Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice

There are conflicting data about gender differences in cardiac function after myocardial infarction (MI), including cardiac rupture and mortality. Using a mouse model of MI, we recently found that the cardiac rupture rate during the first week after MI was significantly lower in females than in males, suggesting that females have attenuated structural remodeling. Thus in this study, we attempted to determine whether: a) females have attenuated remodeling and faster healing during the early phase post-MI, and b) females have better cardiac function and outcome during the chronic phase compared to males. MI was induced in 12-week-old male and female C57BL/6J mice. Signs of early remodeling, including cardiac rupture, infarct expansion, inflammatory response, and collagen deposition, were studied during the first 2 weeks post-MI. Left ventricular remodeling and function were followed for 12 weeks post-MI. We found that males had a higher rate of cardiac rupture, occurring mainly at 3 to 5 days of MI and associated with a higher infarct expansion index. Neutrophil infiltration at the infarct border was more pronounced in males than females during the first days of MI, which were also characterized by increased MMP activity. However, the number of infiltrating macrophages was significantly higher in females at day 4. During the chronic phase post-MI, males had significantly poorer LV function, more prominent dilatation and significant myocyte hypertrophy compared to females. In conclusion, males have delayed myocardial healing, resulting in cardiac rupture, and the survivors have poorer cardiac function and pronounced maladaptive remodeling, whereas females show a better outcome during the development of HF.     

Influence of gender on the response to hemodynamic overload after myocardial infarction

After myocardial infarction (MI), the left ventricle (LV) undergoes ventricular remodeling characterized by progressive global dilation, infarct expansion, and compensatory hypertrophy of the noninfarcted myocardium. Little attention has been given to the response of remodeling myocardium to additional hemodynamic overload. Studies have indicated that gender may influence remodeling and the response to both MI and hemodynamic overload. We therefore determined 1) structural and function consequences of superimposing hemodynamic overload (systemic hypertension) on remodeling myocardium after a MI and 2) the potential influence of gender on this remodeling response. Male and female Dahl salt-sensitive and salt-resistant rats underwent coronary ligation, resulting in similar degrees of MI. One week post-MI, all rats were placed on a high-salt diet. Four groups were then studied 4 wk after initiation of high-salt feeding: MI female, MI female + hypertension, MI male, and MI male + hypertension. Hypertension-induced pressure overload resulted in additional comparable degrees of myocardial hypertrophy in both females and males. In females, hypertension post-MI resulted in concentric hypertrophy with no additional cavity dilation and no measurable scar thinning. In contrast, in males, hypertension post-MI resulted in eccentric hypertrophy, further LV cavity dilation, and scar thinning. Physiologically, concentric hypertrophy in post-MI hypertensive females resulted in elevated contractile function, whereas eccentrically hypertrophied males had no such increase. Female gender influences favorably the remodeling and physiological response to hemodynamic overload after large MI.     

Coronary vessels and cardiac myocytes of middle-aged rats demonstrate regional sex-specific adaptation in response to postmyocardial infarction remodeling

Background

An increasing body of evidence indicates that left ventricular (LV) remodeling, especially the degree of reactive myocardial hypertrophy after myocardial infarction (MI), differs in males and females. Surprisingly, to date, the sex-specific post-MI alterations of the coronary vasculature remain undetermined. Therefore, we tested the hypothesis that adaptive coronary arteriolar and capillary modifications occurring in response to reactive myocyte hypertrophy differ between middle-aged male and female post-MI rats.

Methods

A large MI was induced in 12-month-old male (M-MI) and female (F-MI) Sprague–Dawley rats by ligation of the left coronary artery. Four weeks after surgery, rats with transmural infarctions, greater than 50% of the LV free wall (FW), were evaluated. Sham-operated male (M-Sham) and female (F-Sham) rats served as an age-matched controls.

Results

F-MI and M-MI rats had similar sized infarcts (61.3%?±?3.9% vs. 61.5%?±?1.2%) and scale of LV remodeling, as indicated analogous remodeling indices (1.41?±?0.11 vs. 1.39?±?0.09). The degree of reactive post-MI myocardial hypertrophy was adequate to normalize LV weight-to-body weight ratio in both sexes; however, the F-MI rats, in contrast to males, showed no myocyte enlargement in the LVFW epimyocardium. At the same time, a greater than 50% expansion of myocyte area in the male epimyocardium and in the female endomyocardium was accompanied by a 23% (P?<?0.05) increase in capillary-to-myocyte ratio, indicative of adaptive angiogenesis. Based on arteriolar length density in post-MI hearts, the resistance vessels grew in the male LVFW as well as the septum by 24% and 29%, respectively. In contrast, in females, a significant (30%) expansion of arteriolar bed was limited only to the LVFW. Moreover, in F-MI rats, the enlargement of the arteriolar bed occurred predominantly in the vessels with diameters <30 μm, whereas in M-MI rats, a substantial (two- to threefold) increase in the density of larger arterioles (30 to 50 μm in diameter) was also documented.

Conclusion

Our data reveal that while both sexes have a relatively similar pattern of global LV remodeling and adaptive angiogenesis in response to a large MI, male and female middle-aged rats differ markedly in the regional scale of reactive cardiac myocyte hypertrophy and adaptive arteriogenesis.     

Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction

Contractile dysfunction is common to many forms of cardiovascular disease. Approaches directed at enhancing cardiac contractility at the level of the myofilaments during heart failure (HF) may provide a means to improve overall cardiovascular function. We are interested in gender-based differences in cardiac function and the effect of sarcomere activation agents that increase contractility. Thus, we studied the effect of gender and time on integrated arterial-ventricular function (A-V relationship) following myocardial infarction (MI). In addition, transgenic mice that overexpress the slow skeletal troponin I isoform were used to determine the impact of increased myofilament Ca(2+) sensitivity following MI. Based on pressure-volume (P-V) loop measurements, we used derived parameters of cardiovascular function to reveal the effects of sex, time, and increased myofilament Ca(2+) sensitivity among groups of post-MI mice. Analysis of the A-V relationship revealed that the initial increase was similar between the sexes, but the vascular unloading of the heart served to delay the decompensated stage in females. Conversely, the vascular response at 6 and 10 wk post-MI in males contributed to the continuous decline in cardiovascular function. Increasing the myofilament Ca(2+) sensitivity appeared to provide sufficient contractile support to improve contractile function in both male and female transgenic mice. However, the improved contractile function was more beneficial in males as the concurrent vascular response contributed to a delayed decompensated stage in female transgenic mice post-MI. This study represents a quantitative approach to integrating the vascular-ventricular relationship to provide meaningful and diagnostic value following MI. Consequently, the data provide a basis for understanding how the A-V relationship is coupled between males and females and the enhanced ability of the cardiovascular system to tolerate pathophysiological stresses associated with HF in females.     

Breeding Strategy Determines Rupture Incidence in Post-Infarct Healing WARPing Cardiovascular Research

Background

Von Willebrand A domain Related Protein (WARP), is a recently identified extracellular matrix protein. Based upon its involvement in matrix biology and its expression in the heart, we hypothesized that WARP regulates cardiac remodeling processes in the post-infarct healing process.

Methods and results

In the mouse model of myocardial infarction (MI), WARP expression increased in the infarcted area 3-days post-MI. In the healthy myocardium WARP localized with perlecan in the basement membrane, which was disrupted upon injury. In vitro studies showed high expression of WARP by cardiac fibroblasts, which further increases upon TGFβ stimulation. Furthermore, WARP expression correlated with aSMA and COL1 expression, markers of fibroblast to myofibroblast transition, in vivo and in vitro. Finally, WARP knockdown in vitro affected extra- and intracellular basic fibroblast growth factor production in myofibroblasts. To investigate the function for WARP in infarction healing, we performed an MI study in WARP knockout (KO) mice backcrossed more than 10 times on an Australian C57Bl/6-J background and bred in-house, and compared to wild type (WT) mice of the same C57Bl/6-J strain but of commercial European origin. WARP KO mice showed no mortality after MI, whereas 40% of the WT mice died due to cardiac rupture. However, when WARP KO mice were backcrossed on the European C57Bl/6-J background and bred heterozygous in-house, the previously seen protective effect in the WARP KO mice after MI was lost. Importantly, comparison of the cardiac response post-MI in WT mice bred heterozygous in-house versus commercially purchased WT mice revealed differences in cardiac rupture.

Conclusion

These data demonstrate a redundant role for WARP in the wound healing process after MI but demonstrate that the continental/breeding/housing origin of mice of the same C57Bl6-J strain is critical in determining the susceptibility to cardiac rupture and stress the importance of using the correct littermate controls.     

Cardiac Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase Causes Adverse Myocardial Remodeling following Myocardial Infarction

The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.     

Increased infarct wall thickness by a bio-inert material is insufficient to prevent negative left ventricular remodeling after myocardial infarction

Background

Several injectable materials have been shown to preserve or improve cardiac function as well as prevent or slow left ventricular (LV) remodeling post-myocardial infarction (MI). However, it is unclear as to whether it is the structural support or the bioactivity of these polymers that lead to beneficial effects. Herein, we examine how passive structural enhancement of the LV wall by an increase in wall thickness affects cardiac function post-MI using a bio-inert, non-degradable synthetic polymer in an effort to better understand the mechanisms by which injectable materials affect LV remodeling.

Methods and Results

Poly(ethylene glycol) (PEG) gels of storage modulus G′ = 0.5±0.1 kPa were injected and polymerized in situ one week after total occlusion of the left coronary artery in female Sprague Dawley rats. The animals were imaged using magnetic resonance imaging (MRI) at 7±1 day(s) post-MI as a baseline and again post-injection 49±4 days after MI. Infarct wall thickness was statistically increased in PEG gel injected vs. control animals (p<0.01). However, animals in the polymer and control groups showed decreases in cardiac function in terms of end diastolic volume, end systolic volume and ejection fraction compared to baseline (p<0.01). The cellular response to injection was also similar in both groups.

Conclusion

The results of this study demonstrate that passive structural reinforcement alone was insufficient to prevent post-MI remodeling, suggesting that bioactivity and/or cell infiltration due to degradation of injectable materials are likely playing a key role in the preservation of cardiac function, thus providing a deeper understanding of the influencing properties of biomaterials necessary to prevent post-MI negative remodeling.     

Cardiac stem cell therapy to modulate inflammation upon myocardial infarction

Background

After myocardial infarction (MI) a local inflammatory reaction clears the damaged myocardium from dead cells and matrix debris at the onset of scar formation. The intensity and duration of this inflammatory reaction are intimately linked to post-infarct remodeling and cardiac dysfunction. Strikingly, treatment with standard anti-inflammatory drugs worsens clinical outcome, suggesting a dual role of inflammation in the cardiac response to injury. Cardiac stem cell therapy with different stem or progenitor cells, e.g. mesenchymal stem cells (MSC), was recently found to have beneficial effects, mostly related to paracrine actions. One of the suggested paracrine effects of cell therapy is modulation of the immune system.

Scope of review

MSC are reported to interact with several cells of the immune system and could therefore be an excellent means to reduce detrimental inflammatory reactions and promote the switch to the healing phase upon cardiac injury. This review focuses on the potential use of MSC therapy for post-MI inflammation. To understand the effects MSC might have on the post-MI heart the cellular and molecular changes in the myocardium after MI need to be understood.

Major conclusions

By studying the general pathways involved in immunomodulation, and examining the interactions with cell types important for post-MI inflammation, it becomes clear that MSC treatment might provide a new therapeutic opportunity to improve cardiac outcome after acute injury.

General significance

Using stem cells to target the post-MI inflammation is a novel therapy which could have considerable clinical implications. This article is part of a Special Issue entitled Biochemistry of Stem Cells.     

StemBell therapy stabilizes atherosclerotic plaques after myocardial infarction

Background aims. After a myocardial infarction (MI) atherosclerosis is accelerated leading to destabilization of the atherosclerotic plaque. mesenchymal stromal cells are a promising therapeutic option for atherosclerosis. Previously, we demonstrated a novel stem cell delivery technique, with adipose stem cells coupled to microbubbles (i.e., StemBells) as therapy after MI. In this study, we aim to investigate the effect of StemBell therapy on atherosclerotic plaques in an atherosclerotic mouse model after MI. Methods. MI was induced in atherosclerotic Apolipoprotein E–deficient mice that were fed a high-fat Western diet. Six days post-MI, the mice received either 5?×?10⁵/100 µL StemBells or vehicle intravenously. The effects of StemBell treatment on the size and stability of aortic root atherosclerotic plaques and the infarcted heart were determined 28 days post-MI via (immuno)histological analyses. Moreover, monocyte subtypes and lipids in the blood were studied. Results. StemBell treatment resulted in significantly increased cap thickness, decreased intra-plaque macrophage density and increased percentage of intra-plaque anti-inflammatory macrophages and chemokines, without affecting plaque size and serum cholesterol/triglycerides. Furthermore, StemBell treatment significantly increased the percentage of anti-inflammatory macrophages within the infarcted myocardium but did not affect cardiac function nor infarct size. Finally, also the average percentage of anti-inflammatory monocytes in the circulation was increased after StemBell therapy. Discussion. StemBell therapy increased cap thickness and decreased intra-plaque inflammation after MI, indicative of stabilized atherosclerotic plaque. It also induced a shift of circulating monocytes and intra-plaque and intra-cardiac macrophages towards anti-inflammatory phenotypes. Hence, StemBell therapy may be a therapeutic option to prevent atherosclerosis acceleration after MI.     

黄连素对小鼠心肌梗死后心室重构的作用研究

目的:探讨黄连素(Berberine,BBR)在小鼠心肌梗死(myocardial infarction,MI)后心室重构中的作用,并比较BBR预处理(BBR pre-treatment,preBBR)和BBR后处理(BBR post-treatment,postBBR)给药的效果。方法:将60只C57BL/6小鼠随机分为4组,分别为假手术组、单纯MI对照组、MI+preBBR组及MI+postBBR组,每组15只。MI模型采用前降支结扎法制备。MI+preBBR组在MI模型制备前2周开始用BBR(100 mg·kg~(-1)·d~(-1))每天灌胃,持续至MI后28 d;MI+postBBR组在MI模型制备后4 h开始用BBR(100 mg·kg~(-1)·d~(-1))每天灌胃,持续至MI后28 d。记录实验期间小鼠生存情况。MI后28天采用小动物超声测定左心室收缩功能;取心脏组织,测定心脏大小和重量;ELISA方法测定血浆BNP水平;Masson染色评价心肌纤维化程度。结果:与单纯MI对照组相比,MI+preBBR组及MI+postBBR组小鼠生存率提高、心脏收缩功能增强、心脏变小、心脏重量减轻、血浆BNP水平降低、心肌纤维化明显改善。其中,MI+preBBR组上述指标的改善程度优于MI+postBBR组。结论:BBR可抑制MI后心室重构,且BBR预处理效果优于后处理。     

Bone Marrow Progenitor Cell Therapy-Mediated Paracrine Regulation of Cardiac miRNA-155 Modulates Fibrotic Response in Diabetic Hearts

Diabetes is associated with a higher incidence of myocardial infarction (MI) and increased risk for adverse vascular and fibrogenic events post-MI. Bone marrow-derived progenitor cell (BMPC) therapy has been shown to promote neovascularization, decrease infarct area and attenuate left ventricular (LV) dysfunction after MI. Unlike vascular effects, the anti-fibrosis mechanisms of BMPC, specifically under diabetic conditions, are poorly understood. We demonstrated that intramyocardial delivery of BMPCs in infarcted diabetic db/db mice significantly down-regulates profibrotic miRNA-155 in the myocardium and improves LV remodeling and function. Furthermore, inhibition of paracrine factor hepatocyte growth factor (HGF) signaling in vivo suppressed the BMPC-mediated inhibition of miR-155 expression and the associated protective effect on cardiac fibrosis and function. In vitro studies confirmed that the conditioned media of BMPC inhibited miR-155 expression and profibrotic signaling in mouse cardiac fibroblasts under diabetic conditions. However, neutralizing antibodies directed against HGF blocked these effects. Furthermore, miR-155 over-expression in mouse cardiac fibroblasts inhibited antifibrotic Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene, non-Alu-containing (SnoN) signaling and abrogated antifibrogenic response of HGF. Together, our data demonstrates that paracrine regulation of cardiac miRNAs by transplanted BMPCs contributes to the antifibrotic effects of BMPC therapy. BMPCs release HGF, which inhibits miR-155-mediated profibrosis signaling, thereby preventing cardiac fibrosis. These data suggest that targeting miR-155 might serve as a potential therapy against cardiac fibrosis in the diabetic heart.     

Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction

Premenopausal women are much less prone to develop cardiovascular disease than men of similar age, but this advantage no longer applies after menopause. We previously found that male mice have a significantly higher rate of cardiac rupture than females during the acute phase of myocardial infarction (MI); however, the effects of sexual hormones on chronic remodeling are unknown. We hypothesized that estrogen (E) may protect the heart from chronic remodeling and deterioration of function post-MI, whereas testosterone (T) may have adverse effects. Mice (4 wk old) of both genders were divided into four groups: female groups consisted of 1) sham ovariectomy (S-Ovx) + placebo (P) (S-Ovx + P), 2) S-Ovx + T, 3) Ovx + P, and 4) Ovx + T; and male groups consisted of 1) sham castration (S-Cas)+ P (S-Cas + P), 2) S-Cas + 17beta-estradiol (E), 3) Cas + P, and 4) Cas + E. MI was induced 6 wk later. Echocardiography was performed to assess cardiac function and left ventricular dimensions (LVD). Myocyte cross-sectional area (MCSA) was measured at the end of the study. In females, both testosterone and ovariectomy decreased ejection fraction (EF) and increased LVD, and when combined they aggravated cardiac function and remodeling further. Testosterone significantly increased MCSA. In males, castration or estrogen increased EF and reduced LVD, whereas castration significantly reduced MCSA. Our data suggest that estrogen prevents deterioration of cardiac function and remodeling after MI, but testosterone worsens cardiac dysfunction and remodeling and has a pronounced effect when estrogen levels are reduced.     

Overexpression of apolipoprotein-B improves cardiac function and increases survival in mice with myocardial infarction

Background

The heart produces apolipoprotein-B containing lipoproteins (apoB) whose function is not well understood. The aim of this study was to evaluate importance of myocardial apoB for cardiac function, structure and survival in myocardial infarction (MI) and heart failure (HF).

Methods and results

MI was induced in mice (n = 137) and myocardial apoB content was measured at 30 min, 3, 6, 24, 48, 120 h and 8 weeks post-MI. Transgenic mice overexpressing apoB (n = 27) and genetically matched controls (n = 27) were used to study the effects of myocardial apoB on cardiac function, remodeling, arrhythmias and survival after MI. Echocardiography was performed at rest and stress conditions at baseline, 2, 4 and 6 week post-MI and cumulative survival rate was registered. The myocardial apoB content increased both in the injured and the remote myocardium (p < 0.05) in response to ischemic injury. ApoB mice had 2-fold higher survival rate (p < 0.05) and better systolic function (p < 0.05) post-MI.

Conclusion

Overexpression of apoB in the heart increases survival and improves cardiac function after acute MI. Myocardial apoB may be an important cardioprotective system in settings such as myocardial ischemia and HF.     

Sex differences in intraventricular hemorrhage rates among very low birth weight newborns

Background: The influence of male or female sex on newborn outcomes has been recognized for >30 years. Several studies have observed higher mortality and morbidity in males than in females. It is not clear how this sex difference is sustained in postnatal complications such as intraventricular hemorrhage (IVH), especially in very low birth weight (VLBW) newborns.Objective: This study examined possible sex-related differences in IVH rates among VLBW neonates.Methods: In a retrospective observational study conducted in Hospital Privado, Córdoba, Argentina, data from 332 consecutive VLBW newborns in a 12-year period were reviewed. Maternal factors, labor and delivery characteristics, and neonatal parameters, including the results of cranial ultrasound examination to detect IVH, were compared for males and females. Bivariate and multivariate logistic regression analyses were performed.Results: A total of 322 VLBW newborns were included, 168 males and 154 females. Compared with female neonates, male neonates had a higher risk of overall IVH (26.8% vs 9.7%; odds ratio [OR] = 3.4 [95% CI, 1.8–6.4]; P < 0.001) and for grades III or IV on the Papile scale (16.1% vs 1.9%; OR = 9.6 [95% CI, 2.9–32.5]; P < 0.001). In the multivariate logistic regression model, male sex sustained the association with a greater risk of IVH (OR = 6.8 [95% CI, 3.8–12.0]).Conclusions: IVH was significantly associated with male sex in these VLBW newborns. Because other factors affect these differences, further research is required.     

Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function

Cardiac rupture can be fatal after myocardial infarction (MI). Experiments in animals revealed gender differences in rupture rate; however, patient data are controversial. We found a significantly higher rupture rate in testosterone-treated female mice within 1 wk after MI, whereas castration in males significantly reduced rupture. We hypothesized that testosterone may adversely affect remodeling after MI, exaggerating the inflammatory response and increasing cardiac rupture, whereas estrogen may be cardioprotective, attenuating early remodeling and reducing rupture rate. We studied the effect of gender and hormone manipulation on morphological and histological changes during early remodeling after MI in 4-wk-old male and female C57BL/6J mice and how these events could affect cardiac function. Females were randomly divided into 1) sham ovariectomy + placebo (s-ovx + P), 2) s-ovx + testosterone (T), 3) ovx + P, and 4) ovx + T; males were divided into 1) sham castration + P (s-cas + P), 2) s-cas + 17beta-estradiol (E), 3) cas + P, and 4) cas + E. At 6 wk after gonadectomy and hormone manipulation, MI was induced. Mice were randomly killed 1, 2, 4, 7, and 14 days after MI. The left ventricle was weighed and sectioned for evaluation of MI size, infarct expansion index (IEI), and neutrophil infiltration. Transthoracic echocardiography was performed in conscious mice in the 14-day group before organ harvest. Cardiac rupture rate and IEI were significantly higher in testosterone-treated females and noncastrated males than in controls; these effects were accompanied by enhanced neutrophil infiltration and pronounced deterioration of cardiac function and left ventricular dilatation. Ovariectomy in females and estrogen supplementation in males did not confer significant protection from cardiac rupture, IEI, or neutrophil infiltration. We concluded that, in mice, high testosterone levels enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodeling, as indicated by increased cardiac rupture, and possibly causing deterioration of cardiac function after MI, and, conversely, estrogen seems to have no significant protective effect in the acute phase after MI.     

Predictors of depressive symptoms post-acute coronary syndrome

Objective: We examined the influence of gender on the prevalence of acute coronary syndrome (ACS) and the severity of depressive symptoms post-ACS.Methods: Patients received a Zung self-assessment questionnaire at hospital discharge for unstable angina (UA) or acute myocardial infarction (AMI) and returned it by mail. Major depressive symptoms were diagnosed based on a summed depressive symptoms (SDS) score of >50. Depressive symptomatology was modeled by stepwise multivariable logistic regression with the following predictors: gender, age, hypertension, diabetes mellitus, history of smoking, hypercholesterolemia, peripheral vascular disease, prior stroke, prior myocardial infarction (MI), and prior percutaneous coronary intervention or coronary artery bypass graft surgery. We also modeled severity of depressive symptoms via stepwise multiple linear regression with the same predictor variables.Results: A total of 944 patients were surveyed: 716 men and 228 women, mean (SD) age, 67 (13) years and 71 (12) years, respectively. Of these patients, 250 (35%) men and 103 (45%) women had depressive symptoms (P = 0.005). No significant difference was observed between men and women in rates of cardiac catheterization; severity of coronary artery disease; treatment with antiplatelet agents, β-blockers, angiotensin-converting enzyme inhibitors, or statins; or percutaneous or surgical revascularization rates during or post-ACS. Significant predictors of the presence of depressive symptoms were female gender (odds ratio [OR] = 1.64; 95% CI, 1.19-1.28), diabetes mellitus (OR = 1.42; 95% CI, 1.03-1.97), prior MI (OR = 1.56; 95% CI, 1.15-2.20), and smoking (OR = 1.41; 95% CI, 1.01-1.97). Variables significantly associated with a higher severity of depressive symptoms were female gender, prior MI, smoking, and stroke. Men with prior MI had significantly higher mean (SD) SDS scores than did men without prior MI in all age groups (48.4 [11] vs 44.6 [11], respectively; P < 0.001). In addition, significantly more men with prior MI had depressive symptoms compared with those without prior MI (45% vs 32%; P = 0.001). However, prior MI did not appear to affect SDS scores in women (49.1 [12] for prior MI vs 48.5 [12] for no prior MI; P = NS), and there was no significant difference in the percentage of women who had depressive symptoms with or without a history of prior MI. Depressive symptoms were much more severe in women with UA (SDS = 49.0 [12]) compared with women with AMI (SDS = 45.0 [12]; P = NS), or men with AMI (45.0 [12]; P = 0.004) or UA (46.0 [11]; P = 0.007) (analysis of variance, P = 0.003).Conclusions: Female gender is a significant independent predictor of depressive symptoms and their severity post-UA and post-AMI. History of prior MI is associated with a higher frequency and severity of depressive symptoms in men. These findings call for routine screening for depressive symptoms in men with prior MI and in women who present with ACS.     

Gender-Specific Clinical Characteristics of Deep Q Waves in Hypertrophic Cardiomyopathy

Background: Despite male predominance in the prevalence of hypertrophic cardiomyopathy (HCM), repeated diagnosis at our institute indicates a possible higher prevalence of deep Q waves with HCM in women.Objective: The current study examined gender similarities and differences in the prevalence of deep Q waves in HCM and in the morphologic and electrocardiographic features of HCM with deep Q waves.Methods: Patients with HCM underwent cardiac magnetic resonance (CMR) imaging to identify the prevalence of deep Q waves in electrocardiographic limb leads, and to analyze the relationship between distribution patterns of deep Q waves and those of the localization of maximum amplitude of left ventricular (LV) hypertrophy. Contiguous LV short-axis images were obtained from the base toward the apex.Results: Of the 200 consecutive patients (172 males, aged 20–78 years; 28 females, aged 16–79 years) with HCM who underwent CMR imaging, 10 male and 8 female patients had deep Q waves. Deep Q waves were more prevalent in females with HCM than in their male counterparts (28.6% vs 5.8%, respectively; P < 0.001). Of the 18 patients with deep Q waves, maximum wall thickness was localized at either the basal anterior wall or the midventricular septum in 9 (90%) of the 10 male patients and 6 (75%) of the 8 female patients. In both sexes, the Q wave distribution pattern of I and aVL and of II and aVF indicated localization of maximum hypertrophy at the midventricular septum in 6 (75%) of the 8 patients with the former pattern, and at the basal anterior wall in 9 (90%) of the 10 patients with the latter pattern.Conclusions: Diagnostic deep Q waves were detected more frequently in female patients with HCM than in their male counterparts. In HCM with deep Q waves in limb leads, morphologic and electrocardiographic analysis showed similar features in both sexes. (Gend Med.Keywords: deep Q wave, hypertrophic cardiomyopathy, gender, cardiac magnetic resonance.     

Gender-specific patterns of left ventricular and myocyte remodeling following myocardial infarction in mice deficient in the angiotensin II type 1a receptor

Left ventricular (LV) remodeling after myocardial infarction (MI) results from hypertrophy of myocytes and activation of fibroblasts induced, in part, by ligand stimulation of the ANG II type 1 receptor (AT1R). The purpose of the present study was to explore the specific role for activation of the AT 1a R subtype in post-MI remodeling and whether gender differences exist in the patterns of remodeling in wild-type and AT 1a R knockout (KO) mice. AT 1a R-KO mice and wild-type littermates underwent coronary ligation to induce MI or sham procedures; echocardiography and hemodynamic evaluation were performed 6 wk later, and LV tissue was harvested for infarct size determination, morphometric measurements, and gene expression analysis. Survival and infarct size were similar among all male and female wild-type and AT 1a R-KO mice. Hemodynamic indexes were also similar except for lower systolic blood pressure in the AT 1a R-KO mice compared with wild-type mice. Male and female wild-type and male AT 1a R-KO mice developed similar increases in LV chamber size, LV mass corrected for body weight (LV/BW), and myocyte cross-sectional area (CSA). However, female AT 1a R-KO mice demonstrated no increase in LV/BW and myocyte CSA post-MI compared with shams. Both male and female wild-type mice demonstrated higher atrial natriuretic peptide (ANP) levels after MI, with female wild types being significantly greater than males. However, male and female AT 1a R-KO mice developed no increase in ANP gene expression with MI despite an increase in LV mass and myocyte size in males. These data support that gender-specific patterns of LV and myocyte hypertrophy exist after MI in mice with a disrupted AT 1a R gene, and suggest that myocyte hypertrophy post-MI in females relies, in part, on activation of the AT 1a R. Further work is necessary to explore the potential mechanisms underlying these gender-based differences.     

Effects of timed administration of doxycycline or methylprednisolone on post-myocardial infarction inflammation and left ventricular remodeling in the rat heart

The development of strategies to ameliorate post-myocardial infarction (MI) remodeling and improve function continues to be an area of clinical importance. Use of steroids for this purpose is controversial since the effects of timed treatment on relevant inflammatory, biochemical and structure/function endpoints are unclear. In a previous report, we demonstrated that use of doxycycline pre-treatment improves post-MI remodeling and passive left ventricular (LV) function. However, the effects of timed doxycyline post-MI treatment are unknown. To examine these issues, we performed a study using a rat MI model. Animals were administered one of the following: doxycycline (DOX), the corticosteroid methylprednisolone (MP), or aqueous vehicle. Treatment was given early, short-term (at time of MI to 24 h post-MI) or late, long term (2–7 days post-MI). Animals were sacrificed at 3, 7 or 42 days post-surgery. We assessed LV hemodynamics, pressure–volume, and pressure–scar strains, histomorphometry, inflammation via measurements of myeloperoxidase activity, and matrix metalloproteinase (MMP) activity. Late MP treatment yielded a robust right-shifted pressure–volume curve, which was accompanied by increased scar strains. Late DOX treatment yielded reduced average heart weight and size and preserved scar thickness. DOX treatment did not suppress inflammation, which contrasts with the suppressive effects of MP. Use of early or late MP yielded increased MMP activity in infarcted and non-infarcted regions. Early and late treatment with DOX yielded infarct–associated MMP activity levels comparable to those of vehicle–treated animals. In conclusion, results indicate that late use of MP yields adverse post-MI structure/function outcomes that correlate with suppression of inflammation and increased MMP activity. These observations contrast with those of DOX, in particular, late treatment where improved outcomes were observed in LV structure and were accompanied by the lack of suppression of inflammation.