The regenerative potential of the human heart.
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Animals↗
Biomedical subjects
C Lagrasta
Publications and source records attributed to C Lagrasta.
Motor responses of rat hypertrophic intestine following chronic obstruction.
The present work aims at investigating the changes in motor responsiveness of rat intestine hypertrophied by chronic mechanical obstruction. Motor responses to pharmacological agents and electrical field stimulation (EFS) were studied in hypertrophic ileal segments excised from rats subjected to experimental stenosis (n = 20) and compared with responses of control tissues from sham-operated animals (n = 20). Spontaneous motility and contractile responses to exogenous agents (KCl, acetylcholine and substance P) and EFS (10-s trains every minute, 120 mA, 0.5 ms, 1-10 Hz) were increased in hypertrophic longitudinal segments; however, normalization of motor responses to tissue wet weight revealed a remarkable reduction of contractile efficiency in hypertrophied tissues coupled with a loss of sensitivity to nitric oxide-mediated relaxation. Furthermore, EFS under non-adrenergic non-cholinergic (NANC) conditions unveiled a major role of the cholinergic component over the peptidergic one in the neurogenic contraction of hypertrophic intestine. On the whole, hypertrophic intestinal growth emerges as a dynamic process entailing adaptation of smooth muscle and neuronal structures to the increased functional load imposed by lumen obstruction.
Acetylcholine↗
Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats.
In 47 male adult Wistar rats with 4-wk aortic coarctation (AC) and 39 age-matched sham-operated rats (SO) chronically instrumented for telemetry electrocardiogram recording, we investigated the mechanisms of arrhythmogenesis in moderate cardiac hypertrophy, with an approach from "in vivo" toward the cellular level, analyzing 1) stress-induced cardiac arrhythmias in all rats and 2) myocardial fibrosis in 35 animals and action potential duration and density of hyperpolarization-activated current in 19 others at the ventricular level. Aortic banding increased arterial blood pressure, cardiac weight, and ventricular myocyte volume by 11, 25, and 14%, respectively (P < 0.001-0.05). Ventricular arrhythmias occurred at similar rates in AC and SO rats throughout the stress procedure. Action potential duration and hyperpolarization-activated current were about twice as great and myocardial fibrosis about four times greater in AC animals (P < 0.005-0.05). Electrocardiogram data also revealed more supraventricular arrhythmias in AC rats during the baseline period and after stress and fewer atrioventricular block episodes after stress (P < 0.05). Thus stress-induced supraventricular and atrioventricular nodal, but not ventricular, arrhythmias were affected in moderate cardiac hypertrophy when ventricular morphofunctional alterations were evident.
Action Potentials↗
Recent advances in cardiac hypertrophy.
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Animals↗
[Does apoptosis participate in heart failure?].
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Animals↗
Dependence of temporal variability of ventricular recovery on myocardial fibrosis. Role of mechanoelectric feedback?
OBJECTIVE: The study was aimed at establishing the effect of factors involved in the expression of mechanoelectric feedback in the heart, such as R-R interval and connective tissue, on time dependent changes in ventricular recovery, as determined at the body surface by beat to beat variability of QRST integral maps (BBV-IM). METHODS: We used 15 normal 6-month-old Wistar rats. In each anesthetized animal, we performed a 3-minute continuous recording of 44. The simultaneous chest ECGs. The signals were interactively processed, 1) to determine mean R-R interval and R-R variability throughout the recording period and 2) to compute QRST integral maps from approximately 50 beats belonging to the end of expiration. Then BBV-IM was calculated and expressed as percentage of beats significantly differing from a template. At sacrifice, the amount of myocardial fibrosis was morphometrically evaluated. RESULTS: R-R interval was 149 ms +/- 4, R-R interval variability 0.008 +/- 0.001 and BBV-IM 30.7% +/- 4.4. Myocardial fibrosis expressed as % volume of left ventricular myocardium, numerical density of fibrotic foci and average cross-sectional area of the foci was 3.0% +/- 0.4, 3.8 +/- 0.6 and 4.4 microns(2)/1000 +/- 0.1 respectively, BB-IM was positively correlated to the % volume of fibrosis (r = 0.83, P < 0.0003). Both measurements were positively correlated to R-R interval (BBV-IM: r = 0.83, P < 0.0001; % volume of fibrosis: r = 0.87, P < 0.001) and negatively correlated to cardiac weights (BBV-IM: r = -0.79, P < 0.0005; % volume of fibrosis: r = -0.75, P < 0.001). CONCLUSION: Beat to beat changes in ventricular repolarization attributable to mechanoelectric transduction can be detected at the body surface by means of BBV-IM.
Analysis of Variance↗
The Failing Heart.
Heart failure is a highly lethal condition which carries a shorter life expectancy than most common malignancies. Despite the large number of efforts dedicated to understand why the heart fails, only limited possibilities are available to improve survival. This because the problem is very complex and is dependent upon multiple changes in the anatomical and functional properties of the heart as well as of other organs, together with modifications in systemic and local hormonal and neuronal interactions. This review has been focused on some results obtained in pathologic hearts explanted from subjects with intractable heart failure or in hearts from animals with spontaneous or induced myocardial damage with different degrees of cardiac dysfunction and failure performed in the last few years in our laboratories. Hearts in failure have different alterations at the anatomical, histological and cellular level that may justify, at least in part, the functional impairment and the progressive evolution of the disease. Recent findings of apoptotic myocyte cell death and myocytic hyperplasia are exciting prospectives to be followed with the expectation that new strategies may be discovered to alter the unfavourable outcome of heart failure. However, the complexity of the problem seems to require a large number of efforts before the results obtained can be applied to human beings. Thus, basic researches must be stimulated to explore the mechanisms which allow the development of heart failure despite the persistence in the damaged myocardium of a large number of contractile cells.
Journal Article↗
Quantitative analysis of apoptosis and bcl-2 in Sjögren's syndrome.
OBJECTIVE: To determine whether apoptosis plays a significant role in tissue damage of Sjögren's syndrome (SS). METHODS: We performed a quantitative analysis of programmed cell death on salivary glands of 11 patients. Ten age matched women with sicca syndrome served as controls. Morphometric measurement of the fractional volume of acini and ducts showing DNA strand breaks was performed in sections stained by deoxynucleotidyl transferase assay. The extent of bcl-2 expression was determined in sections labeled with monoclonal antibody. The different cell populations infiltrating the glands were examined in tissues stained with anti-leukocyte common antigen and OPD4 monoclonal antibodies. RESULTS: In patients with SS, 68% of the ductal epithelium was occupied by apoptotic structures, whereas only 12% of acini showed DNA strand breaks. Corresponding values in control salivary glands were 3 and 0.13%. bcl-2 labeling was higher in ducts than in acini of both control and pathologic glands. However, in SS a 43% (p < 0.001) and 75% (p < 0.001) reduction in bcl-2 expression was observed in ductal and acinar epithelium, respectively. In comparison with controls, the numerical density of CD4+ cells and plasma cells scattered throughout the interstitium was 323% and 203% higher (p < 0.001) in SS. Moreover, T helper/inducer lymphocytes represented 52% of the inflammatory foci. CONCLUSION: Apoptosis occurs in minor salivary glands of patients with SS with a prevailing localization on the ductal epithelium in association with downregulation of bcl-2 and a large number of infiltrating CD4+ lymphocytes. Thus, the destruction of glandular tissue and the loss of secretory function in SS is dependent on the activation of the suicide program of epithelial cells.
Aged↗
Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart.
The current investigation was designed to evaluate whether the proportion of mononucleated binucleated, trinucleated and tetranucleated myocytes varies in the left ventricle, interventricular septum and right ventricular free wall with aging, cardiac hypertrophy and ischemic cardiomyopathy. In addition, the number and dimensional properties of myocytes were measured to determine whether a relationship existed between myocyte size and number, and organ hypertrophy. For this purpose, 72 normal hearts were obtained from individuals who died from causes other than cardiovascular disease and compared with 81 hypertrophied hearts and 95 with ischemic cardiomyopathy. The age interval examined varied from 26 to 93 years. The analysis of enzymatically dissociated myocytes in control left ventricles demonstrated that mononucleated, binucleated, trinucleated, trinucleated and tetranucleated myocytes comprised 74%, 25.5%, 0.4% and 0.1% of the entire myocyte population. Similarly, mononucleated myocytes constituted the prevailing cell population of the interventricular septum and right ventricular free wall. Aging, myocardial hypertrophy and ischemic cardiomyopathy did not change the percentage of mononucleated and multinucleated myocyte in the ventricular myocardium. Cardiac hypertrophy and ischemic cardiomyopathy were characterized by comparable increase in myocyte size in spite of a significant difference in the magnitude of myocardial hypertrophy. Myocyte number was increased in hypertrophied hearts, whereas myocyte cell loss occurred in ischemic cardiomyopathy. In conclusion, aging, cardiac hypertrophy and ischemic cardiomyopathy do not alter the fractions of mononucleated and multinucleated myocytes in the myocardium.
Adult↗
Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart.
Conditions of diastolic overload associated with increases in filling pressure trigger apoptosis. Moreover, ischemia alone and ischemia followed by reperfusion induce programmed cell death in myocytes in vitro. On this basis, the possibility was raised that apoptotic myocyte cell death may occur in the surviving myocardium acutely after infarction. Myocardial samples were obtained from the region adjacent to and remote from infarction in patients who died within 10 days from the initial clinical symptoms. Apoptosis was measured quantitatively by the terminal deoxynucleotidyl transferase assay and confirmed biochemically by DNA extraction and agarose gel electrophoresis. This analysis included 20 infarcted and ten control hearts. DNA strand breaks in myocyte nuclei were observed in all 20 infarcted hearts in both the regions bordering on and distant from the necrotic myocardium. However, the number of apoptotic nuclei was greater in the peri-infarcted region than in that away from infarction. Quantitatively, 12% of myocytes in the border zone showed DNA strand breaks, whereas 1% of cells were undergoing apoptosis in the remote myocardium. Moreover DNA laddering was detected biochemically in these two regions of the heart. Thus, apoptosis appears to be a significant complicating factor of acute myocardial infarction increasing the magnitude of myocyte cell death associated with coronary artery occlusion.
Adult↗
Effects of a new angiotensin-converting enzyme inhibitor (idrapril) in rats with left ventricular dysfunction after myocardial infarction.
We evaluated the effects of a new angiotensin-converting enzyme (ACE) inhibitor (idrapril) in terms of hemodynamics and ventricular remodeling after myocardial infarction in rats. The animals were randomly assigned to four experimental groups. Myocardial infarction was induced by left coronary artery ligation in the first two groups treated with either idrapril (300 mg kg-1 day-1) or vehicle for 4 weeks after myocardial infarction. Two groups of sham-operated rats were treated accordingly. Hemodynamics were measured, and the diastole-arrested hearts were analyzed morphometrically to quantify left ventricular (LV) remodeling and infarct size. In infarcted rats, idrapril reduced the arterial systolic blood pressure (SBP) from 128 +/- 10 to 97 +/- 6 mm Hg (p < 0.05) and LV end-diastolic pressure (LVEDP) from 19 +/- 3 to 13 +/- 3 mm Hg (p < 0.01). The decrease in diastolic wall stress conferred by idrapril to infarcted rats (from 499 +/- 99 to 269 +/- 68 dynes mm-2, p < 0.05) was mainly due to a reduction in LVEDP and, to a lesser extent, in LV volume. Idrapril also reduced body and heart weights as compared with those of vehicle-treated animals. Four-week treatment with idrapril initiated immediately after myocardial infarction reduced LVEDP and limited LV wall stress, a major prognostic factor for the progression toward chronic ventricular failure.
Angiotensin-Converting Enzyme Inhibitors↗
Gender differences and aging: effects on the human heart.
OBJECTIVES: This study investigated the changes in myocyte size and number in the left and right ventricles that occur with aging in the female and male heart. BACKGROUND: Differences in life span between women and men may be related to a better preservation of myocardial structure in the female heart with aging. On this basis, the hypothesis was advanced that the aging process has a different impact on the integrity of the myocardium in the two genders. METHODS: Morphometric methodologies were applied to analyze the changes in number and size of ventricular myocytes in the hearts of 53 women and 53 men. The changes in mononucleated and binucleated myocytes with age were determined in enzymatically dissociated cells. The age interval examined varied from 17 to 95 years. RESULTS: Aging was associated with a preservation of ventricular myocardial mass, aggregate number of mononucleated and binucleated myocytes, average cell diameter and volume in the female heart. In contrast, nearly 1 g/year of myocardium was lost in the male heart, and this phenomenon accounted for the loss of approximately 64 million cells. This detrimental effect involved the left and right sides of the heart. In the remaining cells, myocyte cell volume increased at a rate of 158 microns3/year in the left and 167 microns3/year in the right ventricle. CONCLUSIONS: Aging does not lead to myocyte cell loss and myocyte cellular reactive hypertrophy in women, indicating that gender differences may play a significant role in the detrimental effects of the aging process on the heart.
Adolescent↗
Cellular basis of ventricular remodeling after myocardial infarction in rats.
The remodeling of the spared non-ischemic left ventricular myocardium after different time intervals from the occlusion of the left coronary artery was examined in rats. In the presence of large infarcts, ventricular failure developed two to three days after surgery, because of chamber dilation and thinning of the wall, resulting in an average 7.5-fold increase in diastolic stress on the surviving myocardium. Mural thinning of the ventricular wall remote from and bordering the infarction occurred through side-to-side slippage of myocytes and capillaries within the wall. Although an average hypertrophic growth of 22% of the spared myocytes has been found, this amount of hypertrophy was insufficient to restore normal myocardial function. Long-term cardiac restructuring after infarction was characterized by the persistence of chamber dilatation and thinning of the ventricular wall. In addition to the side-to-side slippage, lengthening of the myocytes was an important cause of ventricular changes. As the reactive hypertrophy of the unaffected ventricle was insufficient to re-establish the ratio of ventricular mass to chamber volume, the diastolic stress remained elevated and decompensated eccentric ventricular hypertrophy developed. The anatomical remodeling of the spared left ventricular myocardium is an important conditioning factor in the short- and long-term outcome of ischemic cardiomyopathy.
Animals↗
Effects of an early treatment with lisinopril and isosorbide-5-mononitrate on hemodynamics and late ventricular remodelling in rats with 9-week myocardial infarction.
This study was undertaken to assess whether the converting enzyme inhibitor lisinopril, and the long-acting nitrate, isosorbide-5-mononitrate, affect left ventricle dysfunction and anatomical remodelling in rats with myocardial infarction. Lisinopril, isosorbide-5-mononitrate or vehicle were given to rats (n = 10-14 per group) immediately after coronary artery occlusion (by an intravenous bolus) and then for nine weeks (in drinking water). At the end of the study, left ventricular pressures were measured, the heart arrested in diastole, and infarct size, left ventricular chamber volume and wall thicknesses measured. Lisinopril significantly lowered systemic blood pressure and left ventricular systolic pressure in rats with small (< 15% scarred tissue of the left ventricle) and large (> 15%) infarcts; the weight of the left ventricle (including the septum) was reduced by 24% and 28% in animals with small and large infarcts, respectively. Lisinopril lowered left ventricular end-diastolic pressure (by 33% and 39%) and chamber volume (by 4% and 34%) in rats with small and large infarcts, respectively, compared with controls (NS). The combined anatomical and hemodynamic changes led to a reduction of the circumferential wall stress by 20% and 44% in lisinopril-treated rats with small and large infarcts, respectively (NS). No significant changes were seen in the nitrate-treated hearts compared with controls. Lisinopril, given early after myocardial infarction and continued for nine weeks, significantly affected cardiac hemodynamics and ventricular weights in rats with infarcts of different sizes.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-Converting Enzyme Inhibitors↗
Myocyte cellular hyperplasia and myocyte cellular hypertrophy contribute to chronic ventricular remodeling in coronary artery narrowing-induced cardiomyopathy in rats.
To determine whether cardiac failure produced by chronic coronary artery stenosis was associated with the activation of myocyte cellular hyperplasia in the myocardium, the changes in number and size of left ventricular myocytes were measured in rats 3 months after surgery. The hypertrophied left ventricle was found to possess 44%, 32%, 49%, and 48% fewer mononucleated, binucleated, trinucleated, and tetranucleated myocytes, respectively. In contrast, the hypertrophied right ventricle contained 1.49 x 10(6) more myocytes as a result of a 2.1-fold, 1.4-fold, and 1.4-fold increase in mononucleated, binucleated, and tetranucleated myocytes. Myocyte cell volume was seen to increase 49% and 21% in left and right ventricular myocytes, respectively. The process of myocyte cellular hyperplasia in the right ventricular myocardium was accompanied by capillary proliferation, and these events were responsible for the parallel addition of newly formed cells and capillaries within the wall and mural thickening. Moreover, the in-series insertion of new myocytes contributed to right ventricular dilatation after coronary artery stenosis. In view of the fact that extensive myocardial damage and cell loss may have masked the phenomenon of myocyte cellular hyperplasia in the left ventricle, the presence of DNA synthesis in myocyte nuclei was evaluated at 3 days, 1 week, 2 weeks, 1 month, and 3 months after coronary artery stenosis. Bromodeoxyuridine (BrdU) labeling markedly increased in myocyte nuclei of both ventricles, reaching its peak at 1 and 2 weeks. BrdU labeling of nonmyocyte nuclei also increased but mostly at 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes.
Proliferating cell nuclear antigen (PCNA) is a late growth-regulated gene that is expressed at the G1-S boundary of the cell cycle and is required for DNA synthesis and cell proliferation. Since quantitative results suggest that myocyte hyperplasia occurs in the decompensated human heart, we postulated that induction of the PCNA gene may be present in the failing heart in humans. PCNA protein was detected in myocardial samples obtained from the left and right ventricles of patients with congestive heart failure. Endomyocardial biopsies collected from donor subjects were used as control tissue. The percentage of positively stained myocyte nuclei in the ventricles was established by using PCNA monoclonal antibody and the immunoperoxidase technique. The localization of PCNA in myocytes was confirmed by alpha-sarcomeric actin antibody staining. PCNA labeling was present in left ventricular myocytes of 29 of the 32 hearts examined. In the right ventricle, 24 of the 29 samples showed positive staining. In a subset of 25 patients, the percentage of PCNA-labeled myocyte nuclei was measured and found to constitute 49 +/- 22% of left ventricular myocytes. A similar analysis for the right ventricle, conducted in 21 patients, showed that 49 +/- 19% of the myocyte nuclei exhibited PCNA protein. In addition, mitotic figures in myocytes were documented. A quantitative analysis of this cellular process revealed that 11 myocyte nuclei per 1 million cells exhibited mitotic images in chronic heart failure. Immediately after myocardial infarction, two cells per million showed mitotic division, and this phenomenon was restricted to the region adjacent to the necrotic tissue. No PCNA labeling or nuclear mitotic images were detected in the ventricular myocardium of control subjects. Thus, the observation that diffuse PCNA labeling and myocyte mitotic division are present in hearts with end-stage failure strongly suggests that adult ventricular myocytes are not terminally differentiated cells and that myocyte cellular hyperplasia may constitute a growth reserve mechanism of the diseased heart.
Adult↗
Effects of genetic hypertension and nutritional anaemia on ventricular remodelling and myocardial damage in rats.
OBJECTIVE: In order to determine whether alterations in cardiac function and structure occur early in life in spontaneously hypertensive rats (SHR) and whether the addition of a volume load would affect myocardial growth and haemodynamic performance, SHR were exposed to an iron and copper deficient diet for 12 weeks (SHR-A) and compared with untreated SHR and Wistar Kyoto controls (WKY). RESULTS: Systolic arterial blood pressure increased in SHR, whereas nutritional anaemia prevented the rise of blood pressure in SHR-A. The diet employed provoked a severe hypochromic microcytic anaemia with a marked reduction in blood viscosity and increased volume load on the heart in SHR-A. Genetically determined hypertension alone induced a 16% increase in left ventricular weight and an increase in left ventricular peak systolic pressure (LVPSP) and +dP/dt. The superimposition of anaemia resulted in a 43% expansion in left ventricular weight with a decrease in LVPSP and +dP/dt, and an increase in left ventricular end diastolic pressure. Wall thickening and a preservation of chamber volume occurred in SHR, while SHR-A had a degree of ventricular dilatation which exceeded the extent of wall thickening. However, genetic hypertension was accompanied by myocardial tissue injury which was fully prevented by the addition of nutritional anaemia. Moreover, the capillary volume was decreased in SHR and increased in SHR-A. CONCLUSIONS: Genetically determined hypertension in combination with anaemia results in eccentric ventricular hypertrophy and cardiac dysfunction in spite of an increase in capillary luminal volume and limited structural damage.
Anemia, Hypochromic↗
Spirapril prevents left ventricular hypertrophy, decreases myocardial damage and promotes angiogenesis in spontaneously hypertensive rats.
To test whether angiotensin-converting enzyme (ACE) inhibition may prevent myocardial damage and may affect coronary microvasculature in spontaneously hypertensive rats (SHR), young 5-week-old SHR were treated for 3 months with spirapril and changes in blood pressure (BP) were monitored. Untreated SHR were used as controls. The rats were killed; left ventricular (LV) shape, weight, and wall thickness were examined and the ventricular myocardium was analyzed morphometrically to determine the effect of the drug on the relative amount, number per unit area of myocardium, and average dimension of foci of myocardial scarring. Moreover, volume fraction, surface, numerical density, and diffusion distance for oxygen of the coronary capillaries were analyzed. BP remained 20-30% lower in treated SHR with respect to controls, and LV weight and thickness decreased 20 and 21%, respectively. The number and dimension of the foci of fibrosis were reduced, resulting in an overall 68% decrement in the amount of myocardial damage. Finally, a 28% increment in numerical density of capillary profiles associated with a 13% reduction in their cross-sectional area decreased the diffusion distance for oxygen from the capillary wall to the myocytes by 14% in treated SHR. Spirapril decreases BP and LV weight and thickness in the SHR model of hypertension and substantially improves coronary capillary microvasculature, decreasing hypertensive myocardial damage. These results may be attributed to inhibition of the systemic effects of angiotensin II (AII) as well as to a local protective action of the drug against possible intramyocardial AII production.
Angiotensin-Converting Enzyme Inhibitors↗