High alcohol consumption during pregnancy leads to deleterious effects on fetal cardiac structure... more High alcohol consumption during pregnancy leads to deleterious effects on fetal cardiac structure and it also affects cardiomyocyte growth and maturation. This study aimed to determine whether low levels of maternal alcohol consumption are also detrimental to cardiomyocyte and cardiac growth in the early life of offspring and whether cardiac structure and function in adulthood is affected. Pregnant Sprague-Dawley rat dams were fed a control or 6% (volume/volume) liquid-based ethanol supplemented (isocaloric) diet throughout gestation. At embryonic day 20, the expression of genes involved in cardiac development was analyzed using Real-time PCR. At postnatal day 30, cardiomyocyte number, size, and nuclearity in the left ventricle (LV) were determined stereologically. In 8-month-old offspring, LV fibrosis and cardiac function (by echocardiography) were examined. Maternal ethanol consumption did not alter gene expression of the cardiac growth factors in the fetus or cardiomyocyte number...
Women younger than 75 years with stable angina or acute coronary syndrome have higher cardiac mor... more Women younger than 75 years with stable angina or acute coronary syndrome have higher cardiac mortality than similarly aged men, despite less obstructive coronary artery disease. To determine whether the myocardial structure and coronary microvasculature of women differs from that of men, we performed histological analysis of biopsies from nonischemic left ventricular myocardium from 46 men and 11 women undergoing coronary artery bypass graft surgery who did not have previous cardiac surgery, myocardial infarction, heart failure, atrial fibrillation, or furosemide therapy. The 2 patient groups had similar clinical characteristics, apart from a lower body surface area (BSA) in women ( P =0.0015). Women had less interstitial fibrosis than men ( P =0.019) but similar perivascular fibrosis. Arteriolar wall area/circumference ratio, a measure of arteriolar wall thickness, was 47% greater in women than men ( P =0.012). Cardiomyocyte width and diffusion radius were positively correlated, a...
Globally, approximately 10% of infants are born before full-term. Preterm birth exposes the heart... more Globally, approximately 10% of infants are born before full-term. Preterm birth exposes the heart to the demands of postnatal cardiovascular function before cardiac development is complete. Our aim was to examine, in hearts collected from infants at autopsy, the effects of preterm birth on myocardial structure and on cardiomyocyte development. Heart tissue was collected at perinatal autopsies of 16 infants who died following preterm birth between 23-36 weeks gestation, and survived for 1-42 days; the hearts of 37 appropriately grown stillborn infants, aged 20-40 weeks gestation, were used for comparison. Using confocal microscopy and image analysis, cardiomyocyte proliferation, maturation, ploidy, and size were quantified, and interstitial collagen and myocardial capillarisation measured. Preterm birth resulted in a marked reduction in the proliferation of cardiomyocytes relative to age-matched stillborn infant controls (preterm vs. control P<0.0001). In contrast, preterm birth d...
Background After a period of stable hypertrophy, male spontaneously hypertensive rats (SHR) devel... more Background After a period of stable hypertrophy, male spontaneously hypertensive rats (SHR) develop heart failure between 18 to 24 months of age, with depression of active myocardial function and increased passive stiffness. We tested the hypothesis that chronic ACE inhibition by captopril would prevent and possibly reverse impairment of myocardial function. Methods and Results Male SHR and normotensive Wistar-Kyoto rats (WKY) were assigned to no treatment or captopril treatment (2 g/L in drinking water) begun at ages 12, 18, and 21 months; animals were studied at 24 months of age, or earlier when evidence of heart failure was found in SHR (mean age, 19±2 months). In an additional group, captopril treatment was begun when SHR developed heart failure; surviving animals were studied at 24 months of age. In untreated SHR, relative to WKY, isometric stress development at L max , maximum rate of stress development, and shortening velocity were depressed, whereas passive stiffness was increased, in association with the development of myocardial fibrosis. In the SHR treated before cardiac dysfunction, captopril administration attenuated hypertrophy and prevented contractile dysfunction, fibrosis, and increased passive stiffness. Captopril treatment begun after cardiac function was impaired reduced left ventricular hypertrophy but did not restore intrinsic contractile function or reduce fibrosis or passive stiffness. Conclusions In the male SHR, early treatment with captopril was associated with the most marked attenuation of dysfunction relative to the untreated SHR. Treatment initiated after the onset of heart failure improved clinical signs of heart failure and decreased left ventricular hypertrophy in surviving animals but did not reverse the fibrosis and contractile dysfunction associated with heart failure.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibition treatment enhances ... more Objective To determine whether angiotensin-converting enzyme (ACE) inhibition treatment enhances myocardial vascularization in adolescent and adult spontaneously hypertensive rats (SHRs). Methods Male SHRs were treated from 7 to 14 or from 16 to 24 weeks of age with the ACE inhibitor, perindopril, in either a low dose (0.1 mg/kg per day) or a high dose (1 mg/kg per day). Some rats were concomitantly treated with a bradykinin antagonist. At termination of treatment, the left ventricular wall was extensively sampled and the surface area density and length density of myocardial blood vessels stereologically determined. Results High-dose perindopril treatment prevented the development of hypertension and left ventricular hypertrophy in adolescent SHRs and markedly reduced blood pressure and left ventricular size in adult SHRs. SHRs treated with the low dose of perindopril remained hypertensive, although there were significant reductions in blood pressure and left ventricular growth. High-dose perindopril treatment in adolescent SHRs led to a significant increase in the surface area density of blood vessels in the left ventricle after 4 weeks of treatment and an increase in both the surface area density and length density of blood vessels after 7 weeks of treatment. Co-administration with the bradykinin antagonist did not reverse these effects. In contrast, ACE inhibitor treatment had no effect on myocardial vascularization in adult rats with established hypertension. Conclusion ACE inhibitor treatment enhances vascularization in the adolescent heart through reductions in myocardial mass, but not capillary growth. ACE inhibition in the adult heart with established hypertension reduces left ventricular hypertrophy, but does not enhance myocardial capillarization.
The reported association between calibrated integrated backscatter (cIB) and myocardial fibrosis ... more The reported association between calibrated integrated backscatter (cIB) and myocardial fibrosis is based on study of patients with dilated or hypertrophic cardiomyopathy and extensive (mean 15-34%) fibrosis. Its association with lesser degrees of fibrosis is unknown. We examined the relationship between cIB and myocardial fibrosis in patients with coronary artery disease. Myocardial histology was examined in left ventricular epicardial biopsies from 40 patients (29 men and 11 women) undergoing coronary artery bypass graft surgery, who had preoperative echocardiography with cIB measurement. Total fibrosis (picrosirius red staining) varied from 0.7% to 4%, and in contrast to previous reports, cIB showed weak inverse associations with total fibrosis (r=-0.32, p=0.047) and interstitial fibrosis (r=-0.34, p=0.03). However, cIB was not significantly associated with other histological parameters, including immunostaining for collagens I and III, the advanced glycation end product (AGE) N(...
Journal of cardiovascular translational research, 2013
Vitamin D deficiency is a major worldwide public health problem affecting people of all ages, fro... more Vitamin D deficiency is a major worldwide public health problem affecting people of all ages, from infants to the elderly. Of particular concern is the high incidence of vitamin D deficiency in women during pregnancy and lactation, leading to the exposure of the growing fetus/infant to inadequate levels of vitamin D, which is essential for normal development. Vitamin D deficiency in adulthood is linked to the etiology of hypertension and to a multitude of adverse cardiovascular outcomes. It is now well-established that the antecedents of cardiovascular disease can originate very early in life. The purpose of this review is to highlight how maternal vitamin D deficiency, and its effects in upregulating the fetal renin-angiotensin system and altering cardiomyocyte growth in the fetal heart, has the potential to program long-term vulnerability to cardiovascular disease.
The aim of this study was to determine the effect of vitamin D deficiency from conception until 4... more The aim of this study was to determine the effect of vitamin D deficiency from conception until 4 weeks of age on the development of the heart in rat offspring. Sprague-Dawley (SD) rats were fed either a vitamin D deplete or vitamin D-replete diet for 6 weeks prior to pregnancy, during pregnancy and throughout lactation. Cardiomyocyte number was determined in fixed hearts of offspring at postnatal day 3 and 4 weeks of age using an optical disector/fractionator stereological technique. In other litters, cardiomyocytes were isolated from freshly excised hearts to determine the proportion of mononucleated and binucleated cardiomyocytes. Maternal vitamin D deficiency had no effect on cardiomyocyte number, cardiomyocyte area, or the proportion of mononucleated/binucleated cardiomyocytes in 3-day-old male and female offspring. Importantly, however, vitamin D deficiency led to an increase in left ventricle (LV) volume that was accompanied by an increase in cardiomyocyte number and size, and in the proportion of mononucleated cardiomyocytes at 4 weeks of age. Our findings suggest that exposure to vitamin D deficiency in utero and early life leads to delayed maturation and subsequent enhanced growth (proliferation and hypertrophy) of cardiomyocytes in the LV. This may lead to altered cardiac function later in life.
High alcohol consumption during pregnancy leads to deleterious effects on fetal cardiac structure... more High alcohol consumption during pregnancy leads to deleterious effects on fetal cardiac structure and it also affects cardiomyocyte growth and maturation. This study aimed to determine whether low levels of maternal alcohol consumption are also detrimental to cardiomyocyte and cardiac growth in the early life of offspring and whether cardiac structure and function in adulthood is affected. Pregnant Sprague-Dawley rat dams were fed a control or 6% (volume/volume) liquid-based ethanol supplemented (isocaloric) diet throughout gestation. At embryonic day 20, the expression of genes involved in cardiac development was analyzed using Real-time PCR. At postnatal day 30, cardiomyocyte number, size, and nuclearity in the left ventricle (LV) were determined stereologically. In 8-month-old offspring, LV fibrosis and cardiac function (by echocardiography) were examined. Maternal ethanol consumption did not alter gene expression of the cardiac growth factors in the fetus or cardiomyocyte number...
Women younger than 75 years with stable angina or acute coronary syndrome have higher cardiac mor... more Women younger than 75 years with stable angina or acute coronary syndrome have higher cardiac mortality than similarly aged men, despite less obstructive coronary artery disease. To determine whether the myocardial structure and coronary microvasculature of women differs from that of men, we performed histological analysis of biopsies from nonischemic left ventricular myocardium from 46 men and 11 women undergoing coronary artery bypass graft surgery who did not have previous cardiac surgery, myocardial infarction, heart failure, atrial fibrillation, or furosemide therapy. The 2 patient groups had similar clinical characteristics, apart from a lower body surface area (BSA) in women ( P =0.0015). Women had less interstitial fibrosis than men ( P =0.019) but similar perivascular fibrosis. Arteriolar wall area/circumference ratio, a measure of arteriolar wall thickness, was 47% greater in women than men ( P =0.012). Cardiomyocyte width and diffusion radius were positively correlated, a...
Globally, approximately 10% of infants are born before full-term. Preterm birth exposes the heart... more Globally, approximately 10% of infants are born before full-term. Preterm birth exposes the heart to the demands of postnatal cardiovascular function before cardiac development is complete. Our aim was to examine, in hearts collected from infants at autopsy, the effects of preterm birth on myocardial structure and on cardiomyocyte development. Heart tissue was collected at perinatal autopsies of 16 infants who died following preterm birth between 23-36 weeks gestation, and survived for 1-42 days; the hearts of 37 appropriately grown stillborn infants, aged 20-40 weeks gestation, were used for comparison. Using confocal microscopy and image analysis, cardiomyocyte proliferation, maturation, ploidy, and size were quantified, and interstitial collagen and myocardial capillarisation measured. Preterm birth resulted in a marked reduction in the proliferation of cardiomyocytes relative to age-matched stillborn infant controls (preterm vs. control P<0.0001). In contrast, preterm birth d...
Background After a period of stable hypertrophy, male spontaneously hypertensive rats (SHR) devel... more Background After a period of stable hypertrophy, male spontaneously hypertensive rats (SHR) develop heart failure between 18 to 24 months of age, with depression of active myocardial function and increased passive stiffness. We tested the hypothesis that chronic ACE inhibition by captopril would prevent and possibly reverse impairment of myocardial function. Methods and Results Male SHR and normotensive Wistar-Kyoto rats (WKY) were assigned to no treatment or captopril treatment (2 g/L in drinking water) begun at ages 12, 18, and 21 months; animals were studied at 24 months of age, or earlier when evidence of heart failure was found in SHR (mean age, 19±2 months). In an additional group, captopril treatment was begun when SHR developed heart failure; surviving animals were studied at 24 months of age. In untreated SHR, relative to WKY, isometric stress development at L max , maximum rate of stress development, and shortening velocity were depressed, whereas passive stiffness was increased, in association with the development of myocardial fibrosis. In the SHR treated before cardiac dysfunction, captopril administration attenuated hypertrophy and prevented contractile dysfunction, fibrosis, and increased passive stiffness. Captopril treatment begun after cardiac function was impaired reduced left ventricular hypertrophy but did not restore intrinsic contractile function or reduce fibrosis or passive stiffness. Conclusions In the male SHR, early treatment with captopril was associated with the most marked attenuation of dysfunction relative to the untreated SHR. Treatment initiated after the onset of heart failure improved clinical signs of heart failure and decreased left ventricular hypertrophy in surviving animals but did not reverse the fibrosis and contractile dysfunction associated with heart failure.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibition treatment enhances ... more Objective To determine whether angiotensin-converting enzyme (ACE) inhibition treatment enhances myocardial vascularization in adolescent and adult spontaneously hypertensive rats (SHRs). Methods Male SHRs were treated from 7 to 14 or from 16 to 24 weeks of age with the ACE inhibitor, perindopril, in either a low dose (0.1 mg/kg per day) or a high dose (1 mg/kg per day). Some rats were concomitantly treated with a bradykinin antagonist. At termination of treatment, the left ventricular wall was extensively sampled and the surface area density and length density of myocardial blood vessels stereologically determined. Results High-dose perindopril treatment prevented the development of hypertension and left ventricular hypertrophy in adolescent SHRs and markedly reduced blood pressure and left ventricular size in adult SHRs. SHRs treated with the low dose of perindopril remained hypertensive, although there were significant reductions in blood pressure and left ventricular growth. High-dose perindopril treatment in adolescent SHRs led to a significant increase in the surface area density of blood vessels in the left ventricle after 4 weeks of treatment and an increase in both the surface area density and length density of blood vessels after 7 weeks of treatment. Co-administration with the bradykinin antagonist did not reverse these effects. In contrast, ACE inhibitor treatment had no effect on myocardial vascularization in adult rats with established hypertension. Conclusion ACE inhibitor treatment enhances vascularization in the adolescent heart through reductions in myocardial mass, but not capillary growth. ACE inhibition in the adult heart with established hypertension reduces left ventricular hypertrophy, but does not enhance myocardial capillarization.
The reported association between calibrated integrated backscatter (cIB) and myocardial fibrosis ... more The reported association between calibrated integrated backscatter (cIB) and myocardial fibrosis is based on study of patients with dilated or hypertrophic cardiomyopathy and extensive (mean 15-34%) fibrosis. Its association with lesser degrees of fibrosis is unknown. We examined the relationship between cIB and myocardial fibrosis in patients with coronary artery disease. Myocardial histology was examined in left ventricular epicardial biopsies from 40 patients (29 men and 11 women) undergoing coronary artery bypass graft surgery, who had preoperative echocardiography with cIB measurement. Total fibrosis (picrosirius red staining) varied from 0.7% to 4%, and in contrast to previous reports, cIB showed weak inverse associations with total fibrosis (r=-0.32, p=0.047) and interstitial fibrosis (r=-0.34, p=0.03). However, cIB was not significantly associated with other histological parameters, including immunostaining for collagens I and III, the advanced glycation end product (AGE) N(...
Journal of cardiovascular translational research, 2013
Vitamin D deficiency is a major worldwide public health problem affecting people of all ages, fro... more Vitamin D deficiency is a major worldwide public health problem affecting people of all ages, from infants to the elderly. Of particular concern is the high incidence of vitamin D deficiency in women during pregnancy and lactation, leading to the exposure of the growing fetus/infant to inadequate levels of vitamin D, which is essential for normal development. Vitamin D deficiency in adulthood is linked to the etiology of hypertension and to a multitude of adverse cardiovascular outcomes. It is now well-established that the antecedents of cardiovascular disease can originate very early in life. The purpose of this review is to highlight how maternal vitamin D deficiency, and its effects in upregulating the fetal renin-angiotensin system and altering cardiomyocyte growth in the fetal heart, has the potential to program long-term vulnerability to cardiovascular disease.
The aim of this study was to determine the effect of vitamin D deficiency from conception until 4... more The aim of this study was to determine the effect of vitamin D deficiency from conception until 4 weeks of age on the development of the heart in rat offspring. Sprague-Dawley (SD) rats were fed either a vitamin D deplete or vitamin D-replete diet for 6 weeks prior to pregnancy, during pregnancy and throughout lactation. Cardiomyocyte number was determined in fixed hearts of offspring at postnatal day 3 and 4 weeks of age using an optical disector/fractionator stereological technique. In other litters, cardiomyocytes were isolated from freshly excised hearts to determine the proportion of mononucleated and binucleated cardiomyocytes. Maternal vitamin D deficiency had no effect on cardiomyocyte number, cardiomyocyte area, or the proportion of mononucleated/binucleated cardiomyocytes in 3-day-old male and female offspring. Importantly, however, vitamin D deficiency led to an increase in left ventricle (LV) volume that was accompanied by an increase in cardiomyocyte number and size, and in the proportion of mononucleated cardiomyocytes at 4 weeks of age. Our findings suggest that exposure to vitamin D deficiency in utero and early life leads to delayed maturation and subsequent enhanced growth (proliferation and hypertrophy) of cardiomyocytes in the LV. This may lead to altered cardiac function later in life.
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