Lack of evidence for peripheral alpha1- adrenoceptor blockade during long-term treatment of heart failure with carvedilol

Kubo, Toshihiko; Azevêdo, Eduardo Ribeiro de; Newton, Gary E.; Parker, John D.; Floras, John S.

doi:10.1016/s0735-1097(01)01577-7

Cited by 52 publications

(31 citation statements)

References 30 publications

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“…11 Neither infusion altered HR. Finally, our previous finding (in a larger cohort from the present trial) that β-adrenoceptor antagonism did not increase the gain of the neuroeffector transfer function (MSNA → BP) 28 indicates that this mechanism cannot account for the restoration of MSNA power observed in the present series.…”

Section: Discussioncontrasting

confidence: 59%

“…In this context it is important to emphasize that a key strength of the present experiment is that repeat studies were not performed until a mean of 4 months after initiating therapy, at which time the peripheral α-adrenoceptor antagonist properties of carvedilol had dissipated. 28 Chronic β-blockade in CHF might augment MSNA spectral power at 1 or more of the transduction points in this closed loop. It is evident, however, that the potential role of breathing patterns, BP variability, and the arterial baroreflex regulation of MSNA in restoring the variability of MSNA can be eliminated, or discounted, because the disappearance of LF spectral power at 0.13 Hz in CHF is unrelated to the frequency of breathing; 7 the variability of systolic BP in β-blockade naïve CHF patients is identical to that of sex-and age-matched healthy control subjects 10 (and would not be anticipated to change with β-blockade 29 ); the arterial baroreflex gain, as represented by the power spectral transfer functions relating BP → baroreceptors → central nervous system → MSNA within the very LF, LF and HF ranges is not attenuated, but preserved in CHF and control subjects, 7 and in the present cohort, these transfer functions within the very LF, LF, and HF ranges, reflecting arterial baroreflex regulation of MSNA, were not affected by either carvedilol or metoprolol.…”

Section: Discussionmentioning

confidence: 99%

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Beta-Blockade Restores Muscle Sympathetic Rhythmicity in Human Heart Failure

Kubo

Azevêdo

Newton

et al. 2011

Circ J

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Background: Muscle sympathetic nerve firing rate increases as chronic heart failure (CHF) progresses, yet its oscillation, particularly within the frequency range encompassing 0.13 Hz, diminishes. The current study tested the hypothesis that chronic therapy with lipophilic β-adrenoceptor antagonists augments the modulation of muscle sympathetic nerve activity variability (MSNAV) at this frequency range. Methods and Results:In 21 CHF angiotensin converting enzyme (ACE) inhibitor-treated patients (age: 53±2, ejection fraction: 20±2%), MSNA was recorded before and after 4 months of β-blockade with either metoprolol (up to 50 mg b.i.d.) or carvedilol (up to 25 mg b.i.d.). Harmonic MSNAV was assessed by coarse graining spectral analysis. Both drugs lowered heart rate similarly (-13±2 beats/min; P<0.001) but neither affected MSNA burst frequency (-7±4 bursts/min, not significant). Before β-blockade, harmonic MSNA power in the region encompassing 0.13 Hz was essentially absent. Beta-blockade increased the mean values for total power (from 0.00 to 0.50 Hz; 5.2±0.8 to 6.8±1.2 U 2 ; P<0.001) and for harmonic MSNA spectral power across the 0.1-0.22 Hz frequency range (from 0.48±0.10 to 1.50±0.32 U 2 , F=12.2; P<0.001). Both carvedilol and metoprolol had a similar effect. Conclusions:In patients with CHF receiving ACE inhibitors, adding a β-adrenoceptor antagonist restores low and high frequency harmonic oscillations in MSNA. Beta-1 antagonism is sufficient to achieve this response. Augmented modulation of sympathetic outflow could contribute to the beneficial effects of β-blockade in CHF on sudden death and disease progression. (Circ J 2011; 75: 1400 - 1408

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Beta-Blockade Restores Muscle Sympathetic Rhythmicity in Human Heart Failure

Kubo

Azevêdo

Newton

et al. 2011

Circ J

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“…The effects at 6 months would be consistent with attenuation of the vasodilating effects of carvedilol, as has previously been demonstrated. 21 The results over the 6 months demonstrate a substantial beneficial effect on inhibiting progression of LV remodeling. The underlying mechanisms of this effect are probably multifactorial.…”

Section: Time Course and Potential Mechanisms Of Effects On Remodelingmentioning

confidence: 88%

Effects of Carvedilol on Left Ventricular Remodeling After Acute Myocardial Infarction

et al. 2004

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on behalf of the CAPRICORN Echo Substudy InvestigatorsBackground-The CAPRICORN trial has shown that carvedilol improved outcome in patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors. The aim of this substudy was to determine the effects of carvedilol on left ventricular remodeling in this patient group. Methods and Results-Patients entering the CAPRICORN trial from 13 centers in New Zealand, Australia, and Spain were recruited for this echocardiographic substudy. In 127 patients, quantitative 2D echocardiography was performed according to a standard protocol before randomization and repeated after 1, 3, and 6 months of treatment with carvedilol or placebo. Left ventricular volumes, ejection fraction (Simpson's method), and wall motion score index were determined in a blinded analysis at the Core Echo Laboratory. At 6 months, left ventricular end systolic volume was 9.2 mL less in the carvedilol group than in the placebo group (Pϭ0.023), and left ventricular ejection fraction was 3.9% higher (Pϭ0.015). Left ventricular end diastolic volume and wall motion score index were not statistically different between the 2 groups at 6 months. Conclusions-In patients with left ventricular dysfunction after acute myocardial infarction treated with ACE inhibitors, carvedilol had a beneficial effect on ventricular remodeling, which may, in part, mediate the substantial clinical beneficial effects of carvedilol in this patient population.

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“…15 Moreover, long-term β-adrenoceptor blockade (even with carvedilol) will not counter the adverse consequences of augmented sympathetic neurotransmitter stimulation of vascular α 1 , α 2 , NPY1, or P2X1 receptors. 16,17 Neither the ingestion nor the acute suspension of these drugs should alter the arterial distension-baroreceptor nerve firing relationship that is the core of the investigators' thesis. If her data had been added to the primary analyses, would the key determinations remain significant statistically?…”

Section: Floras Et Al Lvad Pulse Pressure and Msna 2295mentioning

confidence: 99%