Changes in the Ca2+-activated K+ channels of the coronary artery during left ventricular hypertrophy

It has been suggested that impairment of smooth muscle cell (SMC) function by alterations in the Ca2+-activated K+ (KCa) channels accounts for the reduction in coronary reserve during left ventricular hypertrophy (LVH). However, this hypothesis has not been fully investigated. The main goal of this study was to assess whether the properties of KCa channels in coronary SMCs were altered during LVH. In patch-clamp experiments, the whole-cell currents of the KCa channels were reduced during LVH. The unitary current amplitude and open probability for the KCa channels were significantly reduced in LVH patches compared with control patches. The concentration-response curve of the KCa channel to [Ca2+]i was shifted to the right. Inhibition of the KCa channels by tetraethylammonium (TEA) was more pronounced in LVH cells than in control cells. Western blot analysis indicated no differences in KCa channel expression between the control and LVH coronary SM membranes. In contraction experiments, the effect of high K+ concentration on the resting tension of the LVH coronary artery was greater than on that of the control. The effect of TEA on the resting tension of the LVH coronary artery was reduced compared with the effect on the control. Our findings imply a novel mechanism for reduced coronary reserve during LVH.     

Increased Ca2+ signaling after alpha-adrenoceptor activation in vascular hypertrophy

In an effort to explain the increased sensitivity to agonists of hypertrophic vascular muscle, intracellular Ca2+ concentration ([Ca2+]i)-signaling mechanisms were studied in normal and hypertrophic rat aortas from normotensive and coarctation-hypertensive rats. Based on both fura 2 fluorescence and aequorin luminescence measurements, qualitatively different patterns of Ca2+ mobilization occur in normal and hypertrophic rat aortic muscle. Normal rat aortic muscle contracts to phenylephrine with little or no increase in [Ca2+]i, whereas the angiotensin II-induced contraction is accompanied by a marked [Ca2+]i transient. In contrast, hypertrophic rat aortic muscle shows a dramatic increase in Ca2+ signaling after phenylephrine stimulation. Moreover, both the amplitude of the angiotensin-induced [Ca2+]i transient and the contractile sensitivity to this agonist are decreased in the hypertrophic muscle. Our results strongly suggest that the amplitude of the [Ca2+]i transient after agonist stimulation determines the contractile sensitivity and that there is an altered coupling of the alpha-adrenoceptor in the hypertrophic vascular muscle.     

Role of adrenergic receptor system in canine left ventricular hypertrophy

Although sympathetic nervous system and catecholamines have been postulated to play an important role in the development of myocardial hypertrophy, the precise mechanism is still ill-defined. We then developed two experimental canine models; 12 dogs with surgical cardiac denervation by the method of Geis et al, inducing up-regulation of myocardial adrenergic receptors, and 12 dogs with chronic infusion of subhypertensive dose of norepinephrine (NE) at a rate of 0.04 mg/kg/day. After two months, both models induced myocardial hypertrophy, as indicated by significant increases in left ventricular (LV) wall thickness and cell diameter as compared with 14 sham-operated control dogs. Cardiac denervation remarkably depleted myocardial NE contents, while plasma NE remained unchanged. Both alpha-1 and beta receptors were unregulated, Bmax increasing by 90% and 50% respectively. Decrease in myocardial cyclic-AMP content was relatively small as compared with the marked reduction in myocardial NE, probably by the compensatory augmentation of beta receptor system activity. Chronic NE infusion also reduced myocardial NE content possibly due to stimulation of presynaptic alpha-2 receptor inhibiting NE synthesis and release. Number of alpha-1 and beta receptors also increased by 90% and 30% respectively, while myocardial cyclic-AMP content remained unchanged. These observations indicate that neither direct stimulation of NE on the myocardial cell nor increased in cyclic-AMP is the mechanism for cardiac hypertrophy in both models.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary blood flow in experimental canine left ventricular hypertrophy.

To determine whether left ventricular hypertrophy [LVH] altered total and regional coronary blood flow, we inflated a balloon around the ascending aorta of nine dogs; six acute and six sham-operated dogs were controls. After 6 weeks, all dogs were studied with an open chest under anesthesia; the balloons were deflated. There was moderate LVH as shown by increased left ventricular weight and fiber diameter. At rest there were no major differences of coronary flow or resistance per gram of muscle. With maximal coronary vasodilation due to adenosine or carbochrome, mean coronary vascular resistance was 84% higher in LVH than in normal hearts; with isoproterenol, resistance was 54% higher in LVH. These changes were similar in right and left ventricles. Minimal coronary resistance at end diastole also was higher in LVH--64% and 94% for the two sets of vasodilators, respectively. There were no significant differences in capillary or large vessel proportional volumes in LVH and control dogs, but arterial capacity could not be estimated. The raised minimal coronary resistance suggests the possibility that, with stress, coronary flow, especially to subendocardial muscle, might be inappropriate and perhaps cause ischemic damage. However, the changes noted might have been due to coronary arterial responses to raised coronary pressures rather than to hypertrophy itself.     

Progressive left ventricular remodeling in patients with hypertrophic cardiomyopathy and severe left ventricular hypertrophy

OBJECTIVES: The aim of this study was to determine the natural history of patients with hypertrophic cardiomyopathy (HCM) and severe left ventricular hypertrophy (LVH) (i.e., maximal left ventricular wall thickness [MLVWT] >/=30 mm) and whether changes in cardiac morphology influence the course of the disease. BACKGROUND: Severe LVH is common in young and rare among elderly patients with HCM. This has been explained by a high incidence of sudden death. We hypothesized that this age-related difference might be explained by left ventricular wall thinning. METHODS: A total of 106 (age 33 +/- 15 years; 71 males) consecutive patients with severe LVH underwent history taking, examination, electrocardiography, echocardiography, cardiopulmonary exercise testing, and Holter analysis. Survival data were collected at subsequent clinic visits or by communication with patients and their general practioners. In order to assess morphologic and functional changes, 71 (67.0%) patients (mean age 31 +/- 15 years; 47 males) followed at our institution underwent serial (>/=1 year) assessment. RESULTS: Of the 106 patients, the majority (78 [71.6%]) were <40 years of age. During follow-up (92 +/- 50 months [range 1 to 169]), 18 (17.0%) patients died or underwent heart transplantation (13 sudden cardiac deaths, 2 heart failure deaths, 1 heart transplantation, 1 stroke, 1 postoperative death). Five-year survival from sudden death was 90.1% (95% confidence interval [CI] 84.0% to 96.3%), and that from heart failure death or transplantation was 97.7% (95% CI 94.5 to 100). In patients serially evaluated over 85 +/- 51 months, there was an overall reduction in MLVWT of 0.6 mm/year (95% CI 0.31 to 0.81, p = 0.00004). Wall thinning >/=5 mm was observed in 41 patients (57.7%; age 35 +/- 13 years; 28 males). On multivariate analysis, the follow-up duration only predicted wall thinning (0.6 mm/year, 95% CI 0.38 to 0.85, p < 0.00001). CONCLUSIONS: Left ventricular remodeling is common in patients with severe LVH and contributes to the low prevalence of severe LVH seen in middle age and beyond.     

Age and hypertrophy alter the contribution of sarcoplasmic reticulum and Na+/Ca2+ exchange to Ca2+ removal in rat left ventricular myocytes

Age and hypertension contribute significantly to cardiac morbidity and mortality, however the importance of each during the progression of hypertrophy is unclear. This investigation examined the effect of age and hypertension on Ca(2+) handling in rat ventricular myocytes by comparing a genetic model of hypertension and cardiac hypertrophy (spontaneously hypertensive rat, SHR) with its normotensive control (Wistar-Kyoto rat, WKY) at 5 and 8 months of age. Experiments were performed on single left ventricular myocytes isolated from SHR or WKY hearts. Intracellular Ca(2+) was measured optically using fura-2 or fluo-3. SHR myocytes had a significantly larger cell width and volume and a significantly decreased cell length/width ratio at 5 and 8 months compared to normotensive controls. Age had no effect on cell length, width, volume or the length/width ratio. Ca(2+) transient amplitude, sarcoplasmic reticulum (SR) Ca(2+) content and contraction amplitude were unaffected by age or hypertrophy. However at 8 months the contribution of the SR to Ca(2+) uptake during relaxation decreased, with a concomitant increase in the contribution of Na(+)/Ca(2+) exchanger (NCX) function to relaxation, in SHR and WKY myocytes. The incidence of non-synchronous SR Ca(2+) release decreased with age but not hypertrophy in SHR and WKY myocytes. These results show that the changes in Ca(2+) handling observed during progression of mild hypertrophy in SHR are the same as those that occur during ageing in normotensive control animals and can, therefore, be ascribed to maturation rather than hypertrophy.     

Hypertrophic cardiomyopathy is associated with more severe left ventricular dyssynchrony than is hypertensive left ventricular hypertrophy

OBJECTIVE: To evaluate left ventricular (LV) dyssynchrony in patients with left ventricular hypertrophy (LVH), and to compare abnormalities associated with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) using 2D speckle tracking imaging. METHODS: Basal, middle, and apical 2D LV short-axis images were acquired in 43 patients with LVH including 20 with HCM and 23 with HHD, and in 15 age-matched controls. Radial strain, circumferential strain, time interval from the R-wave to peak radial strain (Trs), and time to peak circumferential strain (Tcs) were measured in six equidistant segments at each level of the 3 LV short-axis views using 2D speckle tracking analysis. To assess LV dyssynchrony, Trs(cs)-18SD, the standard deviation (SD) of Trs(cs) in all 18 segments, was calculated. RESULTS: Regional radial strain in the middle and apical short-axis segments was significantly less in patients with HCM than in those with HHD. Regional circumferential strain in the apical short-axis segments was also less in HCM. Trs-18SD and Tcs-18SD were significantly longer in patients with HCM than in age-matched controls and patients with HHD (Trs-18SD: HCM: 88 +/- 32 ms, HHD: 51 +/- 20 ms, control: 45 +/- 12 ms P < 0.001, Tcs-18SD: HCM: 71 +/- 27 ms, HHD: 46 +/- 14 ms, control: 45 +/- 14 ms P < 0.001). CONCLUSIONS: The presence of LVH is thus not always associated with LV dyssynchrony. However, the greater reduction of regional strain and severe LV dyssynchrony in HCM may contribute to the adverse cardiovascular outcomes associated with this disease.     

重症高血压大鼠左心室肥厚时肾上腺髓质素系统的上调

目的探讨肾上腺髓质素(AM)在重症高血压大鼠左心室心肌肥大中的病理生理作用,包括其配体及酰胺化活性。方法试验分为4组：Wistar-Kyoto大鼠为对照组,有卒中倾向的自然发症高血压大鼠组,用卡托普利治疗8周组,用三氯甲噻嗪治疗8周组。AM前体为无活性的甘氨酸基肾上腺髓质素(AM-Gly),AM-Gly经酰胺化转变为成熟的有活性的AM(AM-m)。通过放射性免疫分析,检测血浆和左心室中AM-m、总AM(AM-m AM-G]y)、心房利钠肽含量,以及AM和心房利钠肽基因水平。结果自然发症高血压大鼠组血压、左心室重量、血浆和左心室中心房利钠肽及其mRNA水平均较对照有所升高。血浆中(AM-m： 31％,总AM： 56％)及心室中(AM-m： 84％,总AM： 31％)的AM-m和总AM均较对照组显升高。在左心室组织中自然发症高血压大鼠组(93．2％)的AM-m／总AM比率明显高于对照组。在左心室中的AM的mRNA水平显高于对照组。卡托普利和三氯甲噻嗪降血压和降低肥大左心室中AM-m、总AM、AM的mRNA含量作用相似。结论此高血压模型的肥大心肌中肾上腺髓质素系统上调。作为一个抗重塑的自分泌和(或)旁分泌因子,AM的上调可能改变左心室肥厚的病理生理过程。     

Rapid ventricular filling in left ventricular hypertrophy: II. Pathologic hypertrophy

To define the extent of left ventricular ejection and filling abnormalities in patients with mild hypertension, a non-imaging nuclear probe was used to generate high resolution time-activity curves in 25 patients with an average systolic blood pressure of 154 +/- 20 mm Hg and diastolic pressure of 98 +/- 8 mm Hg. The hypertensive patients did not meet electrocardiographic criteria for left ventricular hypertrophy, and none had evidence of ischemic or other cardiac disease. Compared with 25 age-matched normal subjects who had average systolic and diastolic pressures of 123 +/- 10 and 79 +/- 8 mm Hg, respectively, the hypertensive patients had a significantly lower ejection rate (2.00 +/- 0.20 versus 2.34 +/- 0.36 end-diastolic counts/s for the control group, p less than 0.05) and ejection fraction (58 +/- 4.9 versus 62 +/- 4.4) (p less than 0.05). The hypertensive patients had a markedly lower average rapid left ventricular filling rate (1.87 +/- 0.32 versus 2.69 +/- 0.41 counts/s for the control group, p less than 0.001). Although there was a modest inverse relation between echocardiographic left ventricular mass index and filling rate in the hypertensive patients (r = -0.59, p less than 0.01), 4 of 12 hypertensive patients with normal left ventricular mass index had a depressed filling rate. All of the hypertensive patients with increased left ventricular mass index had an abnormal left ventricular filling rate (less than 1.89 end-diastolic counts/s).(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in Ca2+ cycling proteins and G alpha q signaling after left ventricular assist device support in failing human hearts

OBJECTIVE: Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the G alpha q signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support. METHODS: Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of G alpha q, phospholipase C beta 1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (alpha, beta 1, and beta 2). RESULTS: The paired pre- and post-left ventricular assist device samples revealed that RGS2, a selective inhibitor of G alpha q, was decreased (P < 0.01), while the status of G alpha q, phospholipase C beta 1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level (P < 0.01), while phospholamban abundance was unchanged. CONCLUSIONS: We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C beta 1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.