Chronic Ca2+/Calmodulin-Dependent Protein Kinase II Inhibition Rescues Advanced Heart Failure.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is upregulated in congestive heart failure (CHF), contributing to electrical, structural, and functional remodeling. CaMKII inhibition is known to improve CHF, but its direct cardiac effects in CHF remain unclear. We hypothesized that CaMKII inhibition improves cardiomyocyte function, [Ca2+]i regulation, and ß-adrenergic reserve, thus improving advanced CHF. In a 16-week study, we compared plasma neurohormonal levels and left ventricular (LV)- and myocyte-functional and calcium transient ([Ca2+]iT) responses in male Sprague-Dawley rats (10/group) with CHF induced by isoproterenol (170 mg/kg sq for 2 days). In rats with CHF, we studied the effects of the CaMKII inhibitor KN-93 or its inactive analog KN-92 (n = 4) (70 µg/kg per day, mini-pump) for 4 weeks. Compared with controls, isoproterenol-treated rats had severe CHF with 5-fold-increased plasma norepinephrine and about 50% decreases in ejection fraction (EF) and LV contractility [slope of LV end-systolic pressure-LV end-systolic volume relation (EES)] but increased time constant of LV relaxation (τ). They also showed significantly reduced myocyte contraction [maximum rate of myocyte shortening (dL/dtmax)], relaxation (dL/dtmax), and [Ca2+]iT Isoproterenol superfusion caused significantly fewer increases in dL/dtmax and [Ca2+]iT KN-93 treatment prevented plasma norepinephrine elevation, with increased basal and acute isoproterenol-stimulated increases in EF and EES and decreased τ in CHF. KN-93 treatment preserved normal myocyte contraction, relaxation, [Ca2+]iT, and ß-adrenergic reserve, whereas KN-92 treatment failed to improve LV and myocyte function, and plasma norepinephrine remained high in CHF. Thus, chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system, restoring normal LV and cardiomyocyte basal and ß-adrenergic-stimulated contraction, relaxation, and [Ca2+]iT, thereby playing a rescue role in advanced CHF. SIGNIFICANCE STATEMENT: We investigated the therapeutic efficacy of late initiation of chronic Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition on progression of advanced congestive heart failure (CHF). Chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system and restored normal intrinsic cardiomyocyte basal and ß-adrenergic receptor-stimulated relaxation, contraction, and [Ca2+]i regulation, leading to reversal of CHF progression. These data provide new evidence that CaMKII inhibition is able and sufficient to rescue a failing heart, and thus cardiac CaMKII inhibition is a promising target for improving CHF treatment.

Chronic B-Type Natriuretic Peptide Therapy Prevents Atrial Electrical Remodeling in a Rabbit Model of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is an important and growing clinical problem. Current pharmacological treatments are unsatisfactory. Electrical remodeling has been identified as one of the principal pathophysiological mechanisms that promote AF, but there are no effective therapies to prevent or correct electrical remodeling in patients with AF. In AF, cardiac production and circulating levels of B-type natriuretic peptide (BNP) are increased. However, its functional significance in AF remains to be determined. We assessed the hypotheses that chronic BNP treatment may prevent the altered electrophysiology in AF, and preventing AF-induced activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) may play a role. METHODS AND RESULTS: Forty-four rabbits were randomly divided into sham, rapid atrial pacing (RAP at 600 beats/min for 3 weeks), RAP/BNP, and sham/BNP groups. Rabbits in the RAP/BNP and sham/BNP groups received subcutaneous BNP (20 µg/kg twice daily) during the 3-week study period. HL-1 cells were subjected to rapid field stimulation for 24 hours in the presence or absence of BNP, KN-93 (a CaMKII inhibitor), or KN-92 (a nonactive analog of KN-93). We compared atrial electrical remodeling-related alterations in the ion channel/function/expression of these animals. We found that only in the RAP group, AF inducibility was significantly increased, atrial effective refractory periods and action potential duration were reduced, and the density of ICa, L and Ito decreased, while IK1 increased. The changes in the expressions of Cav1.2, Kv4.3, and Kir2.1 and currents showed a similar trend. In addition, in the RAP group, the activation of CaMKIIδ and phosphorylation of ryanodine receptor 2 and phospholamban significantly increased. Importantly, these changes were prevented in the RAP/BNP group, which were further validated by in vitro studies. CONCLUSIONS: Chronic BNP therapy prevents atrial electrical remodeling in AF. Inhibition of CaMKII activation plays an important role to its anti-AF efficacy in this model.

Effect of Age, Estrogen Status, and Late-Life GPER Activation on Cardiac Structure and Function in the Fischer344×Brown Norway Female Rat.

Age-associated changes in cardiac structure and function, together with estrogen loss, contribute to the progression of heart failure with preserved ejection fraction in older women. To investigate the effects of aging and estrogen loss on the development of its precursor, asymptomatic left ventricular diastolic dysfunction, echocardiograms were performed in 10 middle-aged (20 months) and 30 old-aged (30 months) female Fischer344×Brown-Norway rats, 4 and 8 weeks after ovariectomy (OVX) and sham procedures (gonads left intact). The cardioprotective potential of administering chronic G1, the selective agonist to the new G-protein-coupled estrogen receptor (GPER), was further evaluated in old rats (Old-OVX+G1) versus age-matched, vehicle-treated OVX and gonadal intact rats. Advanced age and estrogen loss led to decreases in myocardial relaxation and elevations in filling pressure, in part, due to reductions in phosphorylated phospholamban and increases in cardiac collagen deposition. Eight weeks of G-protein-coupled estrogen receptor activation in Old-OVX+G1 rats reversed the adverse effects of age and estrogen loss on myocardial relaxation through increases in sarcoplasmic reticulum Ca2+ ATPase expression and reductions in interstitial fibrosis. These findings may explain the preponderance of heart failure with preserved ejection fraction in older postmenopausal women and provide a promising, late-life therapeutic target to reverse or halt the progression of left ventricular diastolic dysfunction.

ß3-Adrenoceptor Impairs Mitochondrial Biogenesis and Energy Metabolism During Rapid Atrial Pacing-Induced Atrial Fibrillation.

BACKGROUND: The ß3-adrenoceptor (ß3-AR) is implicated in cardiac remodeling. Since metabolic dysfunction due to loss of mitochondria plays an important role in heart diseases, we examined the effects of ß3-AR on mitochondrial biogenesis and energy metabolism in atrial fibrillation (AF). METHODS: Atrial fibrillation was created by rapid atrial pacing in adult rabbits. Rabbits were randomly divided into 4 groups: control, pacing (P7), ß3-AR antagonist (L748337), and ß3-AR agonist (BRL37344) groups. Atrial effective refractory period (AERP) and AF induction rate were measured. Atrial concentrations of adenine nucleotides and phosphocreatine were quantified through high-performance liquid chromatography. Mitochondrial DNA content was determined. Real-time polymerase chain reaction and Western blot were used to examine the expression levels of signaling intermediates related to mitochondrial biogenesis. RESULTS: After pacing for 7 days, ß3-AR was significantly upregulated, AERP was reduced, and the AF induction rate was increased. The total adenine nucleotides pool was significantly reduced due to the decrease in adenosine triphosphate (ATP). The P7 group showed decreased activity of F0F1-ATPase. Mitochondrial DNA content was decreased and mitochondrial respiratory chain subunits were downregulated after pacing. Furthermore, expression of transcription factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam), was lower in the P7 group in response to ß3-AR activation. Further stimulation of ß3-AR with BRL37344 exacerbated these effects, together with a significant decrease in the levels of phosphocreatine. In contrast, inhibition of ß3-AR with L748337 partially restored mitochondrial biogenesis and energy metabolism of atria in the paced rabbits. CONCLUSION: The activation of ß3-AR contributes to atrial metabolic remodeling via transcriptional downregulation of PGC-1α/NRF-1/Tfam pathway that are involved in mitochondrial biogenesis, which ultimately perturbs mitochondrial function in rapid pacing-induced AF. The ß3-AR is therefore a potential novel therapeutic target for the treatment or prevention of AF.

ß3-adrenoceptor mediates metabolic protein remodeling in a rabbit model of tachypacing-induced atrial fibrillation.

BACKGROUND: The beta 3-adrenoceptor (ß3-AR) is closely associated with energy metabolism. This study aimed to explore the role of ß3-AR in energy remodeling in a rabbit model of pacing-induced atrial fibrillation (AF). METHODS: Rabbits with a sham-operation or pacing-induced AF were used for this study, and the latter group was further divided into three subgroups: 1) the pacing group, 2) the ß3-AR agonist (BRL37344)-treated group, and 3) the ß3-AR antagonist (SR59230A)-treated group. Atrial electrogram morphology and surface ECG were used to monitor the induction of AF and atrial effective refractory period (AERP). RT-PCR and western blot (WB) were used to show alterations in ß3-AR and metabolic-related protein. RESULTS: RT-PCR and WB results showed that ß3-AR was significantly upregulated in the pacing group, and that it corresponded with high AF inducibility and significantly decreased AERP200 and ATP production in this group. Inhibition of ß3-AR decreased the AF induction rate, reversed AERP200 reduction, and restored ATP levels in the AF rabbits. Further activation of ß3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. Periodic acid Schiff (PAS) and Oil Red O staining showed ß3-AR-dependent glycogen and lipid droplet accumulation in cardiac myocytes with AF. Glucose transporter-4 (GLUT-4) and CD36, key transporters of glucose and fatty acids, were downregulated in the pacing group. Expression of carnitine-palmitoyltransferase I (CPT-1), a key regulator in fatty acid metabolism, was also significantly downregulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of ß3-AR. Furthermore, key regulators of metabolism, peroxisome proliferator-activated receptor-α (PPARα) and PPAR co-activator (PGC-1α) can be regulated by pharmacological intervention of the ß3-AR. CONCLUSIONS: ß3-AR is involved in metabolic protein remodeling in AF. PPARα/PGC-1α signaling pathway might be the relevant down-stream molecular machinery in response to AF-induced activation of ß3-AR. ß3-AR might be a novel target in AF treatment.

Levosimendan restores the positive force-frequency relation in heart failure.

Frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise. In heart failure (HF), this positive force-frequency relation is impaired, and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. A myofilament Ca(2+) sensitizer, levosimendan, has been shown to improve exercise tolerance in HF. This may be due to its beneficial actions on the force-frequency relation and LV-arterial coupling (end-systolic elastance/arterial elastance, E(ES)/E(A)). We assessed the effects of therapeutic doses of levosimendan on the force-frequency relation and E(ES)/E(A) in nine conscious dogs after pacing-induced HF using pressure-volume analysis. Before HF, pacing tachycardia increased E(ES), shortened τ, and did not impair E(ES)/E(A) and mechanical efficiency (stroke work/pressure-volume area, SW/PVA). In contrast, after HF, pacing at 140, 160, 180, and 200 beat/min (bpm) produced smaller a increase of E(ES) or less shortening of τ, whereas E(ES)/E(A) (from 0.56 at baseline to 0.42 at 200 bpm) and SW/PVA (from 0.52 at baseline to 0.43 at 200 bpm) progressively decreased. With levosimendan, basal E(ES) increased 27% (6.2 mmHg/ml), τ decreased 11% (40.8 ms), E(ES)/E(A) increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, E(ES) further increased by 23%, 37%, 68%, and 89%; τ decreased by 9%, 12%, 15%, and 17%; and E(ES)/E(A) was augmented by 11%, 16%, 31%, and 33%, incrementally, with pacing rate. SW/PVA was improved (0.61 to 0.64). In conclusion, in HF, treatment with levosimendan restores the normal positive LV systolic and diastolic force-frequency relation and prevents tachycardia-induced adverse effect on LV-arterial coupling and mechanical efficiency.

Up-regulation and functional effect of cardiac ß3-adrenoreceptors in alcoholic monkeys.

BACKGROUND: Recent studies link altered cardiac beta-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of beta(3)-AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac beta(3)-AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. METHODS: We compared myocyte beta(3)- and beta(1)-AR expression and myocyte contractile ([Ca(2+)](i)), transient ([Ca(2+)](iT)), and Ca(2+) current (I(Ca,L)) responses to beta- and beta(3)-AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self-administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 +/- 0.2 and 3.3 +/- 0.2 g/kg/d, respectively. RESULTS: Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dt(max), -39%, H: 69.8 vs. C: 114.6 microm/s), relaxation (dR/dt(max), -37%, 58.2 vs. 92.9 microm/s), [Ca(2+)](iT) (-34%, 0.23 vs. 0.35), and I(Ca,L) (-25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, beta(1)-AR protein levels decreased by 23% and 42%, but beta(3)-AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to beta-AR agonist, isoproterenol (ISO), and beta(3)-AR agonist, BRL-37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10(-8) M) produced significantly smaller increases in dL/dt(max) (H: 40% vs. C: 71%), dR/dt(max) (37% vs. 52%), [Ca(2+)](iT) (17% vs. 37%), and I(Ca,L) (17% vs. 27%), but BRL (10(-8) M) produced a significantly greater decrease in dL/dt(max) (H: -23% vs. C: -11%), [Ca(2+)](iT) (-30% vs. -11%), and I(Ca,L) (-28% vs. -17%). CONCLUSIONS: Chronic alcohol consumption down-regulates cardiac beta(1)- and up-regulates beta(3)-ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac beta(3)-AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca(2+)](i) regulation and, thus, may precede the development of ACM.

Pathophysiology of anthrax.

Infection by Bacillus anthracis in animals and humans results from accidental or intentional exposure, by oral, cutaneous or pulmonary routes, to spores, which are normally present in the soil. Treatment includes administration of antibiotics, vaccination or treatment with antibody to the toxin. A better understanding of the molecular basis of the processes involved in the pathogenesis of anthrax namely, spore germination in macrophages and biological effects of the secreted toxins on heart and blood vessels will lead to improved management of infected animals and patients. Controlling germination will be feasible by inhibiting macrophage paralysis and cell death. On the other hand, the control of terminal hypotension might be achieved by inhibition of cardiomyocyte mitogen-activated protein kinase and stimulation of vessel cAMP.

Restrictive left ventricular filling pattern does not result from increased left atrial pressure alone.

BACKGROUND: The restrictive filling pattern seen with severe heart failure (HF) may be due to diastolic dysfunction with elevated left ventricular (LV) diastolic pressure or may be merely a manifestation of an overfilled LV as a result of increased left atrial (LA) pressure. We investigated whether the LV restrictive filling pattern is due to elevated LA pressure alone. METHODS AND RESULTS: We studied conscious dogs instrumented to measure LA pressure, LV pressure, and 3 LV diameters. LV filling dynamics were evaluated in 2 situations with similar elevations of LA pressure: in normal animals after rapid volume loading with dextran 500 mL and in animals with pacing-induced HF with restrictive filling. With HF, there was increased LV chamber stiffness and slow relaxation. Volume loading and HF had similar heart rates (129+/-19 versus 131+/-15 bpm) and LA pressure (22.1+/-5.8 versus 22.6+/-3.3 mm Hg). The peak early filling rate (E) was increased with both HF and volume loading. However, in HF, the peak mitral annular velocity (E') was decreased and delayed, and the E deceleration time was shorter. In contrast, with volume loading, E' was increased and not delayed. CONCLUSIONS: The restrictive filling pattern is distinguished from overfilling of a normal ventricle by a reduced and delayed E' and a shortened E deceleration time that reflect slow relaxation and increased LV stiffness.

Orally available levosimendan dose-related positive inotropic and lusitropic effect in conscious chronically instrumented normal and heart failure dogs.

Levosimendan (LS), a Ca(2+) sensitizer, is presently limited to i.v. administration. The dose-related pharmacodynamic effects of newly developed oral LS remain undetermined. We assessed the dose-response relationship of oral LS in nine normal and seven pacing-induced heart failure (HF), conscious, chronically instrumented mongrel dogs. Animals received a placebo capsule on day 1, and then LS was administered at single oral doses of 0.025 (day 2), 0.05 (day 4), and 0.1 (day 8) mg/kg. We serially measured plasma LS concentrations, hemodynamic, and left ventricular (LV) systolic and diastolic functional responses periodically until 12 h after oral LS. In both normal and HF, after three incremental dosages of oral LS, the peak plasma LS concentrations (34.6, 66.8, and 123.2 ng/ml in normal and 38.3, 71.5, and 137.4 ng/ml in HF) were achieved within 2 h in proportion to the dose, parallel to an increased LV contractility (normal, from 5.7 mm Hg/ml placebo to 8.2, 10.5, and 12.6 mm Hg/ml; HF, from 3.7 mm Hg/ml placebo to 5.7, 7.1, and 8.7 mm Hg/ml), and decreased time constant of LV relaxation (tau) (normal, from 28.8 ms of placebo to 25.6, 24.7, and 23.5 mm Hg/ml; HF, from 44.7 ms of placebo to 38.9, 36.4, and 34.6 ms). Compared with placebo, total systemic vascular resistance and mean left atrial pressure were significantly reduced after LS. In HF, oral LS caused a dose-dependent increase of LV-arterial coupling and mechanical efficiency. Heart rate increased only after 0.1 mg/kg LS in normal dogs. In conclusion, oral LS produces vasodilatation and dose-dependent augmentation in LV contractility and relaxation both in normal and HF.

Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy.

BACKGROUND: Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT1) blockade on the development of alcoholic cardiomyopathy. METHODS AND RESULTS: We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg.kg(-1).d(-1) PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT(1) receptor expression. The RAS activation was followed by a progressive fall in LV contractility (E(ES), alcohol-fed dogs 3.9+/-0.8 versus control dogs 8.1+/-1.0 mm Hg/mL); reductions in the peak velocity of myocyte shortening (78.9+/-5.1 versus 153.9+/-6.2 microm/s) and relengthening; and decreased peak systolic Ca2+ transient ([Ca2+]iT) and L-type Ca2+ current (I(Ca,L); P<0.05). Irbesartan prevented the alcohol-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and I(Ca,L). With alcohol plus irbesartan, plasma Ang II, cardiac angiotensin-converting enzyme activity, and AT1 remained close to control values. CONCLUSIONS: Chronic alcohol consumption produces RAS activation followed by progressive cardiac dysfunction. The cardiac dysfunction is prevented by AT1 receptor blockade.

Enhanced inhibition of L-type Ca2+ current by beta3-adrenergic stimulation in failing rat heart.

beta3-adrenergic receptors (AR) have recently been identified in mammalian hearts and shown to be up-regulated in heart failure (HF). beta3-AR stimulation reduces inotropic response associated with an inhibition of L-type Ca2+ channels in normal hearts; however, the effects of beta3-AR activation on Ca2+ channel in HF remain unknown. We compared the effects of beta(3)-AR activation on L-type Ca2+ current (ICa,L) in isolated left ventricular myocytes obtained from normal and age-matched rats with isoproterenol (ISO)-induced HF (4 months after 340 mg/kg s.c. for 2 days). ICa,L was measured using whole-cell voltage clamp and perforated-patch recording techniques. In normal myocytes, superfusion of 4-[-[2-hydroxy-(3-chlorophenyl)ethylamino]propyl]phenoxyacetate (BRL-37,344; BRL), a beta3-AR agonist, caused a dose-dependent decrease in ICa,L with maximal inhibition (21%, 1.1 +/- 0.2 versus 1.4 +/- 0.1 nA) (p < 0.01) at 10(-7) M. In HF myocytes, the same concentration of BRL produced a proportionately greater inhibition (31%) in ICa,L (1.1 +/- 0.2 versus 1.6 +/- 0.2 nA) (p < 0.05). A similar inhibition of ICa,L was also observed with ISO (10(-7) M) in the presence of a beta1- and beta2-AR antagonist, nadolol (10(-5) M). Inhibition was abolished by the beta3-AR antagonist (S)-N-[4-[2-[[3-[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]ethyl]phenyl]benzenesulfonamide (L-748,337; 10(-6) M), but not by nadolol. The inhibitory effect of BRL was attenuated by a nitric-oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (10(-4) M), and was prevented by the incubation of myocytes with pertussis toxin (PTX; 2 microg/ml, 36 degrees C, 6 h). In conclusion, beta3-AR activation inhibits L-type Ca2+ channel in both normal and HF myocytes. In HF, beta3-AR stimulation-induced inhibition of Ca2+ channel is enhanced. These effects are likely coupled with PTX-sensitive G-protein and partially mediated through a NOS-dependent pathway.

Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure.

The new myofilament Ca2+ sensitizer levosimendan (LSM) is a positive inotropic and vasodilatory agent. Its beneficial effects have been demonstrated at rest in congestive heart failure (CHF). However, its effect during exercise (Ex) in CHF is unknown. We assessed the effects of LSM on left ventricular (LV) dynamics at rest and during Ex in eight conscious, instrumented dogs with pacing-induced CHF. After CHF, with dogs at rest, LSM decreased arterial elastance (Ea) and increased LV contractile performance as assessed by the slope of LV pressure-volume (P-V) relation. LSM caused a >60% increase in the peak rate of mitral flow (dV/dtmax) due to decreases in minimal LV pressure and the time constant of LV relaxation (tau). LV arterial coupling, quantified as the ratio of end-systolic elastance (Ees) to Ea, was increased from 0.47 to 0.85%. LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, was improved from 0.54 +/- 0.09 to 0.61 +/- 0.07. These beneficial effects persisted during Ex after CHF. Compared with CHF Ex dogs, treatment with LSM prevented Ex-induced abnormal increases in mean left atrial pressure and end-diastolic pressure and decreased Ees/Ea. With LSM treatment during CHF Ex, the early diastolic portion of the LV P-V loop was shifted downward with decreased minimal LV pressure and tau values and a further augmented dV/dtmax. Ees/Ea improved, and mechanical efficiency further increased from 0.61 +/- 0.07 to 0.67 +/- 0.07, which was close to the value reached during normal Ex. After CHF, LSM produced arterial vasodilatation; improved LV relaxation and diastolic filling; increased contractility, LV arterial coupling, and mechanical efficiency; and normalized the response to Ex.

Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure.

The objective of the present study was to test the hypothesis that endogenous beta(3)-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the beta(3)-AR inhibits cardiac contraction. In the failing myocardium, beta(3)-ARs are upregulated, suggesting that stimulation of beta(3)-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous beta(3)-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific beta(3)-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (E(es)) of the LV pressure-volume relation (18%, 6.2 +/- 0.9 vs. 7.3 +/- 1.2 mmHg/ml, P < 0.05) and the improved LV relaxation time constant (tau; 28.4 +/- 1.9 vs. 26.8 +/- 1.0 ms, P < 0.05). After CHF, the plasma norepinephrine concentration increased eightfold, and L-748,337 produced a larger increase in E(es) (34%, 3.8 +/- 0.7 vs. 5.1 +/- 0.8 mmHg/ml, P < 0.05) and a greater decrease in tau (46.4 +/- 4.2 vs. 41.0 +/- 3.9 ms, P < 0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8 +/- 0.9 vs. 6.8 +/- 0.9%, P < 0.05) and relengthening (33.5 +/- 4.2 vs. 39.7 +/- 4.0 microm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca(2+) concentration regulation. In CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function. Stimulation of beta(3)-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.

Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction.

Diastolic dysfunction may be exacerbated by increased systolic blood pressure (SBP) during exercise. Ang II may contribute to this process. We performed a randomized, double-blind, crossover study of two weeks of candesartan (16 mg) and verapamil (SR 160 mg). The 21 subjects were 64 +/- 10 years old with ejection fraction greater than 50%, no ischemia, mitral flow velocity E/A less than 1, normal resting SBP (< 150 mm Hg), and SBP greater than 200 mm Hg during exercise. Exercise tolerance was assessed using a Modified Bruce Protocol at baseline and after each two-week treatment period, separated by a two-week washout period. Quality of life (QOL) was assessed using the Minnesota Living with Heart Failure questionnaire. During exercise, Ang II levels increased from 29 +/- 18 to 33 +/- 18 pg/ml (P < 0.05). SBP during exercise was 213 +/- 9 mm Hg at baseline and similarly reduced by candesartan (198 +/- 18, P < 0.01) and verapamil (197 +/- 14, P < 0.01). With candesartan, exercise time increased from 793 +/- 182 seconds to 845 +/- 163 seconds (P < 0.05), and QOL improved from 11 +/- 14 to 5 +/- 6 (P < 0.05). In contrast, verapamil did not significantly improve exercise time or QOL. In patients with mild diastolic dysfunction at rest and a hypertensive response to exercise, both Ang II receptor blockade and verapamil blunted the hypertensive response to exercise. Ang II blockade increased exercise tolerance and improved QOL.

Tachycardia exacerbates abnormal left ventricular-arterial coupling in heart failure.

The purpose of this study was to assess the effect of heart rate on left ventricular (LV)-arterial coupling and LV mechanical efficiency before and after heart failure (CHF). The production of LV stroke work (SW) and mechanical efficiency depends on the coupling of the LV and arterial system. The response of LV-arterial coupling to tachycardia may be altered in heart failure. We compared the response of LV-arterial coupling to increased heart rate (HR) in six conscious, instrumented dogs before and after pacing-induced CHF. Coupling was quantified as E(ES)/ E(A), where E(ES) is the slope of end-systolic pressure ( P)-volume ( V) relation, and E(A) is arterial elastance. Mechanical efficiency was determined as the ratio of SW to a total P-V area (PVA). Before CHF, E(ES) and E(A) increased similarly with increased heart rate to 180 min(-1). Thus, E(ES)/ E(A) remained unaltered (0.96 +/- 0.08 vs 0.94 +/- 0.35), and SW/PVA was unchanged (0.62 +/- 0.03 vs 0.59 +/- 0.06). Compared with the results prior to CHF and after CHF the resting E(ES) was decreased, thus both E(ES)/ E(A) (0.58 +/- 0.09) and SW/PVA (0.48 +/- 0.06) were less ( P << 0.05) than baseline. After CHF, an increase in HR to 180 min(-1) increased E(A) but not E(ES), thus E(ES)/ E(A) fell to 0.44 +/- 0.06 ( P << 0.05) and SW/PVA fell to 0.41 +/- 0.05 ( P << 0.05). Under normal conditions, LV-arterial coupling remains optimal during increases in HR. After CHF, tachycardia exacerbates the suboptimal baseline LV-arterial coupling, reducing the efficiency of producing SW.

Diastolic mitral annular velocity during the development of heart failure.

OBJECTIVES: We sought to investigate the mechanism of reduced diastolic mitral annular velocity with diastolic dysfunction, despite elevated left atrial (LA) pressure. BACKGROUND: The peak rate of left ventricular (LV) early diastolic filling (E) and velocity of the mitral annulus due to long-axis lengthening (E(M)) are reduced in mild diastolic dysfunction. With more severe dysfunction, E increases in response to increased LA pressures. In contrast, E(M) decreases, despite increased LA pressure. METHODS: We studied eight dogs instrumented to measure LA pressure, LV pressure, and internal dimensions during the progressive development of heart failure (HF) produced by rapid pacing. RESULTS: Early diastolic filling decreased after four days of pacing from 114 +/- 32 to 88 +/- 22 ml/s (p < 0.05), but with more severe HF, it progressively increased to 155 +/- 32 ml/s (p < 0.05). In contrast, E(M) progressively decreased from 44 +/- 12 mm/s during the control period to 24 +/- 8 mm/s after four weeks (p < 0.05). Although E(M) was related to the time constant of LV relaxation (tau) (R(2) = 0.85), E was not. The latter occurred coincident with termination of the early diastolic LA to LV pressure gradient during all conditions. In contrast, with increasing HF, E(M) was progressively delayed after LA to LV pressure crossover by 37 +/- 12 ms (p < 0.05). The time from E to E(M) was related to tau (R(2) = 0.97). CONCLUSIONS: With slowed relaxation during the development of HF, E(M) is reduced and delayed so that it occurs after early, rapid filling. Thus, with slowed relaxation, E(M) does not respond to the early diastolic LA to LV pressure gradient, because it occurs when LV pressure is greater than or equal to LA pressure.