Paradoxical response to carbonic anhydrase inhibitors in patients with intraretinal cystoid spaces.

Background: Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy. Material and Methods: We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing. Results: We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1, one in CLN3 and another in NR2E3. All patients were followed for at least three years (range 39-63 months). None had systemic abnormalities. Conclusions: Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.

Chronic coronary artery constriction leads to moderate myocyte loss and left ventricular dysfunction and failure in rats.

Coronary artery narrowing, ranging from 19% to 61%, was induced in rats and ventricular performance, myocardial damage, and myocyte hypertrophy were examined 1 mo later. Animals were separated into two groups, exhibiting ventricular dysfunction and failure, respectively. Dysfunction consisted of a 2.4-fold increase in left ventricular end diastolic pressure (LVEDP), 15% decrease in left ventricular peak systolic pressure (LVPSP), 24% reduction in developed pressure (DP), and a 16% depression in-dP/dt. Failure was defined on the basis of a 4.7-fold elevation in LVEDP, and a 26%, 47%, 45%, and 41% decrease in LVPSP, DP, +dP/dt, and -dP/dt. Moreover, in this group, right ventricular end diastolic and systolic pressures increased 5.5- and 1.2-fold. Left and right ventricular weights expanded 23% and 51% with dysfunction and 30% and 56% with failure. Left ventricular hypertrophy was characterized by ventricular dilation and wall thinning which were more severe in the failing animals. Foci of damage were found in both groups but tissue injury was more prominent in the endomyocardium and in failing rats. Finally, myocyte loss in the ventricle was 10% and 20% with dysfunction and failure whereas the corresponding enlargements of the unaffected myocytes were 34% and 53%. Thus, coronary narrowing led to abnormalities in cardiac dynamics with an increase in diastolic wall stress and extensive ventricular remodeling in spite of a moderate loss of myocytes and compensatory reactive hypertrophy of the viable cells.

Cardiac conditioning ameliorates cardiac dysfunction associated with renal hypertension in rats.

To explore the effect of physiologic hypertrophy superimposed on pathologic hypertrophy, hearts from female control rats (C), renal hypertensive rats (H), rats conditioned with a 10-12 wk swimming program (Sw), and hypertensive rats trained by the swimming program (H-Sw) were perfused in an isolated working rat-heart apparatus. Systolic blood pressure was approximately 100 mmHg in C and Sw and was 160 mmHg in H and H-Sw. The swimming program had no effect on blood pressure. Compared with C, heart weight was increased by 30% in Sw, 47% in H, and 77% in H-Sw. At high preload and afterload, cardiac output (milliliters per gram dry LV weight) was decreased in H, increased in Sw, and partially restored towards normal in H-Sw. Ejection fraction, percent fractional shortening, and mean velocity of circumferential fiber shortening were enhanced in Sw, depressed in H, and normalized in H-Sw when compared with C. Coronary flow and myocardial oxygen consumption in this series of hearts were depressed in H, with no restoration in H-Sw, but coronary effluent lactate/pyruvate ratios were only elevated in the hearts of H-Sw. Coronary vascular responses were examined in a second series of experiments which used microspheres. In this series, the depressed coronary flow observed in H was partially restored towards normal in H-Sw and the inner/outer myocardial flow ratio was normal when hearts were perfused at 140 cm aortic pressure but was somewhat depressed in both H and H-Sw when the hearts were perfused at 80 cm aortic pressure. These studies demonstrate that hypertrophic hearts from renal hypertensive rats have diminished coronary flow and depressed cardiac function when they are studied in the isolated working heart apparatus, yet there is no evidence of myocardial ischemia. Superimposition of a chronic swimming program results in increased hypertrophy but restoration of cardiac function partially or completely to normal. Thus, pathologic and physiologic hypertrophy are biologically distinct entities. Physiologic hypertrophy may partially ameliorate the defects associated with pathologic hypertrophy.

Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats.

To evaluate the combined effects of cardiac overload imposed by hypertension and by chronic exercise, male and female rats were made hypertensive by unilateral renal artery stenoses and made to exercise in an 8-10-wk swimming program. Sedentary normotensive animals, sedentary hypertensive animals and normotensive animals exposed to the swimming program were also studied. Hypertension was associated with the development of cardiac hypertrophy, and this was exaggerated in hypertensive swimmers. Actomyosin, Ca2+-myosin, and actin-activated Mg2+-myosin ATPase activities were enhanced in normotensive swimmers, depressed in hypertensives and were normal or increased in hypertensive swimmers. Myosin isoenzyme analysis showed a predominant V1 pattern in normals; an increase in percent V1 isoenzyme is swimmers; a predominant V3 pattern in hypertensives; and a return to the predominant V1 pattern in hypertensive swimmers. These findings suggest that the hypertrophy imposed by hypertension and hypertrophy imposed by physical training using a chronic swimming program are distinctly different biological phenomena. Physical training by swimming prevents the changes in cardiac myosin induced by hypertension despite the exaggeration of hypertrophy.

Chronic nonocclusive coronary artery constriction in rats. Beta-adrenoceptor signal transduction and ventricular failure.

To determine the effects of chronic coronary artery constriction on the relationship between cardiac function and regulation of beta-adrenoceptor signal transduction, the left main coronary artery was narrowed in rats and the animals were killed 5 mo later. An average reduction in coronary luminal diameter of 44% was obtained and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative dP/dt. Significant increases in left and right ventricular weights indicative of global cardiac hypertrophy were observed. Radioligand binding studies of beta-adrenoreceptors, agonist-stimulated adenylate cyclase activity, and ADP ribosylation of 45-kD substrate by cholera toxin were all depressed in the failing left ventricle. In contrast, in the hypertrophic non-failing right ventricle, beta-adrenoreceptor density was preserved and receptor antagonist affinity was increased. In spite of these findings at the receptor level, agonist stimulated cyclic AMP generation was reduced in the right ventricular myocardium. The quantity of the 45-kD substrate was also decreased. In conclusion, longterm nonocclusive coronary artery stenosis of moderate degree has profound detrimental effects on the contractile performance of the heart in association with marked attenuation of adrenergic support mechanisms.

Hypertensive cardiomyopathy. Myocyte nuclei hyperplasia in the mammalian rat heart.

To determine whether long-term hypertension leads to hyperplasia of myocyte nuclei in the heart, a phenomenon suspected to occur in humans, renal hypertension was produced in rats and the animals were killed 8 mo later. Arterial blood pressure remained elevated for approximately 5 mo, but decreased progressively in the last 3 mo so that at 8 mo this parameter was practically identical to that found in controls. Moreover, left ventricular end diastolic pressure was markedly increased in experimental animals in association with a substantial decrease in left ventricular dP/dt. The alteration of these physiological measurements was indicative of severe ventricular dysfunction. Quantitative analysis of the transmural distribution of myocyte nuclei in the left ventricle showed 36 and 23% increases in myocyte nuclei concentration in the epimyocardium and endomyocardium, respectively. These changes in nuclei were accompanied by 25 and 16% reductions in myocyte cell volume per nucleus in the outer and inner layers of the wall. In conclusion, long-term hypertension leads to impairment of ventricular function and proliferation of nuclei in myocytes.

Noncoordinate regulation of alpha-1 adrenoreceptor coupling and reexpression of alpha skeletal actin in myocardial infarction-induced left ventricular failure in rats.

To determine the effects of myocardial infarction-induced left ventricular failure on the regulation of surface alpha-1 adrenoreceptors and signal transduction, large infarcts were produced in rats and the animals killed seven days later. After the documentation of impaired left ventricular pump performance, radioligand binding studies of the alpha-1 adrenoreceptor, norepinephrine-stimulated phosphoinositol turnover, and ADP ribosylation of 41 kD substrate by pertussis toxin were examined in the hypertrophying unaffected myocardium. Moreover, the expression of sarcomeric actin isoforms was analyzed by Northern blots and hybridization with specific oligonucleotide probes. Alpha-1 adrenoreceptor density was found not to be altered in membranes obtained from the spared left ventricular tissue, whereas phosphoinositol turnover was increased 3.1-fold in the viable myocytes of infarcted hearts. Furthermore, pertussis toxin substrate was augmented 2.5-fold in membranes prepared from the surviving left ventricular myocardium. Finally, an upregulation of the skeletal actin isoform was detected in the tissue of the failing left ventricle. In conclusion, the possibility is raised that in the presence of severe myocardial dysfunction and ongoing reactive hypertrophy, effector pathways linked to the alpha-1 adrenoreceptor may stimulate the myocyte hypertrophic response which would tend to normalize cardiac hemodynamics. The reexpression of alpha skeletal actin may be a molecular indicator of the persistance of an overload on the myocardium.

p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability.

In hepatocytes, Na+ influx through nonselective cation (NSC) channels represents a key point for regulation of cell volume. Under basal conditions, channels are closed, but both physiologic and pathologic stimuli lead to a large increase in Na+ and water influx. Since osmotic stimuli also activate mitogen-activated protein (MAP) kinase pathways, we have examined regulation of Na+ permeability and cell volume by MAP kinases in an HTC liver cell model. Under isotonic conditions, there was constitutive activity of p38 MAP kinase that was selectively inhibited by SB203580. Decreases in cell volume caused by hypertonic exposure had no effect on p38, but increases in cell volume caused by hypotonic exposure increased p38 activity tenfold. Na+ currents were small when cells were in isotonic media but could be increased by inhibiting constitutive p38 MAP kinase, thereby increasing cell volume. To evaluate the potential inhibitory role of p38 more directly, cells were dialyzed with recombinant p38alpha and its upstream activator, MEK-6, which substantially inhibited volume-sensitive currents. These findings indicate that constitutive p38 activity contributes to the low Na+ permeability necessary for maintenance of cell volume, and that recombinant p38 negatively modulates the set point for volume-sensitive channel opening. Thus, functional interactions between p38 MAP kinase and ion channels may represent an important target for modifying volume-sensitive liver functions.

Effect of nucleotides on translocation of sugar nucleotides and adenosine 3'-phosphate 5'-phosphosulfate into Golgi apparatus vesicles.

Recent studies from this laboratory have suggested that rat-liver Golgi apparatus derived membranes contain different proteins which can translocate in vitro CMP-N-acetylneuraminic acid, GDP-fucose and adenosine 3'-phosphate 5'-phosphosulfate from an external compartment into a lumenal one. The aim of this study was to define the role of the nucleotide, sugar and sulfate moieties of sugar nucleotides and adenosine 3'-phosphate 5'-phosphosulfate in translocation of these latter compounds across Golgi vesicle membranes. Indirect evidence was obtained suggesting that the nucleotide (but not sugar or sulfate) is a necessary recognition feature for binding to the Golgi membrane (measured as inhibition of translocation) but is not sufficient for overall translocation; this latter event also depends on the type of sugar. Important recognition features for inhibition of translocation of the above sugar nucleotides and adenosine 3'-phosphate 5'-phosphosulfate were found to be the type of nucleotide base (purine or pyrimidine) and the position of the phosphate group in the ribose. Thus, UMP and CMP were found to be competitive inhibitors of translocation of CMP-N-acetylneuraminic acid, while AMP did not inhibit. Structural features of the nucleotides which were less important in inhibition of translocation (and thus presumably in binding) of the above sugar nucleotides and adenosine 3'-phosphate 5'-phosphosulfate were the number of phosphate groups in the nucleotide (CDP and CMP inhibited to a similar extent), the presence of ribose or deoxyribose in the nucleotide, a replacement of hydrogen in positions 5 of pyrimidines or 8 in purines by halogens or an azido group. The sugar or sulfate did not inhibit translocation of the above sugar nucleotides and adenosine 3'-phosphate 5'-phosphosulfate into Golgi vesicles and therefore appear not to be involved in their binding to the Golgi membrane.

Subcellular distribution of "intersecting' beta-N-acetylglucosaminyltransferase in Dictyostelium discoideum. A likely marker for the Golgi apparatus.

Glycoprotein processing in Dictyostelium discoideum is characterized by enzyme catalyzed steps not reported in other organisms. One of these is the formation of a beta 1 --> 4 linkage between GlcNAc and the mannose linked to the core mannose in the alpha 1 --> 6 position of N-glycosides. A simple and sensitive assay for this GlcNAc transferase activity, using a tri-mannose acceptor and a low concentration of UDP-GlcNAc, was developed. Homogenates of the organism were subjected to sub-cellular fractionation by centrifugation in discontinuous sucrose gradients. The specific activity was enriched 4-5-fold in a crude membrane fraction. The transferase was purified 10-12-fold in a membrane fraction that bands on top of 1.1 M sucrose. This fraction was also enriched in nucleotidyldiphosphatase. The enriched fraction was deficient in glucose-6-phosphatase, an endoplasmic reticulum marker. Approx. 80% of the transferase activity was latent, and unavailable to protease. Purified membranes were either subjected to phase separation in Triton X-114, or sodium carbonate extraction or sonication. In each case, the transferase behaved as an intrinsic membrane protein. Several secreted and lysosomal proteins are modified by the enzyme. These data support the idea that the GlcNAc transferase is present as an integral Golgi membrane protein and that at least the catalytic center of the transferase is on the lumenal side of the vesicles.

Excitation-contraction coupling in rat myocardium: alterations with long term ethanol consumption.

The mechanical and electrical effects of chronic ethanol consumption were studied in rats maintained on 40% ethanol and water solution (40% of caloric intake) for a 30 week period and in controls. Left ventricular papillary muscles from male Wistar rats were studied by myography at 30 degrees C, 0.1 Hz stimulation, and external calcium concentration of 2.4 mmol X litre-1. No significant difference was found between alcoholic and control rats with regard to resting tension. Developed tension, time to peak tension, time to one half relaxation, and time to peak shortening were, however, significantly decreased in preparations from the study animals. Velocity of shortening and relengthening at all relative loads studied were depressed in alcoholic preparations. No significant difference was found in action potential between the two groups with regard to resting membrane potential, action potential amplitude, overshoot, or maximum rate of rise of the upstroke. In contrast, the duration at 50% (APD50) and 75% (APD75) of total repolarisation was significantly shorter for action potential in the alcoholic group than in the controls. Thus chronic ethanol ingestion results in an inability to develop normal levels of force, depressed force-velocity relation, and shortening of action potential duration.

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.

Myocyte loss and left ventricular failure characterise the long term effects of coronary artery narrowing or renal hypertension in rats.

OBJECTIVE: The aim was to determine the effects of chronic coronary artery narrowing and two kidney, one clip renal hypertension alone and in combination on ventricular function and myocardial morphology. METHODS: Left coronary stenosis and renal artery clipping were surgically induced in rats and pump dynamics, systolic and diastolic wall stress, cardiac anatomy, and the changes in number and size of left ventricular myocytes were examined 11-13 weeks later. RESULTS: Ventricular failure evolved with each intervention: left ventricular end diastolic pressure was raised, whereas +dP/dt, -dP/dt, stroke volume, cardiac output, and cardiac index were reduced. Calculated ventricular systolic wall stress increased nearly 70% in the three experimental conditions. By contrast, diastolic wall stress was augmented 6.1-fold with coronary stenosis, 4.0-fold with hypertension, and 4.4-fold with combined treatment. These differences were due to variable preservations of wall thickness between the groups. Left ventricular weight expanded 26%, 35%, and 32% with stenosis, hypertension, and a combination of the two, whereas diastolic cavitary volume increased 57%, 35%, and 49%. Corresponding increases in systolic chamber volumes were 156%, 122%, and 154%. Finally, myocyte loss in the ventricle was 25%, 25%, and 37% in coronary narrowing, renal hypertension and a combination of the two with concomitant enlargements of the unaffected myocytes of 47%, 63%, and 65%. CONCLUSIONS: Decompensated eccentric ventricular hypertrophy developed as a result of coronary artery narrowing, renal hypertension, or the two in combination. Coronary artery narrowing, however, may have a greater maladaptive effect on ventricular function than systemic hypertension, and coronary stenosis and hypertension combined because of the more extensive chamber and wall remodelling which sustained greater increases in diastolic wall stress.

Re-expression of alpha skeletal actin and regulation of alpha 1 adrenoceptor signalling in DOCA-salt hypertension in rats.

OBJECTIVE: To determine the effects of increased sympathetic nervous system activity in humoral hypertension on the regulation of surface alpha 1 adrenoceptors and signal transduction, deoxycorticosterone acetate (DOCA) salt hypertension was induced in rats and the animals killed three weeks following the initiation of hypertension. METHODS: Experiments were performed on male Sprague-Dawley rats, weighing 250-300 g, divided into two groups: DOCA-salt (n = 75), and control (n = 60). Radioligand binding studies of the alpha 1 adrenoceptors, noradrenaline stimulated phosphoinositol turnover, ADP ribosylation of 41 kD substrate by pertussis toxin, and myocardial noradrenaline content were measured in the ventricular myocardium. The expression of sarcomeric actin isoforms was examined by northern blot and hybridisation with specific oligonucleotide probes. RESULTS: The density of alpha 1 adrenoceptors was decreased by 51% in DOCA-salt treated rats. However, noradrenaline stimulated phosphoinositol turnover in myocytes from DOCA-salt hearts was not diminished. The relative quantities of pertussis toxin labelled substrates did not differ in experimental and control hearts. Myocardial noradrenaline content was reduced by 60% in DOCA-salt hearts. Northern blots on RNA extracted from hypertrophic hearts of DOCA-salt treated rats showed an upregulation of alpha skeletal actin. CONCLUSIONS: The adrenergic state present in short term DOCA-salt hypertensive hypertrophy is characterised by enhanced signal transduction via the alpha 1 adrenoceptors and the re-expression of alpha skeletal actin in enlarging myocytes.

Effects of experimental phosphate deficiency on action potential characteristics and contractile performance of rat myocardium.

Chronic hypophosphataemia is associated with reversible depression in myocardial performance of the intact heart. To define the basis for this, were studied the mechanical and electrical properties of isolated left ventricular papillary muscles from rats with 6 weeks of phosphorus depletion (P6), 6 weeks of phosphorus repletion and age-matched controls (C). Muscles were perfused with Tyrode's solution (Ca2+ 2.4 mmol.liter-1, 7 = 4.0 mmol . litre-1, dextrose = 5.5 mmol . litre-1) and driven at 0.1 Hz. P6 muscles had slowed isometric relaxation (T1/2R), depressed velocity of shortening and relaxation and prolongation of the transmembrane action potential to 75% of complete repolarisation. These results suggest that the slow relaxation phase may be the result of the prolonged APD75 and that the depressed myocardial performance in the intact heart may be based on impaired relaxation and reduced the velocity of shortening associated with hypophosphataemia. This view is supported by our finding that these alterations are reversible with phosphate repletion.

Size and shape of enzymatically isolated ventricular myocytes from rats and cardiomyopathic hamsters.

Rod-shaped and branched ventricular myocytes from rats and cardiomyopathic hamsters (strain 53.58) were isolated enzymatically, and their widths and lengths were measured in physiological salt solutions containing normal levels of calcium (2.5 mmol). In rats of approximately 200 g body weight, the average myocyte width and length are 25 micron and 115 micron. The isolated cells are also classified according to shape with nearly 50% branched or otherwise irregular. Myocytes of the hearts of the 53.58 strain of cardiomyopathic hamsters at 7 months of age are significantly larger than control hamsters of the same age, indicating that cellular hypertrophy has occurred. Estimates of the number of cells in the ventricles indicate that there is a cell loss of nearly 13% in the myopathic heart. A consideration of the significance of wider and longer myocytes with undiminished myofibrillar mass lead to the conclusion that the decreased contractility displayed by the cardiomyopathic hamster heart must be due, at least in part, to functional defects in the myofibrillar apparatus, in the system of activation, or in cellular integration.

Coronary artery constriction in rats affects the activation of alpha 1 adrenergic receptors in cardiac myocytes.

OBJECTIVE: To determine whether alpha 1 adrenergic receptor mediated myocyte contractility and growth are depressed acutely after non-occlusive coronary artery narrowing, the left coronary artery was constricted in rats and mechanical behaviour, cytosolic calcium, and regulation of alpha 1 adrenergic receptors were examined in myocytes seven days later. METHODS: Coronary artery stenosis was surgically induced in rats and following the estimation of global cardiac performance myocytes were enzymatically dissociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients and noradrenaline stimulated inositol phosphate generation in myocytes were measured in the presence of WB 4101 or after chlorethylclonidine treatment. RESULTS: Estimations of cell mechanics in vitro established that peak shortening was decreased by 36% and 18% in left and right ventricular myocytes of coronary stenosed rats. Time to peak shortening was prolonged by 29% in left and 20% in right myocytes, whereas velocity of shortening was decreased by 27% in left myocytes. These alterations were associated with increases in cell length and width, indicative of myocyte hypertrophy. In addition, coronary stenosis was accompanied by reductions in the expression of alpha 1a and alpha 1b receptor subtypes in myocytes. alpha 1 Adrenergic receptor density and noradrenaline stimulated phosphoinositol turnover were decreased by 30% and 34% in left myocytes. alpha 1a Adrenergic receptor subtype mediated cytosolic calcium concentration and myocyte mechanical performance were also impaired in left myocytes only. The alpha 1a adrenergic receptor subtype antagonist WB 4101 abolished noradrenaline stimulated inositol phosphate generation in myocytes, whereas chlorethylclonidine at large doses only partially inhibited this response. CONCLUSIONS: In conclusion, coronary narrowing leads to defects in the regulation of alpha 1 adrenergic receptors on myocytes which are coupled with attenuation in the transmission of signals, possibly affecting myocyte cell function and ongoing reactive cellular hypertrophy.

Cellular basis of ventricular remodeling after myocardial infarction.

To determine whether acute left ventricular failure associated with myocardial infarction leads to architectural changes in the spared nonischemic portion of the ventricular wall, large infarcts were produced in rats, and the animals were sacrificed 2 days after surgery. Left ventricular end-diastolic pressure was increased, whereas left ventricular dP/dt and systolic pressure were decreased, indicating the presence of severe ventricular dysfunction. Absolute infarct size, determined by measuring the fraction of myocyte nuclei lost from the left ventricular free wall, averaged 63%. Transverse midchamber diameter increased by 20%, and wall thickness diminished by 33%. The number of mural myocytes in this spared region of the left ventricular free wall decreased by 36% and the capillary profiles by 40%. Thus, side-to-side slippage of myocytes in the myocardium occurs acutely in association with ventricular dilation after a large myocardial infarction. In order to analyze the chronic consequences of myocardial infarction on ventricular remodeling, a second group of experiments was performed in which the left coronary artery was ligated and the functional and structural properties of the heart were examined 1 month later. In infarcts affecting an average 38% of the free wall of the left ventricle (small infarcts), reactive hypertrophy in the spared myocardium resulted in a complete reconstitution of functioning tissue. However, left ventricular end-diastolic pressure was increased, left ventricular dP/dt was decreased, and diastolic wall stress was increased 2.4-fold. After infarctions resulting in a 60% loss of mass (large infarcts), a 10% deficit was present in the recovery of viable myocardium. Functionally, ventricular performance was markedly depressed, and diastolic wall stress was increased 9-fold. The alterations in loading of the spared myocardium were due to an increase in chamber volume and a decrease in the myocardial mass/chamber volume ratio that affected both infarct groups. Thus, decompensated eccentric ventricular hypertrophy develops chronically after infarction and growth processes in myocytes are inadequate for normalization of wall stress when myocyte loss involves nearly 40% or more of the cells of the left ventricular free wall. The persistence of elevated myocardial and cellular loads may sustain the progression of the disease state toward end-stage congestive heart failure.

Microvascular spasm as a cause of cardiomyopathies and the calcium-blocking agent verapamil as potential primary therapy.

The origin of cardiomyopathies, a major cause of cardiac disability and death, has been largely unexplained. Pathologic features, common to all cardiomyopathies independent of origin, include ventricular hypertrophy and diffuse scarring with variable amounts of ventricular dilatation. This problem was studied experimentally in 2 models of congestive cardiomyopathy: the hereditary cardiomyopathic Syrian hamster and the hypertensive-diabetic rat. In both the genetic and the acquired disease models, there is focal myocytolytic necrosis followed by healing with focal scars, ventricular wall hypertrophy, ventricular dilatation with congestive heart failure and, ultimately, death. In view of the heterogeneous pathologic features of both diseases, silicone rubber perfusions have been used to study the microcirculation of the heart in these animals; microvascular spasm has been demonstrated early in the disease associated with small areas of myocytolytic necrosis that undergo subsequent fibrosis. Reactive hypertrophy then ensues as a compensatory response to this myocellular necrosis; it is the combination of cell loss and slowly decreasing contractility resulting from the reactive hypertrophy, which culminates in a cardiomyopathy. Administration of verapamil or prazosin to the cardiomyopathic Syrian hamster prevents microvascular spasm and development of cardiomyopathic changes in the myocardium. In view of these and other findings related to the anatomy and hyperreactivity of microcirculation, it is concluded that hypertrophic congestive cardiomyopathies may be caused by focal cell loss due to microvascular spasm and reperfusion injury, with the subsequent development of focal fibrosis and reactive hypertrophy in response to the myocardial necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension.

An abnormal elevation in collagen concentration or myocardial fibrosis occurs in the hypertrophied left ventricle of the rat with renovascular hypertension (RHT). The structural nature and functional consequences of this fibrosis and the mechanisms involved in its appearance were reviewed for various phases of hypertrophy. Within days after the onset of renal ischemia, type I collagen messenger ribonucleic acid is expressed. An interstitial fibrosis follows, characterized by an increased dimension of existing perimysial fibers and the appearance of fibrillar collagen in spaces previously devoid of collagen, together with a perivascular fibrosis of intramyocardial coronary arteries. These expressions of myocardial fibrosis are associated with an increase in diastolic and systolic myocardial stiffness. Endomyocardial fibrosis serves to further increase diastolic stiffness while myocytes encircled by fibrillar collagen become atrophic. Each of these consequences of myocardial fibrosis reduce myocyte length-dependent force generation. At 32 weeks of RHT there is an obvious diastolic and systolic dysfunction of the ventricle together with heart failure that includes ventricular dilatation, wall thinning and reduced ejection fraction. The mechanisms involved in mediating fibrosis in RHT appear to be multiple. Myocyte necrosis and fibroblast proliferation have been associated with elevated circulating angiotensin II. Necrosis in RHT was not seen with captopril pretreatment or in the hypertension and hypertrophy that accompanied infrarenal aorta banding. An alteration in coronary artery permeability may be responsible for the perivascular fibrosis that is not seen with captopril pretreatment. Thus in RHT, the hemodynamic status of the ventricle determines myocyte hypertrophy while the elevation in circulating angiotensin II is responsible for the remodeling of nonmyocyte compartments, including the appearance of myocardial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)