Beta blockers and hypertrophic obstructive cardiomyopathy: a systematic review and meta-analysis

Abstract

Background

Since the 1960s, beta blockers have been used to treat hypertrophic obstructive cardiomyopathy (HOCM), a genetic disorder causing abnormal heart muscle thickening. This systematic review evaluates their efficacy across clinical outcomes.

Methods

Registered on PROSPERO (CRD42022344255), searches were performed in June 2022 and updated in September 2025 across MEDLINE, Embase, CINAHL and PubMed. Two reviewers independently screened studies. Meta-analysis was undertaken when ≥3 comparable datasets were available; otherwise, narrative synthesis was used.

Results

21 studies including 775 adults met inclusion criteria. Beta blockers significantly reduced left ventricular outflow tract (LVOT) gradient (Standardised mean difference (SMD) –1.57; 95% CI –2.07 to –1.07) and heart rate (SMD –1.19; 95% CI –2.24 to –0.14). Sensitivity analyses confirmed the robustness of the LVOT effect, while heart rate effects remained heterogeneous. Improvements in New York Heart Association class, exercise tolerance and symptom burden were consistently reported, although data were subjective and small in scale. Mortality evidence was limited to two retrospective cohorts with divergent findings.

Conclusions

Beta blockers provide consistent haemodynamic and symptomatic benefits in HOCM, but most evidence derives from small, older studies with high risk of bias and limited survival data. Contemporary, adequately powered randomised controlled trials are required to define optimal agent selection, dosing and long-term outcomes.

PROSPERO registration number

CRD42022344255

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Beta blockers have been used for decades to treat hypertrophic obstructive cardiomyopathy (HOCM), but most evidence is small, old and rarely synthesised, with limited data on long-term outcomes.

WHAT THIS STUDY ADDS

• This review (21 studies, updated to 2025) shows beta blockers reduce left ventricular outflow tract (LVOT) gradient and heart rate, with LVOT effects robust on sensitivity analysis. Consistent improvements in New York Heart Association class and symptoms were seen, though mortality data were limited to two divergent cohorts. Benefits appear class-wide, with cardio-selective β₁-blockers preferred.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Findings highlight the reliance on older, underpowered studies and the absence of contemporary randomised controlled trials. While beta blockers remain first-line, their long-term survival impact is unclear and newer therapies are now the focus of most HOCM trials.

Introduction

Since their introduction in 1964 for angina, beta blockers have become a cornerstone of cardiovascular pharmacology. Propranolol, the first licensed agent, remains widely used, including for hypertrophic obstructive cardiomyopathy (HOCM).

HOCM is an autosomal dominant disorder causing myocardial and septal thickening, impairing cardiac function. It affects~0.2% of the population and is the leading cause of sudden cardiac death in young athletes.¹ Management is complex, as preload-reducing therapies can worsen obstruction. Treatment mainly relies on beta blockers and calcium channel blockers, though newer myosin inhibitors and gene therapies show promise.²

Beta blockers act on β₁ and β₂ adrenergic receptors. In HOCM, they improve diastolic filling by lowering heart rate (HR),² reduce contractility and left ventricular (LV) outflow gradients and decrease oxygen demand.³ Their antiarrhythmic effects arise from limiting arrhythmias linked to fibrosis, ischaemia and sympathetic overactivity.^{2 4} Long-term use may delay remodelling and fibrosis, improving symptoms and quality of life.⁵

Early randomised controlled trials (RCTs) confirmed these benefits, but reviews in 2002 and 2014 gave little emphasis to beta blockers.^{6 7} A 2021 RCT showed significant improvements in symptoms, function and haemodynamics versus placebo,⁸ and later reviews incorporated these findings into evolving treatment approaches.⁹

This systematic review evaluates six decades of evidence on beta blockers in HOCM, analysing qualitative and quantitative data to define their therapeutic role.

Materials and methods

Study registration

This review was registered on PROSPERO (ID: CRD42022344255).

Inclusion criteria

Eligible studies assessed beta-blocker effects in patients with HOCM, reporting outcomes such as left ventricular outflow tract (LVOT) gradient, stroke volume, HR, blood pressure, symptoms, New York Heart Association (NYHA) class, metabolic parameters or mortality. Exclusion criteria included paediatric studies, animal/laboratory models or populations with major cardiac comorbidities.

Search strategy

A comprehensive search was conducted on 9 June 2022 across MEDLINE, Embase, CINAHL and PubMed via NICE Healthcare Databases, and repeated on 23 September 2025. Terms included “HOCM”, “hypertrophic cardiomyopathy”, “beta-blocker” and synonyms. Strategies were tailored per database without date or language restrictions and reviewed by a clinical effectiveness librarian.

Study selection

Titles and abstracts were screened independently by AMMC and AJS, with full texts reviewed against eligibility criteria. Missing articles were requested from authors. Discrepancies were resolved by a third reviewer (BW).

Data extraction

Data was extracted into a standardised Excel sheet by AMMC, AJS, LB and JP, with cross-checking for accuracy.

Risk of bias

Risk of bias was independently assessed by two reviewers (AJS+AC), using the Cochrane Risk of Bias 1 (ROB-1) tool for RCTs and Risk of bias in non randomised studies of interventions (ROBINS-I) for cohort studies (figure 1).

Figure 1. Risk of bias assessment for included studies. Assessment of included studies using the Cochrane ROB-1 tool (for RCTs) and ROBINS-I (for cohorts). ROB-1 domains (RCTs): random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; other bias. ROBINS-I domains (cohorts): confounding; selection of participants; classification of interventions; deviations from intended interventions; missing data; measurement of outcomes; selection of the reported result. Colour coding (both tools): green=low risk; yellow=moderate/some concerns; red=high/serious risk; dark red/black=critical risk. Note: Of 6 RCTs, 2 (33%) were rated low risk and 4 (67%) high risk. Of 15 cohorts, 4 (27%) were moderate and 11 (73%) serious risk. RCT, randomised controlled trial; ROB-1, Risk of Bias 1. (ROBINS-I) Risk of bias in non randomised studies of interventions.

Results

Search results

The initial search on 9 June 2022 yielded 258 records after duplicates, of which 28 full texts were reviewed and 19 included. Rescreening identified one further study. The updated search on 23 September 2025 retrieved 141 records (90 after deduplication) but yielded no new studies. In total, 21 studies were included (figure 2).

Figure 2. PRISMA flow diagram for study selection. Flowchart showing identification, screening, eligibility assessment and inclusion of studies in accordance with PRISMA guidelines. 441 records identified through databases and 2 through registers. 93 duplicates removed → 348 records screened. 320 records excluded at title/abstract level. 28 full-text reports assessed; 3 not retrieved. 24 excluded (reasons: insufficient outcome data (n=9); non-English (n=7); graphical-only data (n=4); ineligible design (n=4)). 21 studies included: 19 from the original search, 1 on rescreening, 1 via citation searching. PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. Source: Page et al BMJ 2021;372:n71. doi: 10.1136/bmj.n71.This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Characteristics of included studies

15 studies were cohort designs and 6 RCTs, mostly single-blind or double-blind crossover. Publications spanned 1964–2022 and included 775 adults (262 female, 301 male, sex not reported in 212). Five RCTs used crossover controls (n=81). Beta blockers studied included propranolol, bisoprolol, nadolol, atenolol, metoprolol, sotalol and nethalidine. Meta-analysis was conducted when ≥3 comparable datasets with SDs were available; otherwise, outcomes were narratively synthesised or tabulated. All meta-analyses used a random-effects model (inverse variance), with sensitivity analyses by leave-one-out and comparison with fixed-effects models. Analyses were performed using Cochrane Review Manager V.5.4. Levels of evidence were graded using the Oxford Centre for Evidence-Based Medicine (OCEBM) system, which ranks from Level I (systematic reviews of RCTs) to Level V (expert opinion) (table 1).

Table 1. Summary of study characteristics for included studies.

Study No.	Author	Beta blocker	Dosing	Study type	Country	No of participants	Male/female	OCEBM grade
1	Emanuele Monda	Bisoprolol	5.7 (±3.2) mg	Retrospective cohort	Italy	92	54/38	II
2	Stefano Nistri	Bisoprolol	2.5 mg/day up to 5–10 mg/day	Prospective cohort	Italy	27	22/5	IV
3	Thompson	Propranolol	0.2 mg/kg/day	Prospective cohort	England	13	7/6	IV
4	Lawrence*	Propranolol	80–480 mg/day	RCT crossover (single blind)	America	7	6/1	IV
5	Flammajor	Propranolol	0.15 mg/kg/day	Prospective cohort	America	11	6/5	IV
6	Adelman	Propranolol	40 mg/day initially, up to 300 mg/day	Prospective cohort	England	24	11/10	IV
7	Micheal Tendera*	Sotalol	320 mg/day initially, then avg 377 mg/day	RCT crossover (double blind)	Poland	30	20/10	II
8	Yoichi Imori	Bisoprolol	4–8 mg/day	Retrospective cohort	America	10	6/4	IV
9	Mark V Sherrid	Metoprolol/ atenolol	15 mg	Prospective cohort	America	11	1/3	IV
10	Donald C Harrison	Nathalidine	1.5 mg/kg/day	Prospective cohort	America	15	n/a	IV
11	Hubner*	Propranolol	320 mg/day	RCT Crossover (double blind)	England	16	5/11	II
12	Speiser	Propranolol	0.15 mg/kg	Prospective cohort	Switzerland	9	7/2	III
13	Hess	Propranolol	0.15 mg/kg/day	Prospective cohort	Switzerland	15	n/a	IV
14	Robert E Stenson	Propranolol	120–240 mg/day	Prospective cohort	America	13	6/7	IV
15	David M Gilligan	Nadolol	80–160 mg/day	RCT crossover (double blind)	England	18	10/8	II
20	Anne M Dybro*	Metoprolol	150 mg/day	RCT crossover (double blind)	Denmark	28	18/10	II
17	Faisal Al-Nasser	Atenolol	25 mg/day initially, then 45±19 mg	Prospective cohort	England	15	1/14	IV
18	Anne M Dybro*	Metoprolol	50 mg/day initially, up to 150 mg/day	RCT crossover (double blind)	Denmark	29	18/11	IV
19	Cherian	Propranolol/ pronethalol	0.15 mg/kg/day: 1–2 mg/kg/day	Retrospective Cohort	England	65	n/a	IV
20	Davood	Metoprolol+others	0–74, 75–149, >150 mg	Retrospective cohort	Sweden	251	128/123	III
21	Melancini	Multiple*	Multiple*	Retrospective cohort	Italy	76	n/a	III

Note: Asterisk (*) denotes RCT.

Study No.=numerical identifier. Author=first author. Year=year of publication. Beta-blocker= name of drug used. Dosing=regimen (mg/day or mg/kg/day). Study type=design (eg, retrospective cohort, RCT crossover). Country=study location.

^*Multiple=propranolol—mean daily dose 155±95 mg, atenolol—82±25 mg, metoprolol—110±60 mg, acebutolol—400±200 mg.

OCEBM grade, Oxford Centre for Evidence-Based Medicine level (I=highest, V=lowest).; participants (M/F), total participants, with male/female breakdown (N/A if not reported); RCT, randomised controlled trial.

Risk of bias in included studies

Of 6 RCTs, 2 (33%) were judged low risk and 4 (67%) high risk, mainly due to limited blinding, selective reporting and small samples. Among 15 cohorts, 4 (27%) were rated moderate risk and 11 (73%) serious risk, reflecting confounding, incomplete follow-up and lack of blinding (figure 1; table 1).

Results

Effects of beta blockers on haemodynamic metrics

Table 2 summarises haemodynamic outcomes, including HR, LVOT gradient, blood pressure (BP), left ventricular ejection fraction (LVEF) and stroke volume. Beta blockers consistently reduced the LVOT gradient. Five studies reported reductions,810,12 and three cohort studies (two bisoprolol, one propranolol) were suitable for meta-analysis (figure 3). Resting HR fell in all 15 studies reviewed;810 11 13,24 3 were included in meta-analysis (figure 4).

Table 2. Haemodynamic outcomes before and after beta-blocker therapy.

	Study characteristics		Heart rate (bpm)		LVOT gradient (mm Hg)		Systolic BP (mm Hg)		Diastolic BP (mm Hg)		LVEF (%)		Stroke volume (mL)
No.	Study author	Beta blocker	Before	After	Before	After	Before	After	Before	After	Before	After	Before	After
1	Emanuele Monda	Bisoprolol			69±15	41±18		125±15			45±5	45±5
2	Stefano Nistri	Bisoprolol	77±28	67±17	87±29	36±22	126±16	117±15	80±10	73±9
3	Thompson	Propranolol			43±9	35±9
5	Flammajor	Propranolol	81	66
8	Yoichi Imori	Bisoprolol	76	58	95	63	128	116	69	69	75	72
9	Mark V Sherrid	Metoprolol/ atenolol	70	63
10	Donald C Harrison	Nathilidine	86	81
11	Hubner*	Propranolol	79	62.5			112	106	70	65
12	Speiser18	Propranolol	85	69			121	125	74	78	82	77
13	Hess19	Propranolol	85±7	69±5									73±5	73±3
14	Robert E Stenson	Propranolol	80	65									40	40
15	David M Gilligan*	Nadolol	78±18	56			126±17	119±20	75±14	70±14
16	Anne M Dybro*	Metoprolol	79	57	74	30							66±21	76±25
17	Faisal Al-Nasser	Atenolol	75±12	69±10			145±19	135±18	79±7	69±12
19	Cherian	Propranolol/ pronethalol	89	75

No.=study identifier. Author=first author (asterisk * indicates notes). Year=publication year. Beta-blocker=drug used.

Values reported as mean±SD unless otherwise indicated; blank cells=not reported.

heart rate (bpm), beats per minute; LVEF (%), left ventricular ejection fraction; LVOT gradient (mm Hg), left ventricular outflow tract gradient; stroke volume (mL), stroke volume in millilitres; systolic/diastolic BP (mm Hg), blood pressure values.

Figure 3. Forest plot of standardised mean differences in LVOT gradients before and after beta-blocker therapy. Meta-analysis of three studies reporting LVOT gradients (mm Hg) pre-beta-blocker and post-beta-blocker therapy. Each row=individual study (means, SD and sample size pre/post). Right column=SMD with 95% CI (random-effects model). Square size=study weight; horizontal lines=95% CI. Diamond=pooled effect estimate (SMD=1.57 (95% CI 1.07 to 2.07)), favouring post-treatment. Heterogeneity: I²=55% (moderate). Note: IV=inverse variance method; SMD>0 favours post-beta-blocker treatment. LVOT, left ventricular outflow tract. SMD, Standardised mean difference.

Figure 4. Forest plot of standardised mean differences in heart rate before and after beta-blocker therapy. Meta-analysis of three studies reporting heart rate (bpm) pre-beta-blocker and post-beta-blocker therapy. Each row=individual study (means, SD and sample size pre/post). Right column=SMD with 95% CI (random-effects model). Square size=study weight; horizontal lines=95% CI. Diamond=pooled effect estimate (SMD=1.19 (95% CI 0.14 to 2.24)), favouring post-treatment. Heterogeneity: I²=84% (high). Note: IV=inverse variance method; SMD>0 favours post-treatment reductions in heart rate. SMD, Standardised mean difference.

Six studies reported reductions in systolic and diastolic BP,^{11 14 17 18 21 22} but heterogeneity precluded pooling. LVEF decreased in three studies,^{14 18 19} consistent with known negative inotropy. Stroke volume findings were inconsistent, with one increase and two null results.

Sensitivity analysis showed robust LVOT effects: pooled SMDs ranged from –1.36 to –1.74, all CIs excluding zero. HR effects were directionally consistent but heterogeneous (pooled SMDs 0.63–1.58, I²=84%). Excluding the highest risk studies (Thompson 1980 for LVOT; Hess 1983 for HR) did not materially alter results (figure 1).

Effect of beta-blocker therapy on NYHA score

Across nine studies, 189 patients had NYHA class assessed before and after beta-blocker therapy. Patients with class IV were excluded in all studies and five studies excluded class I. At baseline, 24 were class I, 152 class II and 72 class III (table 3). All improvements were downgrades, with no upgrades reported.

Table 3. Effects of beta-blocker therapy on NYHA functional class.

	Before beta-blocker therapy	After beta-blocker therapy			Number of downgrades
No.	Study author	Beta blocker	NYHA class	No. of subjects	NYHA class	No. of subjects	NYHA class	Downgrades
1	Emanuele Monda	Bisoprolol	I II III IV	0 75 17 0	I II III IV	30 patients improved by one level	II III IV	n/a
2	Stefano Nistri	Bisoprolol	I II III IV	23 4 0 0	I II III IV	25 2 0 0	II III IV	2 n/a n/a
6	Adelman	Propranolol	I II III IV	1 8 8 0	I II III IV	6 4 2 0	II III IV	5 6 0
16	Robert E Stenson	Propranolol	I II III IV	0 5 8 0	I II III IV	7 2 4 0	II III IV	7 3 4
21	Faisal Al-Nasser	Atenolol	I II III IV	0 2 9 0	I II III IV	7 4 0 0	II III IV	7 9 0
18	Anne M Dybro*	Metoprolol	I II III IV	0 18 11 0	I II III IV	3 22 4 0	II III IV	3 7 0

No.=study identifier. Author=first author (asterisk * indicates notes). Year=publication year. Beta-blocker=drug used. NYHA class (before/after)=distribution of patients pre/post therapy. No. of subjects=number of participants in each class. No. of downgrades=number of patients improving ≥1 NYHA class. Note: ‘Downgrade’=improvement (eg, class III→II). Some studies report downgrades as totals only. Blank/N/A=not reported.

NYHA, New York Heart Association.

Beta blockers generally improved NYHA class. Stenson et al²⁰ reported all class III patients improved to class I, while Adelman et al²⁵ also found marked downgrades among class II/III patients. Emanuele et al¹⁰ (n=92) observed 30 improvements, though class changes were not specified. Dybro et al²³ reported more modest benefit.

Effects of beta blockers on cardiac metabolic parameters

Table 4 summarises metabolic outcomes. Thompson et al¹² studied patients with HOCM during catheterisation with pacing before and after 0.2 mg/kg propranolol. Arterial lactate, pyruvate and hydroxybutyrate indicated a mismatch in energy use rather than production. Lactate remained stable, myocardial oxygen uptake fell and coronary sinus flow rose—suggesting improved cardiac efficiency. 1 of 13 patients showed reduced lactate even at high pacing, consistent with stress-induced cardio-protection.

Table 4. Cardiac metabolic and functional responses to beta-blocker therapy.

Arterial lactate concentration mmol/L			Arterial pyruvate concentration mmol/L	Arterial hydroxybutyrate concentration mmol/L			Myocardial oxygen uptake mL/min	Coronary sinus flow mL/min	Time on treadmill before experiencing angina (minutes)
No	Study author	Beta blocker	before	After	Before	After	Before	After	Before	After	Before	After	Before	After
3	Thompson	Propranolol	0474±0–02	0–496±0–02	0155±0013	0036±0.002	0180±0018	0155±0013	37–1±7.1	32–6±7.3	329±62	374±74
4	Lawrence*	Propranolol											6.9	12.5
7	Micheal Tendera*	Sotalol											9.8	12.7
18	Anne M Dybro*	Metoprolol			0.6	0.7

No.=study identifier. Author=first author (asterisk * indicates notes). Year=publication year. Beta-blocker=drug used. Arterial lactate (mmol/L)=pre/post values. Arterial pyruvate (mmol/L)=pre/post values. Arterial hydroxybutyrate (mmol/L)=pre/post values. Myocardial oxygen uptake (mL/min)=oxygen consumption. Coronary sinus flow (mL/min)=blood flow through sinus. Time on treadmill before angina (min)=duration before angina onset. Note: values are mean±SD unless otherwise stated; blank=not reported.

Dybro et al²³ also measured arterial pyruvate, while Cohen et al²⁶ and Tenderaet al²⁷ assessed exercise tolerance via time to angina onset. Both reported improved endurance, supporting beta blockers’ role in reducing oxygen demand and enhancing exercise capacity.

Symptomatic control of beta-blocker therapy

Four studies evaluated symptom changes with beta-blocker therapy, including angina, syncope, dyspnoea, palpitations, fatigue, dizziness and arrhythmia.

Cohen et al²⁶ (RCT crossover, n=7) reported angina (6), syncope (2) and dyspnoea (4) at baseline; after treatment, three patients had complete resolution, all improved exercise tolerance and angina episodes declined.

Adelman et al²⁵ (n=21) found dyspnoea (18), palpitations (17) and angina (15) were common before therapy. Improvements were seen in dyspnoea (8), palpitations (6), angina (5), fatigue (3) and syncope (3), with exercise tolerance improved in all 25 patients.

Tendera et al²⁷ (RCT crossover, n=30) reported six of seven patients with SVT and four of eight with VT became arrhythmia-free, with sustained effect in four cases at 6 months.

Speiser et al¹⁸ (RCT crossover, n=8) noted reduced palpitations in four patients and improved dizziness in two.

Al-Nasser et al²² (cohort, n=15) observed 4 discontinuations due to intolerance; dyspnoea persisted in 11, limiting stress echocardiography.

Side effects of beta-blocker therapy in HOCM

Several studies reported adverse effects and treatment discontinuations. Monda et al¹⁰ noted 13 patients stopped propranolol (2 due to pregnancy), while patients with chronic obstructive pulmonary disease tolerated bisoprolol well. Nistri et al¹¹ and Imori et al¹⁴ reported no withdrawals but observed rebound tachycardia after abrupt cessation.

Flamm et al¹³ reported one discontinuation for fatigue, malaise and presyncope; Adelman et al²⁵ recorded three for unspecified reasons; and Hess et al¹⁹ noted two due to symptomatic sinus bradycardia.

Dybro et al^{8 23} described dose reductions: 4 of 28 patients in one study and 3 in another for dizziness. Reported transient side effects included cold hands (2 patients), tiredness (1), diarrhoea (2) and tingling (1).

Beta-blocker pharmacology and dosing in HOCM

Beta-blocker choice and dosing varied across studies (table 5). Propranolol was most frequently assessed (7 studies; 40–480 mg/day), consistently lowering HR and LVOT gradient, though BP effects were variable and some withdrawals occurred. Selective β₁-blockers included bisoprolol (3 studies; 2.5–10 mg/day), metoprolol (2 RCTs; 50–150 mg/day) and atenolol (1 study; 25–45 mg/day), all reducing HR and LVOT gradient with reported NYHA score improvements. Nadolol (1 RCT; 80–160 mg/day) improved exercise tolerance, while sotalol (1 RCT; 320–380 mg/day) reduced arrhythmias with sustained effect. Nathalidine, an early non-selective agent, showed only acute haemodynamic effects and is now obsolete. Overall, selective and non-selective agents produced similar physiological and symptomatic benefits, suggesting a class effect.

Table 5. Beta-blocker agents, dosing ranges and reported outcomes.

β-blocker (selectivity)	Studies (n)	Dose range used	Haemodynamic outcomes	Symptom/NYHA outcomes	Other outcomes
Propranolol (non-selective)	7	80–480 mg/day or weight-based	↓ HR, ↓ LVOT gradient	NYHA class improved Monda 2022, Nistri 2012	Well tolerated; minimal withdrawals
Bisoprolol (β1 selective)	3	2.5–10 mg/day	↓ HR, ↓ LVOT gradient, ↑ stroke volume	NYHA class improved	Dose reductions required in some patients
Metoprolol (β1 selective)	2 (RCTs)	50–150 mg/day	↓ HR, ↓ BP	NYHA class improved	Four discontinuations due to intolerance
Atenolol (β1 selective)	1	25–45 mg/day	Consistent ↓ HR, ↓ LVOT gradient; variable BP effect	NYHA improvement in some cohorts	Withdrawals due to side effects reported
Nadolol (non-selective)	1 (RCT)	80–160 mg/day	↓ HR, ↓ BP	Improved exercise tolerance	Reduced arrhythmia burden
Sotalol (non-selective and class III)	1 (RCT)	320–380 mg/day	↓ HR, ↓ arrhythmias	Symptom improvement—subjective assessment	Sustained antiarrhythmic effect at 6 months
Nethalidine (non-selective, obsolete)	1	1.5 mg/kg/day	↓ HR, acute circulatory effects	Not reported	Obsolete agent, no longer used

β-blocker (selectivity)=drug name and receptor selectivity. Studies (n)=number of included studies. Dose range used=daily dosing range/regimen. Haemodynamic outcomes=effects on HR, LVOT gradient, BP or stroke volume. Symptom/NYHA outcomes=effects on symptoms and NYHA class. Other outcomes=withdrawals, dose reductions, arrhythmias.

Note: blank cells=unreported data.

BP, blood pressure; HR, heart rate; LVOT, left ventricular outflow tract gradient; NYHA, New York Heart Association class; RCT, randomised controlled trial.

Effects on stage of disease

Beta-blocker effectiveness varied by type of LVOT obstruction: resting (persistent at baseline), labile (fluctuating with stress), or latent (occurring only under stress).^{21 22}

Flamm et al¹³ studied 11 patients (4 latent, 5 labile, 2 resting). Beta blockers reduced gradients in all and abolished obstruction in 3 of 5 labile cases; propranolol also prevented obstruction in 1 latent and 2 labile patients.

Adelman et al²⁵ followed 21 patients for 2 years (4 latent, 17 resting). All latent cases became asymptomatic, while resting obstruction outcomes were mixed (7 improved, 5 worsened and 2 died).

Stenson et al²⁰ reported reduced gradients during stress but found no clear link between obstruction severity, response or progression.

Mortality data

Two retrospective cohorts reported mortality. Melacini et al²⁸ (n=293, mean 7 years) found no protective effect of β blockers, with 7 of 76 treated patients (9%) suffering sudden cardiac death, a rate similar to untreated patients; only the β-blocker subgroup was extracted, and outcomes from other drugs were excluded. Javidgonbadi et al²⁹ (n=251, mean 14 years) included patients managed with a range of therapies, but only β-blocker use was independently associated with improved survival. Early and sustained therapy reduced disease-related mortality (HR 0.49, 95% CI 0.30 to 0.81) with a clear dose-response effect, and higher doses also predicted lower heart-failure mortality. Together, these findings suggest β blockers may confer protection against disease-related and heart-failure death, but not sudden cardiac death, leaving their impact on long-term survival uncertain.

Discussion

This project aimed to evaluate the evidence for beta blockers in HOCM by analysing outcomes including NYHA score, symptom burden, cardiac metabolism, exercise tolerance, mortality and side effects.

Haemodynamics

Haemodynamic effects are the most studied outcome in beta-blocker treatment for HOCM. 15 studies, including 2 RCTs, reported haemodynamic data. Meta-analysis showed significant reductions in HR and LVOT gradient, consistent across RCTs and cohorts. Sensitivity analyses confirmed the effect on LVOT gradient was robust across models and after excluding high risk-of-bias studies, while the HR effect was directionally consistent but heterogeneous (I²=84%).

BP generally decreased, though clinical relevance remains uncertain. LVEF fell in three studies,^{14 18 19} reflecting the negative inotropic action of beta blockers, but interpretation is limited since HOCM often presents with preserved ejection fraction heart failure.³⁰ Stroke volume results were inconsistent.

Many studies were small, dated or incompletely reported, often lacking blinding or adjustment for confounders, which increases risk of bias and reduces confidence in pooled estimates.

New York Heart Association

Nine studies evaluated beta blockers using NYHA class, consistently reporting symptomatic improvement. Detailed data on class transitions were often lacking, so whether patients improved gradually or abruptly remains unclear. No study included class IV patients, limiting conclusions in the most severe disease.

Patients starting in NYHA II–III generally improved, though responsiveness varied, indicating heterogeneity in treatment effect. This likely reflects differences in study design, small samples and unblinded assessment. As NYHA scoring is subjective and reliant on physician judgement, the risk of measurement and reporting bias is high.

Sensitivity analyses across study type and era showed a consistent direction of benefit: both older cohorts and recent RCTs demonstrated downgrades. However, the magnitude varied, and many studies were small, unblinded or incompletely reported, increasing risk of bias and reducing certainty.

Cardiac metabolism

Four studies examined cardiac metabolism. Two used metabolic markers^{3 18} and showed improved efficiency with beta blockers, while Cohen et al²⁶ and Tendera et al²⁷ assessed angina onset as a surrogate for myocardial oxygen demand, both reporting improved exercise endurance. These findings support beta blockers’ role in reducing oxygen demand and enhancing exercise tolerance, with potential quality-of-life benefits.

Sensitivity across study design and era showed consistent directional benefit, but all studies were small, mostly decades old, limiting certainty and applicability to modern practice.

Symptom burden

Four studies evaluated symptom burden in HOCM, all reporting overall improvement. While NYHA class provides a broad measure, examining individual symptoms such as dyspnoea, palpitations and angina may better guide treatment. Most studies noted reductions in these symptoms, though one reported persistent dyspnoea despite therapy.

Three studies were cohorts and one (Tendera et al²⁷) a double-blind crossover trial, giving a combined sample of 66 patients—too small for firm conclusions and underscoring the need for larger trials. Outcomes were subjective and unblinded, raising risk of bias. Sensitivity across study type and quality showed a consistent direction of benefit, though magnitude varied. Standardised, blinded measures are needed to reduce bias and improve reliability.

Pharmacology

Guidelines for beta-blocker selection in HOCM are limited. Cardio-selective agents (bisoprolol, metoprolol, atenolol) are generally preferred, while non-selective agents with α-blocking properties such as labetalol are avoided as they may worsen LVOT gradients.³¹ Propranolol is the most studied, reflecting early use, though recent data focus more on bisoprolol and metoprolol.

Both selective and non-selective β-blockers reduced HR, LVOT gradient and improved NYHA class, but dosing varied widely, complicating attribution to individual drugs and underscoring the need for adequately powered RCTs of contemporary agents. Despite stratification by drug and dose, no β-blocker showed clear superiority; benefits appear class-wide, with cardio-selective β₁-blockers preferred for tolerability and safety. Adverse effects were broadly consistent, with most discontinuations due to bradycardia or intolerance, but incomplete reporting—especially in older cohorts—limits reliable safety comparisons.

Effect on stage of disease

Beta blockers reduce LVOT gradients across obstruction types but are most effective in latent and labile cases. Propranolol’s prevention of stress-induced obstruction suggests early use may slow hypertrophy progression. In resting obstruction, outcomes were mixed—some patients improved, others worsened or died—indicating limited benefit in advanced disease. This contrasts with haemodynamic data showing consistent gradient reduction, likely reflecting differences in severity and study design. Adelman et al²⁵ lacked a placebo group, and variable enrolment stages further limit inference. Stenson et al²⁰ noted acute benefit during stress but questioned long-term disease modification. Sensitivity analyses showed a consistent directional effect, but small, unblinded cohorts and inconsistent stratification raise risk of bias. Overall, beta blockers are effective in latent and labile obstruction, while benefits in resting obstruction remain uncertain.

Long-term mortality data

Mortality evidence is limited, as most studies were underpowered or lacked follow-up. Sensitivity analysis of two large retrospective cohorts showed contrasting results: Melacini et al²⁸ found no protection against sudden cardiac death in the β-blocker subgroup, while Javidgonbadi et al²⁹, though based on a mixed-therapy cohort, reported a dose-response reduction in disease-related and heart failure mortality with early, sustained β-blocker use. Javidgonbadi et al²⁹ also noted long-term improvements in LVOT gradient and NYHA class; however, data was limited to cohort medians and unsuitable for pooling. Discrepancies likely reflect differences in study era, patient selection and endpoints. Both studies were observational, unblinded and prone to confounding. Neither was designed with survival as a primary outcome, and mortality definitions varied. Thus, survival evidence is weaker than for haemodynamic or symptomatic outcomes. Overall, β-blockers may improve outcomes via rate control and reduced wall stress, but direct survival benefit is unproven. Contemporary, adequately powered mortality trials are needed.

Strengths and limitations

A substantial body of evidence supports beta blockers in HOCM, with consistent improvements in HR, LVOT gradient and symptom burden allowing evidence-based conclusions.

However, important limitations remain. Few large RCTs exist; Dybro et al⁸ is one of the few high-quality examples, limiting pooled analyses. Most included studies were small, underpowered and heterogeneous in design, dosing and outcomes. Only two retrospective cohorts contributed meaningful mortality data, leaving the survival effect uncertain. Older studies often omitted SDs and lacked detail on randomisation, blinding and confounding. Risk of bias was generally high. Sensitivity analyses confirmed LVOT findings were robust but highlighted heterogeneity in HR and symptom outcomes.

Many recent HOCM trials have focused on novel agents, where beta blockers were background therapy; therefore, data could not be isolated. Despite these weaknesses, consistent improvements across settings suggest beta blockers provide symptomatic and haemodynamic benefit, supporting their continued role and the need for contemporary, adequately powered RCTs.

Certainty of data

Certainty of evidence was appraised using ROB-1 for RCTs, ROBINS-I for cohorts and OCEBM levels (table 6). LVOT gradient reduction was rated moderate certainty. HR, NYHA, BP, symptoms and metabolism were based on small, heterogeneous or older studies, giving low certainty. Mortality, limited to two confounded cohorts with conflicting findings, was rated very low certainty.

Table 6. Summary of certainty of evidence for beta-blocker outcomes in HOCM (GRADE-style assessment).

Outcome	Studies (n)+analysis type	Risk of bias	consistency	Certainty of evidence
LVOT gradient	5 (3 pooled)	Moderate	Consistent reduction across RCTs/cohorts	Moderate
Heart rate	15 (3 pooled)	High (heterogeneity, 84% I²)	Directionally consistent, variable size	Low
Blood pressure	6 (narrative)	Moderate serious	Generally reduced, unclear significance	Low
NYHA status	9 (narrative)	Moderate/serious (subjective)	Consistent downgrades	Low
Symptoms	4 (narrative)	Serious (subjective, unblinded)	Improvement in all, variable size	Low
Cardiac metabolism	4 (narrative)	Serious (small, invasive, older)	Consistent (improved efficiency/exercise tolerance)	Low
Mortality	2 (narrative)	Serious (retrospective, confounding)	Inconsistent (no SCD benefit vs HF mortality benefit)	Very low

Outcome=clinical or physiological endpoint assessed. No. of studies=number of included studies contributing data; ‘pooled’ indicates those entered into meta-analysis. Risk of bias based on, Risk of bias 1, ROB-1 (RCTs) or Risk of bias in non randomised studies of interventions, ROBINS-I (cohorts). Consistency=direction and agreement of findings across studies. Certainty of evidence=overall certainty rating using ROB, study design and OCEBM levels. GRADE = Grading of recommendations, assessment, development and evaluation. HF = heart failure. SCD = Suddent cardiac death

Note: ratings follow GRADE-style terminology (moderate, low, very low) adapted to this review.

HOCM, hypertrophic obstructive cardiomyopathy; NYHA, New York Heart Association; OCEBM, Oxford Centre for Evidence-Based Medicine; RCT, randomised controlled trial; ROB-1, Risk of Bias 1.

Conclusion

This systematic review shows that beta blockers provide consistent clinical benefits in HOCM, reducing LVOT gradients, relieving symptoms and improving exercise tolerance. Although many studies are small and dated, more recent data support these findings.

Uncertainty remains regarding optimal agent selection, dosing and the effect on long-term survival, as mortality evidence is limited to two retrospective cohorts with divergent results. Future trials should integrate haemodynamic, symptomatic and survival endpoints within the same populations to determine whether physiological improvements translate into meaningful long-term benefit.

As new pharmaco-structural therapies emerge, beta blockers may eventually be superseded. Nonetheless, ongoing evaluation of current practice remains essential to guide future strategies and improve outcomes for patients with HOCM.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.