Differences In Cardiac Remodeling Research Articles

Abstract 12479: Cardiovascular Stroke Nursing Best Abstract Award: Sex Differences in Relationships Between Inflammation and Symptoms in Persons With Heart Failure

Background: Heart failure (HF) is a complex syndrome involving interplay of pathologic processes, such as inflammation and myocardial remodeling. Sex differences in cardiac remodeling and function are linked to differences in inflammation. Female hearts show a pro-inflammatory shift and increased cytokine expression with aging not seen in male hearts. Yet, sex is not often considered in HF interventions. Previous studies suggest sex may moderate the relationship between inflammation and symptoms in cardiometabolic disease, but the relationship in HF is unknown. Purpose: To examine sex differences in inflammation and symptoms in Black adults living with HF. Methods: Black adults living with HF (N=41) were enrolled in this pilot study. Physical symptoms were measured with PROMIS Dyspnea, Heart Failure Somatic Perception Scale (HFSPS), and Multidimensional Fatigue Inventory (MFI). Mood symptoms were measured with Center for Epidemiological Studies Depression Scale (CESD), State-Trait Anxiety Inventory (STAI), and Perceived Stress Scale (PSS). Inflammatory biomarkers were measured via multiplex immunoassay. Xanthine oxidase (XO) activity, an indicator of oxidative stress, was measured via ELISA. Pearson correlations were stratified by sex. Results: The mean age was 57 ± 11 years, and 66% were female. Dyspnea was positively associated with XO activity in both groups. Among females, dyspnea was positively associated with matrix metalloproteinase (MMP)-12 (r=.519, p=.033), interleukin (IL)-6 (p=.564, p=.018), [C-C motif chemokine ligand(CCL)-3, (r=.509, p=.037), and CCL-11 (r=.520, p=.032). HFSPS was positively associated with XO activity among females only (r=.445, p=.014). CCL-11 was positively associated with MFI (r=.616, p=.008), PSS (p=.0537, r=.032), STAI (r=.714, p=.001), and CESD (r=.635, p=.008) symptoms among females but not males. Conclusions: While physical symptoms were associated with similar inflammatory pathways, fatigue and mood symptoms were associated with inflammation among females only. Women may be more vulnerable to inflammation-induced mood changes and fatigue. Further work is needed to better understand how sex modulates the relationship between inflammation and symptoms in persons with HF.

Streptozotocin-Induced Type 1 and 2 Diabetes Mellitus Mouse Models Show Different Functional, Cellular and Molecular Patterns of Diabetic Cardiomyopathy.

The main cause of morbidity and mortality in diabetes mellitus (DM) is cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial in exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has been widely used to produce experimental models of both type 1 and type 2 DM (T1DM and T2DM). Here, we compared these two models for their effects on cardiac structure, function and transcriptome. Different doses of STZ and diet chows were used to generate T1DM and T2DM in C57BL/6J mice. Normal euglycemic and nonobese sex- and age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR and RNA-seq were employed to compare hearts from the three animal groups. STZ-induced T1DM and T2DM affected left ventricular function and myocardial performance differently. T1DM displayed exaggerated apoptotic cardiomyocyte (CM) death and reactive hypertrophy and fibrosis, along with increased cardiac oxidative stress, CM DNA damage and senescence, when compared to T2DM in mice. T1DM and T2DM affected the whole cardiac transcriptome differently. In conclusion, the STZ-induced T1DM and T2DM mouse models showed significant differences in cardiac remodeling, function and the whole transcriptome. These differences could be of key relevance when choosing an animal model to study specific features of DCM.

Abstract 13993: Sex Differences in Cardiac Structure and Function Following Acute Myocardial Infarction: Insights From the PARADISE-MI Echocardiographic Sub-Study

Introduction: Women have a higher incidence of heart failure (HF) hospitalizations than men following acute myocardial infarction (AMI). The extent to which differential cardiac remodeling between men and women might account for this higher risk in women is poorly understood. Hypothesis: Women and men have differences in cardiac remodeling after AMI that are predictive of clinical outcomes. Methods: The Prospective ARNI versus ACE inhibitor trial to Determine Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial randomized patients within 0.5 to 7 days of AMI complicated by left ventricular (LV) dysfunction, pulmonary congestion, or both to sacubitril/valsartan or ramipril. In the pre-specified echocardiographic sub-study, 544 participants were enrolled to undergo protocol echocardiography at the time of randomization and after 8 months. Results: At baseline, women (n=142, 26%) were older, more likely to have a history of hypertension, and less likely to have a history of MI. Women had a higher LV ejection fraction (LVEF), lower LV end-diastolic index (LVEDVi) and end-systolic volume index (LVESVi), and LV mass index, but no difference in left atrium (LA) volume index compared with men (Table). Women had better diastolic function compared with men. The absolute and relative changes in these echocardiographic parameters from baseline to 8 months were not significantly different between women and men. In univariate analyses, baseline LVEF, LVEDVi, LVESVi, LA dimensions and diastolic measurements are associated with primary outcome (Table). Conclusion: In PARADISE-MI, women have higher LVEF and lower indexed LV and LA chamber sizes compared to men following high-risk MI. The changes between baseline and 8-month in LVEF, LV and LA dimensions did not differ significantly between men and women, suggesting that differential cardiac remodeling post-MI may not account for the increased HF risk in women compared with men.

Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial.

Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (-3.40°, -5.96; -0.84, P = 0.011) and fiber shortening (-1.19%, -2.24; -0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14++CD16- monocytes reduced, and Tie2+ monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.

Difference in cardiac remodeling between female athletes and pregnant women: a case control study

ObjectivesThe aim of this study was to detect possible differences in reversible cardiac remodeling occurring in sport training and twin pregnancy. Background: cardiac remodeling occurs in athletes and pregnant women due to training and fetal requirements, respectively. These changes could be apparently similar.Methods21 female elite athletes (23.2 ± 5.3 years), 25 women with twin pregnancies (35.4 ± 5.7 years) and 25 healthy competitive female athletes (controls), age-matched with pregnant women (34.9 ± 7.9 years), were enrolled. This latter group was included to minimize the effect of age on cardiac remodeling. All women evaluated through anamnestic collection, physical examination, 12 leads ECG, standard echocardiogram and strain analysis. Sphericity (SI) and apical conicity (ACI) indexes were also calculated.ResultsPregnant women showed higher LA dimension (p < 0.001) compared to both groups of athletes. LV e RV GLS were significantly different in pregnant women compared to female athletes (p = 0.02 and 0.03, respectively). RV GLS was also different between pregnant women and controls (p = 0.02). Pregnant women showed significantly higher S′ wave compared to female athletes (p = 0.02) but not controls. Parameters of diastolic function were significantly higher in athletes (p = 0.08 for IVRT and p < 0.001 for E/A,). SI was lower in athletes in both diastole (p = 0.01) and systole (p < 0.001), while ACIs was lower in pregnant women (p = 0.04).ConclusionsCardiac remodeling of athletes and pregnant women could be similar at first sight but different in LV shape and in GLS, highlighting a profound difference in longitudinal deformation between athletes and pregnant women. This difference seems not to be related with age. These findings suggest that an initial maternal cardiovascular maladaptation could occur in the third trimester of twin pregnancies.

Effects of caloric overload before caloric restriction in the murine heart

The beneficial effects of caloric restriction (CR) against cardiac aging and for prevention of cardiovascular diseases are numerous. However, to our knowledge, there is no scientific evidence about how a high-calorie diet (HCD) background influences the mechanisms underlying CR in whole heart tissue (WHT) in experimental murine models.In the current study, CR-treated mice with different alimentary backgrounds were subjected to transthoracic echocardiographic measurements. WHT was then analyzed to determine cardiac energetics, telomerase activity, the expression of energy-sensing networks, tissue-specific adiponectin, and cardiac precursor/cardiac stem cell markers.Animals with a balanced diet consumption before CR presented marked cardiac remodeling with improved ejection fraction (EF) and fractional shortening (FS), enhanced OXPHOS complex I, III, and IV, and CKMT2 enzymatic activity. Mice fed an HCD before CR presented moderate changes in cardiac geometry with diminished EF and FS values, but improved OXPHOS complex IV and CKMT2 activity.Differences in cardiac remodeling, left ventricular systolic/diastolic performance, and mitochondrial energetics, found in the CR-treated mice with contrasting alimentary backgrounds, were corroborated by inconsistencies in the expression of mitochondrial-biogenesis-related markers and associated regulatory networks. In particular, disruption of eNOS and AMPK -PGC-1α-mTOR-related axes.The impact of a past habit of caloric overload on the effects of CR in the WHT is a scarcely explored subject that requires deeper study in combination with analyses of other tissues and organs at higher levels of organization within the organ system. Such research will eventually lead to the development of preventative and therapeutic strategies to promote health and longevity.

Identifying Sex‐dependent Markers of Heart Failure and Atrial Myopathy

Heart failure (HF) with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) each represent approximately ½ of current HF cases. HFrEF is a cardiac-centric syndrome, driven by cell loss and dysfunction leading to dilated cardiomyopathy. HFpEF, alternatively, is a systemic syndrome characterized by accumulated risk factors, comorbidities, and a stiff heart with diastolic dysfunction, sometimes clinically presenting as restrictive cardiomyopathy. Recent studies have established that women constitute the majority of patients with HFpEF and that female sex is one of the strongest distinguishing features of HFpEF versus HFrEF. Comorbidities in females include obesity, hypertension, and diabetes. HFrEF or systolic HF is more common in males, and risk factors include smoking and heart attack. While numerous devices and pharmacological agents reduce mortality in HFrEF, no current medications are similarly effective for HFpEF; thus, the un-responsive HFpEF proportion is rising. Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with HF and also demonstrates sex differences in incidence. Both AF and HFpEF have shared risk factors and confer increased risks for adverse cardiovascular outcomes. Since sex-specific variables that contribute to HF development and progression are largely unknown, increasing our knowledge about molecular mechanisms involved in metabolic and structural changes in the male versus female failing heart will allow us to pinpoint possible targets for safer and more effective sex-specific therapeutic strategies. We haves recently developed a mouse model that recapitulates this sexual dimorphism in HF and atrial susceptibility. In this model, female mice only exhibit continuous left ventricular hypertrophy, diastolic dysfunction, preserved ejection fraction, pulmonary congestion, arrhythmia, and reduced exercise tolerance, mimicking the clinical symptoms of restrictive cardiomyopathy. Thus, this mouse line represents a novel tool to interrogate sex differences in cardiac remodeling at the functional, structural, and biochemical level at baseline or with coordinate cardiac or metabolic stress. These mice were generated by crossing the βARKnt line (residues 50-145) with the βARKct line, peptide fragments of the prototypical G protein-coupled receptor (GPCR) kinase (GRK) GRK2 (βARK1). Breeding of βARKnt (NT) with βARKct (M27) single-transgenic mice results in a combination of all four possible genotypes, non-transgenic littermate controls (NLC)/NLC, NT/NLC (TG/NLC), NLC/M27 (NLC/TG), and NT/M27 (TG/TG), born as littermate controls. Heart weight normalized to tibia length (HW/TL) was significantly increased in 9-12 week old female and male TG/NLC and TG/TG mice, but left atrial weight was enhanced only in the TG/TG mice and to a greater extent in females that males. Despite no difference in ventricular myocyte area, ventricular fibrosis, atrial myocyte area, and atrial fibrosis were significantly increased in female NT/M27 mice only. Further, this was accompanied by a significant increase in mitral valve E/A (ventricular relaxation/atrial contraction) ratio in these mice.

Impact of sex on cardiac remodeling and long-term outcomes, following mitral valve replacement.

Differences in cardiac remodeling after mitral valve (MV) surgery between the sexes is poorly understood. Inferior outcomes for females undergoing MV surgery compared with males have been suggested in the literature, although causative factors behind this discrepancy have not been identified. MATERIALSANDMETHODS: In this propensity-matched, retrospective, single-center study, we sought to identify the impact that sex may have on cardiac remodeling and long-term outcomes to better inform clinical decision-making in MV surgical intervention. Outcomes were compared between males and females undergoing MV replacement (MVR) between 2004 and 2018. The primary outcome was cardiac remodeling 1 yearpostoperatively. Secondary outcomes included mortality, stroke, myocardial infarction (MI), reoperation of the MV, and rehospitalization. A total of 311 males and 311 females were included after propensity matching. Both groups demonstrated significant improvement in left atrial remodeling, although only males demonstrated a significant degree of improved left ventricular remodeling while their female counterparts did not. Mortality rates were relatively equivalent between the two groups, although males were more likely to develop sepsis and require rehospitalization due to MI. There has been little research exploring the differences in cardiac remodeling between the sexes after MVR. The results of this study have suggested that MVR is equally safe for both sexes and has demonstrated a difference in the heart's ability to remodel after MVR. The significance of this difference has the potential to result in largely different clinical outcomes for males and females. Further study is necessary to fully elucidate this relationship.

Sex-Specific Effects of Daily Tadalafil on Contraction Kinetics of the Diabetic Heart. The RECOGITO Randomized, Double-Blind, Placebo-Controlled Trial

Background: Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes (T2DM) patients. Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition was shown to counteract maladaptive cardiac changes triggered by diabetes in some studies. Our aim was to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy (DCM). Methods: We performed a 20-week, double-blind, randomized, placebo-controlled trial. Men and women (45–80 years) with controlled T2DM and echocardiographic (ECG) signs of cardiac remodeling were randomly assigned (1:1) to placebo or tadalafil 20 mg once daily. The primary outcome was analyzing the sex-difference in cardiac torsion change, from baseline to 20 weeks. Secondary outcomes included changes in cardiovascular, metabolic, immune and renal function. Efficacy analyses included all patients who received at least one dose of treatment. Findings: Between May 2014 and July 2018, we screened 220 diabetic subjects; 122 met the inclusion criteria and were randomized to tadalafil (n=61) or placebo (n=61). At 20 weeks, the sex-by-treatment interaction documented an improvement in cardiac torsion [-3·40°(-5·96;-0·84, p =0·011)], paralleled by a consensual increase in fiber shortening, in men but not women. Biomarkers of cardiovascular remodeling , titin and hsa-miR-199-5p, improved accordingly. In both sexes, tadalafil reduced TGF-beta and improved albuminuria, renal artery’s resistive index, Klotho , and symmetric-di-methyl-arginine markers . Five months of 20 mg daily tadalafil in patients with DCM was proven safe. The most common adverse reactions were myalgia (9[14·5%]), gastric reflux (6[9·7%]), headache (4[6·4%]) and flushing (2[3·8%]); one SAE occurred in the placebo arm. Interpretation: Continuous PDE5 inhibition could represent a new treatment strategy to target cardiac and renal complications of T2DM, with a different tissue-specific response in men and women. Klotho and hsa-miR-199-5p appear as novel players linking renal disease to DCM progression. Trial Registration: NCT01803828. Funding Statement: Italian Ministry of University and Research, SIR RBSI141LY2. Declaration of Interests: Prof. Isidori reports personal fees from Takeda; non-financial support from Takeda and Ipsen; and grants from Shire and Pfizer outside the submitted work; Prof. Pozzilli reports research contracts and consulting from Eli Lilly, Sanofi, Merck, Merck Sharpt Dohme, Astra Zeneca, Medtronic, Abbott; Dr. Defeudis reports grants from Ibsa, personal fees from Abbott, grants from Novo Nordisk, grants from Kyowa Kirin , personal fees from Roche, outside the submitted work; Prof. Badagliacca reports personal fees from Bayer, personal fees from MSD, personal fees from Dompe, personal fees from GSK, personal fees from Ferrer, personal fees from United Therapeutics, personal fees from Galenica, personal fees from Janssen, outside the submitted work; all others have nothing to disclose. Ethics Approval Statement: The study was performed in the Policlinico Umberto I in Rome (Italy) and approved by the local ethical review board (3083/14), published on public registries (NCT01803828, EUDRACT 2014-000077-39), and conducted under the Declaration of Helsinki and good clinical practice.

Sex-Related Differences in Cardiac Remodeling and Reverse Remodeling After Transcatheter Aortic Valve Implantation in Patients with Severe Aortic Stenosis in a Japanese Population.

Left ventricular (LV) remodeling with aortic stenosis (AS) appears to differ according to sex, but reverse remodeling after transcatheter aortic valve implantation (TAVI) has not been elucidated in a Japanese population. This study aims to determine whether any sex-related differences in LV or reverse remodeling after TAVI exist in the context of severe AS.Of 208 patients who received TAVI for severe AS in our institution, 100 (men, 42; mean age, 83.0 ± 4.9 years) underwent transthoracic echocardiography before and 3 months after TAVI. Despite similar valvular gradients, women with severe AS had lower indexed LV mass (LVMi) than did men (152.3 ± 35.4 versus 173.2 ± 44.6 g/m2, P = 0.005), with smaller indexed LV end-diastolic (LVEDVi) (50.2 ± 13.3 versus 61.4 ± 20.7 mL/m2, P = 0.001) and end-systolic (LVESVi; 17.9 ± 8.7 versus 24.3 ± 13.8 mL/m2, P = 0.006) volumes. After TAVI, women (-6.0% ± 14.4%) had higher reduction in the rate of change of relative wall thickness (RWT) than did men (4.4% ± 19.0%, P = 0.003). Men (-8.9% ± 3.9%) had higher reduction in the rate of change of LVEDVi than did women (1.5% ± 3.3%, P = 0.045). Incidence of LV reverse remodeling defined as a reduction in LVESV of >15% was significantly higher in men (50%) than in women (26%, P = 0.013).In addition to sex differences in the pattern of LV remodeling with AS, reverse LV remodeling after TAVI also differed between sexes.

P1419 Sex-related differences in cardiac remodeling in health and hypertension

Abstract Funding Acknowledgements National Medical Research Council OnBehalf National Heart Centre Singapore BACKGROUND Adverse cardiac remodelling is associated with worse cardiovascular outcomes. Development of left ventricular hypertrophy (defined as increased myocardial mass) is a complex process mediated by myocardial wall thickening and/or ventricular dilatation. Sex-related differences in the relationship between myocardial mass and wall thickening/ventricular dilatation have not been well-described. PURPOSE We examine differences in determinants and patterns of cardiac remodeling between males and females. METHODS Comprehensive cardiovascular magnetic resonance imaging was performed in 1006 participants: 316 healthy volunteers (50% males, 46 ± 14 years) and 690 asymptomatic hypertensive patients (60% males, 57 ± 11 years). Myocardial mass, ventricular volumes and maximal myocardial wall thickness (across 16 myocardial segments) were measured using standardized contouring techniques. Clinically relevant variables (age, weight, height, and adiposity) that demonstrated significant univariate association with myocardial mass (P &amp;lt; 0.05) were selected in the multivariable linear regression model using the forward approach. RESULTS Increased body weight, lower body fat composition and higher systolic blood pressures were independently associated with increased myocardial mass in healthy volunteers (males and females) and hypertensive females. In hypertensive males, only increased body weight and elevated systolic blood pressure were independently associated with increased myocardial mass. The association between myocardial mass and ventricular volumes was almost identical between males and females (P = 0.65 for interaction; Figure). Conversely, there was a significant gender-related difference in the association between wall thickness and myocardial mass after adjusting for potential confounders (P &amp;lt; 0.001 for interaction). Concentric remodeling was initially more evident in males; but further with increase, myocardial mass was associated with greater concentric remodeling in females (Figure). Similar results were observed when analyses were performed separately in healthy volunteers and hypertensive patients. CONCLUSION There were sex-related differences in concentric remodeling at progressive stages of myocardial hypertrophy that may explain the higher prevalence of heart failure with preserved ejection fraction reported in females. Abstract P1419 Figure

Gender Differences in Cardiac Remodeling Induced by a High-Fat Diet and Lifelong, Low-Dose Cadmium Exposure.

Childhood obesity, which is prevalent in developed countries, is a metabolic risk factor for cardiovascular disease. Cadmium (Cd), a ubiquitous environmental toxic metal, also has deleterious effects on the cardiovascular system. However, the combined effects of a high-fat diet (HFD) and lifelong, low-dose Cd exposure on cardiac remodeling remain unclear. This study aims to determine the effects of combined HFD and Cd exposure on cardiac remodeling, as well as gender-specific differences in the response. C57BL/6J mice were exposed to Cd at a low dose (L-Cd, 0.5 ppm) or high dose (H-Cd, 5 ppm) via drinking water from conception to sacrifice. After being weaned, the offspring mice were fed with a HFD (42% kcal from fat) for an additional 10 weeks. H-Cd exposure significantly increased Cd accumulation in the hearts of both parents and their offspring; a HFD showed no added effects on cardiac Cd content. H-Cd exposure increased cardiac metallothionein protein levels only in female mice, regardless of dietary intake. Histological analysis revealed that H-Cd exposure combined with a HFD induced cardiac hypertrophy and fibrosis only in female mice. This was further supported by elevated expression of ANP and COL1A1 protein levels along with COL1A1, COL1A2, and COL3A1 mRNA levels. Profibrotic markers PAI-1, CTGF, and FN were also elevated in HFD/H-Cd-exposed female mice. Levels of the oxidative stress marker 3-NT significantly increased in the hearts of HFD-fed female mice, whereas Cd exposure showed no additional effects. Of all the antioxidant markers examined, levels of CAT significantly increased in mice fed a HFD, regardless of gender and Cd exposure. In summary, a HFD combined with lifelong, low-dose Cd exposure induces cardiac hypertrophy and fibrosis in female but not male mice, a response that is independent of oxidative stress.

HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study.

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure ( P=0.004), diastolic blood pressure (0.012), and more frequently had hypertension ( P<0.001). Compared with WT/WT, H63D/WT and H63D/H63D participants had a 2% to 4% and 4% to 7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45 to 64 was 3.2% (95% CI, 1.3-5.1%) and 1.3% (95% CI, 0.0-2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome ( P>0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

Association of the common genetic polymorphisms and haplotypes of the chymase gene with left ventricular mass in male patients with symptomatic aortic stenosis.

We investigated the association between polymorphisms and haplotypes of the chymase 1 gene (CMA1) and the left ventricular mass index (LVM/BSA) in a large cohort of patients with aortic stenosis (AS). Additionally, the gender differences in cardiac remodeling and hypertrophy were analyzed. The genetic background may affect the myocardial response to pressure overload. In human cardiac tissue, CMA1 is involved in angiotensin II production and TGF-β activation, which are two major players in the pathogenesis of hypertrophy and fibrosis. Preoperative echocardiographic data from 648 patients with significant symptomatic AS were used. The LVM/BSA was significantly lower (p<0.0001), but relative wall thickness (RWT) was significantly higher (p = 0.0009) in the women compared with the men. The haplotypes were reconstructed using six genotyped polymorphisms: rs5248, rs4519248, rs1956932, rs17184822, rs1956923, and rs1800875. The haplotype h1.ACAGGA was associated with higher LVM/BSA (p = 9.84×10−5), and the haplotype h2.ATAGAG was associated with lower LVM/BSA (p = 0.0061) in men, and no significant differences were found in women. Two polymorphisms within the promoter region of the CMA1 gene, namely rs1800875 (p = 0.0067) and rs1956923 (p = 0.0015), influenced the value of the LVM/BSA in males. The polymorphisms and haplotypes of the CMA1 locus are associated with cardiac hypertrophy in male patients with symptomatic AS. Appropriate methods for the indexation of heart dimensions revealed substantial sex-related differences in the myocardial response to pressure overload.

Gender-based differences in cardiac remodeling and ILK expression after myocardial infarction.

BackgroundGender can influence post-infarction cardiac remodeling.ObjectiveTo evaluate whether gender influences left ventricular (LV) remodeling and integrin-linked kinase (ILK) after myocardial infarction (MI).MethodsFemale and male Wistar rats were assigned to one of three groups: sham, moderate MI (size: 20-39% of LV area), and large MI (size: ≥40% of LV area). MI was induced by coronary occlusion, and echocardiographic analysis was performed after six weeks to evaluate MI size as well as LV morphology and function. Real-time RT-PCR and Western blot were used to quantify ILK in the myocardium.ResultsMI size was similar between genders. MI resulted in systolic dysfunction and enlargement of end-diastolic as well as end-systolic dimension of LV as a function of necrotic area size in both genders. Female rats with large MI showed a lower diastolic and systolic dilatation than the respective male rats; however, LV dysfunction was similar between genders. Gene and protein levels of ILK were increased in female rats with moderate and large infarctions, but only male rats with large infarctions showed an altered ILK mRNA level. A negative linear correlation was evident between LV dimensions and ILK expression in female rats with large MI.ConclusionsPost-MI ILK expression is altered in a gender-specific manner, and higher ILK levels found in females may be sufficient to improve LV geometry but not LV function.

Poorer Right Ventricular Systolic Function and Exercise Capacity in Women After Repair of Tetralogy of Fallot

In repaired congenital heart disease, there is increasing evidence of sex differences in cardiac remodeling, but there is a lack of comparable data for specific congenital heart defects such as in repaired tetralogy of Fallot. In a prospective multicenter study, a cohort of 272 contemporary patients (158 men; mean age, 14.3±3.3 years [range, 8-20 years]) with repaired tetralogy of Fallot underwent cardiac magnetic resonance for ventricular function and metabolic exercise testing. All data were transformed to standard deviation scores according to the Lambda-Mu-Sigma method by relating individual values to their respective 50th percentile (standard deviation score, 0) in sex-specific healthy control subjects. No sex differences were observed in age at repair, type of repair conducted, or overall hemodynamic results. Relative to sex-specific controls, repaired tetralogy of Fallot in women had larger right ventricular end-systolic volumes (standard deviation scores: women, 4.35; men, 3.25; P=0.001), lower right ventricular ejection fraction (women, -2.83; men, -2.12; P=0.011), lower right ventricular muscle mass (women, 1.58; men 2.45; P=0.001), poorer peak oxygen uptake (women, -1.65; men, -1.14; P<0.001), higher VE/VCO2 (ventilation per unit of carbon dioxide production) slopes (women, 0.88; men 0.58; P=0.012), and reduced peak heart rate (women, -2.16; men -1.74; P=0.017). Left ventricular parameters did not differ between sexes. Relative to their respective sex-specific healthy control subjects, derived standard deviation scores in repaired tetralogy of Fallot suggest that women perform poorer than men in terms of right ventricular systolic function as tested by cardiac magnetic resonance and exercise capacity. This effect cannot be explained by selection bias. Further outcome data are required from longitudinal cohort studies.

Gender Differences in Cardiac Remodeling and Clinical Outcomes in Chronic Stable Angina Pectoris (from the ACTION Trial)

Our objective was to determine the gender differences in the relation between the echocardiographic parameters of cardiac remodeling and clinical outcomes in patients with chronic stable angina. The baseline ejection fraction (EF), end-diastolic volume, and end-systolic volume were assessed in 7,016 patients in the study "A Coronary disease Trial Investigating Outcomes with Nifedipine gastrointestinal therapeutic system" (ACTION). All-cause and cardiac mortality and incident heart failure were determined after a median of 5.0 years. Cox proportional hazard models were fit to determine the effect of gender on the relation between the echocardiographic parameters and clinical outcomes (interaction p <0.10). The association between the EF and mortality differed significantly between men and women, with women demonstrating a marked increase in risk as the EF decreased, compared to men (interaction p = 0.03, adjusted p = 0.07). Also, a significant interaction by gender was seen for the association between the end-systolic volume and the risk of heart failure (interaction p = 0.01, adjusted p = 0.05). In conclusion, the relation between EF and mortality differed according to gender in patients with chronic coronary disease, with women having a greater risk of adverse outcomes as the EF decreased. Similar findings were observed with the end-systolic and end-diastolic volumes and the risk of heart failure. These findings may reflect inherent gender-based differences in ischemic heart disease and cardiac remodeling and might help to identify women at high risk.

Reverse remodeling and improved function by antihypertensive treatment in hypertensive patients with coronary artery disease

Although antihypertensive therapy reduces cardiovascular events, it is unclear whether there are differences in cardiac remodeling and function between treatments with nifedipine retard and angiotensin-converting enzyme inhibitors (ACE-Is). It is also not clear how antihypertensive therapy influences cardiac remodeling and function. Hypertensive patients with coronary artery disease were randomly assigned to the nifedipine retard (n = 108) or ACE inhibitors groups (n = 102) and treated for 3 years. The primary endpoints were changes in end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) as indices of cardiac remodeling, whereas the secondary endpoints were changes in ejection fraction (EF), stroke volume index (SVI), cardiac index (CI) and regional wall motion as indices of cardiac function. Left ventriculography was performed at baseline and after 3 years of treatment. Fifty-eight and 61 patients, respectively, were subjected to the final analysis. Comparable changes in remodeling and function were obtained in the nifedipine retard group and the ACE-Is group. Both groups showed a significant reduction of EDVI and ESVI, and a significant increase in EF, SVI, and CI, whereas the decreased regional wall motion significantly improved. In both groups, weak but significant correlations were noted between treatment-induced changes of systolic blood pressure and those of primary and secondary endpoints. The above findings show that treatments with nifedipine retard or ACE-Is cause a comparable change in remodeling and cardiac function. Lowering of the blood pressure by either drug leads to reverse remodeling or improvement of cardiac function. In addition to alleviation of coronary artery damage by reducing blood pressure, there is a favorable effect on the left ventricular structure and function. Reducing the blood pressure is critically important for hypertensive patients with coronary artery disease.

Gender differences in post-infarction hypertrophy in end-stage failing hearts

ObjectivesWe explored whether there are gender differences in cardiac remodeling and whether etiology influences organ and cellular remodeling in advanced heart failure (HF). BackgroundSeveral studies have shown a survival benefit for women compared to men with symptomatic HF. This observation may be related to gender differences in cardiac remodeling. MethodsWe studied hearts from 100 patients (72 men and 28 women) receiving cardiac transplantation at our institution. Cardiac morphology was assessed with echocardiography and direct measurement of cardiac mass. Cardiac myocyte volume, length, width, cross-sectional area, and contraction were measured using previously validated techniques. ResultsAmong 50 patients with idiopathic cardiomyopathy (CM), we observed no gender-based differences in cardiac or cellular remodeling. In contrast, among 50 patients with ischemic cardiomyopathy (ICM), the heart weight index was significantly greater in men, and there was a strong trend toward an increased left ventricular (LV) mass index as well. These gender differences in cardiac and LV mass were paralleled by marked gender differences in myocyte volume, such that average myocyte volume was 36% greater in men than in women, in association with a 14% increase in resting cell length. ConclusionsOur studies demonstrate a multilevel gender difference in post-infarction remodeling, with women exhibiting reduced hypertrophy. Our studies further demonstrate that gender differences in cardiac remodeling in ICM are largely related to fundamental differences in cellular remodeling rather than simply differences in infarct size or expansion. Distinctions observed between ischemic and idiopathic CM suggest that gender may influence local myocardial responses to injury.