Hemodynamic Effects of α1-Adrenoceptor Antagonist, Doxazosin, in Patients With Chronic Congestive Heart Failure

Kieback, Arne; Rödiger, Olaf; Jaenecke, Halina; Grohmann, Andrea; Wernecke, Klaus‐Dieter; Baumann, Gert; Felix, Stephan B.

doi:10.1097/01.fjc.0000175874.40543.b1

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…Doxazosin significantly increased SV (Figure 1L), which is consistent with previous reports showing that the drug acutely increased SV in patients with heart failure. 27 These results suggest that carvedilol can decrease contractility but maintain SV by inhibiting both RyR2 and α 1 -AR.…”

Section: Resultsmentioning

confidence: 78%

Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non–β-Blocking R-Enantiomer Carvedilol

Seo,

Yamamoto,

Kirillova

et al. 2023

Circulation

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BACKGROUND: Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown. METHODS: We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure–volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM ( Myh6 R403Q /+ [myosin heavy chain 6]) and iPSC cardiomyocytes derived from patients with HCM ( MYH7 R403Q/+ ) [myosin heavy chain 7]). RESULTS: We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β 1 -blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α 1 -adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α 1 -receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6 R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7 R403Q/+ induced pluripotent stem cell cardiomyocytes. CONCLUSIONS: R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α 1 -adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

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Section: Resultsmentioning

confidence: 78%

Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non–β-Blocking R-Enantiomer Carvedilol

Seo,

Yamamoto,

Kirillova

et al. 2023

Circulation

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“…Their main characteristics are summarized in Table 1 . However, from these, one article 24 presented subgroups only in relative terms (percentage); two publications 33 , 42 failed at quantitatively stratifying by group allocation; one paper 12 corresponded to a cross‐over trial that did not report outcomes at the exact cross‐over period; one record 27 focused on New York Heart Association (NYHA) change; one study 19 described LVEF dynamics through least square means difference; and, in one article, 37 SDs of the MDs of LVEF and ED could not be obtained. These features rendered them unemployable in the quantitative synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…These facts likely disclose high risk of attrition bias. Of note, one other study 33 did manage to report dropouts but did not clarify their cause, this way conceding unclear risk in this domain. In parallel, reporting bias was also an issue, because some RCTs failed to report relevant quantitative data, such as statistics that would have permitted estimation of mean differences (MDs), standard deviations (SDs) or p ‐values.…”

Section: Methodsmentioning

confidence: 99%

Do adrenergic alpha‐antagonists increase the risk of poor cardiovascular outcomes? A systematic review and meta‐analysis

et al. 2022

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Due to concerns regarding neurohormonal activation and fluid retention, adrenergic alpha‐1 receptor antagonists (A1Bs) are generally avoided in the setting of heart disease, namely, symptomatic heart failure (HF) with reduced ejection fraction (HFrEF). However, this contraindication is mainly supported by ancient studies, having recently been challenged by newer ones. We aim to perform a comprehensive meta‐analysis aimed at ascertaining the extent to which A1Bs might influence cardiovascular (CV) outcomes. We systematically searched PubMed, Cochrane Central Register of Controlled Trials and Web of Science for both prospective and retrospective studies, published until 1 December 2020, addressing the impact of A1Bs on both clinical outcomes—namely, acute heart failure (AHF), acute coronary syndrome (ACS), CV and all‐cause mortality—and on CV surrogate measures, specifically left ventricular ejection fraction (LVEF) and exercise tolerance, by means of exercise duration. Both randomized controlled trials (RCTs) and studies including only HF patients were further investigated separately. Study‐specific odds ratios (ORs) and mean differences (MDs) were pooled using traditional meta‐analytic techniques, under a random‐effects model. A record was registered in PROSPERO database, with the code number CRD42020181804. Fifteen RCTs, three non‐randomized prospective and two retrospective studies, encompassing 32 851, 19 287, and 71 600 patients, respectively, were deemed eligible; 62 256 patients were allocated to A1B, on the basis of multiple clinical indications: chronic HF itself [14 studies, with 72 558 patients, including seven studies with 850 HFrEF or HF with mildly reduced ejection fraction (HFmrEF) patients], arterial hypertension (four studies, with 44 184 patients) and low urinary tract symptoms (two studies, with 6996 patients). There were 25 998 AHF events, 1325 ACS episodes, 955 CV deaths and 33 567 all‐cause deaths. When considering only RCTs, A1Bs were, indeed, found to increase AHF risk (OR 1.78, [1.46, 2.16] 95% CI, P < 0.00001, i2 2%), although displaying no significant effect on neither ACS nor CV or all‐cause mortality rates (OR 1.02, [0.91, 1.15] 95% CI, i2 0%; OR 0.95, [0.47, 1.91] 95% CI, i2 17%; OR 1.1, [0.84, 1.43] 95% CI, i2 17%, respectively). Besides, when only HF patients were evaluated, A1Bs revealed themselves neutral towards not only ACS, CV, and all‐cause mortality events (OR 0.49, [0.1, 2.47] 95% CI, i2 0%; OR 0.7, [0.21, 2.31] 95% CI, i2 21%; OR 1.09, [0.53, 2.23] 95% CI, i2 17%, respectively), but also AHF (OR 1.13, [0.66, 1.92] 95% CI, i2 0%). As for HFrEF and HFmrEF, A1Bs were found to exert a similarly inconsequential effect on AHF rates (OR 1.01, [0.5–2.05] 95% CI, i2 6%). Likewise, LVEF was not significantly influenced by A1Bs (MD 1.66, [−2.18, 5.50] 95% CI, i2 58%). Most strikingly, exercise tolerance was higher in those under this drug class (MD 139.16, [65.52, 212.8] 95% CI, P < 0.001, i2 26%). A1Bs do not seem to exert a negative influence on the prognosis of HF—and even...

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Carvedilol Improves Uptake-1 in Patients With Systolic Congestive Heart Failure

Machida

Takechi²,

Fujimoto³

et al. 2012

Journal of Cardiovascular Pharmacology

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Hemodynamic Effects of α1-Adrenoceptor Antagonist, Doxazosin, in Patients With Chronic Congestive Heart Failure

Cited by 3 publications

References 21 publications

Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non–β-Blocking R-Enantiomer Carvedilol

Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non–β-Blocking R-Enantiomer Carvedilol

Do adrenergic alpha‐antagonists increase the risk of poor cardiovascular outcomes? A systematic review and meta‐analysis

Carvedilol Improves Uptake-1 in Patients With Systolic Congestive Heart Failure

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