Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy.

We have previously shown rapid reversal of left ventricular hypertrophy (LVH) with 6 months of spironolactone therapy in patients with resistant hypertension (HTN), preserved left ventricular ejection fraction and no history of heart failure. In this substudy, we investigated the effect of mineralocorticoid receptor blockade with spironolactone on pre-clinical diastolic dysfunction. Thirty-four patients (19 with high and 15 with normal aldosterone levels) were treated with spironolactone and followed with cardiac magnetic resonance with tissue tagging at baseline, 3 and 6 months of treatment. Serum markers of collagen turnover (C-propeptide of type-I procollagen and carboxy-terminal telopeptide of type-I collagen) were measured at baseline and at 6 months. At baseline, patients demonstrated reduced E/A ratio (volumetric normalized peak early filling rate/late filling rate, normalized to left ventricular end-diastolic volume), lower peak early-diastolic mitral annular velocity and lower peak early-diastolic circumferential strain rates compared to the reference values obtained from 45 normal controls without HTN or cardiac disease (all comparisons, P<0.01). No significant change occurred in diastolic filling, relaxation parameters or collagen markers with spironolactone therapy at 6 months irrespective of aldosterone status despite significant reduction in left ventricular mass index in both high- and normal-aldosterone groups. In conclusion, resistant HTN patients with LVH demonstrate significant pre-clinical diastolic dysfunction. Short-term spironolactone therapy may not lead to improvement in diastolic function despite rapid reversal of LVH.

Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease.

Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD). Mineralocorticoid receptor antagonists (MRAs) are effective in the management of resistant hypertension but are not widely used in CKD because of the risk of hyperkalemia. We retrospectively evaluated the long-term effects and safety of MRAs added to a pre-existing antihypertensive regimen in subjects with resistant hypertension associated with stage 3 CKD. In all, 32 patients were treated with spironolactone and 4 with eplerenone for a median follow-up of 312 days. MRAs induced a significant decrease in systolic blood pressure from 162±22 to 138±14 mm Hg (P<0.0001) and in diastolic blood pressure from 87±17 to 74±12 mm Hg (P<0.0001). Serum potassium increased from 4.0±0.5 to 4.4±0.5 mEq l(-1) (P=0.0001), with the highest value being 5.8 mEq l(-1). The serum creatinine increased from 1.5±0.3 to 1.8±0.5 mg dl(-1) (P=0.0004) and the estimated glomerular filtration rate decreased from 48.6±8.7 to 41.2±11.5 ml min(-1) per 1.73 m(2) (P=0.0002). One case of acute renal failure and three cases of significant hyperkalemia occurred. MRAs significantly reduced blood pressure in subjects with resistant hypertension associated with stage 3 CKD, although close biochemical monitoring is recommended because of an increased risk of hyperkalemia and worsening of renal function.

Differential MAP kinase activation and Na(+)/H(+) exchanger phosphorylation by H(2)O(2) in rat cardiac myocytes.

Bursts in reactive oxygen species production are important mediators of contractile dysfunction during ischemia-reperfusion injury. Cellular mechanisms that mediate reactive oxygen species-induced changes in cardiac myocyte function have not been fully characterized. In the present study, H(2)O(2) (50 microM) decreased contractility of adult rat ventricular myocytes. H(2)O(2) caused a concentration- and time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in adult rat ventricular myocytes. H(2)O(2) (50 microM) caused transient activation of ERK1/2 and p38 MAP kinase that was detected as early as 5 min, was maximal at 20 min (9.6 +/- 1.2- and 9.0 +/- 1.6-fold, respectively, vs. control), and returned to baseline at 60 min. JNK activation occurred more slowly (1.6 +/- 0.2-fold vs. control at 60 min) but was sustained at 3.5 h. The protein kinase C inhibitor chelerythrine completely blocked JNK activation and reduced ERK1/2 and p38 activation. The tyrosine kinase inhibitors genistein and PP-2 blocked JNK, but not ERK1/2 and p38, activation. H(2)O(2)-induced Na(+)/H(+) exchanger phosphorylation was blocked by the MAP kinase kinase inhibitor U-0126 (5 microM). These results demonstrate that H(2)O(2)-induced activation of MAP kinases may contribute to cardiac myocyte dysfunction during ischemia-reperfusion.

Enalaprilat blunts reflexive increases in cardiac interstitial norepinephrine in conscious rats.

OBJECTIVE: We have reported that acute administration of enalaprilat, an angiotensin converting enzyme inhibitor, induces less reflexive increase in lumbar sympathetic nerve activity in spontaneously hypertensive rats (SHRs) than nicardipine, a dihydropyridine calcium-channel blocker. The current study was conducted to determine if angiotensin converting enzyme inhibitors likewise suppress cardiac sympathetic activation. DESIGN: Cardiac interstitial levels of norepinephrine were measured in fully conscious SHRs before and after acute blood pressure lowering with enalaprilat or nicardipine. METHODS: Microdialysis probes were inserted into the left ventricular wall of SHRs. Twenty-four to 48 hours post-implantation, myocardial interstitial fluid was collected in fully conscious rats during a 60-min baseline period. Mean arterial pressure was lowered 20 mmHg with intravenous infusion of enalaprilat or nicardipine. During continuous enalaprilat or nicardipine infusion, myocardial interstitial fluid was again collected. Norepinephrine levels were assayed in the perfusate. CONCLUSIONS: Enalaprilat-induced reduction in mean arterial pressure did not significantly increase cardiac interstitial norepinephrine levels. In contrast, nicardipine-induced reduction in blood pressure was associated with a significant increase in interstitial norepinephrine levels. These results indicate that enalaprilat suppresses reflexive sympathetic activation of the heart during acute blood pressure lowering. These results may be clinically relevant in that reductions in end-organ sympathetic stimulation may enhance the long-term cardiovascular benefit of angiotensin converting enzyme inhibitors.

Angiotensin II modulates catecholamine release into interstitial fluid of canine myocardium in vivo.

This study tested the hypothesis that exogenous infusion of angiotensin II (ANG II) leads to the release of catecholamines [norepinephrine (NE) and epinephrine (EPI)] into the cardiac interstitial fluid (ISF) space of dogs with adrenals intact (AI) (n = 7) and with adrenals clamped (AC) (n = 5). LV ISF samples were collected at 3-min intervals during administration of ANG II (100 microM ANG II at 1 ml/min for 10 min) to right atrial neurons via their local arterial blood supply and during electrical stimulation of the stellate ganglia of open-chest anesthetized dogs. In AI dogs, ANG II caused ISF NE to increase fivefold (P < 0.05) without a significant increase in coronary sinus (CS) NE. Electrical stimulation (5 ms, 4 Hz, 8-14 V, and 10 min) of the stellate ganglia caused a similar increase in ISF NE (P < 0.05), accompanied by a sevenfold increase in CS NE (P < 0.05). ISF EPI increased greater than sixfold during ANG II infusion (P < 0.05) and during stellate stimulation. However, during ANG II infusions, aorta plasma EPI levels increased fourfold in AI dogs, whereas in AC dogs, CS NE and EPI levels were unaffected during ANG II infusions. Nevertheless, baseline ISF NE and EPI did not differ and increased to a similar extent during ANG II infusions in AI versus AC dogs. Thus exogenously administered ANG II increases the amount of NE liberated into the ISF independent of the adrenal contribution, the amount matching that induced by electrical stimulation of all cardiac sympathetic efferent neurons. In contrast, NE spillover into the CS occurred only during electrical stimulation of stellate ganglia. NE release and uptake mechanisms within the myocardium are differently affected, depending on how the final common pathway of the sympathetic efferent nervous system is modified.

Genetic variation in angiotensin-converting enzyme does not prevent development of cardiac hypertrophy or upregulation of angiotensin II in response to aortocaval fistula.

BACKGROUND: Experimental and clinical evidence suggests that angiotensin II may be an important mediator of cardiac hypertrophy in response to hemodynamic stress. We investigated the effect of genetic variation in angiotensin-converting enzyme (ACE) on the development of cardiac hypertrophy and left ventricular (LV) dysfunction in response to volume overload. METHODS AND RESULTS: Male heterozygous ACE knockout (1/0) and wild-type (1/1) mice were studied 4 weeks after the creation of an aortocaval fistula (ACF). The LV weight/body weight ratio increased 74% in ACF versus sham-operated control mice but did not differ between genotypes. Echocardiographic circumferential stress versus rate-corrected velocity of circumferential shortening curves demonstrated depressed LV function in ACF versus sham-operated mice but no difference between genotypes. LV ACE activity was higher in 1/1 versus 1/0 mice and in ACF versus sham-operated mice, and it increased significantly more in the 1/1 versus the 1/0 mice after ACF (P<0.001 for effect of genotype, ACF/sham operation, and interaction term). LV angiotensin II was higher in ACF versus sham-operated mice but did not differ between genotypes, despite 3-fold higher LV ACE activity in ACF 1/1 versus ACF 1/0 mice. CONCLUSIONS: ACE underexpression does not prevent cardiac hypertrophy or LV dysfunction in response to volume overload. LV angiotensin II is unaffected by ACE genotype, both at baseline and after volume overload, indicating that the heart can maintain angiotensin II levels across a broad range of genetic ACE variation under both physiological and pathophysiological conditions.

Left ventricular mass and volume: fast calculation with guide-point modeling on MR images.

The authors describe a fast method for calculating left ventricle (LV) mass and volumes from multiplanar magnetic resonance (MR) images. Mathematic models were fitted to a small number of user-selected guide points in 15 healthy volunteers, 13 patients after myocardial infarction, and a canine model of mitral regurgitation in eight dogs. Errors between model and manual contours were small (LV mass, 1.8 g +/- 4.9 [mean +/- SD]; end-diastolic volume, 2.2 mL +/- 4.6; end-systolic volume, 2.3 mL +/- 3.8). Estimates of global function could be obtained in 6 minutes, a time saving of 5-10 times over estimates with manual contouring.

ACE inhibitors in HF restore canine pulmonary endothelial function and ANG II vasoconstriction.

Chronic mitral regurgitation (MR) in dogs results in pulmonary congestion and increased cardiac angiotensin-converting enzyme (ACE) activity and angiotensin (ANG) II levels. ACE could contribute to altered pulmonary vasomotion in heart failure, and ACE inhibitor (ACEI) therapy may normalize pulmonary vasomotion. We evaluated pulmonary artery (PA) responses to ANG II and bradykinin (BK) in control dogs, in dogs with 4 mo of MR, in MR dogs treated with the ACEI ramipril (MR + R), and in control dogs treated with ramipril (C + R). Mean PA systolic pressure increased in MR dogs (21 +/- 4 mmHg) but was normal in MR + R dogs (13 +/- 1 mmHg). Constriction of PA rings to ANG II was depressed in MR dogs. ACEI treatment (MR + R) restored ANG II responsiveness, but peak ANG II response (3.6 +/- 0.2 g) in MR + R dogs remained lower than in C + R dogs (4.7 +/- 0.2 g). Endothelium-dependent relaxation to BK was decreased (-87 +/- 4% C, -65 +/- 4% MR; P < 0.05). Ramipril (MR + R) restored relaxation to BK. This demonstrates that pulmonary congestion results in impaired pulmonary vasomotion to ANG II and BK, which ACEIs could normalize, supporting the use of ACEIs in clinical management of chronic congestive heart failure.

Differential expression of natriuretic peptides and their receptors in volume overload cardiac hypertrophy in the rat.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) upregulation are genetic markers for the chronic hypertrophic phenotype but also have important acute physiologic effects on salt and water balance and blood pressure control. The presence of a dual NP-system led us to hypothesize a differential expression of ANP and BNP in response to an acute hemodynamic stress of volume overload in the left ventricle (LV) and right ventricle (RV). Accordingly, we examined the temporal relationship between the RV and LV expression of ANP and BNP mRNA and NP receptor mRNA levels on days 1, 2, 3, and 7 after induction of aortocaval fistula in the rat. LV end-diastolic pressure was increased 1.5-fold by day 3 and 2.0-fold by day 7 compared to control (P<0.05). LV weight increased by day 7 compared to control (2.34+/-0.04 vs 3.07+/-0.10 mg/g, P<0.05) while RV weight did not change over the 7 days. There was a 7-fold increase of ANP mRNA in LV at day 1, which was sustained through day 7, while LV BNP mRNA levels did not differ from controls over the 7 days. In contrast, RV mRNA transcript levels for ANP and BNP were increased >2-fold by day 2 and this increase was sustained throughout 7 days. NP clearance receptor was decreased by 75% by day 7 in the LV but did not change in the RV. Thus, LV ANP mRNA levels increased before the onset of LV hypertrophy and RV BNP mRNA levels increased in the absence of RV hypertrophy. The disparate response of BNP and the NP clearance receptor transcript levels in the LV and RV may be related to differences in load and/or differential expression of the NP system in the LV and RV in response to acute haemodynamic stress.

2-Tetradecylglycidic acid, an inhibitor of carnitine palmitoyltransferase-1, induces myocardial hypertrophy via the AT1 receptor.

Activation of the antiogensin II, type 1 (AT1) receptor mediates the myocardial response to numerous hypertrophic stimuli. This study tested the hypothesis that 2-tetradecylglycidic acid (TDGA), an oxirane carboxylate inhibitor of mitochondrial carnitine plamitoyltransferase-1, induces myocardial hypertrophy via the AT1 receptor system. Male Sprague-Dawley rats treated with 10 mg TDGA/kg/day for 7 days had a heart wet weight:body weight ratio of 3. 58+/-0.16 mg/g compared with a ratio of 2.79+/-0.07 for rats treated with vehicle (P<0.05). The plasma level of antiogensin II was 117. 75+/-17.39 pg/ml in rats treated with 10 mg TDGA/kg/day compared with 54.0+/-11.38 pg/ml for rats treated with vehicle (P<0.05). The plasma level of angiotensin I in these two groups of rats was not different statistically. Rats treated with TDGA and given drinking water containing 1 mg losartan/ml had a heart wet weight:body weight ratio of 2.84+/-0.05 mg/g. This value was not statistically different from the value measured in rats given drinking water containing 1 mg losartan/ml and treated with vehicle alone. No significant difference in the heart wet weight:dry weight ratio occurred among these groups of rats. Finally, treating rats with TDGA or giving rats drinking water that contained 1 mg losartan/ml altered neither their heart rate nor their mean arterial blood pressure when compared with untreated rats. This data, therefore, suggests that oxirane carboxylates induce myocardial hypertrophy by activating the AT1 receptor independent of changes in systemic hemodynamics.

Differential expression of angiotensin-converting enzyme and chymase in dogs with chronic mitral regurgitation.

The current study tested the hypothesis that angiotensin-converting enzyme (ACE) and chymase expression are subject to different regulatory processes in the heart, as well as the lungs and kidneys and, as a result, have an important effect on the efficacy of ACE inhibitor treatment in modulating tissue angiotensin II (ANG II) levels in heart failure. A total of 18 dogs underwent the induction of mitral regurgitation and were followed for 5 months. Eleven dogs were untreated and seven received the ACE-inhibitor ramipril at a dose of 10 mg PO BID. Seventeen dogs underwent a sham-operation: six of these dogs were treated with ramipril for 3 months (10 mg PO BID) and 11 were untreated and followed for 3 months prior to sacrifice. In mitral regurgitation dogs, ANG II levels were increased >2-fold in left ventricle, lungs, and kidney, but were normalized with ACE inhibitor-treatment only in the left ventricle. In the left ventricle and lungs steady state ACE mRNA levels and ACE activities were increased 2-fold in treated and untreated mitral regurgitation dogs compared to shams (P<0.05, ANOVA). In contrast, chymase mRNA levels were decreased by >50% and chymase activity was increased in left ventricle (LV) of mitral regurgitation dogs (P<0.05). Neither chymase mRNA nor chymase activity could be detected in the kidney; however, kidney ACE mRNA and ACE activity were significantly upregulated in treated and untreated mitral regurgitation dogs (P<0. 05). These results suggest that ACE and chymase expression are regulated differentially in the dog in response to chronic mitral regurgitation and ACE inhibitor treatment. Further, these responses, as well as regulation of ANG II formation, are organ specific.

Evidence for angiotensin-converting enzyme- and chymase-mediated angiotensin II formation in the interstitial fluid space of the dog heart in vivo.

BACKGROUND: We have previously demonstrated that angiotensin II (Ang II) levels in the interstitial fluid (ISF) space of the heart are higher than in the blood plasma and do not change after systemic infusion of Ang I. In this study, we assess the enzymatic mechanisms (chymase versus ACE) by which Ang II is generated in the ISF space of the dog heart in vivo. METHODS AND RESULTS: Cardiac microdialysis probes were implanted in the left ventricular (LV) myocardium (3 to 4 probes per dog) of 12 anesthetized open-chest normal dogs. ISF Ang I and II levels were measured at baseline and during ISF infusion of Ang I (15 micromol/L, n=12), Ang I+the ACE inhibitor captopril (cap) (2.5 mmol/L, n=4), Ang I+the chymase inhibitor chymostatin (chy) (1 mmol/L, n=4), and Ang I+cap+chy (n=4). ISF infusion of Ang I increased ISF Ang II levels 100-fold (P<0.01), whereas aortic and coronary sinus plasma Ang I and II levels were unaffected and were 100-fold lower than ISF levels. Compared with ISF infusion of Ang I alone, Ang I+cap (n=4) produced a greater reduction in ISF Ang II levels than did Ang I+chy (n=4) (71% versus 43%, P<0.01), whereas Ang I+cap+chy produced a 100% decrease in ISF Ang II levels. CONCLUSIONS: This study demonstrates for the first time a very high capacity for conversion of Ang I to Ang II mediated by both ACE and chymase in the ISF space of the dog heart in vivo.

Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation.

Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the hypertrophic response; and 3) load, independent of the RAS, is capable of stimulating cardiac growth.

Changes in left ventricular mass and volumes in patients receiving angiotensin-converting enzyme inhibitor therapy for left ventricular dysfunction after Q-wave myocardial infarction.

OBJECTIVES: We evaluated global and segmental left ventricular (LV) mass and LV mass/volume ratio in patients with LV dysfunction receiving angiotensin-converting enzyme (ACE) inhibitor therapy after acute myocardial infarction (MI). BACKGROUND: ACE inhibitors attenuate LV dilatation and compensatory hypertrophy after acute MI in animal models. However, LV remodeling in patients after acute MI has been largely defined on the basis of changes in chamber volume alone. METHODS AND RESULTS: Twenty-nine patients with LV ejection fraction <40% received the ACE inhibitor ramipril (range 2.5 to 20 mg/day) within 5 days of their first Q-wave MI. Magnetic resonance imaging was performed at baseline and at 3 months, providing global and regional LV volumes and mass from summated serial short-axis slices. Mean arterial blood pressure was unchanged from baseline to 3-month follow-up (89 +/- 10 to 92 +/- 17 mm Hg). LV mass decreased (90 +/- 25 to 77 +/- 21 gm/m2, p < 0.0005) as LV end-diastolic volumes increased (65 +/- 13 to 73 +/- 22 ml/m2, p < 0.01). Global LV mass to volume ratio decreased from 1.40 +/- 0.28 to 1.08 +/- 0.18 gm/ml (p < 0.0001), as did circumferential wall thickness to volume ratio of noninfarcted myocardium at the base of the LV (0.06 +/- 0.02 to 0.05 +/- 0.02 mm/ml, p < 0.001). LV ejection fraction increased from 35 +/- 6 to 40 +/- 9% (p < 0.001) in the presence of an increase in calculated end-systolic wall stress (185 +/- 57 to 227 +/- 54 gm/cm2, p < 0.01). CONCLUSIONS: ACE inhibitor therapy was associated with improved LV function in the face of a decrease in mass to volume ratio of the LV as well as a decrease in wall thickness to volume ratio of noninfarcted myocardium. Whether ACE inhibitor therapy had direct or indirect effects on these changes in LV mass and function are open questions that require further investigation.

Handgrip increases endothelin-1 secretion in normotensive young male offspring of hypertensive parents.

OBJECTIVES: We tested the hypothesis that an abnormal response of plasma endothelin-1 (ET-1) is elicited by handgrip exercise (HG) in young normotensive offspring of hypertensive parents. BACKGROUND: It has been hypothesized that ET-1 is involved in blood pressure control and plays a pathophysiologic role in the development of clinical hypertension. METHODS: Two groups of healthy male subjects, 11 with hypertensive parents (group A) and 10 without a family history of hypertension (group B), underwent 4 min of HG at 50% maximal capacity. Heart rate and blood pressure and plasma levels of ET-1, epinephrine and norepinephrine were measured at baseline, peak HG, and after 2 (R2) and 10 (R10) min of recovery. RESULTS: Group A had higher norepinephrine levels than group B throughout the test (baseline 181+/-32 [SEM] vs. 96+/-12 pg/ml, p < 0.05; peak HG 467+/-45 vs. 158+/-12 pg/ml, p < 0.000001; R2 293+/-46 vs. 134+/-8 pg/ml, p < 0.01; RO1 214+/-27 vs. 129+/-10 pg/ml, p < 0.0005); no significant difference in epinephrine levels was detected. Compared with group B subjects, group A had higher baseline ET-1 levels (1.07+/-0.14 vs. 0.59+/-0.11 pg/ml, p < 0.02), which increased to a greater extent at peak HG (1.88+/-0.31 vs. 0.76+/-0.09 pg/ml, p < 0.005) and R2 (2.46+/-0.57 vs. 1.31+/-0.23 pg/ml, p < 0.05) and remained elevated at R10 (3.16+/-0.78 vs. 0.52+/-0.09 pg/ml, p < 0.002). Multivariate analysis demonstrated that only a family history of hypertension (chi-square=7.59, p=0.0059) and ET-1 changes during HG (chi-square=4.23, p=0.0398) were predictive of blood pressure response to HG and that epinephrine and norepinephrine were not. CONCLUSIONS: The response to HG in offspring of hypertensive parents produced increased ET-1 plasma levels and resulted in a sustained ET-1 release into the bloodstream during recovery compared with offspring of normotensive parents. This may be an important marker for future clinical hypertension.

Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function.

This article reviews diastolic and systolic ventricular interaction, and clinical pathophysiological conditions involving ventricular interaction. Diastolic ventricular interdependence is present on a moment-to-moment, beat-to-beat basis, and the interactions are large enough to be of physiological and pathophysiological importance. Although always present, ventricular interdependence is most apparent with sudden postural and respiratory changes in ventricular volume. Left ventricular function significantly affects right ventricular systolic function. Experimental studies have shown that about 20% to 40% of the right ventricular systolic pressure and volume outflow result from left ventricular contraction. This dependency of the right ventricle on the left ventricle helps to explain the right ventricular response to volume overload, pressure overload, and myocardial ischemia. The septum and its position are not the sole mechanism for ventricular interdependence. Ventricular interdependence causes overall ventricular deformation, and is probably best explained by the balance of forces at the interventricular sulcus, the material properties, and cardiac dimensions.

Can indices of left ventricular function be applied to the right ventricle?

This article compares conventional indices of contractile function in the right and left ventricles. The low operating pressures and left ventricles. The low operating pressures and complex geometry complicate evaluation of right ventricular function. However, when the characteristics of its vascular load are taken into account, the complex right ventricular chamber has pump properties that are similar to the high pressure left ventricular chamber.

Selective induction of the creatine kinase-B gene in chronic volume overload hypertrophy is not affected by ACE-inhibitor therapy.

Hypertrophied and failing myocardium has been shown to undergo creatine kinase (CK) isoform switching, resulting in increased MB and BB components. We tested the hypothesis that chronic volume overload hypertrophy due to mitral regurgitation in the dog causes CK isoenzyme switching and that this could be reversed by angiotensin converting enzyme inhibitor therapy. Thirteen adult mongrel dogs had mitral regurgitation induced by mitral valvular chordal rupture: six were treated with ramipril for 4 months and seven were untreated for 4 months. Twelve dogs were sham-operated: six received ramipril for 3 months and six were untreated. Left ventricular end-diastolic volume increased from 58+/-4 to 104+/-10 ml in untreated (P<0.001) and from 55+/-3 to 91+/-6 ml in treated dogs (P<0.01) as LV mass/volume ratio decreased in both untreated (1. 60+/-0.07 to 1.13+/-0.08 g/ml, P<0.001) and treated dogs (1.44+/-0.06 to 1.20+/-0.08 g/ml, P<0.01). CK-MB isoform was 7.4+/-1.1% in normal shams and increased to 13.5+/-1.9% and 18.1+/-3.0% in both treated and untreated mitral regurgitation dogs; respectively (P<0. 05). Steady state CK-B mRNA increased three-fold in treated and untreated dogs with mitral regurgitation (P<0.003) compared to normals, while CK-M mRNA expression did not differ in all groups. Thus, chronic volume overload hypertrophy of mitral regurgitation induces CK isoform switching by selective induction of the CK-B gene, and ramipril therapy does not affect this isoform switch. This may reflect a response to increased diastolic stress and more efficient energy utilization in the volume overloaded myocardium.