Effects Of Pressure Overload Research Articles

Sex-Dependent Changes in Right Ventricular Gene Expression in Response to Pressure Overload in a Rat Model of Pulmonary Trunk Banding.

Right ventricular hypertrophy (RVH) and subsequent failure are consequences of pulmonary arterial hypertension (PAH). While females are four times more likely to develop PAH, male patients have poorer survival even with treatment, suggesting a sex-dependent dimorphism in right ventricular (RV) hypertrophy/compensation. This may result from differential gene expression in the RV in male vs. female. To date, the sex dependent effect of pressure overload on RV function and changes in gene expression is still unclear. We hypothesize that pressure overload promotes gene expression changes in the RV that may contribute to a poorer outcome in males vs. females. To test this hypothesis, male and female Wistar rats underwent either a sham procedure (sham controls) or moderate pulmonary trunk banding (PTB) (a model of pressure overload induced compensated RV hypertrophy) surgery. Seven weeks post-surgery, RV function was assessed in vivo, and tissue samples were collected for gene expression using qPCR. Compared to sham controls, PTB induced significant increases in the right ventricular systolic pressure, the filling pressure and contractility, which were similar between male and female rats. PTB resulted in an increase in RVH indexes (RV weight, RV weight/tibia length and Fulton index) in both male and female groups. However, RVH indexes were significantly higher in male-PTB when compared to female-PTB rats. Whilst end of procedure body weight was greater in male rats, end of procedure pulmonary artery (PA) diameters were the same in both males and females. RV gene expression analysis revealed that the following genes were increased in PTB-male rats compared with the sham-operated controls: natriuretic peptide A (ANP) and B (BNP), as well as the markers of fibrosis; collagen type I and III. In females, only BNP was significantly increased in the RV when compared to the sham-operated female rats. Furthermore, ANP, BNP and collagen III were significantly higher in the RV from PTB-males when compared to RV from PTB-female rats. Our data suggest that pressure overload-mediated changes in gene expression in the RV from male rats may worsen RVH and increase the susceptibility of males to a poorer outcome when compared to females.

A Computational Cardiac Model for the Adaptation to Pulmonary Arterial Hypertension in the Rat.

Pulmonary arterial hypertension (PAH) imposes pressure overload on the right ventricle (RV), leading to RV enlargement via the growth of cardiac myocytes and remodeling of the collagen fiber architecture. The effects of these alterations on the functional behavior of the right ventricular free wall (RVFW) and organ-level cardiac function remain largely unexplored. Computational heart models in the rat (RHMs) of the normal and hypertensive states can be quite valuable in simulating the effects of PAH on cardiac function to gain insights into the pathophysiology of underlying myocardium remodeling. We thus developed high-fidelity biventricular finite element RHMs for the normal and post-PAH hypertensive states using extensive experimental data collected from rat hearts. We then applied the RHM to investigate the transmural nature of RVFW remodeling and its connection to wall stress elevation under PAH. We found a strong correlation between the longitudinally-dominated fiber-level adaptation of the RVFW and the transmural alterations of relevant wall stress components. We further conducted several numerical experiments to gain new insights on how the RV responds both normally and in the post-PAH state. We found that the effect of pressure overload alone on the increased contractility of the RV is comparable to the effects of changes in the RV geometry and stiffness. Furthermore, our RHMs provided fresh perspectives on long-standing questions of the functional role of the interventricular septum in RV function. Specifically, we demonstrated that an inaccurate identification of the mechanical adaptation of the septum can lead to a significant underestimation of RVFW contractility in the post-PAH state. These findings show how integrated experimental-computational models can facilitate a more comprehensive understanding of the cardiac remodeling events during PAH.

Abstract 273: Pressure Overload Induces Cardiac Insulin Resistance in an Angiotensin II-Independent Manner

Aims: Pressure overload is able to provoke the cardiac insulin resistance via angiotensin II (AngII). However, the direct effect of pressure overload on the myocardial insulin sensitivity was poorly understood. This study was aimed to explore whether and how pressure overload impairs myocardial insulin sensitivity independent of AngII. Methods and Results: To mimic cardiac pressure overload, C57BL/6 mice were subjected to transverse aortic constriction (TAC) for 2 weeks in vivo . Cultured neonatal rat cardiomyocytes (NRCMs) were imposed with mechanical stretch for 24 hours in vitro . Although pressure overload dramatically restrained the glucose uptake and expression of glucose transporter 4 (GLUT4) in the myocardial membrane, it didn’t increase the local expression of AngII in TAC mouse hearts and mechanically-stretched NRCMs. C57BL/6 mice were treated with Enalapril and then subjected to TAC for 2 weeks. The glucose uptake and expression of GLUT4 in the myocardial membrane were dramatically restrained in the left ventricles (LVs) of 2 week TAC mice, which were preserved in mice treated with Enalapril. Angiotensinogen knock out ( ATG -/- ) mice were subjected to TAC for 2 weeks. Angiotensin converting enzyme (ACE)-deficient NRCMs were mechanically stretched. Insulin sensitivity was significantly impaired by TAC in ATG -/- mouse hearts and mechanical stretch in NRCMs evidenced by a notably decreased glucose uptake and expression of GLUT4 in myocardial membrane. Pressure overload impaired the myocardial insulin signals including decreased phosphorylation of insulin receptor, insulin receptor substrate 1 and Akt. Candesartan, an AngII receptor 1 (AT1R) blocker, partly attenuated the myocardial insulin resistance induced by mechanical stress in vivo and in vitro . Conclusion: In conclusion, we unraveled that pressure overload is able to provoke myocardial insulin resistance independent of AngII which was partly mediated by AT1R.

21 Feature tracking cardiac magnetic resonance to assess LV mechanics in different cardiac overload caused by aortic valve disease

Background In aortic valve disease, left ventricular (LV) dimensions and ejection fraction are important parameters for decision making. However, the effects of pressure overload caused by aortic stenosis or/and volume overload, due to aortic regurgitation, lead to different LV remodelling, concentric and eccentric hypertrophy, respectively, which may differently alter LV mechanics. We aimed to characterise LV mechanics, in terms of longitudinal strain/deformation using feature tracking cardiac magnetic resonance (FT-CMR) in patients with various degree of aortic stenosis and aortic regurgitation and preserved LV ejection fraction (LVEF). Methods Seventy-one patients (14 with normal valve function, 29 with aortic stenosis and 28 with aortic regurgitation), mean age 45 ± 19 years, 70% men, who underwent clinically indicated CMR and showed preserved LVEF (>50%) were included. LV volumes, LVEF and mass were measured on steady-state free precession (SSFP) cine images. FT-CMR analysis was performed offline using tissue-tracking software (CVI42, Circle Cardiovascular Imaging Inc.) to estimate LV global longitudinal strain (GLS) from two long-axis SSFP cine images (Figure 1). To correct for the LV remodelling process, LV GLS was corrected for LV end-diastolic volume. Results There were significant differences in LV volumes, mass and ejection fraction across the 3 groups of patients (Table 1): patients with aortic regurgitation showed significantly larger LV volumes, and lower LVEF compared to patients with normal aortic valve function and patients with aortic stenosis. There were no differences in LV GLS across the groups. However, after correcting for LV end-diastolic volume, patients with aortic regurgitation showed more impaired LV GLS as compared to the other groups. Conclusions LV mechanics significantly differ across normal functioning and different type of aortic valve dysfunction (stenosis and regurgitation), with aortic regurgitation showing the most impaired LV GLS corrected for LV end-diastolic volume, despite preserved LVEF.

The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on the Pressure Overload-Induced Progression of Cardiac Hypertrophy to Cardiac Failure

We investigated the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC), which was isolated from the roots of Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (Papilionaceae) (MKL), on the progression of cardiac hypertrophy to failure in a rat model of abdominal aortic banding (AAB)-induced pressure overloading. Endothelial dysfunction is central to pressure overload-induced cardiac hypertrophy and failure. It would be useful to clarify whether MHBFC could prevent this dysfunction. The effects of pressure overload were assessed in male Sprague–Dawley rats 6 weeks after AAB using the progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats exhibited a greater progression to heart failure and had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, and evidence of left ventricular hypertrophy (LVH). LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These symptoms could be prevented by treatment with MHBFC at daily oral doses of 6 and 12 mg/kg for 6 weeks. The progression to cardiac failure, which was demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial natriuretic peptide (ANP) mRNA, could also be prevented. Furthermore, MHBFC partialy rescued the downregulated nitric oxide signaling system, whereas inhibited the upregulated endothelin signaling system, normalizing the balance between these two systems. MHBFC protected the endothelium and prevented the pressure overload-induced progression of cardiac hypertrophy to cardiac failure.

Interstitial expansion in pressure overload left ventricular hypertrophy

Background Diffuse myocardial fibrosis (DMF) is an important factor in cardiac disease, but until recently could only be accurately assessed with biopsy. We hypothesised that DMF measured by Equilibrium contrast CMR (EQ-CMR) is elevated in cardiac pressure overload (hypertension and aortic stenosis), that the degree of DMF will track the clinical severity of pressure overload and cardiac effects, and as such DMF may be a key biomarker in assessing the cardiac effects of pressure overload.

The Effects of Pressure Overload on Cardiac Geometry and Function are Aggravated by Aging

The aging heart undergoes structural and functional alterations, which are reminiscent of changes observed in the failing heart, and may thus increase the vulnerability of the aging heart to develop heart failure in response to mechanical overload. To investigate the effect of aging on left ventricular (LV) remodeling and dysfunction we subjected mice to pressure overload by transverse aortic constriction (TAC) at 3 and 24 months of age. Eight weeks after TAC, LV geometry, LV function and heart as well as lung weights were measured. Aging minimally affected cardiac geometry and function in sham operated animals. TAC not only induced LV hypertrophy, but also reduced fractional shortening in both age groups. However, only in 24 months old mice, TAC induced LV dilation from 3.5±0.2 mm in Sham mice to 4.4±0.2 mm in TAC mice and systolic dysfunction, demonstrated by a decrease in the rate of rise of LV pressure at 40 mmHg (dP/dtP40; Sham 7910±460 vs. TAC 4940±360 mmHg/s) as well as diastolic dysfunction evidenced by a decrease in dP/dtmin (Sham −6810±430 vs. TAC −5025±462 mmHg/s) and an increase in LV end diastolic pressure from 5±1 mmHg in Sham mice to 12±3 mmHg in TAC mice (all p<0.05). In conclusion, the effects of pressure overload on cardiac geometry and function are aggravated by aging.

Effect of Pressure Overload on Cardioprotection via PI3K-Akt: Comparison of Postconditioning, Insulin, and Pressure Unloading

Postconditioning (PC) and insulin exert cardioprotection by activating phosphatidylinositol-3 kinase (PI3K) signaling. Because pressure overload exacerbates ischemia-reperfusion (IR) injury, we tested the hypothesis that (i) pressure overload attenuates PC- and insulin-induced cardioprotection, an effect caused by reduced PI3K-Akt signaling and (ii) pressure unloading confers cardioprotection comparable to either PC or insulin. Infarct size (IS) and levels of relevant proteins (i.e., Akt, glycogen synthase kinase-3beta (GSK-3beta), 3'-phosphoinositide dependent kinase 1 (PDK1), phosphatase and tensin homolog on chromosome ten (PTEN)) were determined in hearts subjected to IR. Pressure overload increased IS in association with changes in protein levels consistent with reduced PI3K-Akt signaling (i.e., ischemic reperfused vs. normoxic hearts). PC and insulin reduced IS but it was greater in hearts perfused at the higher, than the lower, pressure. Wortmannin (PI3K inhibitor) partially reversed PC-induced cardioprotection, with IS being greater in the high-pressure group. Pressure unloading during reperfusion caused the most marked reduction in IS whereas pressure loading abolished PC-induced cardioprotection. Nonetheless, the phospho-Akt/total Akt ratios and phospho-GSK-3beta levels were unaffected by perfusion pressure in insulin-treated or postconditioned hearts. Moreover, protein levels were similar in pressure-unloaded and pressure-loaded hearts. Pressure overload reduces PI3K-Akt signaling following IR. However, a differential in PI3K-Akt signaling was not observed in ischemia-reperfused, insulin-treated, and postconditioned hearts, suggesting involvement of pathways other than PI3K-Akt for the effect of pressure on IS. Importantly, pressure unloading at reperfusion represents a novel and effective cardioprotective maneuver.

Effect of pressure overload on cardioprotection of postconditioning: comparison to pressure unloading

This study tests the hypothesis that pressure overload attenuates cardioprotective effect of postconditioning. Accordingly, following stabilization, Langendorff‐perfused hearts of male rats were subjected to regional ischemia (I; 40 min) followed by reperfusion (R; 2 hrs) with perfusion pressure set at either 80 or 160 cmH2O. Postconditioning was induced by six cycles of I and R (10 sec. each) immediately at the end of index I followed by continuous R (n=7‐10 hearts/condition). Comparisons were made to pressure unloading which consisted of perfusion of heats at 160 cmH2O during the stabilization and I periods followed by switchover to 80 cmH2O during R (n=6 hearts). Elevation in perfusion pressure resulted in larger infarcts (p<0.05). Postconditioning reduced infarct size at either pressure (p<0.05); nonetheless, a significant differential persisted between hearts perfused at the high and low perfusion pressures. Interestingly, pressure unloading markedly reduced infarct size, an effect more prominent than that conferred by postconditioning. The results provide evidence for the deleterious impact of pressure overload on postconditioning‐induced cardioprotection. Further, the marked cardioprotective effect of pressure unloading suggests involvement of cardioprotective pathways that may be distinct from those mobilized by postconditioning. Supported by AHA, Southeast Affiliate.

KATP activation prevents progression of cardiac hypertrophy to failure induced by pressure overload via protecting endothelial function

We investigated the effects of iptakalim, a new ATP-sensitive potassium channel (K(ATP)) opener providing endothelial protection, on the progression of cardiac hypertrophy to failure in a rat model of pressure overloading caused by abdominal aortic banding (AAB). Endothelial dysfunction is central to cardiac hypertrophy and failure induced by pressure overload. It would be useful to clarify whether iptakalim could prevent this. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, evidence of left ventricular hypertrophy (LVH), and transition to heart failure. LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These could be prevented by treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg for 6 weeks. Progression to cardiac failure, demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial and B-type natriuretic peptide mRNA, could also be prevented. The downregulated nitric oxide signalling system was enhanced, whereas the upregulated endothelin signalling system was inhibited, resulting in normalization of the balance between these two systems. Iptakalim protected the endothelium and prevented progression of cardiac hypertrophy to failure induced by a pressure overload.

Upregulation of cardiac matrix Gla protein expression in response to hypertrophic stimuli

Matrix Gla protein (MGP) expression is increased in cardiac hypertrophy, but the precise mechanisms regulating its expression are unknown. Here we characterized the effect of pressure overload and myocardial infarction in vivo as well as mechanical stretch and hypertrophic agonists in vitro on MGP expression. When angiotensin II (Ang II) was administered by osmotic minipumps, left ventricular (LV) MGP mRNA levels increased significantly from 6 h to 2weeks, whereas intravenous arginine8-vasopressin increased LV MGP mRNA levels within 4 h. During post-infarction remodeling process, MGP mRNA levels were elevated at 24 h (1.3-fold, p<0.05) and the maximal increase was observed at 4 weeks (2.8-fold, p<0.01). Ang II increased MGP mRNA levels 20% (p<0.05) in neonatal rat cardiac myocytes and 40% (p<0.05) in cardiac fibroblasts, whereas endothelin-1 decreased MGP mRNA levels 30% (p<0.01) in myocytes and had no effect in fibroblasts. Cyclic mechanical stretch resulted in reduction of MGP gene expression in both cardiac myocytes and fibroblasts. These results demonstrate that MGP is rapidly upregulated in response to cardiac overload well before the development of LV hypertrophy and post-infarction remodeling process. Our results also suggest that Ang II may be involved in mediating load-induced activation of MGP expression.

Abstract 392: Increased Oxidative Stress and Apoptosis as Mechanisms for Adverse Effects of Chronic Pressure Overload and Catecholamine Stress in Mice with Cardiac Overexpression of Type 5 Adenylyl Cyclase

Studies with cardiac overexpression of type 6 adenylyl cyclase (AC6) suggest it protects against cardiac stress. Less is known about cardiac overexpression of AC5. We generated transgenic (Tg) mice with cardiac specific overexpression of AC5 and examined both the effects of pressure overload induced by 1 wk of transverse aortic banding (TAC) and 1 wk of chronic isoproterenol (ISO) delivered by osmotic mini-pump (n=8/group). TAC induced greater, p&lt;0.05, left ventricular (LV) hypertrophy, as assessed by LV/body weight, in AC5 Tg (4.9±0.2) compared with wild type (WT) (4.0±0.1) and exhibited a significant decrease, p&lt;0.05, in LV ejection fraction (LVEF) (58±4%) where LVEF was maintained in WT (75±1%). TUNEL analysis shows that apoptosis in AC5 Tg was twice that in WT, p&lt;0.05. This was confirmed by a 2-fold increase in activity of caspase 3 in AC5 Tg compared to WT mice, p&lt;0.05. The AC5 Tg began to develop heart failure as reflected by increased, p&lt;0.05, lung/body weight (10.2±1.6) vs WT (6.4±0.2). In the heart, the antioxidant manganese superoxide dismutase (MnSOD), quantified by western blotting, was decreased by 40% in AC5 Tg compared to WT mice, p&lt;0.05, after 1 wk of aortic banding. Chronic ISO also induced a greater, p&lt;0.05, decrease in LVEF (48±4%) compared to WT (60±2%). 100 microM of ISO stimulation increased cell viability by 36% and decreased apoptosis by 34% (p&lt;0.05 vs LacZ control). MnSOD was upregulated by 2.9-fold in AC5 knockdown myocytes after treatment with ISO for 48 hrs. These results demonstrate that cardiac overexpression of AC5 exerts adverse effects on oxidative stress and apoptosis in response to both chronic pressure overload and catecholamine stress.

Short-term effects of pressure overload on the expression of genes involved in calcium homeostasis

We investigated whether in the isolated perfused rat heart acute pressure overload may affect the expression of genes involved in calcium homeostasis, namely sarcolemmal L-type Ca2+ channel, Na+/Ca2+ exchanger, sarcoplasmic reticulum Ca2+-ATPase, phospholamban, and ryanodine receptor. Hearts were subjected to 210 min of perfusion under the following conditions: (i) standard working heart perfusion with preload and afterload set at 20 and 100 cm, respectively; (ii) working heart perfusion at high afterload (180 cm); (iii) retrograde infusion of St. Thomas' Hospital cardioplegic solution. In all models gene expression was determined by RT-PCR. Significant decrease in the expression of the sarcoplasmic reticulum Ca2+-ATPase gene was observed in the high afterload group. No significant change in the expression of any other gene was observed in any group. The reported effect was not detected after 60 min of perfusion, and it was blunted in the presence of the protein kinase C inhibitor chelerythrine, while the calcineurin inhibitor cyclosporin A was ineffective. In conclusion, the sarcoplasmic reticulum Ca2+-ATPase gene is downregulated after short-term (210 min) perfusion at high afterload, possibly through a protein kinase C-dependent pathway. This mechanism might play a relevant pathophysiological role in the response to pressure overload and in the development of hypertrophy.

Cyclic GMP/Protein Kinase G Phosphorylation of Smad3 Blocks Transforming Growth Factor-β–Induced Nuclear Smad Translocation

See related article, pages 185–192 In response to hemodynamic overload, the heart undergoes a complex adaptive remodeling process that involves cardiac myocyte hypertrophy, transformation of fibroblast into myofibroblast, high-level expression of extracellular matrix (ECM) proteins, interstitial fibrosis, and cell death.1 Differentiation of cardiac fibroblasts into myofibroblasts is critical to the production and deposition of collagens and plays a decisive role in myocardial fibrosis and morphological alterations during the progression of adaptive myocardial hypertrophy to decompensation and heart failure.1,2 Among the plethora of identified fibrogenic factors, transforming growth factor (TGF)-β3 plays a fundamental role in hypertrophic and fibrotic remodeling of the heart, where it regulates cardiomyocyte growth, fibroblast activation, and ECM deposition.4,5 The expression of ventricular TGF-β mRNA and protein is increased in numerous models of pathological cardiac hypertrophy and in cardiac cells in response to putative hypertrophic stimuli.6,7 In vitro, TGF-β activates myofibroblast transformation and increases ECM production.7 Blockade of TGF-β signaling is predicted to blunt fibrosis.5 Recent studies from Chen et al8 convincingly demonstrated that disruption of TGF-β signaling by inducible dominant-negative mutation of the TGF-β receptor type II (TβRII) gene significantly reduced the pressure overload–induced myofibroblast transformation and interstitial fibrosis in mouse heart. Thus, there is considerable interest in understanding how signaling by TGF-β receptors is transduced and how the inevitable damage produced could be mitigated. Of the 3 isoforms of TGF-β expressed in mammals,9,10 TGF-β1 is expressed in the adult heart, where it is secreted by cardiomyocytes and myofibroblasts and retained in significant amounts in ECM as a latent cytokine. Recent advances have led to clear description of downstream of TGF-β signal transduction pathways initiated by binding of TGF-β to membrane-bound heteromeric receptor kinases (TβRI and TβRII) that transduce intracellular signals via both Smad and non-Smad pathways …

Effect of pressure overload and its recovery on the rat carotid artery: change of vascular reactivity and remodeling process

Compared to chronic hypertension, little is known about the pathophysiology of acute hypertension and its recovery. To characterize this, we investigated the functional and structural properties of the common carotid arteries (CCA) from 35 rats. We established a unilateral and reversible carotid arterial hypertension model using the partial transverse aortic constriction (TAC) technique. By TAC, the right CCAs were made to endure a pressure-overload environment, while the left CCAs remained under normotension. The TACs were removed 2 weeks later, which unloaded the hypertensive effects. We compared the contractile, histological, and molecular responses of the CCA before TAC, during TAC (the hypertension period), and after removal of TAC (the recovery period). Vessel contractility was nearly abolished during 2 weeks of TAC. The recovery process from hypertension showed an initial hypercontractile period within a week. The relaxation response due to acetylcholine, as measured during the recovery period, showed a longer time course than the contractility for recovering its magnitude. During the hypertension period, the media thickness increased and this persisted throughout the recovery period. Apoptosis of the endothelial layer was significantly increased during the hypertension period and this disappeared 2 weeks after recovery. Expression of endothelial NO synthase was not detectable at the end of the hypertension period, but this gradually returned to the basal level after 2 weeks of recovery. Although increased contractility is usually expected in chronic hypertensive vessels, an abrupt pressure overload decreases contractility and the endothelium-dependent relaxation. It also increases endothelial apoptosis and the media thickness. These findings have clinical relevance, and they could be applied to human acute and severe hypertension and its recovery.

194 Isoform expression and total activity of protein kinase C in the heart during early postnatal development: effect of pressure overload

194 Isoform expression and total activity of protein kinase C in the heart during early postnatal development: effect of pressure overload

Associations of aortic and mitral regurgitation with body composition and myocardial energy expenditure in adults with hypertension: the Hypertension Genetic Epidemiology Network study

Background It has been reported that aortic regurgitation, mitral valve regurgitation, or both are associated with lower body mass index, an index of body adiposity. However, the relations of valvular regurgitation to body composition and myocardial bioenergetic expenditure have not been previously investigated in a population-based sample. Methods We selected 1496 patients with hypertension who did not have diabetes mellitus to participate in the Hypertension Genetic Epidemiology Network (HyperGEN) study. We excluded participants with severe aortic or mitral stenosis or with known coronary heart disease. Bioimpedance was used to assess body composition. Echocardiography was used to assess left ventricular (LV) structure and function and to calculate myocardial workload (expressed as energy expenditure) from end-systolic stress, ejection time, and stroke volume. The study sample was divided into groups without mitral or aortic regurgitation (control subjects, n = 1175), with mild valvular regurgitation (1+, n = 246), and with at least moderate (≥2+) mitral or aortic regurgitation (n = 75). Results The mean patient age was higher with more severe valvular insufficiency. Sex distribution and blood pressure were similar among the 3 groups. Body mass index and fat mass were significantly lower with more severe valvular regurgitation, whereas fat-free mass was only slightly lower in the group with ≥2+ regurgitation compared with control subjects. Skinfold thicknesses (brachial and subscapular) were lower with more severe valvular regurgitation, whereas self-reported physical activity per week was similar among the 3 groups. LV mass and circumferential end-systolic stress were higher with more severe valvular regurgitation. Noninvasively estimated myocardial energy expenditure was slightly higher in participants with 1+ valvular regurgitation and was significantly higher with ≥2+ regurgitation. Ejection fraction was mildly lower with ≥2+ aortic insufficiency, mitral insufficiency, or both. Midwall shortening and stress-corrected midwall shortening did not differ among groups. Conclusions In a population-based sample of adults with hypertension and without diabetes mellitus, known coronary heart disease, or significant valvular stenosis, mitral and aortic regurgitation were associated with higher LV mass and total myocardial biomechanical workload but with lower body fat mass and slightly lower body fat-free mass, which suggests that global myocardial bioenergetic expenditure is elevated by concomitant valvular regurgitation beyond the effect of pressure overload caused by hypertension.

Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse.

This study tested the hypothesis that atrial natriuretic peptide has direct antihypertrophic actions on the heart by modulating expression of genes involved in cardiac hypertrophy and extracellular matrix production. Hearts of male, atrial natriuretic peptide-null and control wild-type mice that had been subjected to pressure overload after transverse aortic constriction and control unoperated hearts were weighed and subjected to microarray, Northern blot, and immunohistochemical analyses. Microarray and Northern blot analyses were used to identify genes that are regulated differentially in response to stress in the presence and absence of atrial natriuretic peptide. Immunohistochemical analysis was used to identify and localize expression of the protein products of these genes. Atrial natriuretic peptide-null mice demonstrated cardiac hypertrophy at baseline and an exaggerated hypertrophic response to transverse aortic constriction associated with increased expression of the extracellular matrix molecules periostin, osteopontin, collagen I and III, and thrombospondin, as well as the extracellular matrix regulatory proteins, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3, and the novel growth factor pleiotrophin compared with wild-type controls. These results support the hypothesis that atrial natriuretic peptide protects against pressure overload-induced cardiac hypertrophy and remodeling by negative modulation of genes involved in extracellular matrix deposition.

Effects of Pressure Overload and its Recovery on Vascular Reactivity and Remodeling of the Rat Carotid Artery

Background and Objectives:The Vascular system exhibits altered morphological and functional properties during hypertension and after anti-hypertensive therapy. To characterize such changes, the contractile, histological and molecular responses in the common carotid arteries (CCA) were compared in 35 rats. Materials and Methods:By partial transverse aortic constriction (TAC), the right CCAs were made to lie under a high pressure environment, while the left CCAs remained under normotension, the latter being used as control vessels. The ligations were removed after two weeks, to enable the recovery process to begin. Results:The vessel contractility, two weeks after the TAC, was nearly abolished. The recovery process from high pressure showed an initial hypercontractile period of around 1-2 week after recovery, prior to the subsequent decline to a normal contractility after 2 weeks. The relaxation response due to acetylcholine was minimal at the end of the hypertensive period, recovered slowly, and reached a normal magnitude after 4 weeks. A high pressure increases the medial thickness & area, and enhances the adventitial tissue formation. These changes persist during the first 4 weeks of recovery, after which normotension returns. Apoptosis at the endothelial layer was significantly increased two weeks after the TAC, but normalized two weeks after recovery. The expression of ecNOS was not detect 2 weeks after the TAC, but gradually returned to a basal level at 2 weeks after the untying. Conclusion:A high blood pressure causes decreases in the contractility and endothelium-dependent relaxation. It also increases endothelial apoptosis, the medial thickness & area, and enhances the adventitial tissue formation. The recovery processes from high blood pressure are not uniform, but show different normalizations among the structural, contractile and apoptotic parameters. (Korean Circulation J 2003;33 (10):936-948)

Effect of Pressure Overload on Angiotensin Receptor Expression in the Rat Heart During Early Postnatal Life

P. Oliviéro, C. Chassagne, F. Kolar, C. Adamy, F. Marotte, J.-L. Samuel, L. Rappaport and B. Ostadal. Effect of Pressure Overload on Angiotensin Receptor Expression in the Rat Heart During Early Postnatal Life. Journal of Molecular and Cellular Cardiology (2000) 32, 1631–1645. The development of cardiac hypertrophy during neonatal life and in adults implies different processes. The angiotensin II (Ang II) system is involved in the development of cardiac hypertrophy in adults, but its role in neonates remains unclear. The aim of this study was to estimate the influence of increased hemodynamic load on the developmental pattern of the AT1/AT2 receptor expression in the heart. Two-day-old rats submitted to abdominal aortic constriction (AC) or sham operation were sacrificed 2 h, and 1, 3, and 8 days after surgery. Ang II was evaluated in sera and immunohistology was performed to define the cardiac hypertrophy process. The Ang II receptor subtypes 1 and 2 were quantified at the receptor and mRNA levels by125I-Ang II binding and RT-PCR, respectively. Ang II content in sera increased transiently 2 h after surgery in the AC group. In sham-operated, AT1 and AT2 decreased throughout the period studied at both mRNA and receptor levels. However, the AT1 mRNA level decrease was more pronounced than that of AT2 (by 57% and 27%, respectively). AC not only prevented the postnatal decrease in AT mRNA level but resulted in an increase in AT1 mRNA 8 days after surgery (P<0.05). Besides in the AC groups, AT2 mRNA levels but not those of AT1 mRNA were linearly correlated with the left ventricular mass. At the receptor level, a significant transient (1 day after surgery) increase in both AT1 and AT2 was observed. In conclusion, our data demonstrated that imposition of pressure overload soon after birth altered the pattern of AT receptor expression.