The subcellular localization of calcium ion in mammalian myocardium.

This study was designed to investigate the proposition that subcellular calcium is sequestered in specific sites in mammalian myocardium. 29 functioning dog papillary muscles were fixed through the intact vascular supply by means of osmium tetroxide containing a 2% concentration of potassium pyroantimonate (K(2)H(2)Sb(2)O(7).(4)H(2)O). Tissue examined in the electron microscope showed a consistent and reproducible localization of the electron-opaque pyroantimonate salts of sodium and calcium to distinct sites in the tissue. Sodium pyroantimonate was found exclusively in the extracellular space and clustered at the sarcolemmal membrane. Calcium pyroantimonate, on the other hand, identified primarily by its susceptibility to removal by chelation with EGTA and EDTA, was consistently found densely concentrated in the lateral sacs of the sarcoplasmic reticulum and over the sarcomeric I bands. M zones were virtually free of precipitate. The implications of these findings with respect to various parameters of muscle function are discussed.

Ultrastructural alterations produced in mammalian myocardium by variation in perfusate ionic composition.

This study describes the changes produced in the subcellular morphology of mammalian myocardium when perfusate sodium, calcium, and chloride concentrations are varied. By means of a recently developed perfusion technique, functioning dog papillary muscles were perfused with isotonic solutions of varying ionic compositions. Examination of the tissue in the electron microscope revealed that control muscles showed satisfactory preservation of ultrastructure, demonstrating that the protocol itself did not create significant morphological artefact. Low sodium chloride perfusion produced dilatation of both transverse tubules and longitudinal sarcoplasmic reticulum elements. Low sodium or high calcium concentrations produced dilation of tubular elements of the longitudinal sarcoplasmic reticulum while leaving transverse tubules intact. High calcium perfusion produced mitochondrial swelling and vacuolization. Mitochondrial precipitate, both crystalline and amorphous in form, was observed and presumed to be calcium phosphate, either alone or mixed with calcium carbonate. The possibility that the morphological changes observed might indicate subcellular loci of specific ion permeability is discussed. A correlation of the known kinetic behavior of sodium and calcium ions in mammalian myocardium with the ultrastructural alterations produced is suggested.

Disruption of the myocardial extracellular matrix leads to cardiac dysfunction.

MMP activity with disruption of structural collagen has been implicated in the pathophysiology of dilated cardiomyopathy. To examine the role of this enzyme in cardiac function, a transgenic mouse was created that constitutively expressed human collagenase (MMP-1) in the heart. At 6 months of age, these animals demonstrated compensatory myocyte hypertrophy with an increase in the cardiac collagen concentration due to elevated transcription of type III collagen. Chronic myocardial expression of MMP-1 produced loss of cardiac interstitial collagen coincident with a marked deterioration of systolic and diastolic function at 12 months of age. This is the first animal model demonstrating that direct disruption of the extracellular matrix in the heart reproduces the changes observed in the progression of human heart failure.

Sympathetic innervation modulates ventricular impulse propagation and repolarisation in the immature rat heart.

OBJECTIVE: When cardiac sympathetic innervation in neonatal rats is retarded by antiserum to nerve growth factor, there is a corresponding increase in the QT interval on ECG. Since the propagation of the cardiac impulse and the repolarisation of cardiac cells both contribute to the QT interval, the aim of this study was to determine the role of sympathetic innervation in modulating ventricular impulse propagation and repolarisation. METHODS: Neonatal rats were treated for the first 10 days of life with nerve growth factor (NGF), its antiserum (As), or placebo. Standard microelectrode techniques were used to study the transmembrane action potential characteristics of subendocardial (ventricular septal) and subepicardial ventricular myocardium. Bipolar surface electrograms were used to record the velocity of impulse propagation and electron microscopy to examine the intercalated discs. RESULTS: In the subendocardium, the phase 0 upstroke velocity of the action potential (dV/dtmax) was lowest in the As treated rats. The latter group also showed the slowest conduction velocity. There were no differences in control action potential durations in the endocardium among the three groups, but in the epicardial tissues, action potential duration was longest in the As treated group. Thus the dispersion in action potential duration was smallest in the As treated animals. Electron microscopic studies of the intercalated discs of ventricular myocytes showed significant enhancement of nexal junction formation in NGF treated rats, whereas As treated animals showed a retarded pattern of both nexal and desmosomal junction formation. CONCLUSIONS: The differences in ultrastructure, conduction, and repolarisation seen in As and NGF treated animals may explain the prolonged QT interval seen in the As treated group.

Dyslipidemia, gender, and the role of high-density lipoprotein cholesterol: implications for therapy.

Cardiovascular disease, which kills more US women than all cancers combined, may pose an even greater risk for women than for men. For example, the risk factors, testing modalities, presenting symptoms and the therapeutic choices made for women with coronary artery disease are significantly different from those for men. Low levels of high-density lipoprotein cholesterol (HDL-C), <35 mg/dL in men and <45 mg/dL in women, is associated with a greater risk of coronary artery disease and more progression of angiographically demonstrated disease in women, while increasing HDL-C has a more cardioprotective effect in the female than in the male population. The total cholesterol-to-HDL-C ratio is also more predictive of coronary artery disease in women than in men. Because average HDL-C levels in women are approximately 10 mg/dL higher than in men, target HDL-C should be higher (>45 mg/dL) in women. This is not yet reflected in clinical guidelines. Diabetes is particularly hazardous in women, and low HDL-C levels constitute a disproportionate risk for coronary artery disease in diabetic women compared with diabetic men. Regrettably, although lipid-lowering drugs have been shown to be effective in women, they are more rarely prescribed for women than for men.

Gender-specific aspects of obesity.

Obesity, an increasingly prevalent and difficult-to-treat condition in the United States, affects more women than men. The distribution of body fat differs in the genders, with women carrying more fat "on" their frames and men more likely to exhibit central obesity, carrying weight "within" their frames. Changes in body distribution of fat occur with reproductive cycling and childbearing in women. Obesity in females can have important consequences for fertility, and menopause is accompanied by a significant increase in the waist-hip ratio in females, an important factor in raising their risk for coronary artery disease. Dieting and exercise have different consequences in the two genders: men, unlike women, maintain HDL levels and lose central obesity simply by dieting, while women require exercise in addition to restricted caloric intake to produce the same effects. Recent advances in elucidating the molecular pathobiology of obesity have not yet been examined with respect to gender. With very few exceptions, this is also true of studies examining the usefulness of anorexics in initiating and maintaining weight loss. More gender-specific information is required in these two last, newer areas of obesity-related investigation.

Women's health: not for women only.

Because most medical investigation traditionally has been restricted to men, many of our models of normal human physiology and of the pathophysiology of disease are skewed. The current interest in women's health has led us to concentrate on the differences between men and women; indeed, a survey of already published data reveals that there are significant variations in the normal function of virtually all the systems in the body. Furthermore, each of the sexes experiences disease differently in many important respects: coronary artery disease is a well-understood example of how gender determines the pathobiology of illness. As our understanding of the impact of gender on the mechanism of disease expands, our treatment of illness will become more focused and accurate. Sex-specific prescribing may well become the norm as the science of gender-specific medicine expands.

Gender-specific physiology: how real is it? How important is it?

A predominantly male model of disease, and thus a tendency to restrict medical investigation to men, has led to a skewing of our perceptions of both normal human physiology and the pathophysiology of illness. Because of social and economic factors, research programs focused on aspects of women's health and disease (other than reproductive) have become more common over the past decade. The present literature review of gender-specific physiology covers the roles of gonadal hormones, especially in the nervous system; depression; the cytochrome P-450 system; the cardiovascular system, the immune system; saliva; and the gastrointestinal tract. All in all, there are revealed important differences, and some surprising similarities, between the genders in disease conditions and drug responses.

Gender and the heart: sex-specific differences in normal anatomy and physiology.

Important sex-specific differences in the normal anatomy and physiology of the myocardium exist. It is essential to consider these differences in assessing the meaning of cardiac symptoms in men and women and in constructing strategies for the prevention and treatment of cardiovascular illness.

The anatomic matrix as a factor in susceptibility to lethal arrhythmias in a canine model of sudden cardiac death.

In a previously reported canine model of sudden cardiac death, its authors heavily weighted the role of the autonomic nervous system in determining whether or not a combined stress of submaximal exercise and ischemia would produce a fatal arrhythmia the setting of a healed anterior wall myocardial infarction. This morphologic study of that model reveals that anatomic factors are also relevant to vulnerability to sudden death: dogs who developed ventricular fibrillation in response to such a stress (susceptible) had significantly more of the left ventricle (LV) infarcted than dogs who survived the stress (resistant): 13.14% (+/- 2.67 S.E.M.) as compared with 4.01% (+/- 2.11 S.E.M.). Moreover, areas of fibrosis were spread more widely throughout the ventricle and septum in susceptible as compared with resistant animals, which consistently showed more homogeneous areas of infarct largely confined to the apical portion of the LV. While the autonomic nervous system may well be relevant to survival to stress in an animal which has survived a myocardial infarction, we conclude that there are important anatomic factors which determine vulnerability.

Coronary artery disease in women.

Although most women cite breast and reproductive cancers as the diseases they most fear, in fact cardiovascular disease is much more likely to kill them: 500,000 American women die each year of diseases of the heart and blood vessels compared with 189,000 who die of all cancers combined. Women's focus on breast, uterine, and ovarian cancer is very much socially and culturally determined. It reflects an outmoded image of women as valuable principally by virtue of their ability to bear and raise children. While women died at about the age of 48 at the turn of the century, biomedical science was extended their life span to the point that a girl born today has an average life expectancy of 86 years. The focus of recent biomedical investigation reflects the changing experience and expectations of women, who will live a full third of their lives beyond the period of reproductive viability. Since 1988, a flood of new information established that the epidemiology, risk factors, clinical features, outcome and therapeutic choices physicians make for female patients with cardiovascular disease are significantly different from those of men. Regrettably, most of the new information we have acquired was almost exclusively harvested from data on Caucasian women: black women often are less than 10% of study populations. The information we do have, however, shows striking differences between women of different races in the severity and outcome of diseases of the heart and blood vessels: black women have significantly higher mortality rates from stroke and myocardial infarction than do white women. Intensive research has achieved gratifying corrections in the promptness with which physicians diagnose women with cardiovascular disease and in the aggressiveness of the therapy they offer to female patients. The result has been a reversal of the trend for women to have worse outcomes from revascularization procedures than men.

Cellular mechanisms of normal growth in the mammalian heart. I. Qualitative and quantitative features of ventricular architecture in the dog from birth to five months of age.

This paper describes the qualitative and quantitative composition of dog myocardium over the first 5 months of life. The quantitative composition of dog right and left ventricle over this period does not vary. A stereological analysis of electron micrographs representing 32,000 micron2 of tissue surface revealed that 79% of the heart is made up of myofibers, whereas 21% is extracellular space. Twenty-eight percent of the extracellular compartment by volume is vasculature (tissue was preserved by immersion rather than vascular perfusion); 72% is occupied by nonvascular elements and "empty" space. In contrast to the remarkable constancy of quantitative composition of the whole myocardium, myocyte shape and dimensions and the arrangement of intercellular connections vary dramatically over the age period studied. In early postnatal life, the morphology of blood vessels, many of which have completely partitioned lumina, also changes significantly.

Cellular mechanisms of normal growth in the mammalian heart. II. A quantitative and qualitative comparison between the right and left ventricular myocytes in the dog from birth to five months of age.

This paper describes and contrasts the changes in myocytes taken from the right and left ventricules of dog heart over the first 5 months of life. The development of the two populations of cells differs in important respects: sarcomeric volume, the proportion of the myocyte occupied by the contractile apparatus, and the volume and surface area of the transverse tubular system all were greater on the average in the left than in the right ventricle (P less than 0.001). Other intracellular structures also changed significantly as development progressed, but did so in both chambers; the surface area and surface-to-volume (s/v) ratio of both right and left ventricular myocytes increased with age (P less than 0.001) as did mitochondrial and mitochondrial-myocyte volume (P less than 0.001). The surface area (P less than 0.01) and the s/v ratio of the mitochondria (P less than 0.001) also increased with development. Nuclear and nuclear myocyte volume grew smaller with age in both chambers (P less than 0.002), as did the surface area (P less than 0.001) and the s/v ratio of the nucleus (P less than 0.01). Not only does myocyte composition change quantitatively, striking changes in intracellular architecture and the appearance and arrangement of intracellular organelles occur during postnatal life.

Cardiovascular disease in women: gender-specific aspects of hypertension and the consequences of treatment.

The epidemiology, clinical course, response to treatment, and ultimate outcome of essential hypertension vary as a function of gender. Three early trials on hypertension reported an increase in all-cause mortality in treated white women compared with black women or with men of both races. Later studies, however, suggest that drug therapy has similar and beneficial effects in hypertensive men and women. Women may tolerate hypertension better than do men. Diastolic hypertension correlates with higher mortality from coronary artery disease in men than in women. Special considerations apply to treating the hypertensive woman. Use of oral contraceptives may precipitate or accentuate the problem. In contrast, in the postmenopausal female, estrogen replacement may actually improve hypertension, via several mechanisms. These include the impact of the hormone on vasomotricity, its enhancement of baroreceptor sensitivity, and its impact on the hyperinsulinemia characteristic of menopause. Treatment of hypertension must be individualized with respect to gender. More data on the consequences of treatment of women with hypertension are needed, particularly longterm studies to assess the impact of treatment on mortality.

Developmental changes in impulse conduction in the canine heart.

We studied the age-related changes that occur in conduction in Purkinje fiber bundles (PF) from adult and 8-wk-old dogs. As PF are stretched, conduction velocity increases to a maximum when bundle length is approximately 1.5 times control. Conduction velocity in adult PF was significantly faster than that in 8-wk PF at all bundle lengths, the maximum being 2.32 +/- 0.45 m/s (mean +/- SD) in adult and 1.56 +/- 0.59 m/s in 8-wk-old dogs. At greater than 1.5 times control length, conduction velocity decreased, as did resting potential, action potential amplitude, and upstroke velocity. At 1.5 times control length, the ratio of PF to collagen in the bundles increased, and structural changes consistent with both unbuckling and unfolding of the cell membranes were seen. At greater degrees of stretch, cleft size diminished, and intracellular edema was noted. In sum, structural changes in cardiac PF can explain the changes in conduction velocity that occur with stretch. At all degrees of stretch, however, velocity is faster in PF from adult than from young dogs.