Moderate Pressure Overload Research Articles

Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure.

Cardiometabolic disorders encompass a broad range of cardiovascular complications associated with metabolic dysfunction. These conditions have an increasing share in the health burden worldwide due to worsening endemic of hypertension, obesity, and diabetes. Previous studies have identified Tumor Protein p53-inducible Nuclear Protein 2 (Trp53inp2) as a molecular link between hyperglycemia and cardiac hypertrophy. However, its role in cardiac pathology has never been determined in vivo. In this study, we generated a cardiac specific knockout model of Trp53inp2 (Trp53inp2-cKO) and investigated the impact of Trp53inp2 inactivation on the pathogenesis of heart failure under mechanic or/and metabolic stresses. Based on echocardiography assessment, inactivation of Trp53inp2 in heart led to accelerated onset of HFrEF in response to pressure-overload, with significantly reduced ejection fraction and elevated heart failure marker genes comparing to the control mice. In contrast, inactivation of Trp53inp2 ameliorated cardiac dysfunction induced by combined stresses of high fat diet and moderate pressure overload (Cardiometabolic Disorder Model). Moreover, Trp53inp2 inactivation led to reduced expression of glucose metabolism genes in lean, pressure-overloaded hearts. However, the same set of genes were significantly induced in the Trp53inp2-cKO hearts under both mechanical and metabolic stresses. In summary, we have demonstrated for the first time that cardiomyocyte Trp53inp2 has diametrically differential roles in the pathogenesis of heart failure and glucose regulation under mechanical vs. mechanical plus metabolic stresses. This insight suggests that Trp53inp2 may exacerbate the cardiac dysfunction during pressure overload injury but have a protective effect in cardiac diastolic function in cardiometabolic disease.

A Neonatal Mouse Model for Pressure Overload: Myocardial Response Corresponds to Severity.

The heart regeneration after apical resection and myocardial infarction in neonatal mice has been studied for years. However, the response of neonatal mouse heart under pressure overload is seldom explored. This study aimed to induce pressure overload in neonatal mice through a transverse aortic constriction (TAC) with different-gauge needles so as to investigate the effect of pressure overload on cardiomyocyte proliferation and hypertrophy in these mice. Myocardial hypertrophy was evaluated by echocardiographic, pathological, and molecular analyses. Cardiomyocyte proliferation was detected by immune-staining of phospho-histone H3, Ki67, and 5-bromo-2-deoxyuridine. Mild pressure overload induced with a 30-gauge needle stimulated cardiomyocyte proliferation, adaptive hypertrophy, and angiogenesis. The heart function was not hampered even 21 days after the surgery. Moderate pressure overload induced with a 32-gauge needle led to pathological myocardial hypertrophy, fibrosis, and heart failure 7 days after the surgery. The gene and protein expression levels of markers of hypertrophy and fibrosis increased in 32-gauge TAC group compared with that in sham and 30-gauge TAC groups. The mice barely survived after severe pressure overload induced with a 34-gauge needle. The findings of this study might provide new insights into cardiomyocyte proliferation and hypertrophy in neonatal mice under pressure overload.

Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling

BackgroundCombined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested. Methods and ResultsWe examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice. ConclusionThese findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide– cGMP–PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure.

Lack of beta3 integrin signaling contributes to calpain-mediated myocardial cell loss in pressure-overloaded myocardium.

Although cardiac hypertrophy initially ensues as a compensatory mechanism, it often culminates in congestive heart failure. Based on our earlier studies that calpain and beta3 integrin play cell death and survival roles, respectively, during pressure-overload (PO) hypertrophy, we investigated if the loss of beta3 integrin signaling is a potential mechanism for calpain-mediated cardiomyocyte death during PO. beta3 Integrin knockout (beta3) and wild-type mice were used to induce either moderate or severe PO in vivo for short-term (72-hour) and long-term (4-week) transverse aortic constriction. Whereas wild-type mice showed no changes during moderate PO at both time points, beta3 mice exhibited both enrichment of the mu-calpain isoform and programmed cell death of cardiomyocytes after 4-week PO. However, with severe PO that caused increased mortality in both mice groups, cell death was observed in wild-type mice also. To study calpain's role, calpeptin, a specific inhibitor of calpain, was administered through an osmotic mini-pump at 2.5 mg/kg per day beginning 3 days before moderate transverse aortic constriction or sham surgery. Calpeptin administration blocked both calpain enrichment and myocardial cell death in the 4-week PO beta3 mice. Because beta3 integrin contributes to cardioprotective signaling, these studies indicate that the loss of specific integrin function could be a key mechanism for calpain-mediated programmed cell death of cardiomyocytes in PO myocardium.

Lack of JunD Promotes Pressure Overload–Induced Apoptosis, Hypertrophic Growth, and Angiogenesis in the Heart

The Jun family of activator protein 1 (AP-1) transcription factors (c-Jun, JunB, and JunD) is involved in fundamental biological processes such as proliferation, apoptosis, tumor angiogenesis, and hypertrophy. The role of individual AP-1 transcription factors in the stressed heart is not clear. In the present study we analyzed the role of JunD in survival, hypertrophy, and angiogenesis in the pressure-overloaded mouse heart after thoracic aortic constriction. Mice lacking JunD (knockout [KO]) showed increased mortality and enhanced cardiomyocyte apoptosis and fibrosis associated with increased levels of hypoxia-induced factor-1alpha, vascular endothelial growth factor (VEGF), p53, and Bax protein and reduced levels of Bcl-2 protein after 7 days of severe pressure overload compared with wild-type (WT) siblings. Cardiomyocyte hypertrophy in surviving KO mice was enhanced compared with that in WT mice. Chronic moderate pressure overload for 12 weeks caused enhanced left ventricular hypertrophy in KO mice, and survival and interstitial fibrosis were comparable with WT mice. Cardiac function, 12 weeks after operation, was comparable among shams and pressure-overloaded mice of both genotypes. In addition, KO mice exposed to chronic pressure overload showed higher cardiac capillary density associated with increased protein levels of VEGF. Thus, JunD limits cardiomyocyte hypertrophy and protects the pressure-overloaded heart from cardiac apoptosis. These beneficial effects of JunD, however, are associated with antiangiogenic properties.

Right ventricular upregulation of the Ca 2+ binding protein S100A1 in chronic pulmonary hypertension

The Ca 2+ binding protein S100A1 increases the Ca 2+ release from the sarcoplasmatic reticulum by interacting with the ryanodine receptor. In order to understand whether this effect might be operative in the early course of hypertrophy, when myocardium is able to meet increased workload, we investigated the expression of S100A1 in a model of moderate right ventricular hypertrophy. The pulmonary arteries of nine pigs were embolised three times with Sephadex G-50. After 70 days, all pigs showed a moderate pulmonary hypertension. Right ventricular tissue of embolised animals showed a significant increase of connective tissue and enlargement of myocyte diameters. In controls, we found a differential expression of S100A1 with significantly lower S100A1 protein levels in right ventricular compared to left ventricular tissue. In pulmonary hypertension, S100A1 expression increased significantly in hypertrophied right ventricles while it was unchanged in left ventricular tissue. No change was observed in the expression of SERCA2a and phospholamban. Our data show, for the first time, that moderate pressure overload results in an upregulation of S100A1. This may reflect an adaptive response of myocardial Ca 2+ homeostasis to a higher workload.

Energetics of acute pressure overload of the porcine right ventricle. In vivo 31P nuclear magnetic resonance.

In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.

Left ventricular structure and function by echocardiography in ultraendurance athletes

To determine left ventricular (LV) structural and functional changes induced by ultraendurance exercise training, M-mode LV echograms and Doppler recordings of LV inflow velocity in 26 triathletes and 17 normal subjects were studied. All triathletes trained 20 to 40 hours/week in swimming, cycling and running for more than 2 years. Structurally, triathletes had normal LV systolic and diastolic cavity dimensions, but increased wall thickness (1.05 ± 0.26 vs 0.80 ± 0.27 cm in normal subjects, p < 0.001), increased relative wall thickness, or h/R ratio (0.41 ± 0.10 cm vs 0.33 ± 0.11 cm in normal subjects, p < 0.001), and increased LV mass (226 ± 60 vs 143 ± 54 g in normal subjects, p < 0.001). LV mass correlated closely with mean exercise blood pressure during an 8-hour exercise test in 14 triathletes (r = 0.88). Systolic function at rest was similar in both groups, with no differences in fractional shortening or end-systolic stress. Diastolic LV function measured by digitized M-mode echo was similar in normal subjects and triathletes, with no differences in peak rates of cavity enlargement and wall thinning by echocardiogram. In contrast, the Doppler-derived ratio of early-to-late LV inflow velocities was slightly increased in triathletes (p < 0.05). It is concluded that ultraendurance training produces a physiologic pattern of moderate pressure overload LV hypertrophy, in proportion to the hemodynamic load imposed during prolonged exercise. Unlike the abnormal hypertrophy of systemic hypertension, early diastolic function remains normal in the triathlete heart.

Effects of moderate pressure overload cardiac hypertrophy on the distribution of creatine kinase isozymes.

Myocardial activities and isozyme distributions of creatine kinase (CK) and lactate dehydrogenase (LDH) were measured in rats with moderate pressure overload hypertrophy. Three weeks after aortic banding, the ratio of left ventricular (LV) weight to body weight increased by 30%. Values for enzyme activity in the hypertrophied LV were compared to values for control rats as well as to the contralateral relatively unaffected right ventricle (RV). In rats with moderate LV hypertrophy, total CK activity was unchanged. The percent MB-CK increased significantly (p less than 0.01) only in the hypertrophied LV, from 13 +/- 1% to 19 +/- 1% of total CK, while the sum of MM and mitochondrial-CK decreased from 86 +/- 3 to 80 +/- 3% (p less than 0.01). LDH activity increased (p less than 0.05) only in the hypertrophied ventricle from a control of 2.90 +/- 0.13 to 3.21 +/- 0.13 IU/mg protein, while the ratio of LDH activity at high to low substrate increased from 0.12 +/- 0.02 to 0.14 +/- 0.02 (p less than 0.05). Thus, the development of moderate pressure overload hypertrophy in the LV is associated with normal levels of total CK, but the percentage of MB-CK increases selectively in the primarily affected ventricle. Also, total LDH and LDH activity at high to low substrate concentration increases significantly in LV hypertrophy.

Left ventricular adaptation to sustained pressure overload in the conscious dog.

The early adaptation to aortic stenosis was studied in eight conscious dogs previously instrumented with a left ventricular micromanometer and ultrasonic crystals measuring left ventricular minor equator, left ventricular major axis, and ventricular wall thickness. Data were compared during control, acute inflation of a supravalvular aortic cuff occluder and 24 hours after aortic stenosis with and without beta-blockade. Acute aortic stenosis increased peak systolic pressure and end-systolic pressure with a decrease of percent systolic shortening of minor diameter (% delta L). Twenty-four hours after aortic constriction for heart rates, end-diastolic dimensions, and systolic pressures similar to those measured during acute aortic stenosis, % delta L was significantly increased, compared with acute aortic constriction, and was close to control values. End-systolic diameter was not significantly different from control during sustained pressure overload, although end-systolic stress was increased by 26.7 +/- 6.1% (P less than 0.01 with control), representing a leftward shift of the end-systolic stress-diameter relation. Similar results were obtained under beta-blockade. We conclude that there is, in this model of moderate pressure overload, a nonsympathetic increased inotropic state very early after aortic constriction.

Myofilament-polyribosome association in muscle cells of rat left atrium after short-term hypertension.

Hypertension was induced in uninephrectomized Wistar rats by administration of deoxycorticosterone acetate (DOCA) and by addition of NaCl to their drinking water. The ultrastructure of atrial and ventricular cells of left hearts was compared after short-term (2 and 6 weeks) increased blood pressure. No morphological features could distinguish cells of treated animals from cells of normotensive rats after 2 weeks of treatment. The sarcoplasm of the atrial cells of 6-week-treated hypertensive rats presented an abnormally high number of helical arrangement of ribosomes often associated with abundant unorganized thick filaments, irregular nuclear profiles showing foldings and convolutions, and enlarged mitochondria. The only fine structural changes observed in the ventricular cells of the same animals was a moderate mitochondrial enlargement. The described alterations of atrial cells probably correspond to enhanced synthesis of contractile elements associated with increased nuclear-cytoplasmic exchanges; their absence in ventricular cells suggests that short-term and moderate pressure overload induces adaptative changes in left atrial cells at a stage when ventricular cells have morphological characteristics close to normal cells.

Cardiac enlargement mechanisms with exercise training and pressure overload

The effects of exercise training were examined in the adult male rat heart using biochemical and fiber size measurements. These effects have been compared with those observed following simulated pathological cardiac enlargement associated with both moderate and severe pressure overloads. The combination of desoxycorticosterone acetate (DOCA) injections and salt loading for 21 to 25 days produced a moderate pressure overload (146 ± 5 mm Hg systolic pressure) when compared to control animals (132 ± 3 mm Hg). A 10% increase in left ventricular mass and increased fiber size accompanied the moderate pressure overload. There was no evidence for cellular proliferation in the left ventricle of DOCA injected animals. Abdominal aortic constriction for 21 to 25 days produced a severe pressure overload (210 ± 5 mm Hg) and increased left ventricular mass by 35%. There was evidence that fiber growth and cell proliferation had been stimulated. In contrast to pressure overload stimuli, 80 to 90 days of treadmill exercise did not increase left ventricular mass above control levels. There was no evidence for either increased fiber size or cellular proliferation; however, exercise established a relative left ventricular enlargement by allowing left ventricular mass to increase at approximately normal rate while simultaneously reducing the overall growth rate of the animal. The data indicate that the mechanism for achieving relative cardiac enlargement during exercise training is in direct contrast with the cardiac enlargement mechanism employed during either DOCA injection or aortic constriction.