Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis

There is ample evidence that regular exercise exerts beneficial effects on left ventricular (LV) hypertrophy, remodeling and dysfunction produced by ischemic heart disease or systemic hypertension. In contrast, the effects of exercise on pathological LV hypertrophy and dysfunction produced by LV outflow obstruction have not been studied to date. Consequently, we evaluated the effects of 8 weeks of voluntary wheel running in mice (which mitigates post-infarct LV dysfunction) on LV hypertrophy and dysfunction produced by mild (mTAC) and severe (sTAC) transverse aortic constriction. mTAC produced ~40% LV hypertrophy and increased myocardial expression of hypertrophy marker genes but did not affect LV function, SERCA2a protein levels, apoptosis or capillary density. Exercise had no effect on global LV hypertrophy and function in mTAC but increased interstitial collagen, and ANP expression. sTAC produced ~80% LV hypertrophy and further increased ANP expression and interstitial fibrosis and, in contrast with mTAC, also produced LV dilation, systolic as well as diastolic dysfunction, pulmonary congestion, apoptosis and capillary rarefaction and decreased SERCA2a and ryanodine receptor (RyR) protein levels. LV diastolic dysfunction was likely aggravated by elevated passive isometric force and Ca(2+)-sensitivity of myofilaments. Exercise training failed to mitigate the sTAC-induced LV hypertrophy and capillary rarefaction or the decreases in SERCA2a and RyR. Exercise attenuated the sTAC-induced increase in passive isometric force but did not affect myofilament Ca(2+)-sensitivity and tended to aggravate interstitial fibrosis. In conclusion, exercise had no effect on LV function in compensated and decompensated cardiac hypertrophy produced by LV outflow obstruction, suggesting that the effect of exercise on pathologic LV hypertrophy and dysfunction depends critically on the underlying cause.     

Changes in contraction-relaxation coupling in experimental cardiac hypertrophy in the guinea pig

Guinea pig myocardium resembles human myocardium with respect to the mechanisms which regulate contractility (enzymatic activity of myosine, functional activity of the sarcoplasmic reticulum). Guinea pig left ventricular hypertrophy (LVH) is therefore a good experimental model for the study of human LVH. The mechanical properties of 5 months old female guinea pigs' left ventricular papillary muscle, 3 weeks after constriction of the abdominal aorta (N = 10), were investigated. Ten papillary muscles of operated control animals and eight of normal guinea pigs submitted to 20 minutes hypoxia were also studied. The animals had no signs of cardiac failure after constriction of the abdominal aorta but the increase in the ratio of heart to body weight (p less than 0.001) confirmed the LVH. When compared with the operated controls, there was a decrease of the maximum velocity of contraction at zero load, of the velocity of contraction with preload alone (Vc), of the total isometric force normalized for the section of the muscle(s) and of the positive peak of the derivative of the isometric force normalized for section (+ dF/s) (p less than 0.001 for each parameter). The parameters of relaxation were also abnormal: decreased velocity of isotonic relaxation with preload only (Vr) and of the negative peak of the derivative of the isometric force normalized for section (- dF/s) (p less than 0.001 for each parameter), and an increase in the half relaxation time (t1/2) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional differences of left ventricular hypertrophy induced by either arterial hypertension or aortic valve stenosis

The aim of this study was to reveal functional differences of left ventricular (LV) hypertrophy induced by either aortic stenosis (AS) or arterial hypertension (AH) assessed by strain-rate imaging. Twenty patients with AS and 19 patients with AH were enrolled. In the 2 groups, coronary artery disease was ruled out invasively. All subjects underwent echocardiographic studies, including strain-rate imaging studies of LV long- and short-axis function. Eight patients underwent follow-up examinations after aortic valve replacement, and 20 healthy volunteers served as a control group. LV end-diastolic posterior wall thickness was not different between the 2 patient groups (12.7 +/- 2.5 mm in AS vs 12.8 +/- 1.6 mm in AH) but was significantly increased compared with the control group (8.5 +/- 1.1 mm). The LV ejection fraction was within normal limits in all groups but significantly lower in the patient groups (54 +/- 9% in AS, 55 +/- 6% in AH) compared with the control group (66 +/- 3%). Radial and longitudinal systolic strain rates were depressed in patients with AS compared with those with AH and controls (radial 1.6 +/- 0.6 vs 2.6 +/- 0.6 and 3.8 +/- 0.6 s(-1), respectively, p <0.005). After valve replacement, longitudinal strain rate remained unchanged, but radial strain rate gradually increased (1.6 +/- 0.6 vs 2.1 +/- 0.8 s(-1), p = NS). In parallel, the ejection fraction gradually improved and LV hypertrophy gradually diminished. In conclusion, despite the same degree of LV wall thickness, AS and AH have different impacts on the rate of LV deformation.     

Left auricular hypertrophy in aortic stenosis in adults

Left atrial hypertrophy (LAH) was noted from the electrocardiograms of 72 of 98 adult patients (81%) who underwent hemodynamic evaluation of calcified aortostenosis (CAS). The relations between LAH and clinical, echographic and hemodynamic findings are specified. The frequency of LAH was not higher in cases of a history of hypertension, angina pectoris, lipothymia or exercise-induced syncope. In contrast, dyspnea was more frequently associated with LAH (84%) than not (17%). An approximately linear relation was seen between LAH and the mean pulmonary capillary pressure, the mean rate of circumferential decrease (RCF), the coefficient of muscle rigidity (ks of Mirsky), the left ventricular mass (LVM) and the left ventricle-aorta gradient. LAH is, therefore, a frequent sign in patients presenting CAS. Its origin is multifactorial, with a predominance of increased mean capillary pressure in cases of clinical signs of poor safety.     

Effects ofl-propionylcarnitine on electrical and mechanical alterations induced by amphiphilic lipids in isolated guinea pig ventricular muscle

Summary We examined the effects ofl-propionyl-carnitine (Prop.C), a short-chain acylcarnitine, on amphiphile (l-lysophosphatidylcholine orl-palmitoylcarnitine)-induced electrophysiological and ultrastructural changes in isolated guinea pig ventricular papillary muscles, under acidic conditions (pH 6.9). Conventional microelectrode, tension-recording, and electron microscope techniques were used. Both amphiphiles, at a concentration of 10^–4 M, significantly decreased the resting membrane potential, action potential amplitude, and action potential duration, but increased the developed and resting tension. Such amphiphile-induced electrical changes were not observed in muscles pretreated with the beta-blocker, atenolol, although the mechanical changes remained unaffected. The application of Prop.C (10^–2 M), in the continued presence of the amphiphiles caused a return of the action potential duration and the developed tension to the control level. However, the resting potential and action potential amplitude remained unaffected; in fact, the maximum upstroke velocity ( ) of the action potential tended to decrease further. Pretreatment with Prop.C prevented all the amphiphile-induced electrophysiological and mechanical changes, except for . Electron microscopic studies revealed that amphiphile-induced ultrastructural changes were prevented, at least in part, in the presence of Prop.C. Thus, Prop.C antagonizes some of deleterious effects of amphiphiles, such as lysophosphatidylcholine and palmitoylcarnitine, upon the electrical and mechanical activities of the ventricular muscle, under acidic conditions.     

Catecholamine induced cardiac hypertrophy

Cardiac hypertrophy was induced in adult female Wistar rats by daily subcutaneous injections of isoproterenol (0.3 mg/kg body weight). Heart weight increased 39% after eight days of treatment. Left ventricular pressure development (positive dP/dt) in hearts four days after hypertrophy induction was significantly increased, while negative dP/dt remained unchanged. RNA polymerase activity in isolated myocyte and nonmyocyte nuclei was stimulated 29 and 23%, respectively 24 h after a single isoproterenol injection. In the myocyte fraction, RNA polymerase activation progressively increased up to four days of treatment and then returned to control values after eight days. In the nonmyocyte nuclear subset, RNA polymerase activity showed no further stimulation and gradually returned to control values after eight days of treatment. Chromatin template function was substantially stimulated in the early stage (one to four days) of hypertrophy in both myocyte and nonmyocyte fractions. Titration of chromatin against a fixed amount of RNA polymerase (5 micrograms) in the presence of rifampicin and heparin showed that less chromatin from hypertrophied hearts was required to saturate the enzyme. These results indicate that both myocyte and nonmyocte chromatin from hypertrophied hearts can support greater enzyme binding than normal chromatin. The alkaline sucrose density centrifugation profile of DNA in myocyte and nonmyocyte chromatin from day 4 hypertrophied hearts was less fragmented. These observations suggest that during the early phase of isoproterenol-induced cardiac hypertrophy, enhanced RNA polymerase activity and chromatin template function play a coordinated role in RNA synthesis. The increased template activity could be due to alterations in chromatin composition which was indicated by the change in their enzyme binding capacity and DNA fragmentation profile.     

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.     

Ethanol-induced alterations in lymphocyte function in the guinea pig

Infections and chronic liver injury are common causes of morbidity and mortality in alcoholics, and both of these may be related to an altered immune response. This study describes a guinea pig model of chronic ethanolism designed to selectively study the cellular immune system in a setting free from the malnutrition, socioeconomic deprivation, and severe underlying hepatic dysfunction seen in human disease. Animals were given 2.5 g/kg/day of ethanol as a 15% solution in 0.9% NaCl or isocaloric-dextrose-saline control solution intraperitoneally in 2 divided doses for 5 weeks. At 2 weeks, the mean serum ethanol level 1 hr after treatment was 20.4 mM (range 8.9-30.6) while the mean serum acetaldehyde level was 55.1 microM (range 17.0-111). At 5 weeks the serum levels for ethanol and acetaldehyde were 20.1 mM (13.3-32.9) and 41.5 microM (2.4-87.6), respectively. Weight gain was persistent throughout the study and did not differ significantly between ethanol and control groups. After 5 weeks of treatment, lymphocyte response to the mitogens, phytohemagglutinin, and concanavalin A was significantly decreased in the ethanol treated group (p less than 0.05). Response to the specific antigen, picrylated human serum albumin, T & B cell per cent and number, skin test reactivity, peripheral white blood cell count, total lymphocyte count, and migration inhibitory factor production were not significantly altered by 5 weeks of ethanol treatment. Therefore, in a controlled animal model of chronic ethanolism, we observed a significant depression of lymphocyte blastogenic response which may, in part, explain the increased propensity to infection by intracellular pathogens seen in alcoholics.     

Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig.

Here we show that the relaxation induced by stimulation of the vagus nerve in the presence of cholinergic (muscarinic) and adrenergic blockade in the isolated stomach of the guinea pig is mediated by nitric oxide (NO). This is substantiated by inhibition of vagal relaxation by NG-monomethyl-L-arginine, an inhibitor of NO synthesis. The effect of NG-monomethyl-L-arginine was partially reversed by coincubation with L-arginine but not with D-arginine. NO activates soluble guanylate cyclase, and relaxation of the stomach induced by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue, further supporting our conclusions. The relaxant effect of vagal stimulation was also ablated by hexamethonium, an inhibitor of ganglionic nicotinic receptors, thereby showing that ganglionic transmission did not rely on NO, through its release from preganglionic neurons. However, hexamethonium did not inhibit the gastric relaxation brought about by increasing the intragastric pressure, which is also mediated by NO as previously described by us. The selective inhibition by hexamethonium of only the vagally mediated relaxation but not of the pressure-induced relaxation of the stomach indicates the existence of at least two separate neuronal pathways able to generate NO and bring about gastric accommodation of food or fluid.     

Iconoclasts topple adaptive myocardial hypertrophy in aortic stenosis.

For more than 30 years, the development of concentric left ventricular(LV) hypertrophy in pressure overload was considered adaptivebecause the parallel deposition of new sarcomeres and the correspondingLV wall thickening succeeded in normalizing LV systolic wallstress despite the high intracavitary systolic pressure.¹ Inaortic stenosis, the validity of this paradigm was demonstratedby haemodynamic studies, which established an inverse relationshipbetween LV systolic wall stress and LV ejection fraction (EF)and by clinical outcome studies, which demonstrated worse post-operativeprognosis if LV performance fell below this inverse LV wallstress–LVEF relationship.^2,3 This clinical paradigm ofadaptive myocardial hypertrophy developing during progressionof aortic stenosis clearly withstood the test of time despitethe mounting epidemiological evidence of LV hypertrophy beingassociated with excess cardiac mortality and despite the ominoussignificance of LV hypertrophy in congenital aortic stenosis. Kupari et al.⁴ were the first to challenge the time-honoured     

Investigation of impaired coronary vasodilator reserve in the guinea pig heart with pressure induced hypertrophy.

Impaired coronary reserve and increased minimal coronary resistance have been documented in several animal models of left ventricular hypertrophy. There is controversy whether the increased minimal coronary resistance is due to vascular or extravascular causes. To test the hypothesis that pressure-overloaded left ventricular hypertrophy (LVH) is associated with a vascular defect, studies were performed using isolated buffer-perfused guinea pig hearts taken 72 +/- 6 days post-aortic banding (LVH n = 13) and compared to sham-operated controls (n = 12). The pressure flow relationship was determined over the range 30-70 mmHg. We defined an extravascular compression index as the percentage increase in flow during maximal arteriolar dilation when systolic forces were excluded during prolonged diastole (2 +/- 0.2 s). In LVH, coronary reserve was reduced (141 +/- 5.5% v 231.7 +/- 24.1%) P less than 0.01 and minimal coronary resistance was increased (4.55 +/- 0.44 v 3.70 +/- 0.37 mmHg.ml-1.min-1.g-1) P less than 0.05. The extravascular compression index was increased in LVH (36.8 +/- 1.4 v 30.5 +/- 2.3%) P less than 0.05. Systole caused a greater increase in resistance in the LVH group than in controls (1.73 +/- 0.26 v 0.95 +/- 0.14 mmHg.ml-1.min-1.g-1) P less than 0.05. These data indicate that during diastole there is impaired minimal coronary resistance of vascular origin. Systole impaired flow to a greater extent in hypertrophied hearts, further reducing the coronary reserve.     

外源性钙调素入核转运及其在大鼠心肌肥厚时的变化

目的　探讨大鼠心肌细胞核对外源性钙调素入核转运的调节机制及其在大鼠心肌肥厚时的变化。方法　制备腹主动脉缩窄心肌肥厚大鼠模型、差速离心提纯心肌细胞核、酶学方法测定钙 ATP酶活性、荧光分光光度计测定荧光标记钙调素向细胞核转入量。结果　离体纯化的大鼠心肌细胞核在ATP存在下 ,外源性钙调素经核孔向核内转运量具有显著钙离子浓度依赖性 ,随核外钙离子浓度的增加而递增 (P <0 0 5 )。在钙离子浓度为 10 -3 mol/L时 ,钙 ATP酶抑制剂thapsigargin (5μmol/L)、兰尼碱受体拮抗剂钌红 (rutheniumred ,5 0 μmol/L)和IP3 受体拮抗剂肝素 (10 μg/ml)使外源性钙调素的细胞核孔转运分别降低 90 %、2 0 %和 89% (P <0 0 5 )。腹主动脉缩窄术后 4周大鼠心肌显著肥厚 ,伴有明显的血流动力学异常 ,与对照组相比 ,腹主动脉缩窄心肌肥厚大鼠外源钙调素入核转运明显减少 (P <0 0 5 ) ,心肌细胞核钙 ATP酶活性显著下降 (P <0 0 0 1)。结论　外源性钙调素入核转运可能受核外钙离子浓度和核钙摄取、释放系统所调节 ,心肌肥厚时 ,钙调素入核转运减少、心肌细胞核钙 ATP酶活性下降 ,可能在相对稳定核功能紊乱的调节中起负性反馈作用。     

Role of alpha 1-adrenoceptor activity in progression of cardiac hypertrophy in guinea pig hearts with pressure overload

To elucidate the role of alpha 1- and beta-adrenergic activities in pressure overload hypertrophy, changes of alpha 1- and beta-adrenoceptors were measured by radioligand binding assay, and the preventive effects of alpha 1- and beta-adrenoceptor blockade on cardiac hypertrophy were assessed in guinea pigs after aortic banding. Five days after banding, dry weight of left ventricle had not increased, though wet weight increased due to marked intercellular oedema. In this period, the maximum binding capacity of [3H] prazosin increased to 31.1 (SEM 2.2) fmol.mg-1 from (sham operation) 17.0(2.1) fmol.mg protein-1, p less than 0.01, whereas the maximum binding capacity of [3H]dihydroalprenolol did not increase: 143(16) fmol.mg-1 (banded) v 153(13) fmol.mg-1 (sham). Three weeks after aortic banding, the maximum binding capacity of both ligands increased to 45.6(5.5) fmol.mg-1 and 232(21) fmol.mg-1, respectively, accompanied by a significant increase in left ventricular dry weight, from 0.46(0.02) mg.g-1 (sham) to 0.62(0.08) mg.g-1 (banded), p less than 0.01. Continuous subcutaneous administration of the alpha 1-blocker bunazosin (0.1 mg.kg-1.d-1) significantly attenuated the increase in left ventricular dry weight whereas the beta-blocker propranolol (5 mg.kg-1.d-1) did not: 0.55(0.03) v 0.66(0.04) mg.g-1 respectively, after 3 weeks. These results show that pressure overload elicited an increase in myocardial alpha 1-adrenoceptors before the onset of cardiac hypertrophy, and that an alpha 1-blocker could prevent the development of hypertrophy in the pressure overloaded heart.     

辛伐他汀对大鼠心肌肥厚的防治作用及其与钙通道的关系

目的 探讨辛伐他汀对心肌肥厚的防治作用及其与钙通道活动的关系.方法 采用腹主动脉缩窄术建立心肌肥厚动物模型.尾动脉无创测量大鼠收缩压.称量心脏重量/体重(HW/BW)、左心室重量/体重(LVW/BW)比值.采用超声心动图检测动物心脏构型及射血功能.应用RT-PCR和Western blot分别检测心肌L-型钙通道亚单位Cav1.2(α,C)、T-型钙通道亚单位Cav3.1 (α1G)、Cav3.2(α1H)mRNA及其蛋白表达的变化.结果 (1)腹主动脉缩窄+辛伐他汀组(AAC+SIM组)大鼠收缩压130 mm Hg(1 mm Hg=0.133 kPa)明显低于腹主动脉缩窄组(AAC组)189mm Hg,P<0.05.HW/BW比值AAC+SIM组3.37 mg/g明显低于AAC组3.94 mg/g,P<0.01.LVW/BW比值AAC+SIM组2.33 mg/g明显低于AAC组2.95 mg/g,P<0.01.室间隔厚度AAC+SIM组2.01 mm明显低于AAC组2.31 mm,P<0.01.左心室后壁厚度AAC+SIM组1.89 mm明显低于AAC组2.19 mm,P<0.01.(2)AAC+SIM组大鼠心肌T-型钙通道亚单位α1G、α1H mRNA和蛋白表达均显著低于AAC组,P均<0.01,但L-型钙通道亚单位α1 C mRNA和蛋白表达两组间比较差异无统计学意义.结论 辛伐他汀对腹主动脉缩窄所致的心肌肥厚具有明显的防治作用,其作用机制可能与其抑制T-型钙通道亚单位α1G、α1H mRNA和蛋白的重新再表达有关,但与L-型钙通道亚单位α1C mRNA和蛋白表达无关.     

Vectorcardiographic comparison of left ventricular hypertrophy in idiopathic hypertrophic subaortic stenosis, aortic stenosis, and aortic regurgitation

Frank vectorcardiograms in 21 patients with idiopathic hypertrophic subaortic stenosis and asymmetric septal hypertrophy (IHSS), 25 patients with severe aortic valve stenosis (AS), and 20 patients with severe aortic regurgitation (AR) were analyzed. Patients with mixed valvular lesions, pulmonary hypertension, coronary artery disease, or QRS width ≥ 0.12 sec. were excluded. The QRS loops were analyzed at 10 msec. intervals (0.01 to 0.07 sec.), and mean spatial vectors were derived. Spatial magnitude, azimuth, and elevation were measured. The magnitudes of the 0.01 and 0.02 sec. vectors were significantly larger in AR than in AS (p < 0.01 and p < 0.05, respectively). The magnitude of the midloop vectors (0.04 sec.) was largest in AS (p < 0.02) while the 0.05 sec. vector was largest in AR (p < 0.01). No significant differences in azimuth, elevation, time of maximal spatial vector, or QRS duration were noted among the three groups. Only two of 21 patients with IHSS demonstrated the pattern of pseudo-infarction. In the remaining patients, the analyzed vectors failed to distinguish the asymmetric septal hypertrophy of IHSS from the concentric hypertrophy of AS.