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Biomedical subjects

B H Lorell

Publications and source records attributed to B H Lorell.

At least 37 records · Page 2Linked to original sources
PubMed1999

Gender differences in molecular remodeling in pressure overload hypertrophy.

OBJECTIVES: The objective of this study was to examine gender differences in left ventricular (LV) function and expression of cardiac genes in response to LV pressure overload due to ascending aortic stenosis in rats. BACKGROUND: Clinical studies have documented gender differences in the pattern of adaptive LV hypertrophy. Whether these differences result from intrinsic differences in molecular adaptation to pressure overload between men and women, or are related to other factors is not known. METHODS: Male (n = 8) and female (n = 8) Wistar rats underwent ascending aortic stenosis and were studied 6 weeks after banding with gender-matched control rats (male n = 7; female n = 7). The LV contractile reserve was examined in isolated hearts from each group. We compared LV messenger ribonucleic acid (mRNA) levels of atrial natriuretic factor (ANF), beta-myosin heavy chain, sarcoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) and Na+-Ca2+ exchanger. Reverse transcriptase polymerase chain reaction was used to identify estrogen receptor transcript in cardiac myocytes and LV tissue. RESULTS: The magnitude of LV hypertrophy (LVH) and systolic wall stress were similar in male and female animals with LVH. Male LVH hearts demonstrated a depressed contractile reserve; in contrast, contractile reserve was preserved in female LVH hearts. The expression of beta-myosin heavy chain and ANF mRNA was greater in male versus female LVH hearts. Sarcoplasmic reticulum Ca2+-ATPase mRNA levels were depressed in male LVH but not in female LVH compared with control rats, and Na+-Ca2+ exchanger mRNA levels were increased similarly in both male and female LVH hearts. Estrogen receptor transcript was detected in both adult male and female cardiac myocytes and LV tissue. CONCLUSIONS: There are significant gender differences in the LV adaptation to pressure overload despite a similar degree of LVH and systolic wall stress in male and female rats. There is the potential for estrogen signaling through the adult myocyte estrogen receptor in both male and female rats to contribute to gender differences in gene expression in pathologic hypertrophy.

Adaptation, Physiological↗
PubMed1998

A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.

BACKGROUND: Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. METHODS: We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days. RESULTS: There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone. CONCLUSIONS: Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure.

Aged↗
PubMed1998

Atrial natriuretic peptide has different effects on contractility and intracellular pH in normal and hypertrophied myocytes from pressure-overloaded hearts.

BACKGROUND: Atrial natriuretic peptide (ANP) depresses contractility in left ventricular myocytes. Its expression is upregulated in pressure-overloaded hypertrophied hearts; however, the effects of ANP on contractility in hypertrophied myocytes are not known. Our aims were (1) to examine the cellular mechanisms of this depression in contractility in normal myocytes and (2) to test the hypothesis that the effects of ANP on contractility differ in hypertrophied myocytes from rats with ascending aortic stenosis. METHODS AND RESULTS: We measured the myocyte shortening as an index of contractility, [Ca2+]i with fluo 3, and pHi with seminaphthorhodafluor-1 (SNARF-1). In normal control myocytes (n=26), ANP caused a concentration-dependent depression of contractility and reduction in pHi. In the presence of 10(-6) mol/L ANP, fractional cell shortening was 78+/-5% of baseline (P<0.05) and pHi was reduced by 0.16+/-0.04 U from baseline (P<0.01) without changes in [Ca2+]i. The magnitude of the depression of contraction caused by ANP was similar to that caused by intracellular acidification induced by an NH4Cl pulse. The effects of ANP on contractility and pHi were prevented in the presence of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), which inhibits the Na+/H+ exchanger. In hypertrophied myocytes (n=23), ANP did not depress either myocyte contractility or pHi at concentrations of either 10(-8), 10(-7), or 10(-6) mol/L. ANP caused no change in pHi or the [Ca2+]i transient in hypertrophied myocytes. The cGMP level was increased and Na+/H+ exchanger mRNA levels were normal in left ventricles from aortic stenosis rats compared with controls. CONCLUSIONS: ANP directly depresses contractility in normal myocytes via intracellular acidification, which decreases myofilament [Ca2+]i sensitivity. In contrast, ANP causes no effects on contractility and pHi in hypertrophied myocytes, suggesting a suppression in the coupling of the ANP-cGMP intracellular signaling pathway to the Na+/H+ exchanger.

Animals↗
PubMed1998

Chronic L-arginine treatment increases cardiac cyclic guanosine 5'-monophosphate in rats with aortic stenosis: effects on left ventricular mass and beta-adrenergic contractile reserve.

OBJECTIVES: We tested the hypothesis that nitric oxide (NO) cyclic guanosine 5'-monophosphate (GMP) signaling is deficient in pressure overload hypertrophy due to ascending aortic stenosis, and that long-term L-arginine treatment will increase cardiac cyclic GMP production and modify left ventricular (LV) pressure overload hypertrophy and beta-adrenergic contractile response. BACKGROUND: Nitric oxide cyclic GMP signaling is postulated to depress vascular growth, but its effects on cardiac hypertrophic growth are controversial. METHODS: Forty control rats and 40 rats with aortic stenosis left ventricular hypertrophy ([LVH] group) were randomized to receive either L-arginine (0.40 g/kg/day) or no drug for 6 weeks. RESULTS: The dose of L-arginine did not alter systemic blood pressure. Animals with LVH had similar LV constitutive nitric oxide synthase (cNOS) mRNA and protein levels, and LV cyclic GMP levels as compared with age-matched controls. In rats with LVH L-arginine treatment led to a 35% increase in cNOS protein levels (p = 0.09 vs untreated animals with LVH) and a 1.7-fold increase in LV cyclic GMP levels (p < 0.05 vs untreated animals with LVH). However, L-arginine treatment did not suppress LVH in the animals with aortic stenosis. In contrast, in vivo LV systolic pressure was depressed in L-arginine treated versus untreated rats with LVH (163 +/- 16 vs 198 +/- 10 mm Hg, p < 0.05). In addition, the contractile response to isoproterenol was blunted in both isolated intact hearts and isolated myocytes from L-arginine treated rats with LVH compared with untreated rats with LVH. This effect was mediated by a blunted increase in peak systolic intracellular calcium in response to beta-adrenergic stimulation. CONCLUSIONS: Left ventricular hypertrophy due to chronic mechanical systolic pressure overload is not characterized by a deficiency of LV cNOS and cyclic GMP levels. In rats with aortic stenosis, L-arginine treatment increased cardiac levels of cyclic GMP, but it did not modify cardiac mass in rats with aortic stenosis. However, long-term stimulation of NO-cyclic GMP signaling depressed in vivo LV systolic function in LVH rats and markedly blunted the contractile response to beta-adrenergic stimulation.

Adrenergic beta-Agonists↗
PubMed1998

Hypertrophic remodeling: gender differences in the early response to left ventricular pressure overload.

OBJECTIVES: To identify gender differences in left ventricular remodeling, hypertrophy, and function in response to pressure overload due to ascending aortic banding in rats. BACKGROUND: Gender may influence the adaptation to pressure overload, as women with aortic stenosis have greater degrees of left ventricular hypertrophy and better left ventricular function than men. METHODS: Fifty-two weanling rats underwent ascending aortic banding (16 males, 18 females), or sham surgery (9 males, 9 females). At 6 and 20 weeks, rats underwent transthoracic echo Doppler studies, and closed-chest left ventricular pressures with direct left ventricular puncture. Perfusion-fixed tissues from eight rats were examined morphometrically for myocyte cross-sectional area and percent collagen volume. RESULTS: At 6 weeks after aortic banding, left ventricular remodeling, extent of hypertrophy, and function appeared similar in male and female rats. At 20 weeks, male but not female rats showed an early transition to heart failure, with onset of cavity dilatation (left ventricular diameter=155% vs. 121% of same-sex sham), loss of concentric remodeling (relative wall thickness=102% vs. 139% of sham), elevated wall stress (systolic stress=266% vs. 154% of sham), and diastolic dysfunction (deceleration of rapid filling=251% vs. 190% of sham). Left ventricular systolic pressures were higher in female compared with male rats (186+/-20 vs. 139+/-13 mm Hg), while diastolic pressures tended to be lower (14+/-4 vs. 17+/-4 mm Hg). CONCLUSIONS: Gender significantly influences the evolution of the early response to pressure overload, including the transition to heart failure in rats with aortic stenosis.

Adaptation, Physiological↗
PubMed1997

Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts.

BACKGROUND: Mechanisms in addition to diastolic calcium overload may contribute to diastolic dysfunction in hypertrophied hearts. In this study, we tested the hypothesis that failure to maintain a low ADP concentration in hypertrophied hearts contributes to diastolic dysfunction by inhibiting the rate of cross-bridge cycling. METHODS AND RESULTS: By perfusing isolated rat hearts with pyruvate and 2-deoxyglucose (2DG), we were able to perturb [ADP] with minimal changes in [ATP] and [inorganic phosphate] or the contribution of glycolytic ATP to ATP synthesis. The effects of 2DG were compared in aortic-banded (LVH, n=5) and sham-operated (control, n=5) rat hearts. 31P NMR spectroscopy was used to measure the concentrations of phosphorus-containing compounds. We found a threefold increase of left ventricular end-diastolic pressure (LVEDP) in LVH during 2DG perfusion, and this increase was concomitant with a threefold increase in intracellular free [ADP]. The [ADP] in the control hearts was maintained <40 micromol/L, and no change in LVEDP was observed. A linear relationship between increases in [ADP] and LVEDP was found (r2=.66, P=.001). Furthermore, the capacity of the creatine kinase reaction, a major mechanism for maintaining a low [ADP], was decreased in LVH (P=.0001). CONCLUSIONS: Increased [ADP] contributes to diastolic dysfunction in LVH, possibly due to slowed cross-bridge cycling. Decreased capacity of the creatine kinase reaction to rephosphorylate ADP is a likely contributing mechanism to the failure to maintain a low [ADP] in LVH.

Adenosine Diphosphate↗
PubMed1997

Load-induced growth responses in isolated adult rat hearts. Role of the AT1 receptor.

BACKGROUND: Stimulation of the angiotensin II type 1 (AT1) receptor by angiotensin II appears to be mandatory for the acute load-induced hypertrophic response of cultured neonatal rat cardiocytes, but its role in the adult heart is controversial. We tested the hypothesis that AT1 receptor blockade will inhibit the acute induction of proto-oncogenes and protein synthesis by the elevation of systolic wall stress in isolated beating adult rat hearts. METHODS AND RESULTS: Using the established isovolumic perfused heart preparation under constant coronary flow, we found that an increment in left ventricular balloon volume generated an increase in systolic wall stress. The induction of left ventricular c-fos and c-myc mRNA (Northern blotting) was assessed in hearts subjected to increased systolic load without AT1 blockade (No AT1, n = 11) and with AT1 blockade (AT1, n = 11, losartan 40 mg.kg-1.d-1 x 5 days followed by 10(-5) mol/L infusion during perfusion). Flaccid hearts (no left ventricular balloon) served as controls (C, n = 9). The stimulation of new protein synthesis in response to increased systolic load was measured by incorporation of [3H]phenylalanine into cardiac proteins. Elevation of systolic load was associated with a twofold (P < .05) increase in c-fos and c-myc mRNA levels that was not blocked by losartan. The rate of [3H]phenylalanine incorporation into cardiac proteins was increased 2.7-fold (P < .01) in hearts subjected to increased systolic load compared with control hearts. However, AT1 receptor blockade with losartan did not prevent the stimulation of [3H]phenylalanine incorporation (881 +/- 97 versus 923 +/- 82 nmol.g protein-1.h-1, P = NS). CONCLUSIONS: In contrast with immature myocytes subjected to stretch, the acute growth responses induced by systolic pressure overload in adult rat hearts do not depend on AT1 receptor activation.

Angiotensin Receptor Antagonists↗
PubMed1997

Effects of the nitric oxide donor sodium nitroprusside on intracellular pH and contraction in hypertrophied myocytes.

BACKGROUND: We compared the effects of the nitric oxide donor sodium nitroprusside (SNP) on intracellular pH (pHi), intracellular calcium concentration ([Ca2+]i) transients, and cell contraction in hypertrophied adult ventricular myocytes from aortic-banded rats and age-matched controls. METHODS AND RESULTS: pHi was measured in individual myocytes with SNARF-1, and [Ca2+]i transients were measured with indo 1 simultaneously with cell motion. Experiments were performed at 37 degrees C in myocytes paced at 0.5 Hz in HEPES-buffered solution (extracellular pH = 7.40). At baseline, calibrated pHi, diastolic and systolic [Ca2+]i values, and the amplitude of cell contraction were similar in hypertrophied and control myocytes. Exposure of the control myocytes to 10(-6) mol/L SNP caused a decrease in the amplitude of cell contraction (72 +/- 7% of baseline, P < .05) that was associated with a decrease in pHi (-0.10 +/- 0.03 U, P < .05) with no change in peak systolic [Ca2+]i. In contrast, in the hypertrophied myocytes exposure to SNP did not decrease the amplitude of cell contraction or cause intracellular acidification (-0.01 +/- 0.01 U, NS). The cGMP analogue 8-bromo-cGMP depressed cell shortening and pHi in the control myocytes but failed to modify cell contraction or pHi in the hypertrophied cells. To examine the effects of SNP on Na(+)-H+ exchange during recovery from intracellular acidosis, cells were exposed to a pulse and washout of NH4Cl. SNP significantly depressed the rate of recovery from intracellular acidosis in the control cells compared with the rate in hypertrophied cells. CONCLUSIONS: SNP and 8-bromo-cGMP cause a negative inotropic effect and depress the rate of recovery from intracellular acidification that is mediated by Na(+)-H+ exchange in normal adult rat myocytes. In contrast, SNP and 8-bromo-cGMP do not modify cell contraction or pHi in hypertrophied myocytes.

Animals↗
PubMed1997

Angiotensin AT1 receptor inhibition. Effects on hypertrophic remodeling and ACE expression in rats with pressure-overload hypertrophy due to ascending aortic stenosis.

BACKGROUND: We tested the hypothesis that long-term administration of the specific angiotensin II subtype 1 (AT1)-receptor blocker BMS-186295 will regress hypertrophy and modify left ventricular angiotensin converting enzyme (ACE) expression in rats with ascending aortic stenosis. METHODS AND RESULTS: Six weeks after surgery, rats with ascending aortic stenosis were randomized to receive either the AT1-receptor blocker BMS-186295 50 mg.kg-1.d-1 (n = 49), amlodipine 2.5 mg.kg-1.d-1 (n = 48) as a positive control for systemic vasodilation, or no drug (n = 48) and compared with sham-operated rats (n = 39). Drug treatment was continued for 15 weeks. Left ventricular ACE mRNA levels were measured by ribonuclease protection assay. The left ventricular/body weight ratio was increased 43% in hearts from rats with untreated left ventricular hypertrophy (LVH) versus control hearts (P < .05). However, there was no difference in either the left ventricular/body weight ratio (2.78 +/- 0.08 versus 2.81 +/- 0.20 mg/g; P = NS) or myocyte cross-sectional area in the AT1-blocker-treated versus untreated LVH hearts. Amlodipine also showed no effect on regression of hypertrophy. In vivo left ventricular systolic pressure was significantly higher in untreated LVH versus sham-operated rats (193 +/- 8 versus 118 +/- 4 mm Hg; P < .05), and there was a similar severe elevation of left ventricular systolic pressure in the AT1-blocker- and amlodipine-treated LVH groups (189 +/- 9 and 188 +/- 16 mm Hg; P = NS versus untreated LVH). In vivo left ventricular end-diastolic pressure was higher in the untreated LVH than in the sham-operated rats (14.8 +/- 2.3 versus 7.0 +/- 0.5 mm Hg; P < .05). Left ventricular end-diastolic pressure was lower in the AT1-blocker-treated (11.0 +/- 1.7 mm Hg) and amlodipine-treated rats (11.5 +/- 1.8 mm Hg) and was similar to left ventricular end-diastolic pressure in the sham-operated rats (P = NS). Left ventricular ACE mRNA levels were elevated in untreated LVH rats but were normalized in both the AT1-blocker-treated rats and amlodipine-treated rats. CONCLUSIONS: Long-term AT1-receptor blockade did not regress LVH in rats with persistent systolic pressure overload due to ascending aortic stenosis. However, both AT1-receptor blockade and amlodipine improved in vivo left ventricular end-diastolic pressure in association with the normalization of left ventricular ACE mRNA levels.

Angiotensin Receptor Antagonists↗
PubMed1997

Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research.

The SEP identified priorities to support in future basic and clinical research and pointed out directions likely to result in advances against heart failure. The list is not intended to be all-encompassing and does not address, for example, exciting lines of work already under way. Rather, the recommendations are designed to point out gaps in current knowledge not being adequately addressed and highly promising new directions. Although the incidence of heart failure continues to grow, emerging lines of research provide hope that research advances will eventually lead to more effective treatment and ultimately to prevention. This research will be well served by bringing the latest multidisciplinary approaches and the best investigators to focus on the problems of heart failure. It is hoped the efforts of distinguished expert entities such as the task force and SEP will be a useful guide in addressing the needs of the biomedical community and assisting in its success.

Animals↗
PubMed1997

Endothelin and angiotensin II stimulation of Na+-H+ exchange is impaired in cardiac hypertrophy.

We compared the effects of endothelin-1 (ET-1) on intracellular pH, intracellular [Ca2+]i, and cell contraction in hypertrophied adult ventricular myocytes from ascending aortic banded rats and age-matched controls. Intracellular pH (pH(i)) was measured in individual myocytes with SNARF-1, and [Ca2+]i was measured with indo-1, simultaneous with cell motion. Experiments were performed at 36 degrees C in myocytes paced at 0.5 Hz in Hepes-buffered solution (pH(o) 7.40) containing 1.2 mM CaCl2. At baseline, calibrated pH(i), diastolic and systolic [Ca2+]i values, and the amplitude of cell contraction were similar in hypertrophied and control myocytes. Exposure of the control myocytes to 10 nM ET-1 caused an increase in the amplitude of cell contraction to 163+/-22% of baseline (P < 0.05), associated with intracellular alkalinization (pH(i) + 0.08+/-0.02 U, P < 0.05) and a slight increase in peak systolic [Ca2+]i (104+/-11% of baseline, P < 0.05). In contrast, in the hypertrophied myocytes, exposure to ET-1 did not increase the amplitude of cell contraction or cause intracellular alkalinization (-0.01+/-0.02 U, NS). Similar effects were observed in the hypertrophied and control myocytes in response to exposure to 10 nM angiotensin II. ET-1 also increased the rate of recovery from intracellular acidosis induced by the washout of NH4Cl in the control cells, but did not do so in the hypertrophied cells. In the presence of 10 microM 5-(N-ethyl-N-isopropyl)-amiloride, which inhibits Na+-H+ exchange, ET-1 did not cause a positive inotropic effect or intracellular alkalinization in control cells. The activation of protein kinase C by exposure to phorbol ester caused intracellular alkalinization and it increased the rate of recovery from intracellular acidification induced by an NH4Cl pulse in control cells but not in hypertrophied cells. ET-1, as well as angiotensin II, and phorbol ester, fail to stimulate forward Na+-H+ exchange in adult hypertrophied myocytes. These data suggest a defect in the coupling of protein kinase C signaling with Na+-H+ exchange in adult hypertrophied myocytes.

Amiloride↗
PubMed1997

The restriction of diffusion of cations at the external surface of cardiac myocytes varies between species.

In cardiac muscle sarcolemmal structures such as T-tubules, caveolae and negatively charged protein-polysaccharides may affect the rate of cation exchange on the external surface of the cells. To test this hypothesis, we examined the rate of external cation exchange in adult rabbit and rat ventricular myocytes using a rapid solution switcher to change the bulk external solution within 4 ms. To assess the rate of diffusion of monovalent cations, we increased [K+]o from 4.4 to 6.6 or 8.8 mM and measured the time required to achieve a stable membrane depolarization. In rat myocytes, the mean time to 90% depolarization (t90) was significantly longer than that in rabbit myocytes (137 and 64 ms, respectively) and the difference in t90 was not associated with the cell size. To assess the time course of exchange of external Ca2+, we rapidly exposed the myocytes to 0 Ca2+-2 mM EGTA solution at specific time points before action potentials or voltage clamp steps, and measured the rate of alteration of the normalized peak [Ca2+]i transient (Fluo-3) or Ca2+ current. Exposure to 0 Ca2+-2 mM EGTA solution caused a decline in the intracellular calcium transient. In rat myocytes, the rate of decline in the [Ca2+]i transient was much slower (t90 > 1500 ms, the time required for 90% decline) than for the rabbit (t90 = 295 ms). Also, the rate of decline in the Ca2+ current was prolonged in rat myocytes (t90 = 910 ms) compared with rabbit myocytes (t90 = 241 ms). These data indicate that there is a restricted space on the external surface of sarcolemma which limits diffusion of divalent cations more markedly than monovalent cations. The extent of this limitation of cation diffusion varies between species, and may have functional significance.

Animals↗
PubMed1996

Long-term angiotensin-converting enzyme inhibition with fosinopril improves depressed responsiveness to Ca2+ in myocytes from aortic-banded rats.

BACKGROUND: We have previously shown that long-term ACE inhibition with fosinopril prolongs survival and improves ventricular function despite persistent severe left ventricular pressure overload in ascending aortic-banded rats with left ventricular hypertrophy during the transition from compensation to failure. METHODS AND RESULTS: To study the cellular mechanism of the effects of long-term ACE inhibition on the modification of the transition to failure in pressure-overload hypertrophy, we measured simultaneous intracellular Ca2+ transients and myocyte shortening in isolated left ventricular myocytes from fosinopril-treated aortic-banded rats (n = 9), untreated aortic-banded rats (n = 9), and normal age-matched control rats (n = 10). Fosinopril therapy was begun 6 weeks after banding and was continued until week 21 after banding, when the animals were killed. Collagenase-dissociated myocytes loaded with indo 1-AM were paced at 3 Hz at 36 degrees C and superfused at [Ca2+]o of 0.6, 1.2, and 3.0 mmol/L. In myocytes from untreated aortic-banded rats, peak systolic [Ca2+]i was higher than in control myocytes, and the relationship between myocyte shortening and [Ca2+]i was depressed relative to control myocytes, implicating impaired responsiveness to Ca2+. Long-term fosinopril treatment improved both myocyte shortening and the relationship of shortening to [Ca2+]i (P < .05 versus myocytes from untreated aortic-banded rats). Maximal Ca(2+)-activated force was depressed in chemically skinned left ventricular fibers from untreated aortic-banded hypertrophied rats relative to age-matched controls but not in the fosinopril-treated aortic-banded rats. CONCLUSIONS: Long-term ACE inhibition improves responsiveness to Ca2+ in the presence of normalization of maximal Ca(2+)-activated force in aortic-banded rats subjected to persistent pressure overload. This may contribute to the favorable effects whereby ACE inhibition modifies the transition from compensated hypertrophy to failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Pericardial effusion in patients with cancer: outcome with contemporary management strategies.

OBJECTIVE: To investigate the clinical presentation and current management strategies of pericardial effusion in patients with malignancy. DESIGN: Retrospective single centre, consecutive observational study. SETTING: University hospital. PATIENTS: 93 consecutive patients with a past or present diagnosis of cancer and a pericardial effusion, including 50 with a pericardial effusion > 1 cm. RESULTS: Of the 50 patients with pericardial effusions > 1 cm, most had stage 4 cancer (64%), were symptomatic at the time of presentation (74%), and had right atrial collapse (74%). Twenty patients were treated conservatively (without pericardiocentesis) and were less symptomatic (55% v 87%, P = 0.012), had smaller pericardial effusions (1.5 (0.4) v 1.8 (0.5), P = 0.02), and less frequent clinical (10% v 40%, P = 0.02) and echocardiographic evidence of tamponade (40% v 97%, P < 0.001) than the 30 patients treated invasively with initial pericardiocentesis (n = 29) or pericardial window placement (n = 1). Pericardial tamponade requiring repeat pericardiocentesis occurred in 18 (62%) of 29 patients after a median of 7 days. In contrast, only four (20%) of 20 patients in the conservative group progressed to frank clinical tamponade and required pericardiocentesis (P = 0.005 v invasive group). The overall median survival was 2 months with a survival rate at 48 months of 26%. Survival, duration of hospital stay, and hospital charges were similar with both strategies. By multivariable analysis, the absence of symptoms was the only independent predictor of long-term survival (relative hazards ratio = 3.2, P = 0.05). Survival was similar in the 43 patients with cancer and pericardial effusions of < or = 1 cm. CONCLUSION: Asymptomatic patients with cancer and pericardial effusion can be managed conservatively with close follow up. In patients with symptoms or clinical cardiac tamponade, pericardiocentesis provides relief of symptoms but does not improve survival and has a high recurrence rate. Surgical pericardial windows or possibly percutaneous balloon pericardiotomy should be used for recurrences and should be considered for initial treatment.

Cardiac Tamponade↗
PubMed1995

Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy. Chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure.

BACKGROUND: Although chronic pressure overload may progress to left ventricular (LV) failure, the pathophysiology of this transition is not well understood. In addition, the effects of chronic angiotensin-converting enzyme (ACE) inhibition on this transition are largely undefined. METHODS AND RESULTS: To examine changes in LV structure and function during the transition to heart failure, rats with LV hypertrophy due to banding of the ascending aorta (LVH, n = 22) and age-matched sham-operated rats (n = 6) were studied 6, 12, and 18 weeks after aortic banding. Two-dimensionally guided transthoracic M-mode echocardiograms and transmitral Doppler spectra were recorded for assessment of LV geometry and systolic and diastolic functions. LVH rats were randomized to no treatment (n = 10) or treatment with the ACE inhibitor fosinopril (50 mg/kg per day, n = 12) after the baseline echocardiogram. Six weeks after banding, LVH rats had increased LV wall thickness with normal cavity dimensions and supranormal endocardial systolic shortening. However, midwall shortening was mildly depressed, and a restrictive diastolic filling pattern was present. After 18 weeks of untreated pressure overload, LV wall thickness was unchanged, but cavity dilation, a fall in endocardial shortening, and further deterioration of diastolic filling were evident. In contrast to untreated LVH rats, the fosinopril-treated rats showed no change in LV diastolic cavity dimension, and systolic and diastolic functions did not deteriorate or improved. Closed chest LV systolic pressures at 18 weeks were not different in LVH or LVH-fosinopril rats (197 versus 198 mm Hg), although end-diastolic pressure was higher in the untreated rats (18 versus 11 mm Hg). Calculated LV systolic wall stress was lower in fosinopril-treated than untreated LVH rats. The severity of LV diastolic filling abnormalities correlated strongly with operating LV chamber stiffness (r = .88, P < .0001). CONCLUSIONS: This model of pressure overload is characterized initially by concentric LV hypertrophy with compensated LV chamber performance; however, markedly abnormal diastolic filling is present. The transition from compensated hypertrophy to early failure is heralded by LV dilation, impairment of systolic function, and progression of the abnormalities in LV filling. Chronic ACE inhibition in rats with supravalvular aortic banding (1) does not change in vivo LV systolic pressure but prevents increased LV cavity size and increased LV wall stress and (2) attenuates impairment of (or improves) both systolic and diastolic functions. The effects of fosinopril could be explained in part by inhibition of an intracardiac renin-angiotensin system.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Angiotensin II-induced growth responses in isolated adult rat hearts. Evidence for load-independent induction of cardiac protein synthesis by angiotensin II.

Cardiac myocyte hypertrophy often occurs in response to both hemodynamic and neurohumoral factors. To study whether activation of the renin-angiotensin system by itself may induce a cardiac growth response, the acute effects of angiotensin II on cardiac protein synthesis were studied in isolated rat hearts. New protein synthesis in isolated buffer-perfused adult rat hearts was measured by incorporation of [3H]phenylalanine into cardiac proteins during a 3-hour perfusion protocol. Angiotensin II (1 x 10(-8) mol/L), administered alone or in combination with the alpha 1-blocker prazosin (1 x 10(-7) mol/L), stimulated protein synthesis in both ventricles. The rate of [3H]phenylalanine incorporation into cardiac proteins was 3.9-fold (P < .005) and 2.6-fold (P < .01) higher in angiotensin II-perfused (n = 6) than in vehicle-perfused (n = 6) left and right ventricles, respectively. The induction of new protein synthesis by angiotensin II was blocked by the angiotensin II type 1 (AT1) receptor antagonist losartan (1 x 10(-7) mol/L, n = 5). To study the pathways of angiotensin signal transduction, protein kinase C (PKC)-epsilon as well as cardiac c-fos and c-jun mRNA levels were analyzed. Angiotensin II (1 x 10(-8) mol/L, n = 20) resulted in a transient translocation of PKC-epsilon from the cytosol to the cellular membrane. However, compared with phorbol ester stimulation (phorbol 12-myristate 13-acetate [PMA], 1 x 10(-7) mol/L; n = 20), angiotensin II effects on PKC translocation were significantly less pronounced and required a more prolonged stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1995

Glycolytic inhibition: effects on diastolic relaxation and intracellular calcium handling in hypertrophied rat ventricular myocytes.

We tested the hypothesis that glycolytic inhibition by 2-deoxyglucose causes greater impairment of diastolic relaxation and intracellular calcium handling in well-oxygenated hypertrophied adult rat myocytes compared with control myocytes. We simultaneously measured cell motion and intracellular free calcium concentration ([Ca2+]i) with indo-1 in isolated paced myocytes from aortic-banded rats and sham-operated rats. There was no difference in either the end-diastolic or peak-systolic [Ca2+]i between control and hypertrophied myocytes (97 +/- 18 vs. 105 +/- 15 nM, 467 +/- 92 vs. 556 +/- 67 nM, respectively). Myocytes were first superfused with oxygenated Hepes-buffered solution containing 1.2 mM CaCl2, 5.6 mM glucose, and 5 mM acetate, and paced at 3 Hz at 36 degrees C. Exposure to 20 mM 2-deoxyglucose as substitution of glucose for 15 min caused an upward shift of end-diastolic cell position in both control (n = 5) and hypertrophied myocytes (n = 10) (P < 0.001 vs. baseline), indicating an impaired extent of relaxation. Hypertrophied myocytes, however, showed a greater upward shift in end-diastolic cell position and slowing of relaxation compared with control myocytes (delta 144 +/- 28 vs. 55 +/- 15% of baseline diastolic position, P < 0.02). Exposure to 2-deoxyglucose increased end-diastolic [Ca2+]i in both groups (P < 0.001 vs. baseline), but there was no difference between hypertrophied and control myocytes (218 +/- 38 vs. 183 +/- 29 nM, respectively). The effects of 2-deoxyglucose were corroborated in isolated oxygenated perfused hearts in which glycolytic inhibition which caused severe elevation of isovolumic diastolic pressure and prolongation of relaxation in the hypertrophied hearts compared with controls. In summary, the inhibition of the glycolytic pathway impairs diastolic relaxation to a greater extent in hypertrophied myocytes than in control myocytes even in well-oxygenated conditions. The severe impairment of diastolic relaxation induced by 2-deoxyglucose in hypertrophied myocytes compared with control myocytes cannot be explained by greater diastolic Ca2+ overload, which implicates an increase in myofilament Ca(2+)-responsiveness as a possible mechanism.

Adenosine Triphosphate↗