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PubMed1991

Varying amounts of stretch stimulus regulate stretch-induced muscle hypertrophy in the chicken.

1. The effects of different amounts of passive stretch per day and number of days of stretch on muscle hypertrophy in the chicken patagialis (PAT) muscle were determined. 2. Stretch for 24 hr per day (h/d) resulted in a more rapid hypertrophy both on a wet and dry tissue basis (P less than 0.001) than stretch for 4 h/d. 3. Stretch increased PAT weight 43% and 25% in 24 h/d and 4 h/d treatments, respectively, after 10 days of stretch, but by day 25 of stretch there was no difference between treatments. 4. In a second experiment, the PAT muscle was hypertrophied and then the effects of intermittent stretch (4 h/d) on regression of hypertrophy (muscle atrophy) were investigated. 5. Intermittent stretch (4 h/d) for 5 and 10 d significantly (P less than 0.001) inhibited regression of hypertrophied muscle. 6. The results of the present study indicate that stretch-induced hypertrophy can be modulated by varying the amount of stretch applied per day. 7. Intermittent stretch can be used to inhibit the regression which occurs when a continuous stretch stimulus is removed. 8. Intermittent stretch is a useful model for investigating mechanisms of muscle hypertrophy and inhibition of muscle atrophy.

Animals↗
PubMed1993

Coronary vasodilator reserve in untreated and treated hypertensive patients with and without left ventricular hypertrophy.

OBJECTIVES: This study was initiated to compare the coronary reserve in treated hypertensive patients with and without left ventricular hypertrophy with that in untreated patients. BACKGROUND: Coronary reserve is impaired in hypertensive patients with left ventricular hypertrophy and normal coronary arteries. Moreover, basal coronary resistance is elevated in hypertensive patients without left ventricular hypertrophy. METHODS: Coronary reserve was measured with a coronary Doppler catheter before and after a maximally vasodilating dose of intracoronary papaverine (peak/rest flow velocity ratio) in 16 control subjects and 37 hypertensive patients with normal epicardial coronary arteries. Among 20 untreated hypertensive patients, myocardial mass was increased in 11 (group 2a) and normal in 9 (group 2b). Seventeen patients had been treated effectively for at least 1 year; nine (group 3a) had persistent left ventricular hypertrophy, and eight (group 3b) had no left ventricular hypertrophy before treatment. Left ventricular volumes and ejection fraction were normal in all groups. RESULTS: Coronary reserve was moderately reduced in group 2b (3.5 +/- 0.6 vs. 5.2 +/- 0.8 in control subjects, p < 0.001) and markedly diminished in groups 2a and 3a (2.5 +/- 0.5 and 2.7 +/- 0.4, respectively; all p < 0.001 vs. control subjects). In group 3b, coronary reserve was comparable to that of control subjects (5.1 +/- 1.4). CONCLUSIONS: The reduction in coronary reserve observed in untreated hypertensive patients with normal myocardial mass suggests that structural abnormalities of the coronary microvasculature may occur before left ventricular hypertrophy. Treated patients with normal mass before treatment had a coronary reserve comparable to that of normotensive control subjects, whereas normalization of arterial pressure with persistent left ventricular hypertrophy was associated with a marked impairment of coronary reserve.

Adult↗
PubMed1995

Influence of left ventricular hypertrophy on left ventricular function during dynamic exercise in the presence or absence of coronary artery disease.

OBJECTIVES: We investigated the influence of left ventricular hypertrophy in the presence or absence of coronary artery disease on hemodynamic characteristics during exercise in subjects without previous myocardial infarction. BACKGROUND: Left ventricular hypertrophy has been found to increase the vulnerability of the myocardium to the development of ischemia. However, the independent influences of left ventricular hypertrophy and coronary artery disease have not been assessed in humans. METHODS: Symptom-limited supine leg exercise tests were performed by 78 patients. They were classified into the following subgroups: no coronary artery disease or left ventricular hypertrophy (group I, n = 30), left ventricular hypertrophy only (group II, n = 12), coronary artery disease only (group III, n = 20) and both left ventricular hypertrophy and coronary artery disease (group IV, n = 16). Mean left ventricular mass index was 105, 158, 109 and 159 g/m2 in groups I to IV, respectively. RESULTS: Pulmonary artery wedge pressure increased from 6 +/- 3 (mean +/- SD) mm Hg at rest to 10 +/- 5 mm Hg at peak exercise in group I, from 8 +/- 2 to 18 +/- 8 mm Hg in group II (p < 0.05 vs. group I), from 6 +/- 3 to 23 +/- 6 mm Hg in group III (p < 0.01 vs. group I) and from 8 +/- 4 to 30 +/- 7 mm Hg in group IV (p < 0.01 vs. group I; p < 0.01 vs. group II; p < 0.05 vs. group III). Multiple regression analysis showed that the number of diseased coronary vessels and left ventricular mass index were independent predictors of peak pulmonary artery wedge pressure (F = 59.2 and 19.1, respectively; multiple correlation coefficient r = 0.74, p < 0.0001). CONCLUSIONS: Left ventricular hypertrophy and coronary artery disease independently increased left ventricular filling pressure during supine leg exercise. Severe left ventricular dysfunction was induced by exercise when both conditions were present.

Adult↗
PubMed1995

Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy.

OBJECTIVES: This study of hypertensive left ventricular hypertrophy 1) assessed myocardial shortening in both the circumferential and long-axis planes, and 2) investigated the relation between geometry and systolic function. BACKGROUND: In hypertensive left ventricular hypertrophy, whole-heart studies have suggested normal systolic function on the basis of ejection fraction-systolic stress relations. By contrast, isolated muscle data show that contractility is depressed. It occurred to use that this discrepancy could be related to geometric factors (relative wall thickness). METHODS: We studied 43 patients with hypertensive left ventricular hypertrophy and normal ejection fraction (mean +/- SD 69 +/- 13%) and 50 clinically normal subjects. By echocardiography, percent myocardial shortening was measured in two orthogonal planes; circumferential shortening was measured at the endocardium and at the midwall, and long-axis shortening was derived from mitral annular motion (apical four-chamber view). Circumferential shortening was related to end-systolic circumferential stress and long-axis shortening to meridional stress. RESULTS: Endocardial circumferential shortening was higher than normal (42 +/- 10% vs. 37 +/- 5%, p < 0.01) and midwall circumferential shortening lower than normal in the left ventricular hypertrophy group (18 +/- 3% vs. 21 +/- 3%, p < 0.01). Differences between endocardial and midwall circumferential shortening are directly related to differences in relative wall thickness. Long-axis shortening was also depressed in the left ventricular hypertrophy group (18 +/- 6% in the left ventricular hypertrophy group, 21 +/- 5% in control subjects, p < 0.05). Midwall circumferential shortening and end-systolic circumferential stress relations in the normal group showed the expected inverse relation; those for approximately 33% of the left ventricular hypertrophy group were > 2 SD of normal relations, indicating depressed myocardial function. There was no significant relation between long-axis shortening and meridional stress, indicating that factors other than afterload influence shortening in this plane. CONCLUSIONS: High relative wall thickness allows preserved ejection fraction and normal circumferential shortening at the endocardium despite depressed myocardial shortening in two orthogonal planes.

Adult↗
PubMed1995

Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients.

OBJECTIVES: This study sought to achieve an understanding of the true structural heterogeneity of hypertrophic cardiomyopathy. BACKGROUND: The diversity and clinical significance of the morphologic expression of hypertrophic cardiomyopathy have not been fully defined within this broad disease spectrum. METHODS: Patterns of left ventricular hypertrophy were characterized by two-dimensional echocardiography in a large study cohort of 600 patients (7 to 79 years old, mean age 45; 393 [66%] men) consecutively studied at two referral centers. RESULTS: Left ventricular wall thickness was 15 to 52 mm (mean [+/- SD] 22.3 +/- 5). A multitude of patterns of asymmetric left ventricular hypertrophy were identified, with the most common showing diffuse involvement of substantial portions of both ventricular septum and free wall. Of 16 possible patterns of left ventricular hypertrophy, 12 (78%) were identified among the 600 patients. Hypertrophy most commonly involved two left ventricular segments (228 patients [38%]) or three or more segments (202 patients [34%]), but was also localized to one segment in a substantial number of patients (170 [28%]). The anterior portion of the ventricular septum was the region of the left ventricle that most frequently showed thickening (573 patients [96%]), and was also the predominant site of hypertrophy in most patients (492 patients [83%]). Patterns of wall thickening that were either concentric (i.e., symmetric) or confined to the apex were particularly uncommon (in 1% each). CONCLUSIONS: 1) In hypertrophic cardiomyopathy, the distribution of left ventricular hypertrophy is characteristically asymmetric and particularly heterogeneous, encompassing most possible patterns of wall thickening, from extensive and diffuse to mild and segmental, and with no single morphologic expression considered typical or classic. 2) A greater extent of left ventricular hypertrophy was associated with younger age and more marked mitral valve systolic anterior motion and outflow obstruction but showed no relation to either magnitude of symptoms or gender.

Adolescent↗
PubMed2004

Comparison of the prognostic value of left ventricular hypertrophy in African-American men versus women.

Echocardiographically determined left ventricular (LV) hypertrophy may be a stronger risk factor of cardiovascular disease (CVD) for women than for men, although it is unclear whether reported gender differences are real or attributable to confounding. We evaluated echocardiographic LV hypertrophy (defined as LV mass/height(2.7) >/=51 g/m(2.7)) collected from the African-American population of the Atherosclerosis Risk in Communities Study. Incident CVD events (57 in men, 62 in women) were determined during a median follow-up of 4.9 years (interquartile range 4.3 to 5.6) and included nonfatal myocardial infarction, cardiac death, coronary revascularization, and stroke. We conducted 2 analyses. First, we created matched samples of 340 men and 812 women who had LV hypertrophy based on propensity score and estimated the gender-specific incidence rate ratios and population-attributable risks. Second, we evaluated the complete cohort (604 men and 1,113 women) with Poisson's regression after adjusting for age, body mass index, hypertension, diabetes mellitus, ratio of total cholesterol to high-density lipoprotein cholesterol, current smoking, and education level. LV hypertrophy was significantly predictive of incident CVD, and the association shown by analyses of matched propensity scores was similar in men and women (incidence rate ratio 1.88 vs 1.92, p = 0.97 for men, population-attributable risk 0.22 vs 0.26, p <0.07 for women). In the multivariate analysis, we found comparable effect estimates for LV hypertrophy (incidence rate ratio 1.66 vs 2.09, p = 0.55 for men; population-attributable risk 0.24 vs 0.32, p <0.07 for women). Thus, LV hypertrophy is a strong predictor of CVD in African-Americans, and the effect of LV hypertrophy on CVD is similar in men and women.

Black or African American↗
PubMed2005

Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice.

Early diabetic nephropathy is characterized by renal hypertrophy that is mainly due to proximal tubular hypertrophy. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, and its signaling has been reported to regulate protein synthesis and cellular growth, specifically, hypertrophy. Therefore, we examined the effect of mTOR signaling on diabetic renal hypertrophy by using the specific inhibitor for mTOR, rapamycin. Ten days after streptozotocin-induced diabetes, mice showed kidney hypertrophy with increases in the phosphorylation of p70S6kinase and the expression of cyclin kinase inhibitors, p21(Cip1) and p27(Kip1), in the kidneys. The intraperitoneal injection of rapamycin (2 mg/kg/day) markedly attenuated the enhanced phosphorylation of p70S6kinase, the increment of cyclin-dependent kinase inhibitors, and renal enlargement without any changes of clinical parameters, including blood glucose, blood pressure, and food intake. Overexpression of a constitutive active form of p70S6kinase resulted in increased cell size of cultured mouse proximal tubule cells; thus, activation of p70S6kinase causes hypertrophy of proximal tubular cells. Our findings suggest that activation of mTOR signaling causes renal hypertrophy at the early stage of diabetes.

Animals↗
PubMed2004

Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis.

OBJECTIVES: Gap junctions (GJ) are important determinants of conduction. In advanced heart failure alterations of the major ventricular GJ protein, connexin 43 (Cx43) are found. However, changes in Cx43 expression during the progression from compensated cardiac hypertrophy to heart failure, especially in humans, have not been studied extensively. The aim of the present study was to investigate changes in Cx43 expression and distribution in compensated and decompensated left ventricular (LV) hypertrophy in pressure-overloaded human hearts with valvular aortic stenosis (AS). METHODS: We measured Cx43 levels by Western blot and quantitative immunoconfocal microscopy of LV septum biopsies from three groups of patients with AS (group I (n=9): ejection fraction (EF)>50%; group II (n=12): EF 30-50%; group III (n=9): EF<30%). LV biopsies from six patients with mitral valve stenosis and two donor hearts served as controls. RESULTS: Only the early phase of LV hypertrophy (AS-I) was characterized by extensive Cx43 lateral staining. As compared to controls, the AS-I group showed a 44.3% increase in Cx43 protein, which was reflected in an augmented number of GJs per 100 microm(2) intercalated disc area (control: 62.5+/-6.4 vs. AS-I: 79.8+/-4, p<0.001) and an increased GJ surface density (control: 0.00547 vs. AS-I: 0.00724 microm(2)/microm(3), p<0.01). Decompensated LV hypertrophy (AS-III) was specified by reduced percentage of the Cx43 signal per myocyte area (control: 1.74% vs. AS-III: 1.31%, p<0.01) or per intercalated disc (control: 18.3% vs. AS-III: 11.3%, p<0.005). Mean GJ area and GJ number per intercalated discs in the AS-III group were decreased significantly by, respectively, 42.5% and 36.4% as compared to control. In addition, decompensated LV myocardium showed a markedly heterogeneous spatial distribution of Cx43. CONCLUSION: The quantity and spatial distribution of Cx43 differs markedly between compensated and decompensated LV hypertrophy in human patients with AS. Upregulation of Cx43 in compensated hypertrophy may represent the immediate adaptive response to increased load, whereas diminished and heterogeneous Cx43 distribution in decompensated hypertrophy may play maladaptive roles culminating in heart failure and ventricular arrhythmias.

Aged↗
PubMed2005

The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes.

OBJECTIVE: Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca2+]i-rise caused by 3 h of Fas activation are dependent on the Fas-->phospholipase C (PLC)-->1,4,5-inositol trisphosphate (1,4,5-IP3)-->sarcoplasmic reticulum (SR) [Ca2+]i release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy. METHODS: The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence. RESULTS: Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP3R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP3 pathway), genistein and by the PI3K blocker LY294002. CONCLUSIONS: Fas-mediated hypertrophy is dependent on the 1,4,5-IP3 pathway, which is functionally inter-connected to the PI3K/AKT/GSK3beta pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy.

Animals↗
PubMed2004

Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.

Histone deacetylases (HDACs) modulate cell growth and differentiation by governing chromatin structure and repressing the activity of specific transcription factors. We showed previously that HDAC9 acts as a negative regulator of cardiomyocyte hypertrophy and skeletal muscle differentiation. Here we report that HDAC4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation by interacting with and inhibiting the activity of Runx2, a transcription factor necessary for chondrocyte hypertrophy. HDAC4-null mice display premature ossification of developing bones due to ectopic and early onset chondrocyte hypertrophy, mimicking the phenotype that results from constitutive Runx2 expression in chondrocytes. Conversely, overexpression of HDAC4 in proliferating chondrocytes in vivo inhibits chondrocyte hypertrophy and differentiation, mimicking a Runx2 loss-of-function phenotype. These results establish HDAC4 as a central regulator of chondrocyte hypertrophy and skeletogenesis and suggest general roles for class II HDACs in the control of cellular hypertrophy.

Animals↗
PubMed2005

Pain and calf hypertrophy associated with spontaneous repetitive discharges treated with botulinum toxin.

OBJECTIVE: To report a case of neurogenic calf hypertrophy associated with root lesion responsive to botulinum toxin (BTX). In addition, we systematically review the literature for cases of muscle hypertrophy associated with radiculopathy. METHODS: A 56-year-old man with a previous history of S1 root lesion presented with marked calf hypertrophy, muscle pain, cramps, fasciculations, and increased CK level. Magnetic resonance imaging and muscle biopsy confirmed true muscle hypertrophy. Electromyography (EMG) showed signs of chronic denervation-reinnervation in the right S1 myotome, with greatly increased spontaneous activity (SA) (fasciculations and complex repetitive discharges). Botox(R) was injected in 3 occasions on 4 sites on the right gastrocnemius (20U per site). Symptoms, CK level and SA on EMG (quantified) were evaluated. RESULTS: The patient improved clinically, CK level and SA steadily decreased. CONCLUSIONS: The literature review failed to identify a unique causative factor for muscle hypertrophy related to neurogenic lesions. BTX treatment was effective in our patient with muscle hypertrophy associated with SA. SIGNIFICANCE: We provide further evidence that spontaneous activity secondary to nerve lesion may cause focal muscle hypertrophy. Treatment with BTX should be considered in these conditions.

Anti-Dyskinesia Agents↗
PubMed2004

Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is an inherited primary disorder of the myocardium characterised by clinical heterogeneity. The severity and rate of progression of hypertrophy is an important factor in prognosis, and is likely to be dependent on factors including age, the disease-causing gene mutation, environmental influences and genetic modifiers. METHODS: To study the influence of age on progression of hypertrophy, 62 patients with hypertrophic cardiomyopathy followed up for a minimum of 2 years were studied to determine the changes in left ventricular hypertrophy based on transthoracic M-mode and 2D echocardiography. DNA studies were performed to determine the role of the angiotensin-converting enzyme (ACE) gene deletion polymorphism in modulating progression of left ventricular hypertrophy. RESULTS: Sixty-two patients were followed-up over a period of 6.0 +/- 3.2 years (range 2-16 years). Patient data were analysed in two age groups: group 1 (patients aged < or = 30 years at first echocardiogram) had an increase in left ventricular septal wall thickness from 23.8 +/- 8.9 to 28.8 +/- 8.7 mm (p < 0.001), while group 2 (patients aged > 30 years) had a smaller but significant increase from 17.8 +/- 4.2 to 19.5 +/- 6.2 mm (p < 0.05). DNA analysis of the ACE gene deletion polymorphism showed those with the deletion/deletion (D/D) genotype had a greater progression of left ventricular hypertrophy compared to those carrying the other ACE genotypes (increase in hypertrophy: 6.2 +/- 3.3 vs. 1.7 +/- 4.2 mm; p < 0.01, D/D vs. I/D genotype; 2.8 +/- 5.8 mm; p = ns, D/D vs. I/I genotype). This association was independent of age, body mass and resting blood pressure. CONCLUSIONS: Progression of left ventricular hypertrophy is most evident in the first 3 decades of life, but is also observed in older age groups. Presence of the ACE gene D/D polymorphism may be an important marker to identify those individuals with hypertrophic cardiomyopathy who are likely to have more progressive disease, and therefore at higher risk of adverse clinical outcomes.

Adult↗
PubMed2005

Impact of left ventricular hypertrophy late after aortic valve replacement for aortic stenosis on cardiovascular morbidity and mortality.

AIMS: The goal of this study was to assess the prevalence of left ventricular (LV) hypertrophy in patients with aortic stenosis late (>6 months) after aortic valve replacement and its impact on cardiac-related morbidity and mortality. METHODS AND RESULTS: In a single tertiary centre, echocardiographic data of LV muscle mass were collected. Detailed information of medical history and angiographic data were gathered. Ninety-nine of 213 patients (46%) had LV hypertrophy late (mean 5.8 +/- 5.4 years) after aortic valve replacement. LV hypertrophy was associated with impaired exercise capacity, higher New York Heart Association dyspnoea class, a tendency for more frequent chest pain expressed as higher Canadian Cardiovascular Society class, and more rehospitalizations. 24% of patients with normal LV mass vs. 39% of patients with LV hypertrophy reported cardiac-related morbidity (p = 0.04). In a multivariate logistic regression model, LV hypertrophy was an independent predictor of cardiac-related morbidity (odds ratio 2.31, 95% CI 1.08 to 5.41), after correction for gender, baseline ejection fraction, and coronary artery disease and its risk factors. Thirty seven deaths occurred during a total of 1959 patient years of follow-up (mean follow-up 9.6 years). Age at aortic valve replacement (hazard ratio 1.85, 95% CI 1.39 to 2.47, for every 5 years increase in age), coexisting coronary artery disease at the time of surgery (hazard ratio 3.36, 95% CI 1.31 to 8.62), and smoking (hazard ratio 4.82, 95% CI 1.72 to 13.45) were independent predictors of overall mortality late after surgery, but not LV hypertrophy. CONCLUSIONS: In patients with aortic valve replacement for isolated aortic stenosis, LV hypertrophy late after surgery is associated with increased morbidity.

Adult↗
PubMed1997

Relation of electrocardiographic left ventricular hypertrophy with and without T-wave changes to systemic blood pressure, body mass, and serum lipids and blood glucose levels in Japanese men.

Left ventricular (LV) hypertrophy, especially combined with an abnormal ST-T, is considered 1 of many coronary risk factors. Seven hundred forty-nine Japanese men were selected according to their electrocardiographic findings, i.e., normal electrocardiogram, LV hypertrophy without an abnormal ST-T segment, LV hypertrophy with a flat T wave, and LV hypertrophy with a negative T wave. Coronary risk factors were compared among these 4 age-matched groups. Groups with LV hypertrophy with negative or flat T waves had larger body mass index (24.9 vs 22.9 kg/m2), higher mean systemic blood pressure (111 vs 95 mm Hg), larger LV mass (265 vs 157 g), higher blood glucose (110 vs 100 mg/dl), higher serum triglyceride (148 vs 122 mg/dl), higher total cholesterol (206 vs 198 mg/dl), and lower high-density lipoprotein cholesterol (47 vs 54 mg/dl) than the normal group or the group with LV hypertrophy without T-wave change. Among these risk factors, blood pressure and glucose remained higher even after the adjustment by body mass index or by body mass index and blood pressure. Electrocardiographic LV hypertrophy with a changed T wave signified higher risk of coronary artery disease in Japanese men.

Blood Glucose↗
PubMed2003

Assessment of sarcoplasmic reticulum Ca2+-uptake during the development of left ventricular hypertrophy.

Cardiac sarcoplasmic reticulum (SR) sequesters Ca(2+) and plays a crucial role in the regulation of intracellular Ca(2+). Its functional properties are central to the excitation-contraction cycle of cardiac muscle. In this study, we hypothesized that alterations in SR function occur during the development of left ventricular (LV) hypertrophy. LV hypertrophy was produced in Lewis rats by the one-kidney, one-clip (1K1C) procedure. LV tissues were obtained from 1K1C rats 1 week (mild, N=7), 4 weeks (moderate, N=7), and 8 weeks (severe, N=7) post-surgery and from the corresponding age-matched, sham-operated controls (N=7 at each stage). In all of these rats, the ratio of LV weight (g) to body weight (kg) was determined and considered as an index for LV hypertrophy. In addition, the ratio of lung weight (g) to body weight (kg) was determined and considered as an index for pulmonary congestion and heart failure. In each LV specimen, SR Ca(2+)-uptake and tissue Ca(2+)-ATPase (CAA) level were determined. In 1K1C rats, LV hypertrophy increased by 21, 40, and 90% at 1, 4, and 8 weeks post-surgery, respectively, compared to the age-matched, sham-operated rats, whereas pulmonary congestion did not occur at 1 and 4 weeks but increased significantly by about 21% at 8 weeks. Further, both SR Ca(2+)-uptake and immunodetectable CAA level did not change at 1 week, increased (54%) to the same extent at 4 weeks, and decreased (42%) by approximately the same extent at 8 weeks in 1K1C rats compared to the age-matched, sham-operated rats. In summary, as LV hypertrophy evolved, Ca(2+)-uptake and CAA expression did not change in the early, increased in the moderate, and then declined in the later stages of hypertrophy development. The increase in Ca(2+)-uptake and CAA expression suggests, at the cellular level, a compensatory response to LV hypertrophy, while the decline at later stages indicates the transition to heart failure.

Animals↗
PubMed2002

Old and new tools to dissect calcineurin's role in pressure-overload cardiac hypertrophy.

In the last several years, a number of experiments have implicated a pivotal role of the calcium/calmodulin-calcineurin dependent pathway as a final common signaling mechanism by which diverse hypertrophic stimuli converge to mediate hypertrophic responses in cardiomyocytes. Calcineurin inhibitors, i.e. cyclosporine A (CsA) and FK506, can interrupt the pathway, thereby preventing cardiac hypertrophy. The data that convincingly support this novel hypothesis were derived either from in vitro studies in cultured cardiomyocytes or from in vivo studies in transgenic mice. However, when the hypothesis was tested in clinically relevant animal models of cardiac hypertrophy, controversial results and conclusions emerged. In conventional models of cardiac hypertrophy, two questions remain to be answered: (1) whether calcineurin is activated in hypertrophied cardiac muscle, and (2) whether calcineurin inhibitors prevent cardiac hypertrophy. In addition, clinical observations have revealed that calcineurin inhibitors appear to exert pro-hypertrophic effects in organ transplant recipients. The controversies suggest that current calcineurin inhibitors are blunt tools for testing the hypothesis in pressure-overload hypertrophy in vivo, because there are so many confounding effects that are associated with systemic administration of the drugs. As such, new genetic approaches may overcome some of the problems associated with pharmacological inhibitors. This invited review will focus on the controversies surrounding the ability of calcineurin inhibition to prevent conventional (pressure-overload) cardiac hypertrophy and the new genetic approaches to address the question.

A Kinase Anchor Proteins↗
PubMed1998

Clenbuterol induces cardiac hypertrophy with normal functional, morphological and molecular features.

OBJECTIVE: Several pharmacological agents have been shown to produce 'physiological' or 'pathological' hypertrophy based on their functional characteristics. The aim of this study was to examine the features of cardiac hypertrophy induced by the selective beta 2-adrenergic agonist, clenbuterol. METHODS: Cardiac hypertrophy was induced in 7-week-old Sprague-Dawley rats by daily injections of clenbuterol for 3 weeks. Thyroxine and isoproterenol were also used to produce cardiac hypertrophy to serve as positive controls for physiological and pathological hypertrophy, respectively. Left ventricular function was determined using an isolated rat heart preparation. Ventricular samples were used for morphological examination while interstitial collagen was measured using high-pressure liquid chromatography. Expression of sarcoplasmic reticulum Ca(2+)-ATPase2a (SERCA2a) and phospholamban (PLB) were measured by dot blot analysis. RESULTS: Clenbuterol treatment induced 26% left ventricular hypertrophy. These hearts demonstrated normal systolic isovolumic parameters and diastolic (active relaxation and passive stiffness) function. In addition, left ventricular concentration of collagen and morphology was normal as were the expression of SERCA2a and PLB mRNA. CONCLUSION: These results suggest that clenbuterol-induced hypertrophy is 'physiological' in terms of its function, extracellular structure and gene expression.

Adenosine Triphosphatases↗
PubMed1997

Cardiac hypertrophy determines digitalis action on intracellular Ca2+ in human myocardium.

Ventricular hypertrophy alters transporters associated with digitalis action, but the outcome of digitalis treatment on intracellular cations in the hypertrophied human myocardium remains unknown. Using double-barreled Ca2+-selective microelectrodes, we simultaneously measured Ca2+ activity and membrane potential in myocardial samples from patients without and with ventricular hypertrophy, prior to and following exposure to strophanthidin, a prototype digitalis. We found that ventricular hypertrophy is associated with greater strophanthidin-induced increase in diastolic Ca2+ levels compared to that observed in the absence of hypertrophy. Furthermore, in hypertrophied myocardium the magnitude of the increase in Ca2+ induced by strophanthidin was inversely related to increase in myocardial mass. Thus, the extent of ventricular hypertrophy determines digitalis action on intracellular Ca2+ within the human myocardium.

Adult↗