Improvement In Left Ventricular Diastolic Function Research Articles

Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart

Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H(2)O(2) in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG+DM) and nontransgenic wildtype littermates (WT+DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG+DM at 8 wk were significantly lower than those in WT+DM (58 +/- 3 vs. 71 +/- 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT+DM and TG+DM mice. In contrast, diastolic function was impaired in WT+DM and was improved in TG+DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 +/- 1.2 vs. 8.9 +/- 0.7 ms, P < 0.01). The TG+DM values were comparable with those of WT+Control (tau; 7.8 +/- 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM.

Sustained improvement in left ventricular diastolic function after alcohol septal ablation for hypertrophic obstructive cardiomyopathy

Impaired diastolic function is responsible for many of the clinical features of hypertrophic cardiomyopathy. In patients with hypertrophic obstructive cardiomyopathy (HOCM) whose symptoms are refractory to medical therapy, alcohol septal ablation (ASA) reduces left ventricular (LV) outflow tract gradient, with short-term improvement in LV diastolic function. Little is known about the longer term impact of ASA on diastolic function. We evaluated LV diastolic function at baseline and 1- and 2-year follow-up after successful ASA. In 30 patients (58+/-15 years, 22 men) who underwent successful ASA, New York Heart Association class was lower at 1-year follow-up compared with baseline (3.0+/-0.5 to 1.5+/-0.7; P<0.0001). LV outflow tract gradient (76+/-37 to 19+/-12; P<0.0001), interventricular septal thickness (19+/-2 to 14+/-2; P<0.0001), and left atrial volume (26+/-5 to 20+/-4; P<0.0001) were decreased. Significant improvement in E-wave deceleration time, isovolumic relaxation time, early diastolic mitral lateral annular velocity (E'), mitral inflow propagation velocity (V(p)), ratio of transmitral early LV filling velocity (E) to early diastolic Doppler tissue imaging of the mitral annulus (E/E'), and E/V(p) were observed at 1 year following successful ASA. These changes persisted in the subset cohort (n=21) for whom 2-year data were available. Successful ASA for HOCM leads to significant and sustained improvement in echocardiographic measures of diastolic function, which may contribute to improved functional status after successful ASA.

Effect of Resistance and Circuit Exercise Training on Left Ventricular Diastolic Function in Obese Adolescents

Left ventricular (LV) diastolic dysfunction is an early indicator of cardiac dysfunction which predicts mortality in patients with cardiovascular disease and the general population. LV diastolic dysfunction, independent of LV hypertrophy or hypertension, has been documented in obese adults. However, no studies have determined the effect of obesity on diastolic function in obese children and the impact of different exercise training modalities on diastolic function are unknown. PURPOSE: To examine whether obesity is associated with diastolic dysfunction in children and whether resistance or circuit exercise training improves diastolic function in these subjects. METHODS: 44 obese adolescents were selected to participate in either a circuit training (n=21, 12.3±0.4yrs, BMI 30.8±0.8), resistance training (n=13, 12.2±0.2yrs, BMI 31.9±1.9) or non-exercise control intervention (13.7±0.7yrs, BMI 30.2±2.6) for 8 weeks. 15 lean controls were recruited for comparison to the obese subjects (13.3±0.5 yrs, BMI 20.5±0.7). All subjects had repeated echocardiographic assessment to determine LV size and diastolic function (E/E' primary outcome measure). DEXA was used to assess changes in body composition in the obese subjects. RESULTS: Compared to lean controls, obese subjects exhibited significantly impaired diastolic function (E/E' 6.86±0.20 vs 8.16±0.26, p < 0.01). LV structure did not changes with either type of training (LVMass- circuit 137. 6±6.5 to 143.0±7.1g; resistance-160.7±11.6 to 167.2±14.7g, both P=NS). Resistance training improved tissue Doppler diastolic function (E/E' 8.17±0.4to 7.06±0.3, p < 0.01), with no changes observed in the circuit trained group (E/E' 8.28±0.2 to 8.34±0.2, P=NS). Resistance training also resulted in an increase in lean body mass (41.2±3.07kg to 42.1±2.0kg, p < 0.05), accompanied by a significant loss in total body fat as a percentage (49.6±1.4% to 48.5±1.5%). These improvements in body composition were not seen in the circuit trained group. CONCLUSIONS: Diastolic function is impaired in obese children and a supervised 8-week resistance training exercise program improves body composition and diastolic function in obese adolescents, independent of changes in LV size and BP. This is in contrast to a supervised 8 week circuit training program which resulted in no significant improvements in LV diastolic function or body composition. Improvement in diastolic function in obese children may therefore relate to changes in lean body mass and the metabolic impact of enhanced insulin sensitivity.

Clinical Outcomes After Cardiac Resynchronization Therapy: Importance of Left Ventricular Diastolic Function and Origin of Heart Failure

Cardiac resynchronization therapy (CRT) improves functional outcomes in patients with severe systolic heart failure. Whether the effects of CRT on left ventricular (LV) diastolic function and clinical outcomes are influenced by the cause as either ischemic or nonischemic cardiomyopathy (CM) has not been well established. A total of 57 patients (age 60 +/- 11 years; 25% women; LV ejection fraction 25 +/- 5%) were studied before and 4 +/- 2 months after CRT by echocardiography. Heart failure cause was ischemic CM in 19 and nonischemic CM in 38. Measurements of LV systolic and diastolic function were determined by 2-dimensional and Doppler echocardiography with Doppler tissue imaging of regional myocardial velocities. Clinical outcome events were assessed at long-term follow-up and included hospitalization for heart failure exacerbation, heart transplantation, or cardiac-related death. There were significant increases in LV ejection fraction, reductions in end-systolic volumes, and improved LV systolic dyssynchrony in both groups. However, significant improvements in LV diastolic function were observed only in the patients with nonischemic CM. Clinical events occurred in 53% of the ischemic group versus 26% of the nonischemic group (P < .05) after 20 +/- 11 months of CRT. Univariate and multivariate analysis revealed that Doppler-estimated LV filling pressures were predictors of clinical outcome events. After CRT patients with ischemic CM exhibit lack of improvement in LV diastolic function despite favorable effects on LV systolic performance. The Doppler-derived LV filling indices may be an important predictor of long-term clinical outcomes after CRT.

Improvements in Left Ventricular Diastolic Function After Cardiac Resynchronization Therapy Are Coupled to Response in Systolic Performance

To determine the short-term effects of cardiac resynchronization therapy (CRT) on measurements of left ventricular (LV) diastolic function in patients with severe heart failure. Cardiac resynchronization therapy improves systolic performance; however, the effects on diastolic function by load-dependent pulsed-wave Doppler transmitral indices has been variable. Fifty patients with severe heart failure were evaluated by two-dimensional Doppler echocardiography immediately prior to and 4 +/- 1 month after CRT. Measurements included LV volumes and ejection fraction (EF), pulsed-wave Doppler (PWD)-derived transmitral filling indices (E- and A-wave velocities, E/A ratio, deceleration time [DT], diastolic filling time [DFT], and isovolumic relaxation time). Tissue Doppler imaging was used for measurements of systolic and diastolic (Em) velocities at four mitral annular sites; mitral E-wave/Em ratio was calculated to estimate LV filling pressure. Color M-mode flow propagation velocities were also obtained. After CRT, LV volumes decreased significantly (p < 0.001) and LVEF increased >5% in 28 of 50 patients (56%) and were accompanied by reduction in PWD mitral E-wave velocity and E/A ratio (both p < 0.01), increased DT and DFT (both p < 0.01), and lower filling pressures (i.e., E-wave/Em septal; p < 0.01). Patients with LVEF response < or =5% after CRT had no significant changes in measurements of diastolic function; LV relaxation (i.e., Em velocities) worsened in this group. In heart failure patients receiving CRT, improvement in LV diastolic function is coupled to the improvement in LV systolic function.

Effect of Losartan on Left Ventricular Diastolic Function in Patients With Nonobstructive Hypertrophic Cardiomyopathy

In hypertrophic cardiomyopathy (HC), diastolic dysfunction of the left ventricle is a prominent feature caused by myocardial hypertrophy and fibrosis. Angiotensin II has trophic and profibrotic effects on the heart, and the blockade of angiotensin II receptors reverses hypertrophy and fibrosis in human cardiac diseases and in animal HC. This study investigated the short-term (6 months) effects of losartan 100 mg/day in 20 patients with nonobstructive HC, with an emphasis on left ventricular (LV) diastolic dysfunction, compared with 10 patients with HC who were not treated. At the final evaluation, significant changes were observed in the losartan group: a left atrial diameter decrease (p<0.0001), a tissue Doppler early (Ea) mitral annulus diastolic velocity increase (p=0.003) and an E/Ea ratio decrease (p=0.0002), and a significant decrease in plasma levels of the aminoterminal fragment of pro-brain natriuretic peptide (NT-pro-BNP) from a median of 860 to 606 pg/ml (p=0.001). A significant correlation was found between percentage changes in NT-pro-BNP and the E/Ea ratio from baseline to 6 months (r=0.61, p=0.002). In the 2 groups, echocardiographic LV wall and cavity measures did not change. In conclusion, in selected patients with nonobstructive HC, losartan during a 6-month period improved LV diastolic function.

Pioglitazone Improves Left Ventricular Diastolic Function in Patients With Essential Hypertension

Left ventricular (LV) hypertrophy and diastolic dysfunction, which are common cardiac consequences of hypertension, are modified by insulin resistance. The present study assessed the hypothesis that primary treatment of insulin resistance may reverse such cardiac changes in hypertensive patients. A total of 30 patients with essential hypertension were enrolled in this study. In echocardiographic examinations, LV mass index, the peak velocity ratio of early diastolic to atrial filling (E/A), and the E-wave deceleration time (DcT) were determined. Insulin sensitivity test with steady-state plasma glucose (SSPG) method, oral glucose tolerance test, and blood samplings for measurement of adiponectin and matrix metalloproteinase (MMP)-2 were also performed. Six months after treatment with pioglitazone (30 mg/day), an insulin sensitizer, these examinations were repeated. Pioglitazone significantly increased E/A and decreased DcT, without a change in LV mass index. These improvements in diastolic properties were much greater in subjects with a marked (>or==3.3 mmol/L) decrease in SSPG (n=11) than the others (n=19), although the decrease in glucose levels did not differ between the two groups. In addition, the changes in E/A and DcT were closely correlated with the decrease in SSPG. Pioglitazone treatment significantly elevated plasma adiponectin and MMP-2 levels, and the increase in MMP-2 was positively correlated with the increase in adiponectin. The present findings demonstrate that pioglitazone improves LV diastolic function without LV mass regression in hypertensive patients in proportion to the amelioration of insulin resistance. These findings suggest that increased adiponectin and MMP may be involved in the beneficial effect of pioglitazone on diastolic function.

Left Ventricular Diastolic Function Improvement by Carvedilol Therapy in Advanced Heart Failure

Carvedilol treatment in chronic heart failure (CHF) patients has been demonstrated to reduce mortality by improving cardiac systolic function and reducing left ventricular adverse remodeling. However, the effects of the drug on left ventricular (LV) filling are less studied. In this study we evaluated early and long-term diastolic cardiac modifications by an echo-Doppler method during carvedilol therapy in patients with advanced CHF and pseudonormal or restrictive filling pattern. We studied 58 patients with severe but stable CHF (39 in class NYHA III and 19 in IV) having systolic and diastolic dysfunction caused by idiopathic or ischemic cardiomyopathy. Thirty-two patients were randomized to receive previous treatment plus carvedilol (group 1) and 26 continued standard therapy (group 2). In all subjects we evaluated LV volumes, LV mass, LV ejection fraction (EF), and the following transmitral filling parameters: early wave (E), atrial wave (A), E/A ratio, deceleration time (DT), and isovolumetric releasing time (IVRT). After 4 months of therapy, the carvedilol group showed a significant increase of A wave (P < 0.001), DT (P < 0.0001), IVRT (P < 0.0001), and a significant reduction of E/A ratio (P < 0.0005) with respect to group 2. Further improvement was observed at 12 months (A P < 0.0005; DT P < 0.00002; IVRT P < 0.000004; E/A P < 0.0008), although an E wave reduction was observed in group 1 with respect to controls (P < 0.001). Moreover, after 1 year of follow-up a reduction of systolic volume (P < 0.001) and pulmonary pressure (P < 0.0001) and consequent increase of EF (P < 0.001) was observed in the carvedilol group. Carvedilol treatment improved diastolic function in CHF with severe diastolic and systolic impairment at early time, converting a restrictive or pseudonormal filling pattern into an altered pattern. These changes remained significant after 1 year of therapy together with improvement in systolic function.

Effect of Transcatheter Atrial Septal Defect Closure in Children on Left Ventricular Diastolic Function

The acute impact of transcatheter atrial septal defect (ASD) closure on left ventricular (LV) diastolic function was assessed in 15 consecutive children, and pre- and postclosure data were compared with those in a matched group of controls. The data indicate that transcatheter ASD closure leads to an immediate improvement in LV diastolic function as assessed by septal myocardial Doppler tissue imaging and LV inflow velocity propagation. The improvement in LV diastolic properties correlates with the degree of right ventricular volume overload.

Effect of spironolactone on chamber stiffness and diastolic function associated with regression of myocardial fibrosis in dilated cardiomyopathy

We investigated whether spironolactone-induced regression of myocardial fibrosis is associated with improvement of left ventricular (LV) diastolic function in dilated cardiomyopathy (DCM). Methods and Results: Tissue Doppler echocardiography, LV catheterization and biopsies were performed in 10 DCM patients before and after 12 months of treatment with spironolactone. The biochemical index of coupling between the synthesis (PIP) and degradation (CITP) of collagen type-I revealed the presence of 2 subgroups: 5 with PIP/CITP < 40 (GroupA) and 5 with PIP/CITP > 40 (GroupB). After the treatment, collagen volume fraction (CVF), LV chamber stiffness, and diastolic strain-rate were significantly improved in GroupB accompanied with a reduction of PIP/CITP, but not in GroupA (Table). CVF correlated with PIP/CITP (r = 0.70). Conclusions: Spironolactone improves LV diastolic function and chamber stiffness accompanied with regression of fibrosis in patients with higher PIP/CITP. [Display omitted]

AT2receptor and apoptosis during AT1receptor blockade in reperfused myocardial infarction in the rat

We assessed whether upregulation of the angiotensin II (AngII) type 2 receptor (AT2R) during AngII type 1 receptor (AT1R) blockade might induce apoptosis in the in vivo rat model of reperfused myocardial infarction (RMI) and whether addition of an AT2R blocker abolishes that effect. We measured in vivo hemodynamics and left ventricular (LV) systolic and diastolic function (echocardiograms/Doppler), and ex vivo infarct size (triphenyl tetrazolium chloride), regional AT1R and AT2R proteins (immunoblots), and apoptosis (TUNEL assay and DNA ladder) after regional anterior RMI (60 min ischemia, 90 min reperfusion) in Sprague-Dawley rats randomized to intravenous AT1R blockade with candesartan (1 mg/kg, n = 9) or saline (controls, n = 14) over 30 min before RMI, and sham (n = 8). We also assessed the effect of AT2R blockade (PD123319, 10 mg/kg i.v.) plus candesartan on infarct size and apoptosis. Compared to controls, candesartan significantly (p < 0.001) limited increases in left atrial pressure, improved positive LV dP/dtmax and negative dP/dtmin, normalized LV ejection fraction, improved LV diastolic function, limited infarct expansion, decreased infarct size and apoptosis, and increased AT2R protein (not AT1R) in the reperfused ischemic zone. There were no changes in sham hearts. PD123319 abolished the candesartan-induced decrease in infarct size and LV dysfunction but not the decrease in apoptosis. Thus, during AT1R blockade in the in vivo rat model of RMI, regional AT2R upregulation contributes to the beneficial effect on infarct size and LV dysfunction but not on apoptosis, suggesting that the apoptosis is AT1R not AT2R-mediated.

Left ventricular diastolic function assessed using tissue Doppler imaging in elderly athletes

Recent evidences have demonstrated that age-related impairment in left ventricular (LV) function could be partly prevented by regular endurance training [1,2]. However, echocardiographic studies on the effect of physical exercise on LV diastolic function in older people have yielded conflicting results; some authors have demonstrated that regular physical exercise improves LV diastolic function [2]; some others have shown an impaired early diastolic LV filling similar to that of their sedentary peers [3,4]. We investigated the LV diastolic function in a group of elderly individuals with a lifelong history of endurance training by using pulsed tissue Doppler imaging (TDI) method, which has been recently applied for the evaluation of LV diastolic function [5,6]. Twenty normotensive competitive elderly runners (aged 67.6±4.5 years) of the National Veterans Sport Club of Pisa with mild myocardial hypertrophy were compared to 20 matched healthy sedentary volunteers without myocardial hypertrophy. TDI of diastolic velocities of the basal lateral segment and of the basal interventricular septum in the apical four-chamber view were performed. We measured two diastolic waves, early (Em) and atrial (Am). In addition, the isovolumetric relaxation time (IVRTm) of each segment was measured as the interval from the aortic component of the second heart sound to the peak of the early diastolic wave.

2683 Reverse remodelling of left atrium and improvement of left-ventricular diastolic function after catheter ablation for lone atrial fibrillation

2683 Reverse remodelling of left atrium and improvement of left-ventricular diastolic function after catheter ablation for lone atrial fibrillation

Evaluation of left ventricular diastolic function from spectral and color M-mode Doppler in genetically altered mice

Doppler indices of transmitral flow are commonly used to assess noninvasively left ventricular (LV) diastolic function in species larger than mice. The objective of our study was to characterize patterns of LV diastolic function in 2 genetically altered mouse models using Doppler- and color M-mode echocardiography. Phospholamban (PLB) reversibly inhibits the sarcoplasmic reticulum Ca2+ ATPase (SERCA) and is a key regulator of myocardial relaxation. Twelve-week-old PLB knockout mice (PLB/KO) were examined in parallel with age-matched transgenic mice expressing a mutant form of PLB (PLB/N27A) that exhibited superinhibition of SERCA. Transmitral Doppler flow indexes, including isovolumic relaxation time, the ratio of peak early-to-late filling velocities, and deceleration time of peak early transmitral velocity indicate impaired diastolic filling in the PLB/N27A mutants, but improved LV diastolic function in the PLB/KO mice. In addition, a relatively load-independent parameter of LV relaxation measured by color M-mode Doppler, the propagation velocity of early flow into the LV cavity confirmed the observed differences. We conclude that transmitral filling patterns and color M-mode flow propagation velocity reflect changes in myocardial relaxation in mice with genetically altered levels of PLB and may be useful tools to characterize LV diastolic function in other mouse models of disease. (J Am Soc Echocardiogr 2002;15:1065-73.)

New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment.

As described in Part I of this 2-part article,1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear understanding of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function. Conceptually, the mechanisms that cause abnormalities in diastolic function that lead to the development of diastolic heart failure can be divided into factors intrinsic to the myocardium itself (myocardial) and factors that are extrinsic to the myocardium (extramyocardial; Table 1). Myocardial factors can be divided into structures and processes within the cardiac muscle cell (cardiomyocyte), within the extracellular matrix (ECM) that surrounds the cardiac muscle cell, and that activate the autocrine or paracrine production of neurohormones. Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure. Myocardial and extramyocardial mechanisms, cellular and extracellular mechanisms, and neurohumoral activation each play a role in the development of diastolic heart failure caused by ischemia, pressure-overload hypertrophy, and restrictive and hypertrophic cardiomyopathy. View this table: Table 1105290. Diastolic Heart Failure: Mechanisms ### Cardiomyocyte Diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves. These include changes in calcium homeostasis caused by (1) abnormalities in the sarcolemmal channels responsible for short- and long-term extrusion of calcium from the cytosol, such as the sodium calcium exchanger and the calcium pump; (2) …

EFFECT OF VERAPAMIL IN ELDERLY PATIENTS WITH LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AS A CAUSE OF CONGESTIVE HEART FAILURE

SUMMARYFifteen elderly patients with normal left ventricular (LV) systolic function and New York Heart Association functional class II‐III were studied. The effect of verapamil on LV diastolic function was assessed by congestive heart failure (CHF) score, treadmill exercise test, and Doppler echocardiography at baseline, and after each three‐month treatment period (placebo or verapamil 120 mg once daily), separated by a one‐week washout period before crossover. Blood pressure, heart rate, LV ejection fraction, LV mass, and cardiac output were unaltered by placebo or verapamil. Verapamil treatment significantly improved CHF score at 3 months (3.5 ± 0.5, p&lt;0.05) compared with baseline (5.6 ± 0.5) or placebo (5.5 ± 0.5). The exercise time was similar at baseline (7.4 ± 1.2 min) and after placebo (7.4 ± 1.3 min) treatment but significantly (p&lt;0.05) increased after verapamil (8.3 ± 1.2 min) treatment. The ratio of mitral A wave duration/pulmonary venous atrial systolic reversal duration increased after verapamil (1.11 ± 0.08) treatment compared with placebo (0.91 ± 0.07, p&lt;0.05) and baseline (0.89 ± 0.08) which had similar durations. The isovolumic relaxation time was significantly (p&lt;0.05) decreased from 84 ± 12 ms at baseline and 86 ± 13 ms with placebo to 73 ± 9 ms with verapamil. The results of this study suggest that in elderly patients with Doppler evidence of diastolic dysfunction as the cause of CHF, three months treatment with verapamil can improve CHF, increase exercise tolerance and improve LV diastolic function.

Diaspirin Cross-Linked Hemoglobin Fails to Improve Left Ventricular Diastolic Function after Fluid Resuscitation from Hemorrhagic Shock

In severe hemorrhagic shock, left ventricular (LV) diastolic dysfunction is an early sign of cardiac failure due to compromised myocardial oxygenation. Immediate fluid replacement or, in particular, administration of a hemoglobin-based oxygen carrier (diaspirin cross-linked hemoglobin; DCLHb) improves myocardial oxygenation; therefore, positive effects on LV diastolic function could be expected. The effects of fluid resuscitation from severe hemorrhagic shock with DCLHb were investigated in 20 anesthetized domestic pigs. After generation of a critical left anterior descending coronary artery stenosis (narrowing of the artery until disappearance of reactive hyperemia after a 10-second complete vessel occlusion), hemorrhagic shock (mean arterial blood pressure 45 mm Hg) was induced within 15 min by controlled blood withdrawal and maintained for 60 min. Fluid resuscitation consisted of replacement of the plasma volume withdrawn during hemorrhage by infusion of either 10% DCLHb (DCLHb group, n = 10) or 8% human serum albumin (HSA) oncotically matched to DCLHb (HSA group, n = 10). After completion of resuscitation, an observation period of 60 min elapsed. Measurements of central hemodynamics, myocardial oxygenation, and LV diastolic function were performed at baseline, after induction of critical coronary artery stenosis, after 60 min of hemorrhagic shock, immediately after resuscitation, and 60 min later. While 5 out of 10 animals treated with HSA died within the first 20 min after fluid resuscitation from acute LV pump failure, all DCLHb-treated animals survived until the end of the protocol (p < 0.05). Despite superior myocardial oxygenation due to augmentation of the arterial O₂ content as well as of coronary perfusion pressure, no beneficial effects on LV diastolic function were observed after infusion of DCLHb. Peak velocity of LV pressure decrease (dp/dt_min) did not reveal significant differences between the two groups. Immediately after completion of fluid resuscitation with DCLHb, the time constant of LV diastolic relaxation (τ) was prolonged when compared with HSA-treated animals (p < 0.05), indicating retardation of early LV diastolic relaxation. Our data suggest that DCLHb fails to improve LV diastolic function after fluid resuscitation from severe hemorrhagic shock. However, positive effects on myocardial perfusion and oxygenation result in a significant reduction of the mortality of severe hemorrhagic shock.

Chronic therapy with an ET(A/B) receptor antagonist in conscious dogs during progression of congestive heart failure. Intracellular Ca(2+) regulation and nitric oxide mediated coronary relaxation.

Although it is known that endothelin (ET-1) is elevated in heart failure (HF), it remains unclear if chronic ET(A/B) receptor antagonism affects the progression of HF, particularly by affecting coronary vasoactivity and left ventricular (LV) diastolic function. We examined the effects of an ET(A/B) receptor antagonist, L-753,037 (oral bid for 6 weeks, n=7), and vehicle (n=8) in conscious dogs with previously implanted aortic, coronary sinus and left atrial catheters, LV pressure gauge, aortic flow probe, LV dimension crystals and pacers. Baseline hemodynamics were similar in the two groups. During the development of rapid pacing-induced HF, treatment with the ET(A/B) antagonist significantly reduced total peripheral resistance and increased cardiac output compared to vehicle. After 2 weeks of pacing, LV diastolic function (tau) was improved (P<0.05) in the ET(A/B) antagonist group (+6+/-2 ms) compared to the vehicle group (+12+/-2 ms). In addition, ET(A/B) antagonist treatment attenuated the increase in mean left atrial pressure and LV end-diastolic pressure that occurred during heart failure in vehicle-treated animals. However, LV systolic function (LV dP/dt, fractional shortening and Vcfc) neither at rest nor in response to dobutamine was altered by ET(A/B) antagonist treatment. Also, ET(A/B) antagonist treatment did not affect the progressive increases in LV dimension. After 6 weeks of pacing, maximal Ca(2+) transport in isolated cardiac sarcoplasmic reticulum (SR) was reduced (P<0.02) in the vehicle-treated compared to the ET(A/B) antagonist-treated dogs (1.34+/-0.09 vs. 1.60+/-0.06 micromol/mg/min, respectively). The improvement in SR function in the ET(A/B) antagonist-treated dogs was associated with a significant attenuation of the reduction in protein expression of SERCA2a and calsequestrin observed in the vehicle-treated dogs. Coronary arteries isolated from the dogs treated with the ET(A/B) antagonist exhibited enhanced (P<0.01) coronary endothelium-dependent relaxation compared to the vehicle group, while coronary responses to an NO donor were identical in the two groups. Plasma NO levels in the coronary sinus during the late stage of HF were higher (P<0.05) in the ET(A/B) antagonist group (40+/-2 microM) compared to the vehicle group (18+/-2 microM). We conclude that in conscious dogs during the development of HF induced by rapid pacing, chronic inhibition of ET(A/B) receptors does not affect resting myocardial contractile function nor reserve, but reduces vascular resistance and improves LV diastolic function. After 6 weeks of pacing, the reduction in intracellular Ca(2+) regulation by the SR is also attenuated, and endothelium-dependent coronary relaxation is improved, which appears to be related to the preservation of coronary NO levels.

Left Ventricular Function in Patients with Obstructive Sleep Apnoea Syndrome before and after Treatment with Nasal Continuous Positive Airway Pressure

Background: Previous studies have yielded disparate results regarding the effect of obstructive sleep apnoea (OSA) syndrome on left ventricular (LV) function. Objectives: In order to clarify this, we performed a prospective study investigating OSA patients with no history of systemic hypertension, coronary artery disease, myocardial, pericardial or valvular problems, asthma or chronic obstructive pulmonary disease before and after treatment with nasal continuous positive airway pressure (nCPAP). Methods: Fifteen patients (3 women, 12 men) with an apnoea/hypopnoea index >15 (mean ± SD = 52 ± 21) were studied with complete polysomnography, ambulatory blood pressure monitoring, M-mode two-dimensional echocardiography and pulsed Doppler echocardiography in two phases, i.e. before and after 12–14 weeks of nCPAP therapy. We measured systolic and diastolic blood pressure (BP) separately in the daytime and night-time, isovolumic relaxation time (IVRT), the ratio of peak early filling velocity (E) to peak late velocity (A) diastolic transmitral flow (E/A), posterior wall thickness (PWT) and septal thickness (IVST). The shortening fraction (SF) was also calculated. Eleven overweight non-apnoeic normal subjects matched for age were used as the control group. Results: Our results showed that the patient group exhibited, before treatment, LV diastolic, but not systolic, dysfunction compared with the normal group (IVRT = 94.3 ± 11.6 ms, p < 0.05; E/A = 0.94 ± 0.26, p < 0.02; SF = 39.9 ± 4.1%, not significant (NS); IVST = 9.9 ± 1.2 mm, NS; PWT = 8.3 ± 1.2 mm, NS). Moreover, the patient group developed diastolic hypertension both in the daytime and night-time (BP/diastolic/daytime = 93.3 ± 9.2 mm Hg, BP/diastolic/night-time = 90.3 ± 10.7 mm Hg). After 12–14 weeks of nCPAP treatment (no change in body mass index), significant improvement in LV diastolic function and a drop in blood pressure were noticed (IVRT = 85.6 ± 8.8 ms, p < 0.05; E/A = 1.07 ± 0.3, p < 0.05; BP/diastolic/daytime = 86.3 ± 5.5 mm Hg, p < 0.02; BP/diastolic/night-time = 83.9 ± 8.6 mm Hg, p < 0.05) in our patient group. Conclusions: We conclude that repetitive apnoeas/hypopnoeas are very important factors in the development of both LV diastolic dysfunction and diastolic systemic hypertension in patients with OSA syndrome. Treatment with nCPAP leads to significant improvement in both ventricular function and systemic hypertension.

THE EFFECTS OF MONOTHERAPY OR COMBINED THERAPY WITH AN ANGIOTENSIN CONVERTING ENZYME INHIBITOR FOLLOWING INITIAL TREATMENT WITH CALCIUM CHANNEL BLOCKERS ON RESIDUAL CARDIOVASCULAR ABNORMALITIES

The effects of sequential therapy with angiotensin-converting enzyme inhibitor (cilazapril) on left ventricular (LV) mass, LV diastolic function, and carotid artery distensibility were evaluated in 90 hypertensive patients whose blood pressure controlled below 140/90 mmHg with a calcium channel blocker monotherapy. The possibility of predicting the efficacy of cilazapril based on evaluation of biochemical and genetic markers of the renin-angiotensin system was examined. Before cilazapril therapy, LV diastolic function and carotid artery distensibility were significantly impaired in 32 patients with residual LV hypertrophy compared with patients without LV hypertrophy. Cilazapril improved the LV mass in these patients with LV hypertrophy and improved LV diastolic function in a subset of 20 patients with elevated plasma renin activity. Patients with residual LV hypertrophy accompanied by cardiovascular functional abnormalities. Subsequent treatment with cilazapril significantly improved LV morphology and function in those with residual LV hypertrophy or elevated plasma renin activity.