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H N Sabbah

Publications and source records attributed to H N Sabbah.

At least 19 recordsLinked to original sources
PubMed2001

Late sodium current is a novel target for amiodarone: studies in failing human myocardium.

V. A. Maltsev, H. N. Sabbah and A. I. Undrovinas. Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium. Journal of Molecular and Cellular Cardiology (2001) 33, 923-932. The authors recently reported the existence of a novel late Na(+)current (I(NaL)) in ventricular cardiomyocytes (VC) isolated from both normal and failing human hearts. Both in failing human and canine VC, partial block of I(NaL)normalized action potential (AP) duration and abolished early after depolarizations (EADs). The most recent computer simulation studies indicate a significant contribution of the persistent Na(+)current into the ion current balance on the plateau of VC AP as well as its important role in the dispersion of AP duration across the ventricular wall. The data thus indicate a possibility for I(NaL)to be a new therapeutic target. The present study tested a hypothesis that I(naL)could be a novel target for amiodarone (AMIO). Midmyocardial VC isolated from left ventricle of explanted failing human hearts were measured by a whole-cell clamp. I(NaL)was effectively blocked by AMIO in therapeutic concentrations, with IC(50)being 6.7+/-1.1 microM (mean+/-S.E.M., n=16 cells). At the same time, AMIO (5 microM ) produced almost no effect on the transient Na(+)current (IC(50)=87+/-28 microM, n=8). AMIO significantly shifted the steady-state inactivation (SSI) curve of I(NaL)towards more negative potentials and accelerated decay time course in a dose-dependent manner. At 5 microM, AMIO shifted SSI by 21+/-3 mV (n=7) and decreased the decay time constant from 0.67+/-0.05 s to 0.37+/-0.04 s (n=5, P<0.004). Evaluation of AMIO binding to different Na(+)channel (NaCh) states by means of mathematical models describing dose-dependent SSI shift and decay acceleration was consistent with an action that AMIO blocks NaCh preferentially in inactivated and activated states rather than in resting state. The authors conclude that the late Na(+)current is effectively blocked by AMIO and represents a new target for the drug in patients with chronic heart failure (HF).

Amiodarone↗
PubMed2001

Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure.

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered 'on demand' and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic(trade mark) signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca(2+) transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

Animals↗
PubMed2001

Apoptosis in heart failure: a real problem?

Progressive left ventricular (LV) dysfunction is a characteristic feature of the failing heart. The mechanism or mechanisms that drive this progression are not known. In recent years, we advanced a working hypothesis that progressive LV dysfunction in heart failure results, in part, from ongoing loss of cardiomyocytes. More recently evidence emerge based on studies in animals with heart failure and in explanted failed human hearts that ongoing cardiomyocyte death through apoptosis occurs in heart failure, a finding that supports the original hypothesis. While these findings created considerable enthusiasm, some skepticism remains even today as to whether cardiomyocyte apoptosis plays an important role in the progression of heart failure. The evidence garnered over the past few years, when considered in aggregate, does favors apoptosis as a key culprit in the progression of the heart failure. Nonetheless, additional key studies are needed to determine if direct inhibition of apoptosis with specific pharmacologic probes prevents progressive LV dysfunction in heart failure. Only then can one fully appreciate the importance of cardiomyocyte apoptosis in the pathophysiology of heart failure.

Animals↗
PubMed2000

Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure.

OBJECTIVES: The purpose of this study was to determine if therapy with beta-blockade is associated with reduced cardiomyocyte apoptosis. BACKGROUND: Chronic treatment with beta-adrenergic blocking agents has been shown to improve left ventricular (LV) ejection fraction and attenuate progressive LV remodeling in heart failure (HF). Cardiomyocyte apoptosis has also been shown to occur in the failing heart. METHODS: Moderate HF was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to three months therapy with metoprolol (MET, 25 mg twice daily, n = 7) or to no therapy at all (n = 7). At the end of three months, dogs were sacrificed, and nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in LV tissue using the TUNEL assay. The number of cardiomyocytes with positive nDNAf labeling per 1,000 was quantified in LV regions bordering old infarcts and in regions remote from infarcts. Endonuclease activity and expression of the antiapoptotic protein Bcl-2 and the proapoptotic proteins Bax and caspase-3 were also evaluated in LV tissue. RESULTS: The number of nDNAf events per 1,000 cardiomyocytes was lower in dogs treated with MET compared with untreated dogs with HF in the border regions (0.35 +/- 0.07 vs. 5.32 +/- 0.77, p < 0.001) as well as the remote regions (0.07 +/- 0.05 vs. 0.39 +/- 0.12, p < 0.05). Endonuclease activity was also significantly lower in MET-treated compared with untreated dogs (25 +/- 3 vs. 37 +/- 2 ng [3H]DNA rendered soluble/min/mg protein). Western blotting for Bcl-2, Bax and caspase-3 showed increased expression of Bcl-2, decreased expression of caspase-3 and no change in Bax in MET-treated compared with untreated dogs. CONCLUSIONS: Chronic therapy with MET attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of ongoing cardiomyocyte loss through apoptosis may be one mechanism through which beta-blockers elicit their benefits in HF.

Adrenergic beta-Antagonists↗
PubMed2000

Effects of dopamine beta-hydroxylase inhibition with nepicastat on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.

BACKGROUND: Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF). METHODS AND RESULTS: Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus-arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86+/-20 versus 13+/-14 pg/mL, P:<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28+/-4 and 39+/-17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3+/-10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not CONCLUSIONS: In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.

Animals↗
PubMed2000

Abnormal mitochondrial respiration in failed human myocardium.

Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced organelle size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.

Adult↗
PubMed2000

Passive epicardial containment prevents ventricular remodeling in heart failure.

BACKGROUND: We examined the effects of passive containment of the cardiac ventricles with a surgically placed epicardial prosthetic wrap on indexes of left ventricular (LV) remodeling in dogs with heart failure. METHODS: Heart failure (LV ejection fraction 30% to 40%) was produced in 12 dogs by intracoronary microembolization. Six dogs underwent mid-sternotomy and pericardiotomy with placement of a preformed-knitted polyester device (Acorn Cardiac Support Device [CSD], Acorn Cardiovascular, Inc, St. Paul, MN) snugly around the ventricles and anchored to the atrioventricular groove. Six dogs did not undergo surgery and served as controls. Dogs were followed for 3 months prior to sacrifice. RESULTS: In controls, LV end-diastolic volume increased after 3 months (67 +/- 12 versus 83 +/- 8 ml; p = 0.04), while in CSD-treated dogs, it decreased (68 +/- 10 versus 61 +/- 10 ml; p = 0.002). CSD-containment of LV size was associated with increased LV systolic fractional area of shortening, while in controls, fractional area of shortening decreased. CSD-treated dogs also showed amelioration of myocyte hypertrophy and attenuation of interstitial fibrosis compared to controls. CONCLUSIONS: In dogs with heart failure, passive epicardial containment of the ventricles with the Acorn CSD ameliorates LV remodeling and improves LV systolic function.

Animals↗
PubMed2000

Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure.

OBJECTIVES: In this study, we examined the effects of long-term therapy with bosentan on the progression of LV dysfunction and remodeling in dogs with moderate HF. BACKGROUND: Acute intravenous administration of bosentan, a mixed endothelin-1 type A and type B receptor antagonist, was shown to improve left ventricular (LV) function in patients and dogs with heart failure (HF). METHODS: Left ventricular dysfunction was induced by multiple, sequential intracoronary microembolizations in 14 dogs. Embolizations were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to three months of therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all (control, n = 7). RESULTS: In untreated dogs, EF decreased from 35 +/- 1% before initiating therapy to 29 +/- 1% at the end of three months of therapy (p = 0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 71 +/- 3 vs. 84 +/- 8 ml, p = 0.08; ESV: 46 +/- 2 vs. 60 +/- 6 ml, p = 0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34 +/- 2% before initiating therapy to 39 +/- 1% at the end of three months of therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 +/- 3 vs. 71 +/- 4 ml, p = 0.05; ESV: 48 +/- 2 vs. 43 +/- 3 ml, p = 0.01). Furthermore, compared with untreated dogs, dogs treated with bosentan showed significantly less LV cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis. CONCLUSIONS: In dogs with moderate HF, long-term therapy with bosentan prevents the progression of LV dysfunction and attenuates LV chamber remodeling. The findings support the use of mixed endothelin-1 receptor antagonists as adjuncts to the long-term treatment of HF.

Animals↗
PubMed2000

Hemodynamic effects of a novel sodium channel activator in dogs with chronic heart failure.

The use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure (HF) is limited by proarrhythmic and positive chronotropic effects. In the present study, we compared the hemodynamic effects of intravenous LY366634 (LY), a Na+ channel enhancer, with dobutamine (DOB), in eight dogs with HF produced by intracoronary microembolizations. We also determined whether intravenous LY has synergistic effects when combined with digoxin. After baseline measurements, infusion of DOB was initiated at a dose of 2 micrograms/kg/min and increased until an increase of heart rate (HR) 30% of baseline or ventricular arrhythmias developed. Once hemodynamics returned to baseline, LY was infused at a dose of 2 micrograms/kg/min and increased until the LV fractional area of shortening (FAS), determined echocardiographically, reached a similar level as with DOB. Both drugs increased FAS equivalently compared to baseline (DOB, 24 +/- 3 to 47 +/- 2; LY, 27 +/- 2 to 46 +/- 2%). DOB increased HR from 78 +/- 4 min-1 at baseline to 107 +/- 7 min-1 at maximal dose (p < 0.05) and provoked serious arrhythmias in one dog. In contrast, LY infusion did not increase HR (82 +/- 7 vs. 80 +/- 8 min-1) or elicit arrhythmias. After 1 week of oral digoxin, dogs were infused again with LY. A lower dose of LY was needed to achieve the same increase in FAS compared to LY alone, but this was not statistically significant. The combination of LY with digoxin did not increase HR or evoke arrhythmias. We conclude that in dogs with HF, intravenous LY improves LV function to the same extent as DOB without increasing HR or evoking ventricular arrhythmias. The combination of LY with digoxin elicits a safe positive inotropic response.

Animals↗
PubMed2000

Cell death, tissue hypoxia and the progression of heart failure.

An important feature of heart failure is the progressive deterioration of left ventricular function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known. We and others have advanced the hypothesis that this hemodynamic deterioration results from progressive intrinsic contractile dysfunction of viable cardiomyocytes and/or from ongoing loss of cardiomyocytes. This review will focus on the concept of ongoing cardiac myocyte loss as a contributing factor to the progression of left ventricular dysfunction that characterizes the heart failure state. Specifically, the discussion will center on apoptosis or "programmed cell death" as a potential mediator of cardiomyocyte loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Studies have also shown that cardiomyocyte apoptosis occurs following acute myocardial infarction, in the hypertrophied heart as well as in the aging heart; conditions frequently associated with the development of failure. While available data support the existence of myocyte apoptosis in the failing heart, lacking are studies which address the importance of myocyte apoptosis in the progression of LV dysfunction. As part of this discussion, we will address this issue and construct a case in support of a concept that the failing myocardium is subject to regional hypoxia, an abnormality that can potentially trigger cardiomyocyte apoptosis. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if exact physiologic and molecular factors that trigger apoptosis in the heart can be identified, the stage will be set for the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.

Animals↗
PubMed2000

Effect of delay on racial differences in thrombolysis for acute myocardial infarction.

OBJECTIVE: To analyze the effect of delay times on racial differences in thrombolysis for acute myocardial infarction. BACKGROUND: Lower rates of thrombolytic therapy in blacks with acute myocardial infarction have recently been reported, but the reasons for this disparity are unknown. We hypothesized that lower rates of thrombolysis are caused by delay in presentation after symptom onset. METHODS: From November 1992 through November 1996, consecutive patients with a first acute myocardial infarction presenting to a large, urban teaching hospital were prospectively enrolled. Delay times were determined retrospectively from review of medical records. Patients were prospectively followed up for in-hospital cardiac events and death. A multivariable regression model was built to relate presentation times and other variables to thrombolysis administration. RESULTS: A total of 395 patients were included in the study, of which 33% were black. Symptom onset to emergency department presentation and door-to-needle times were significantly longer in blacks. Thrombolysis was administered significantly less often in blacks compared with whites (47% vs 68%, P =.001). Black race and age above 60 years were independently associated with delayed presentation and prolonged door-to-needle times. Black race, time to presentation, and non-Q-wave myocardial infarction were independently associated with not receiving thrombolysis. In-hospital mortality rates were similar in both groups. CONCLUSIONS: Blacks presented later than whites for first acute myocardial infarction. Late arrival strongly influenced the rate of thrombolysis administration. Lower rates of thrombolysis and prolonged door-to-needle times were apparent in blacks after adjustment for delay times and other clinical factors, a finding that merits further investigation.

Adult↗
PubMed1999

Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart.

BACKGROUND: Increased expression of Ca2+-sensitive protein kinase C (PKC) isoforms may be important markers of heart failure. Our aim was to determine the relative expression of PKC-beta1, -beta2, and -alpha in failed and nonfailed myocardium. METHODS AND RESULTS: Explanted hearts of patients in whom dilated cardiomyopathy or ischemic cardiomyopathy was diagnosed were examined for PKC isoform content by Western blot, immunohistochemistry, enzymatic activity, and in situ hybridization and compared with nonfailed left ventricle. Quantitative immunoblotting revealed significant increases of >40% in PKC-beta1 (P<0.05) and -beta2 (P<0.04) membrane expression in failed hearts compared with nonfailed; PKC-alpha expression was significantly elevated by 70% in membrane fractions (P<0.03). PKC-epsilon expression was not significantly changed. In failed left ventricle, PKC-beta1 and -beta2 immunostaining was intense throughout myocytes, compared with slight, scattered staining in nonfailed myocytes. PKC-alpha immunostaining was also more evident in cardiomyocytes from failed hearts with staining primarily localized to intercalated disks. In situ hybridization revealed increased PKC-beta1 and -beta2 mRNA expression in cardiomyocytes of failed heart tissue. PKC activity was significantly increased in membrane fractions from failed hearts compared with nonfailed (1021+/-189 versus 261+/-89 pmol. mg-1. min-1, P<0.01). LY333531, a selective PKC-beta inhibitor, significantly decreased PKC activity in membrane fractions from failed hearts by 209 pmol. min-1. mg-1 (versus 42.5 pmol. min-1. mg-1 in nonfailed, P<0.04), indicating a greater contribution of PKC-beta to total PKC activity in failed hearts. CONCLUSIONS: In failed human heart, PKC-beta1 and -beta2 expression and contribution to total PKC activity are significantly increased. This may signal a role for Ca2+-sensitive PKC isoforms in cardiac mechanisms involved in heart failure.

Adolescent↗
PubMed1999

Reduced sarcoplasmic reticulum Ca(2+)-uptake and expression of phospholamban in left ventricular myocardium of dogs with heart failure.

The purpose of this study was to examine the sarcoplasmic reticulum (SR) Ca(2+)-uptake and the expression of phospholamban (PLB) and Ca(2+)-ATPase (CAA) in left ventricular (LV) and right ventricular (RV) myocardium of 6 normal (NL) dogs and 6 dogs with chronic heart failure (HF). In addition, gene expression of PLB and CAA was also examined in LV myocardium of NL and HF dogs. HF (LV ejection fraction 23+/-2%) was produced by multiple sequential intracoronary microembolizations. Oxalate-dependent Ca(2+)-uptake was measured in isolated membrane vesicles. Using specific dog myocardial monoclonal antibody, the expression of CAA, PLB and calsequestrin (CSQ) were measured in sodium dodecyl sulfate extract prepared from LV and RV tissue. Steady-state mRNA levels were determined by Northern hybridization using specific cDNA clones of PLB, CAA, CSQ, and glyceraldehyde-3-phosphate dehydrogenase (GADPH), a house keeping gene. SR Ca(2+)-uptake of NL and HF dogs increased with increasing Ca(2+)concentrations and reached a plateau at 3 microm in both LV and RV. Total capacity (134+/-9 v 224+/-10 nmol(45)Ca/mg protein/10 min, P<0.05) and maximal velocity (15+/-2 v 2 nmol(45)Ca/mg protein/min, P<0.05) of the SR to sequester Ca(2+)was significantly lower in LV myocardium of HF dogs compared to NL, whereas the Hill coefficient and the affinity of the Ca(2+)-pump for Ca(2+)were unchanged. LV tissue levels of the PLB and CAA, normalized to noncollagen protein or to CSQ and the PLB and CAA mRNA levels, normalized to CSQ or GADPH mRNA, were also significantly lower in HF dogs compared to NL. In RV myocardial tissue, no significant differences in total capacity of SR to sequester Ca(2+), maximal velocity of SR Ca(2+)-uptake, the affinity and Hill Coefficient of the Ca(2+)-pump for Ca(2+), or tissue levels of PLB and CAA were observed between NL dogs compared to HF dogs. We conclude that SR Ca(2+)-uptake and SR PLB and CAA protein and gene expression levels are reduced in LV myocardium of dogs with chronic HF. These abnormalities can lead to Ca(2+)-overload and subsequent global LV dysfunction.

Animals↗
PubMed1999

Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current.

We previously showed that a canine model of chronic heart failure (HF) produced by multiple coronary microembolizations manifests ventricular arrhythmias similar to those observed in patients with chronic HF. In the present study, we used single canine cardiomyocytes isolated from the left ventricle (LV) of normal dogs (n = 13) and dogs with HF (n = 15) to examine the cellular substrate of these arrhythmias. Action potentials (APs) and ion currents were measured by perforated and whole cell patch clamp, respectively. We found prolonged APs and alterations of AP duration resulting in early afterdepolarizations (EADs) at the low pacing rates of 0.5 Hz and 0.2 Hz. Na+ channel blockers saxitoxin (STX, 100 nM) and lidocaine (90 microM) reduced AP duration dispersion and abolished EADs in HF cardiomyocytes. The steady-state current (Iss)-voltage relation, in the voltage range from -25 mV to 25 mV analogous to the AP plateau level, was significantly shifted inward in HF cardiomyocytes. STX and lidocaine shifted the Iss-voltage relationship in an outward direction. The shifts produced by both drugs was significantly greater in cardiomyocytes of dogs with HF, indicating an increase in inward current. In the experimental configuration in which K+ currents were blocked, the density of the steady-state Ca2+ current (ICa) was found to decrease in HF cardiomyocytes by approximately 33%. In contrast, the density of the steady-state Na+ current (INa) significantly (P < 0.01) increased in HF cardiomyocytes (0.17 +/- 0.06 pA/pF) compared with normal cells (0.08 +/- 0.02 pA/pF). The relative contribution of INa to the net inward current was greater in HF cardiomyocytes, as evident from the increased ratio of INa/ICa (from 0.22 to 0.68). These observation support a hypothesis that anomalous repolarization of HF cardiomyocytes is due, at least in part, to an increased steady-state inward Na+ current.

Animals↗
PubMed1999

Clinical predictors of heart failure in patients with first acute myocardial infarction.

BACKGROUND: The occurrence of heart failure associated with an acute myocardial infarction has a strong adverse effect on long-term morbidity and mortality. The prediction and prevention of heart failure could influence these adverse events. METHODS AND RESULTS: We studied 483 consecutive patients who had their first acute myocardial infarction and who were admitted within 24 hours of the onset of symptoms. Heart failure was defined as the presence of pulmonary rales or an S3 gallop, or the presence of alveolar or interstitial edema by radiograph. Baseline demographic data, determination of peak creatine phosphokinase level, echocardiographic left ventricular ejection fraction, blood pressure, and pulse were obtained. Heart failure occurred in 41.6% (201 of 483) of the patients. We observed a bimodal occurrence of heart failure with an early occurrence at admission in 4% (20 of 483) followed by a second increase beginning after the fourth day of admission in 39% of the remaining patients (181 of 463). Predictors of early heart failure were older age, diabetes mellitus, or previous cardiac symptoms, whereas the predictors of heart failure after the fourth day included the same demographic predictors in addition to a history of hypertension, male sex, increased peak creatine phosphokinase level and heart rate, and decrease in left ventricular ejection fraction. In-hospital death occurred in 5.3% compared with 1.4% (P =.012) in patients who did and did not have heart failure, respectively. The occurrence of heart failure during hospital admission also adversely affected the 18-month follow-up, with 14.9% deaths in the patients with heart failure and 6.4% in those without heart failure (P =.002). CONCLUSION: Heart failure is frequently associated with acute myocardial infarction and occurs with a bimodal distribution and is associated with increased risk of death during hospitalization and during 18 months of follow-up. Predictors of early heart failure include previous medical conditions and age. The second peak occurrence can be predicted by similar characteristics in addition to increased peak creatine phosphokinase level, decreased left ventricular ejection fraction, and increased heart rate.

Aged↗
PubMed1999

Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure.

The objective of the present study was to determine the effects of early long-term monotherapy with the angiotensin II AT1-receptor antagonist valsartan on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Studies were performed in 30 dogs with moderate HF produced by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction was 30-40%. Two weeks after the last embolization, dogs were randomized to 3 mo of oral therapy with low-dose valsartan (400 mg twice daily, n = 10), to high-dose valsartan (800 mg twice daily, n = 10), or to no treatment at all (control, n = 10). Treatment with valsartan significantly reduced mean aortic pressure and LV end-diastolic pressure compared with control. In untreated dogs, LV ejection fraction decreased (37 +/- 1 vs. 29 +/- 1%, P = 0.001) and end-systolic volume (ESV) and end-diastolic volume (EDV) increased (81 +/- 5 vs. 92 +/- 5 ml, P < 0.001; 51 +/- 3 vs. 65 +/- 3 ml, P = 0.001, respectively) after 3 mo of follow-up compared with those levels before follow-up. In dogs treated for 3 mo with low-dose valsartan, ejection fraction was preserved (37 +/- 1 vs. 38 +/- 2%, pretreatment vs. posttreatment) as was ESV but not EDV. In dogs treated for 3 mo with high-dose valsartan, ejection fraction decreased (35 +/- 1 vs. 31 +/- 2%, P = 0.02) and ESV and EDV increased in a manner comparable to those levels in controls. Valsartan had no significant effects on cardiomyocyte hypertrophy or on the extent of interstitial fibrosis. We conclude that, for dogs with moderate HF, early long-term therapy with the AT1-receptor blocker valsartan decreases preload and afterload but has only limited benefits in attenuating the progression of LV dysfunction and chamber remodeling.

Angiotensin Receptor Antagonists↗
PubMed1999

The cellular and physiologic effects of beta blockers in heart failure.

Enhanced and sustained cardiac adrenergic drive occurs in heart failure (HF) and contributes, in part, to the progression of left ventricular (LV) dysfunction and remodeling that are characteristic of this disease state. Enhanced sympathetic drive in HF can lead to downregulation and desensitization of cardiac beta-adrenergic receptors with a consequent impairment of myocardial reserve and exercise tolerance. This sympathoadrenergic maladaptation can also lead to cellular abnormalities in the failing heart, manifested by defects in calcium handling of the sarcoplasmic reticulum, by defects in myocardial energetics, and by ongoing loss of cardiomyocytes through necrosis or apoptosis. Chronic treatment with beta blockers in patients with HF and in animals with experimentally induced HF has been shown to reverse, prevent, or, at the least, arrest many, if not all, of these adverse processes. Beta blockers improve function of the failing LV, prevent or reverse progressive LV dilation, chamber sphericity, and hypertrophy, and consequently have positive impact on cardiac remodeling. Beta blockers also reduce heart rate and LV wall stress, leading to reduced myocardial oxygen consumption, a clear benefit to the failing heart. Beta blockers can also improve the intrinsic contractile function of cardiomyocytes and have also been shown to improve myocardial energetics in HF, possibly through desirable changes in substrate utilization. Recent studies from our laboratories have also shown that beta blockers can attenuate cardiomyocyte apoptosis in HF. These benefits provide strong reinforcement to the clinical findings that beta blockers are highly beneficial for the management of patients with chronic HF and, when properly used, afford unequivocal reductions in mortality and morbidity in this patient population. At present, there is general agreement that increased cardiac sympathetic drive occurs in HF and may potentially be an important contributor to the progression of LV dysfunction and chamber remodeling that is characteristic of this disease state. Experimental studies in animal models of HF as well as clinical studies in patients with HF have suggested that chronic therapy with beta blockade is effective in preventing the progression of LV dysfunction and remodeling, the latter evidenced by reversal and/or prevention of progressive LV dilation and chamber sphericity. Results of recent multicenter clinical trials support these findings and have made it abundantly clear that long-term therapy with beta blockade inhibits clinical progression and has a major impact on mortality and morbidity in patients with HF that is at least as favorable, if not better, than that observed with angiotensin-converting enzyme (ACE) inhibitors. Beta blockers improve mortality and morbidity in HF and also improve LV ejection fraction (EF), a beneficial feature that, until recently, has only been attributed to positive inotropic agents.

Adrenergic beta-Antagonists↗