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PubMed1983

Relation of hemodynamic load to left ventricular hypertrophy and performance in hypertension.

Left ventricular hypertrophy and dysfunction in patients with hypertension are often poorly related to the level of blood pressure. To evaluate the reasons for this, 100 untreated patients (44 +/- 14 years) with essential hypertension were studied using cuff blood pressure and quantitative echocardiography to measure left ventricular mass index and end-diastolic relative wall thickness as 2 indexes of left ventricular hypertrophy. Left ventricular hypertrophy, as measured by either left ventricular mass index or end-diastolic relative wall thickness, correlated weakly with all indexes of blood pressure including systolic, diastolic, and mean blood pressure (r = 0.16 to 0.32). In contrast, end-diastolic relative wall thickness, an index which assesses the severity of concentric hypertrophy, showed a closer direct relation with total peripheral resistance (r = 0.52 p less than 0.001) and a significant inverse relation with cardiac index (r = -0.47, p less than 0.001). Left ventricular performance as assessed by fractional systolic shortening of left ventricular internal dimensions was not significantly related to left ventricular mass index, blood pressure, or peak systolic wall stress, but declined significantly with increasing mean systolic wall stress (r = -0.42, p less than 0.001) and even more with increasing end-systolic wall stress (r = -0.71, p less than 0.001). It is concluded that in patients with hypertension (1) left ventricular hypertrophy is correlated only modestly with measurements of resting blood pressure; and (2) the classic pattern of concentric left ventricular hypertrophy, as measured by relative wall thickness, is more closely related to the "typical" hypertensive abnormality of elevated peripheral resistance, suggesting that these anatomic and hemodynamic changes may be pathophysiologically interdependent. Furthermore, left ventricular performance declines when the pressure overload in hypertension is not offset by compensating hypertrophy, allowing wall stresses to increase.

Adolescent↗

PubMed1984

Effects of long-term cardiac hypertrophy on coronary vasodilator reserve in SHR rats.

The effects of long-term left ventricular (LV) hypertrophy on coronary vascular reserve have not been extensively investigated. To test the hypothesis that the duration of LV hypertrophy may modulate coronary vascular reserve, a newly developed pulsed Doppler flowmeter was used to compare the characteristics of coronary reactive hyperemia in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The data suggest that coronary reactive hyperemic responses in the rat are markedly different from those in larger animals and humans, e.g., peak/rest blood flow velocity ratio and the repayment/debt area ratio were 30 to 50% of those observed in larger laboratory animals. Because minimal coronary vascular resistance is similar in the rat and larger animals, the relatively high myocardial oxygen consumption at rest and consequent high myocardial blood flow at rest probably account for the alteration of coronary reactive hyperemia in the rat. In SHR rats, the characteristics of coronary reactive hyperemia decreased during developing (3-month-old) and peak (7-month-old) LV hypertrophy compared with those in their age-matched WKY controls. However, in 12-month-old SHR rats with stable LV hypertrophy, the coronary reactive hyperemic response was similar to that of 12-month-old WKY rats. Mean arterial pressures were significantly elevated in each of the 3 SHR groups. These data suggest a significant decrement in coronary vascular reserve during actively developing and peak LV hypertrophy, but the decrement disappears during stabilized hypertrophy. These studies suggest that the duration of LV hypertrophy may modulate the interaction between pathologic increases in cardiac mass and growth of the coronary vasculature.

Animals↗

PubMed2001

Insulin-like growth factor-1 improves postischemic recovery in hypertrophied hearts.

BACKGROUND: Severe myocardial hypertrophy is associated with decreased tolerance to ischemia compared with normal hearts. We hypothesized that treatment with insulin-like growth factor-1 (IGF-1) improves postischemic myocardial recovery by increasing glucose uptake during ischemia and early reperfusion. METHODS: Banding of the thoracic aorta in 10-day-old rabbits created pressure-overload hypertrophy. At 5 weeks of age (severe hypertrophy), aortic banded and sham-operated isolated hearts underwent 30 minutes of normothermic ischemia with or without IGF-1 in the preischemic perfusate and cardioplegia followed by 30 minutes of reperfusion. RESULTS: 2-Deoxyglucose uptake (31P-NMR) and phosphatidylinositol-3-kinase (PI-3-kinase) activity were significantly lower in hypertrophied hearts. Insulin-like growth factor-1 restored glucose uptake and PI-3-kinase activity to control levels in the hypertrophied hearts and both effects were blocked by wortmannin (a PI-3-kinase inhibitor). Postischemic developed pressure was significantly improved in IGF-1-treated hearts compared with untreated or IGF-1+wortmannin-treated hypertrophied hearts. CONCLUSIONS: These data indicate that IGF-1 improves glucose uptake and tolerance to ischemia in hypertrophied hearts. Myocardial IGF-1 effects are likely mediated through a PI-3-kinase-dependent pathway.

Animals↗

PubMed2001

Remodeling by ventricular pacing in hypertrophying dog hearts.

OBJECTIVE: Asynchronous electrical activation of the left ventricle (LV), induced by ventricular pacing (VP), reduces mechanical load in early- and enhances it in late-activated regions. Consequently, chronic VP leads to asymmetric hypertrophy. We investigated whether such locally induced myocardial hypertrophy also occurs in the presence of pressure overload hypertrophy (POH). METHODS: POH was induced by aortic banding in puppies. At age 9 months, seven dogs were paced at the right ventricular (RV) apex at physiological heart rate for 6 months (POH-pace group), while four POH dogs served as POH-control group. Changes in volume of the LV cavity and the total LV wall and of five LV wall sectors were measured by means of 2D-echocardiography and X-ray marker detection. RESULTS: During the last 6 months of the protocol the volume of the five LV wall sectors increased in the POH-control group, ranging from 27+/-9 to 30+/-5% (mean+/-S.D.). In POH-pace animals sector wall volume in the four sectors at intermediate to long distance from the pacing site increased to a similar extent (ranging from 31+/-16 to 35+/-17%), but wall volume in the early-activated apical septum increased significantly less (17+/-21%). In these hearts myocyte diameter was significantly smaller in the apical septum than in the lateral LV wall. The regional difference in wall volume changes (19+/-21%) was significantly smaller in the POH-pace group than in chronically paced, non-hypertrophic, canine hearts in a previous study from our laboratory (43+/-14%). CONCLUSIONS: In hypertrophying hearts chronic pacing at the RV apex suppresses the development of hypertrophy in the early-activated apical septum but does not cause additional hypertrophy in late-activated regions, as is the case in non-hypertrophic hearts. The latter suggests that the local growth response is reduced in hypertrophying hearts.

Analysis of Variance↗

PubMed1983

Compensatory hypertrophy in the heart after myocardial infarction in the rat.

Hypertrophy after myocardial infarction would be a very important process for compensation of damaged myocardium and preservation of cardiac function. Fifty-four female Sprague-Dawley rats were studied 5 weeks after randomization to infarct operation, sham operation and control groups. At sacrifice, anteroapical infarcts ranging from 1 to 51% of left ventricle were present in the infarct operated group. When classified according to infarct size, groups with the largest infarcts (greater than 15 to 30% and greater than 30%) had significant (p less than 0.001) cardiac cellular hypertrophy in the noninfarcted myocardium of the septum and anterior walls (fiber diameter 15.9 +/- 2.3 and 14.5 +/- 2.3 microns, respectively) compared with the control group (12.0 +/- 1.8 microns). Because of cardiac hypertrophy, remaining noninfarcted myocardial area, as estimated from serial histologic sections of the heart, was normal in the greater than 15 to 30% infarct group (area 1.35 cm2) compared with the control group (1.43 cm2); however, because hypertrophy plateaued in the greater than 30% infarct group, myocardial area was significantly decreased (1.06 cm2, p less than 0.001), but was still more than expected without hypertrophy. We suggest that hypertrophy accompanies large infarction in the rat and is a compensation for preserving tissue volume lost by infarction. This compensatory response appears to have limitations, such that when very large amounts of myocardium become necrotic, there is not enough hypertrophy to return myocardial volume to normal.

Animals↗

PubMed1985

Right ventricular myocardial infarction in patients with chronic lung disease: possible role of right ventricular hypertrophy.

To determine the relation between right ventricular hypertrophy and right ventricular myocardial infarction in patients with chronic lung disease, the records of 28 patients with chronic lung disease, inferior myocardial infarction and significant coronary artery disease (group I) and 20 patients with right ventricular hypertrophy, chronic lung disease without inferior myocardial infarction or significant coronary artery disease (group II) were reviewed. Chronic lung disease was diagnosed by clinical criteria, chest radiographs and pulmonary function tests. All patients had postmortem examinations. Patients in group I were classified into two subgroups: group Ia (without right ventricular hypertrophy) and group Ib (with right ventricular hypertrophy). Right ventricular wall thickness was 3.3 mm +/- 0.5 in group Ia, 6.0 mm +/- 1.1 in group Ib and 8.8 mm +/- 2.4 in group II (group Ia versus Ib, p less than 0.001; group Ia versus II, p less than 0.001; group Ib versus II, p less than 0.001). Eleven patients (78.6%) in group Ib (chronic lung disease with both right ventricular hypertrophy and inferior myocardial infarction) had right ventricular myocardial infarction compared with only 3 patients (21.9%) in group Ia (chronic lung disease without right ventricular hypertrophy and with inferior myocardial infarction) (p less than 0.008). Isolated right ventricular myocardial infarction occurred in four patients (20%) in group II (chronic lung disease with right ventricular hypertrophy, but without evidence of infarction of the left ventricle or significant coronary artery disease). There was no significant difference in the extent of anatomic coronary disease in groups Ia and Ib.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Quantitative structural analysis of the myocardium during physiologic growth and induced cardiac hypertrophy: a review.

The quantitative structural properties of the ventricular myocardium during postnatal physiologic growth are compared with those accompanying an increased load in the adult rat heart to determine whether induced cardiac hypertrophy is a pathologic condition or simply a form of well compensated accelerated growth. The expansion of the ventricular myocardium during maturation shows a remarkable degree of well balanced compensatory response, because the capillary microvasculature, parenchymal cells and subcellular components of myocytes all grow in proportion to the increase in cardiac mass. In contrast, the increases in myocyte diameter and length caused by pressure hypertrophy, volume hypertrophy and infarction-induced hypertrophy are consistent with concentric, eccentric and a combination of concentric and eccentric hypertrophic growth of the whole ventricle, respectively. These cellular shape changes may represent a compensatory response of the myocardium at the cellular level of organization that tends to minimize the effects of an increased pressure or volume load, or both, on the heart. Cardiac hypertrophy, however, may also show alterations affecting capillary luminal volume and surface and the mitochondrial to myofibril volume ratio, which indicate an inadequate growth adaptation of the component structures responsible for tissue oxygenation and energy production. Thus, hypertrophy of the adult heart differs from that during physiologic growth, and the hypertrophied myocardium may exhibit structural abnormalities that can be expected to increase its vulnerability to ischemia.

Blood Pressure↗

PubMed1986

The prevalence and correlates of echocardiographic left ventricular hypertrophy among employed patients with uncomplicated hypertension.

To determine the prevalence and correlates of echocardiographic left ventricular hypertrophy among subjects in a general population, we studied 621 employed subjects. Patients with uncomplicated essential hypertension in a worksite-based treatment program included 145 with borderline hypertension and 316 with sustained hypertension by World Health Organization criteria. Normotensive subjects were randomly selected from members of the same unions. M-mode echocardiographic left ventricular dimensions were used to calculate left ventricular mass and other indexes of left ventricular anatomy. The specificity of 13 echocardiographic criteria of left ventricular hypertrophy was determined in normotensive individuals, and the prevalence of left ventricular hypertrophy by each criterion was assessed in patients with borderline or sustained essential hypertension. The results suggest that the most suitable reference standard for detection of left ventricular hypertrophy in a heterogeneous urban population utilizes sex-specific cutoff values for left ventricular mass index of 110 g/m2 or greater for women and 134 g/m2 or greater for men. With 97% specificity, the prevalence of left ventricular hypertrophy by these criteria is approximately 12% among patients with borderline hypertension and 20% among patients with relatively mild, uncomplicated sustained essential hypertension. Wall thickness measurements performed slightly less well. At similar levels of blood pressure, black patients were more likely than white patients to exhibit concentric left ventricular hypertrophy, especially among borderline hypertensive patients. Left ventricular hypertrophy occurred in patients with sustained hypertension who also exhibited increased cardiac output, strongly associated with low plasma renin activity.

Adult↗

PubMed1996

Myocardial protection in chronic volume-overload hypertrophy of immature rat hearts.

OBJECTIVE: The benefit of cardioplegic cardiac arrest for protection of the immature myocardium is controversial. We therefore investigated the efficacy of (1) topical hypothermia alone (2) slow cooling by coronary perfusion hypothermia and (3) cardioplegic cardiac arrest plus topical cooling for protection of isolated immature rat hearts (age: 28 days). METHODS: The isolated perfused rat heart model was used. Hearts were subjected to 8 h of global ischemia at 10 degrees C. The study was conducted after clinically relevant conditions of volume-overload myocardial hypertrophy had been established non-invasively by lifelong feeding of a diet low in iron. Parameters of left ventricular function, endothelial function, the metabolic status and myocardial injury were measured. RESULTS: Topical hypothermia provided superior protection of hypertrophied hearts with recovery of maximum developed left ventricular pressure and rate of pressure rise at 41.2% +/- 22.3% and 34.5% +/- 20.7% (mean +/- standard deviation) of preischemic values (P < 0.05 versus slow cooling and versus cardioplegia plus topical hypothermia). The same pattern of recovery was observed among control hearts. The recovery of endothelial function following protection by topical hypothermia alone measured 55% +/- 41% in hypertrophied hearts and 62% +/- 37% in control hearts, but was not recordable in all other groups. In hypertrophied hearts post-ischemic myocardial high energy content was significantly improved with topical hypothermia alone for protection when compared to the other methods. Creatine kinase leakage during reperfusion did not differ significantly among the experimental groups. CONCLUSION: Rapid cooling by topical hypothermia along provides superior protection of hypertrophied- and non-hypertrophied-immature rat hearts to additional slow pre-arrest cooling. Use of St. Thomas' Hospital cardioplegic solution No.2 (STS 2) does not improve protection, and even hinders functional recovery in hypertrophied immature hearts. Endothelial injury caused by cold asanguinous perfusates, including cardioplegia, interferes with the recovery of vascular function, which in turn, may limit mechanical function.

Age Factors↗

PubMed2003

Glycolysis and pyruvate oxidation in cardiac hypertrophy--why so unbalanced?

Cardiac hypertrophy, induced by chronic pressure or volume overload, is associated with abnormalities in energy metabolism as well as characteristic increases in muscle mass and alterations in the structure of the heart. Hypertrophied hearts display increased rates of glycolysis and overall glucose utilization, but rates of pyruvate oxidation do not rise in step with rates of pyruvate generation. Glycolysis and glucose oxidation, therefore, become markedly less 'coupled' in hypertrophied hearts than in non-hypertrophied hearts. Because the pyruvate dehydrogenase complex (PDC) contributes so powerfully to the control of glucose oxidation, we set out to test the hypothesis that the function of PDC is impaired in cardiac hypertrophy. In this review we describe evidence indicating that the alterations in glucose metabolism in hypertrophied hearts cannot be explained simply by changes in PDC expression or control. Additional mechanisms that may lead to an altered balance of pyruvate metabolism in cardiac hypertrophy are discussed, with commentaries on possible changes in pyruvate transport, NADH shuttles, lactate dehydrogenase, and amino acid metabolism.

Animals↗

PubMed2000

Cardiocyte cytoskeleton in hypertrophied myocardium.

The Frank-Starling mechanism, by which load directly regulates muscle length and thus performance is the means by which the mechanics and energetics of cardiac muscle are regulated on a beat-to-beat basis. When this short-term compensation for increased load is insufficient, the long-term compensation of cardiac hypertrophy ensues. The simplest and most direct mechanism for load regulation of cardiac mass would obtain if an analog of the short-term Frank-Starling mechanism of functional regulation operated in the long-term time domain of mass regulation; that is, if heart muscle were able to directly transduce increased load into growth. It is now clear that load does indeed serve as a direct regulator of cardiac mass in the adult. Cardiac hypertrophy, at the levels of intact animal, isolated tissue, and cultured cells, is a direct response of the adult mammalian cardiocyte to increased load, modified by but without the requisite involvement of factors external to the cell. The extent to which such hypertrophy is compensatory is critically dependent on the type of hemodynamic overload that serves as the hypertrophic stimulus. Thus, cardiac hypertrophy is not intrinsically maladaptive; rather, it is the nature of the inducing load rather than hypertrophy itself that is responsible for the frequent deterioration of initially compensatory hypertrophy into the congestive heart failure state. As one example reviewed here of this load specificity of maladaptation, increased microtubule network density is a persistent feature of severely pressure overloaded, hypertrophied and failing myocardium which imposes a viscous load on active myofilaments during contraction.

Actin Cytoskeleton↗

PubMed2001

Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes.

1. Oxidative mechanisms have been implicated in neonatal cardiomyocyte hypertrophy. We and others have shown that a HMG-CoA reductase inhibitor preserves endogenous antioxidant enzyme activity and inhibits cardiac hypertrophy in vivo. We therefore have examined whether noradrenaline (NA) induces the generation of reactive oxygen species (ROS) during its induction of neonatal cardiomyocyte hypertrophy and whether simvastatin, a HMG-CoA reductase inhibitor, attenuates ROS production and thus NA-induced hypertrophy of cardiomyocytes. 2. NA increased the intracellular ROS levels in a concentration-dependent manner. This increase of ROS was significantly inhibited by simvastatin and catalase. Prazosin partially suppressed NA-induced increase of ROS and beating, while preincubation with both prazosin and propranolol completely abolished NA-evoked increase of ROS and beating. Simvastatin did not affect NA-induced increase of beating. 3. The NA-induced increase of protein content was partially suppressed by prazosin and completely abolished by preincubation with both prazosin and propranolol. Simvastatin inhibited the increase of NA-induced increase of RNA content and [(3)H]-leucine incorporation in a concentration-dependent manner. Mevalonic acid (MVA) reversed the inhibition of NA-induced RNA and protein increase by simvastatin. Catalase also inhibited the NA-induced increase of RNA and protein. 4. We conclude that the inhibitory effects of simvastatin on myocyte hypertrophy were associated with its antioxidant effects and inhibition of MVA-metabolism pathway in neonatal rat cardiomyocytes. NA-induced increases of intracellular ROS and cardiomyocyte hypertrophy requires both alpha and beta adrenoceptors activation in neonatal rat cardiomyocytes. The increases of ROS induced by NA is required for hypertrophy.

Adrenergic alpha-Agonists↗

PubMed2002

Peroxisome proliferator-activated receptor-gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats.

Endothelin-1 (ET-1) causes cardiac hypertrophy, and ET receptor antagonists inhibit the development of cardiac hypertrophy in vitro and in vivo. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the family of nuclear receptors, suppresses activator protein-1 (AP-1). We investigated the effects of the thiazolidinediones troglitazone and pioglitazone, activators of PPAR gamma, on cardiac hypertrophy due to pressure overload provoked by abdominal aortic banding (AB) in rats. Rats were divided into four groups: sham operation with vehicle treatment (n=5); AB surgery with vehicle treatment (n=6); AB surgery with troglitazone treatment (100 mg x kg(-1) x day(-1); n=5); and AB surgery with pioglitazone treatment (10 mg x kg(-1) x day(-1); n=8). Treatments were started 7 days before AB surgery, and left ventricular (LV) hypertrophy was assessed 24 h after surgery. The ratio of LV weight/body weight (BW) was significantly increased in AB rats compared with sham-operated rats; treatment of AB rats with troglitazone or pioglitazone significantly inhibited the increase in LV weight/BW. Expression of ET-1 mRNA was markedly enhanced in the left ventricles of AB rats; treatment with troglitazone or pioglitazone lowered expression significantly. Suppression of cardiac hypertrophy by pioglitazone treatment was accompanied by a decrease in expression of the gene encoding brain natriuretic factor, a molecular marker for cardiac hypertrophy, in AB rats. Because the ET-1 gene has AP-1 response elements in its 5'-flanking region, the thiazolidinediones troglitazone and pioglitazone may inhibit cardiac hypertrophy partly through suppression of AP-1-induced ET-1 gene up-regulation.

Analysis of Variance↗

PubMed1988

Relationship between the high-energy phosphate content and various left ventricular functional parameters of the normal and hypertrophied heart after global ischemia and reperfusion.

Using an isolated rat heart preparation (Langendorff perfusion, perfusion pressure 100 cm H2O) the correlation between the high-energy phosphate content and various left ventricular (lv) functional parameters of the hypertrophied heart (spontaneous hypertensive rats lv/body weight ratio 3.6 +/- 0.5 x 10(-3) was determined after normo- (30 min) and hypothermic (25 degrees C, 120 min) cardioplegic arrest and reperfusion, and compared with normal hearts (Wistar rats lv/body weight ratio 2.0 +/- 0.3 x 10(-3). St. Thomas Hospital solution was used as the cardioplegic agent. Before ischemia hypertrophied hearts had a significantly higher developed left ventricular pressure, pressure rate product and dp/dtmax, but a significantly lower ATP and total adenine nucleotide content. Irrespective of the mode and temperature of cardiac arrest there was a strong correlation both for normal and for hypertrophied hearts between the high-energy phosphate content expressed as ATP, total adenine nucleotides or the "energy charge" and the left ventricular functional parameters pressure rate product and dp/dtmax. The correlation coefficient ranged from 0.80 to 0.89 and was highest when the ATP content was plotted against pressure rate product (r = 0.89). There was a different slope for normal and hypertrophied hearts with a steeper decline of the left ventricular function in hypertrophied hearts for any given reduction of the myocardial adenine nucleotide content. Our results indicate that a similar reduction of the ATP or total adenine nucleotide content in both the normal and hypertrophied heart reduces left ventricular function to a greater degree in the hypertrophied heart.

Adenosine Diphosphate↗

PubMed1987

Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy.

In patients with hypertension, a pattern of left ventricular hypertrophy on the electrocardiogram is associated with a risk of sudden death in excess of the risk attributable to hypertension alone. We therefore investigated the frequency of complex ventricular arrhythmias by means of 48-hour ambulatory electrocardiographic monitoring in 100 treated hypertensive patients, of whom 50 had electrocardiographic evidence of left ventricular hypertrophy and 50 did not, and in 50 normotensive controls. The groups were matched for age, sex, and smoking habits, and the two hypertensive groups were matched for blood-pressure levels before and after antihypertensive therapy. Nonsustained ventricular tachycardia, defined as greater than or equal to 3 complexes at a rate greater than or equal to 120 beats per minute, occurred in 14 (28 percent) of the 50 patients with an electrocardiographic pattern of left ventricular hypertrophy, in 4 (8 percent) of the 50 patients without hypertrophy (P less than 0.05), and in 1 (2 percent) of the control subjects. Eight of the 50 patients (16 percent) with hypertrophy had episodes of nonsustained ventricular tachycardia longer than 5 complexes, whereas no patients without hypertrophy and no controls had such episodes. The group with nonsustained ventricular tachycardia was characterized by a high left ventricular mass on echocardiography and a high prevalence of ST-T abnormalities on electrocardiography. Ventricular tachycardia was not closely related to blood-pressure levels, nor was it associated with diuretic therapy or hypokalemia. The clinical importance of these arrhythmias is uncertain. Nevertheless, our data suggest that complex ventricular arrhythmias occur commonly in hypertensive patients with left ventricular hypertrophy and may contribute to the higher incidence of sudden death in these patients.

Cardiomegaly↗

PubMed2003

Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy.

An unresolved question in cardiac biology is whether distinct signaling pathways are responsible for the development of pathological and physiological cardiac hypertrophy in the adult. Physiological hypertrophy is characterized by a normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is associated with an altered pattern of cardiac gene expression, fibrosis, cardiac dysfunction, and increased morbidity and mortality. The elucidation of signaling cascades that play distinct roles in these two forms of hypertrophy will be critical for the development of more effective strategies to treat heart failure. We examined the role of the p110alpha isoform of phosphoinositide 3-kinase (PI3K) for the induction of pathological hypertrophy (pressure overload-induced) and physiological hypertrophy (exercise-induced) by using transgenic mice expressing a dominant negative (dn) PI3K(p110alpha) mutant specifically in the heart. dnPI3K transgenic mice displayed significant hypertrophy in response to pressure overload but not exercise training. dnPI3K transgenic mice also showed significant dilation and cardiac dysfunction in response to pressure overload. Thus, PI3K(p110alpha) appears to play a critical role for the induction of physiological cardiac growth but not pathological growth. PI3K(p110alpha) also appears essential for maintaining contractile function in response to pathological stimuli.

Adaptation, Physiological↗

PubMed1982

Derangements in myocardial purine and pyrimidine nucleotide metabolism in patients with coronary artery disease and left ventricular hypertrophy.

Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content of myocardium that are postulated to play a role in the pathogenesis of muscle dysfunction in these disorders. The present study examined myocardium of patients with coronary artery disease, left ventricular hypertrophy, or neither of these two abnormalities, to determine whether derangements in purine and pyrimidine nucleotide metabolism occur in humans. In patients with coronary artery disease, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was reduced and ranged between 60% and 86% of the amount found in the epicardium. In patients without coronary artery disease or ventricular hypertrophy, endocardial content of these nucleotides was equal to or greater than that of epicardium. Endocardial and epicardial content of inosine was increased in patients with coronary artery disease, and after vein bypass grafting inosine content fell to the levels observed in myocardium of patients with normal coronary arteries. In patients with left ventricular hypertrophy, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was also reduced and ranged between 64% and 88% of the epicardial content. In contrast to results obtained in patients without left ventricular hypertrophy, epicardial content of GTP, UTP, and CTP was increased by 131%, 123%, and 132% in hypertrophied myocardium. Thus the changes noted in myocardial nucleotide content in patients are similar to those noted in animal models of occlusive coronary disease and ventricular hypertrophy. These results suggest that the pathophysiological abnormalities in nucleotide metabolism noted in animal models also occur in human myocardium.

Adenine Nucleotides↗

PubMed1998

Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure.

Receptor-mediated Gq signaling promotes hypertrophic growth of cultured neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy. Although initially compensatory, hypertrophy can proceed by unknown mechanisms to cardiac failure. We used adenoviral infection and transgenic overexpression of the alpha subunit of Gq to autonomously activate Gq signaling in cardiomyocytes. In cultured cardiac myocytes, overexpression of wild-type Galphaq resulted in hypertrophic growth. Strikingly, expression of a constitutively activated mutant of Galphaq, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in Galphaq overexpressing mice and in transgenic mice expressing high levels of wild-type Galphaq. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 and Jun kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy whereas high level Gq activation results in cardiomyocyte apoptosis. The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggests a plausible mechanism for the progression of compensated hypertrophy to decompensated heart failure.

Adenoviridae↗