodium excretion after oral sodium load than those with the CC genotype (n = 11) (135 +/- 95 vs. 24 +/- 133 mmol/liter/day; p < 0.05). Serum aldosterone levels were found to be decreased after oral sodium load in hypertensive subjects with the TT and CT genotypes only (-37 +/- 45 and -38 +/- 51 pg/ml, respectively; all p < 0.01) but not in those with the CC genotype (-12 +/- 30 pg/ml, n.s.). Such differences were not found in normotensive subjects., Conclusions: Hypertensive subjects with the -344 CC genotype of the aldosterone synthase promoter are characterized by a pattern of early eccentric left ventricular hypertrophy. Differences in renal sodium handling across the genotypes might contribute to this finding.

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treatment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT1 and Ang T2 gains clinical importance. In cell cultures, the number of surface AT1 is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phospholipase C mediated pathways. In this respect, the AT1 behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT1 regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth factors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT1A and AT1B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT1, in the adrenals was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiological events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described.(ABSTRACT TRUNCATED AT 250 WORDS)