Abstract

Beta-blockers are universally used as a first-choice pharmacological treatment to aid patients suffering from hypertrophic cardiomyopathy (HCM). They act by lowering the heart rate and myocardial contractility, which is the force at which the heart contracts, thereby, easing left ventricular outflow tract obstruction and improving diastolic filling. However, clinical response and tolerability to beta-blocker treatment can vary substantially between patients, despite suffering from the same condition. It can relieve symptoms significantly in some, have minimal effect or even cause side effects in others, making hypertrophic cardiomyopathy difficult to treat.

This research paper will investigate the factors that explain the variation in clinical response and tolerability to beta-blocker therapy among patients with hypertrophic cardiomyopathy. To address this, the paper will explore four interacting factors that cause this variation in clinical response and tolerability to beta-blockers. First, left ventricular tract obstruction is examined, including how the outflow blockage in the heart differs between patients, its resting versus provoked presentation and how this affects whether beta-blockers actually reduce symptoms. Next, genetic variation and HCM phenotypes are examined, including how differences in the ADRB1 and CYP2D6 genes can alter beta-blocker response, and how obstructive and non-obstructive HCM, as well as distinct phenotypes such as classic HCM and adverse remodelling, can influence treatment response through differences in cardiac structure and function. Thirdly, diet and symptom severity are considered as additional, environmental factors that cause an alternative clinical response to beta-blocker therapy. Finally, the limitations and risks associated with treating HCM with beta-blockers are explored, including dosing issues, worsened Raynaud’s phenomenon, differences between drug types and rare but serious side effects. Together, these factors demonstrate that beta-blocker response in HCM cannot be attributed to a single cause, but instead reflects the interaction of cardiac anatomy, drug pharmacology, individual physiology and genetic variation.

Introduction

Hypertrophic cardiomyopathy (HCM) is a heart condition in which the muscle in the left ventricle becomes abnormally thick. The thickening can interfere with the heart’s ability to fill with and pump blood, potentially resulting in symptoms like fatigue, shortness of breath, dizziness and fainting. In severe cases, HCM can even lead to abnormal heart rhythms, heart failure and an increased risk of sudden cardiac death. One of the medications commonly used to treat patients with HCM is beta-blockers. Beta-blockers are a type of medication that reduce the effects of adrenaline on the heart, resulting in a slower heart rate and decreased contraction. By reducing the heart’s workload and allowing for more blood to fill up in the ventricle, beta-blockers can relieve symptoms and improve cardiac function in some patients with HCM. However, the effectiveness of beta blockers varies among individuals, and not all patients will experience the same degree of symptom relief. Therefore, understanding the factors that contribute to these different responses to beta blockers is important for determining the most effective treatment for improving and managing HCM.

Left Ventricular Outflow Tract Obstruction

Left ventricular outflow tract obstruction (LVOTO) is one of the defining haemodynamic features of hypertrophic cardiomyopathy. It occurs when blood flow from the left ventricle to the aorta is physically blocked, forcing the heart to generate a higher pressure gradient when ejecting blood and reducing the volume of blood delivered per contraction. LVOTO is measured by the highest pressure gradient of at least 30mmHg at the left ventricular (LV) outflow, present either at rest or on provocation (Vilcant & Hai, 2022). In a healthy heart, the pathway bordered by the interventricular septum and the anterior leaflet of the mitral valve remains wide and unobstructed throughout each contraction. However, in HCM, thickening of the septum narrows this pathway. In most patients with HCM, the front leaflet of the mitral valve moves toward the septum during systole, a movement known as systolic anterior motion (SAM). This further restricts the outflow tract and frequently causes mitral regurgitation at the same time (Vilcant & Hai, 2022). Unlike a fixed, regular structural blockage, LVOTO is dynamic in nature; its severity depends on loading conditions, heart rate and contractility, meaning it can worsen during exercise or emotional stress and ease at rest. LVOTO is common in HCM, present in around 75% of patients overall (Lederman et al., 2025), and about two-thirds of HCM patients specifically have an obstructive form of the disease (Vilcant & Hai, 2022). 

Non-vasodilating beta-blockers, which slow the heart rate and lower cardiac output without widening or relaxing blood vessels (Pucci et al., 2016), are adjusted to the highest dose patients can tolerate. These are the main oral drug treatments for symptomatic obstructive HCM. They act via a negative inotropic and chronotropic effect – reducing heart rate and myocardial contractility – to reduce obstruction and improve diastolic filling (Mathai & Williams, 2022). This mechanism is supported by direct trial evidence: in a randomised, double-blind, placebo-controlled crossover trial of 29 patients with obstructive HCM, metoprolol (a prescription beta-blocker) significantly reduced the LVOT gradient and improved stroke volume compared with placebo, demonstrating its effectiveness (Dybro et al., 2021). Approximately two-thirds of HCM patients can be managed solely with medical therapy, becoming asymptomatic or only slightly symptomatic, often with a more than 50% reduction in LVOT gradient on echocardiography (Mathai & Williams, 2022). However, as there were only 29 patients, this is a small sample size, which reflects the limitations of this study. 

While a study directly linking septal thickness and beta-blocker response was not established in this research, the severity of the structural abnormality appears closely tied to the type of obstruction a patient presents with, potentially influencing how a rate and contractility lowering drug performs. In a study of patients undergoing septal myectomy, those with latent obstruction (a resting gradient below 30 mmHg but a provoked gradient of 30 mmHg or higher) had significantly lower septal thickness than patients with resting obstruction, despite the two groups showing similarly reduced ability to perform physical activities beforehand (Lu et al., 2017). This suggests that anatomical severity and the resting-versus-provoked difference are related variables, even if the precise effect on beta-blocker response specifically remains an open question warranting further study. 

Patients suffering with left ventricular tract obstruction do not experience it uniformly: it may be present at rest, or it may only appear under provocation such as exercise or a Valsalva manoeuvre (Vilcant & Hai, 2022). This distinction is crucial because patients with latent (provoked-only) obstruction have been shown to have milder underlying septal hypertrophy than those with resting obstruction (Lu et al., 2017). Since beta-blockers act primarily on heart rate and contractility, these are variables that are most influential during exertion; this raises the possibility that their effectiveness may differ between patients whose obstruction is primarily exertional and those whose obstruction persists at rest. However, this should be viewed as a possible effect of this specific drug class rather than a definite explanation. 

A further complication in evaluating beta-blocker response is that gradient reduction and symptomatic improvement do not always have a linear relationship. In the same randomised metoprolol trial, despite a significant reduction in LVOT gradient and improved stroke volume, exercise capacity, maximum oxygen consumption and NT-proBNP levels were not affected significantly (Dybro et al., 2021). The limited improvement in exercise performance may be explained by an approximately 25% decrease in peak heart rate, which counteracted the increase in stroke volume (Weissler-Snir et al., 2023). This finding directly demonstrates that a beta-blocker can measurably improve the LVOT gradient while leaving a patient’s functional symptoms largely unchanged, complicating how “response” should be defined and measured in this population. 

To summarise, LVOT obstruction is a good illustration of dynamic versus static obstruction, resting versus provoked obstruction, and the dissociation between gradient reduction and symptomatic improvement, all of which contribute to how a particular patient will respond to beta-blocker therapy, but the exact interaction of these factors with anatomic severity is an area that needs further investigation. These factors do not act in isolation, setting the physiological stage upon which the drug-class and dosing considerations covered next, and the genetic and biochemical factors such as CYP2D6 metabolism and ADRB1 genotype covered later in this paper, further compound to produce the wide variation in beta-blocker response observed across HCM patients.

Genetics and Phenotypes: Genetic Variation

The differences in patients’ responses to beta-blocker therapy described previously may be due to multiple biological factors, specifically genetic variation. Although factors like LVOT obstruction influence the patient’s ability to tolerate the treatment, genetic differences may play a vital role in the way the medication functions inside the patient’s body. Two genes that hold particular significance in this claim are the ADRB1 and CYP2D6, both of which create fluctuations in the clinical responses to beta-blocker therapy. 

The ADRB1 gene encodes the β1 adrenergic receptor, a protein that is predominantly found in the cardiovascular system. These receptors are then activated by adrenaline and noradrenaline, leading to an increase in both heart rate and the force of cardiac contraction. Beta blockers have the ability to counteract the workload on the heart by reducing the activity and stimulation of the receptors (Frishman, 2003). Due to the drug’s target being the 1 adrenergic receptors, any mutation or genetic variation in the ADRB1 gene, the gene responsible for the production of the receptors, may lead to varied responses in patients with hypertrophic cardiomyopathy (HCM) (Raimoglou et al., 2024). This could help explain why patients with HCM do not respond identically to the use of beta blockers as treatment. 

There are multiple, naturally occurring genetic variations in the ADRB1 gene, also known as polymorphisms. A research study from 2024 investigated two specific polymorphisms within the ADRB1 gene named Ser49Gly and Arg389Gly. These genetic variants can occur in many different genotypes, the following of which are studied: Ser49Ser, Ser49Gly, Gly49Gly, Arg389Arg, Arg389Gly and Gly389Gly (Raimoglou et al., 2024). The researchers carried out various tests on these genetic groups to try to see whether there were fluctuations in the cardiac characteristics and clinical responses to beta-blocker therapy. After comparing the results, researchers found significant results that patients who had the Ser49Ser genotype experienced significant reductions in both ventricular ectopic beats and NT-proBNP levels. Interestingly, patients with the Gly49 carriers, Ser49Gly and Gly49Gly, did not undergo significant changes (Raimoglou et al., 2024). In contrast, all patients in the Arg389 group, regardless of their genotype, did not show significant differences between each other in their responses to the beta-blocker medication (Raimoglou et al., 2024). Overall, this exemplifies that even genotypes within the same polymorphism will be unable to yield uniform results to the drug, indicating it is possible genetic variation in the ADRB1 gene can lead to differences in the response to beta-blocker therapy. 

While variation in the ADRB1 gene can influence the receptors targeted by the medication, genetic mutations also have the ability to affect the drug’s ability to be processed in the body. One example is the CYP2D6 gene, which encodes an enzyme involved in the metabolism of drugs. Metoprolol, a beta blocker, is mainly metabolised by the CYP2D6 enzyme, with roughly 80% of the drug being metabolised through this process (Meloche et al., 2020). As a result, variations in this gene lead to different amounts of enzyme activity between individuals. This means that the same amount of metoprolol may be processed at different rates, leading to different amounts of the medication being available to the patient and therefore altering the effectiveness of the drug (Meloche et al., 2020). 

This difference in enzyme activity is reflected in the different phenotypes of the CYP2D6 gene. These phenotypes include poor, intermediate, normal and ultrarapid metabolisers. Poor metabolisers have reduced CYP2D6 activity, causing metoprolol to be cleared much more slowly, potentially leading to more exposure to the medicine. Similarly, individuals with more CYP2D6 activity may eliminate metoprolol more quickly, leading to lower exposure and a possibly weaker beta blocker. A systematic review and meta-analysis from 2020 reinforces this relationship and found that poor metabolisers had the ability to reduce heart rate and blood pressure more than non-poor metabolisers (Meloche et al., 2020). These findings suggest that genetic variations in drug metabolism may influence the response to metoprolol. 

The consequences of variable exposure to the drug may be more significant than just the effectiveness of beta-blocker therapy, as they also extend into tolerability and side effects. Due to poor metabolisers having greater exposure to metoprolol, beta blockers could become so prominent that there is an excess amount of heart rate reduction. The meta-analysis found that bradycardia, an abnormally slow heart rate, appeared more often with poor metabolisers (Meloche et al., 2020). Bradycardia creates side effects including dizziness, fatigue and fainting, creating higher levels of intolerability. The results of the systematic review indicate that variation in the CYP2D6 gene may play a role in both how effective beta-blocker treatment is, as well as how tolerable the treatment is for HCM patients. 

Taken together, the ADRB1 and CYP2D6 genes both provide compelling yet unique evidence that supports how genetics may influence beta-blocker therapy. The ADRB1 gene may affect the receptors that beta blockers target, whereas the CYP2D6 gene affects the rate at which the drugs are metabolised. Overall, the genetic differences in hypertrophic cardiomyopathy patients may influence both the effectiveness of the drug and the severity of the symptoms that beta blockers cause in patients. Ultimately, the evidence heavily suggests that genetics may be one of many factors that help explain the various responses and side effects that occur in patients with HCM. The findings in the research study demonstrate that there is an association between different clinical results and different genotypes within the same polymorphism (Raimoglou et al., 2024). Similarly, the meta-analysis found that multiple phenotypes in the CYP2D6 gene lead to both variable symptoms in patients as well as different amounts of effectiveness (Meloche et al., 2020). Together, these findings show that drug target variation and drug metabolism variation may help explain why patients and beta blockers respond differently with identical treatment. 

There are many possible phenotypes among individuals diagnosed with hypertrophic cardiomyopathy. The main ones are obstructive HCM and non-obstructive HCM. The difference between these phenotypes is that obstructive HCM is characterised by a thickening of the septum, the wall that separates the left and right ventricles. This thickening can cause obstruction of blood flow from the left ventricle to the aorta. As for non-obstructive HCM, the heart muscle swells but it does not hinder blood flow (Penn Medicine, 2025). 

Other phenotypes of hypertrophic cardiomyopathy include the classic HCM phenotype and adverse remodelling. The classic HCM phenotype is the most common phenotype of individuals with HCM, as 75% of patients experience it. The phenotype consists of a hypertrophied LV, where the left ventricle abnormally thickens, as well as a nondilated LV, which is when the left ventricle is not widened or enlarged, remaining a relatively normal size, and hyperdynamic LV occurs when the left ventricle is contracting very strongly, resulting in a high ejection fraction (EF) of >65%. Additionally, 70% of patients of the classic HCM phenotype experience LVOT obstruction as an associated feature. Although classic HCM can emerge at any age, it generally begins in adolescence and is typically completed by early adulthood (Soler et al., 2018). As for adverse remodelling, 15-20% of patients experience the phenotype. It is identified by the gradual reduction in systolic and diastolic function, with EF dropping to 50-65%. To add on, the phenotype is linked to atrial fibrillation, decreased or absent LVOT, the progressive thinning of the left ventricle wall, increased symptoms and functional limitations, as well as moderate to severe LA and LV dilation. Patients with adverse remodelling have an increased risk of sudden cardiac death (SCD) of 3-5% per year compared to other phenotypes of HCM. This highlights the clinical significance of diagnosing adverse remodelling, as it can alter various treatments for patients, such as considering the use of prophylactic ICD and the evaluation for heart transplants prior to the development of symptoms (Soler et al., 2018). 

These phenotypes can affect beta-blocker treatment response in several ways. For obstructive HCM, beta-blocker treatment may cause a decrease in heart rate, lengthening the diastolic filling phase. Due to this, patients with a stiffly compliant left ventricle may fill more effectively before the next beat. Although beta-blockers can improve resting gradients and symptoms, they do not significantly increase maximum exercise capacity or peak oxygen uptake. Beta-blockers also frequently result in fatigue and exercise intolerance, which can simulate worsening heart symptoms (Smith et al., 2025). As for non-obstructive HCM, the heart rate is also lowered to increase the diastolic filling time. Research and investigations have proven that beta-blockers cause heart rate slowing, which reduces myocardial oxygen demand while exercising. They also relieve symptoms including chest discomfort and shortness of breath. However, different patients and HCM phenotypes may respond differently to beta-blockers (Hypertrophic Cardiomyopathy Association.org, 2024).

Diet and Severity of Symptoms

Diet is another factor that contributes to differences in the clinical characteristics of patients with HCM. HCM is primarily a genetic disease associated with mutations in genes involved in the structure and contraction of cardiac muscle. However, people with similar genetic causes of HCM can experience different levels of cardiac hypertrophy, dysfunction and symptoms. This variation suggests that environmental and metabolic factors may interact with genetic susceptibility and influence how HCM develops (Meder et al., 2018). 

Diet is relevant because the heart requires a continuous supply of energy to maintain normal cardiac function. Research has identified metabolic changes in genetic forms of HCM, suggesting that abnormal energy production and metabolism may contribute to cardiac abnormalities (Meder et al., 2018). Therefore, diet may act as an environmental factor that influences disease progression in individuals who already have a genetic predisposition to HCM, rather than directly causing the condition. Nollet et al. (2023) investigated this relationship using wild-type (WT) and heterozygous (HET) mice. The HET mice carried a Mybpc3 mutation associated with HCM, while the WT mice did not. The mice were fed either a Western diet (WD) or normal chow (NC) for eight weeks. This allowed researchers to compare the effects of a Western diet in mice with and without a genetic susceptibility to HCM (Nollet et al., 2023). The results showed that the Western diet caused systemic metabolic disruption in both WT and HET mice. However, only the HET mice fed the Western diet developed significant cardiac hypertrophy and dysfunction. These mice showed impaired cardiac function, including reduced left ventricular ejection fraction and worsening left ventricular strain (Nollet et al., 2023). This suggests that the Western diet had a greater effect on cardiac function when combined with a response to beta-blocker therapy. Therefore, it would be inappropriate to conclude that a Western diet causes differences in beta-blocker response based only on this study. The findings therefore support the possibility that genetic and environmental factors can interact to influence disease severity. 

The study also identified changes in cardiac metabolism. Western diet-fed mice showed reduced oxidative phosphorylation and increased levels of potentially harmful lipids in the heart (Nollet et al., 2023). Oxidative phosphorylation is an important mitochondrial process that produces ATP, which provides energy for cells. Since the heart has a high energy demand, changes in energy production may affect its ability to function effectively. The reduction in oxidative phosphorylation therefore suggests that the Western diet altered the energy metabolism of the heart. Changes in fatty-acid metabolism were also observed. Acylcarnitines accumulated in the cardiac tissue of Western diet-fed HET mice, suggesting that fatty-acid metabolism was impaired (Nollet et al., 2023). The researchers also found differences in proteins involved in fatty-acid oxidation between WT and HET mice. Together, these findings suggest that the genetically susceptible hearts had a reduced ability to adapt to the metabolic stress caused by the Western diet (Nollet et al., 2023). 

This research is relevant to the research question because it demonstrates that factors outside the primary genetic mutation may influence the clinical characteristics and severity of HCM. The findings support the idea that genetic susceptibility and environmental factors can interact rather than acting independently. This is consistent with research identifying metabolic disturbances as an important factor in HCM and recognising the variation in how the disease is expressed between individuals (Meder et al., 2018). 

However, there are limitations when applying these findings to human patients. Most importantly, Nollet et al. (2023) conducted the experiment using mice rather than humans, and the genetically modified HET mice cannot be assumed to respond identically to human patients. Additionally, the Western diet used in the experiment cannot be assumed to represent the exact diets consumed by humans. The study also investigated cardiac function and metabolism rather than whether diet affected the effectiveness or tolerability of HCM medications. Beta-blockers are commonly used in HCM treatment, particularly for symptomatic patients with obstructive HCM, as they can reduce heart rate and improve symptoms (Ommen et al., 2024); however, current evidence does not establish that diet directly determines how effectively a patient responds.

Overall, diet should be considered a potential modifying factor rather than a direct cause of differences in HCM or beta-blocker response. The research suggests that a Western diet may increase metabolic stress and cardiac dysfunction in individuals who are genetically susceptible to HCM. However, further research in human patients is required to determine whether these findings apply directly to human HCM and whether dietary factors influence treatment outcomes.

Limitations and Risks

Beta blockers are one of the most effective and standard medicines in treating hypertrophic cardiomyopathy, but rare genetic variations and unique physiological differences can completely alter how patients respond to these medications. 

Different types of beta blockers come with different risks and limitations depending on how they target receptors in the body. Cardioselective beta blockers primarily target B1 receptors in the heart to lower heart rate and blood pressure, making it safer to use for people with mild lung issues, though it can still cause symptoms of fatigue, dizziness or cold hands. Additionally, at high doses, these beta-1 blockers can lose their selectivity and start to affect beta-2 receptors located in the lungs, creating major risks for patients with COPD and asthma. Additionally, because these medications blunt the body’s natural adrenaline response, patients might experience severe fatigue and dizziness while exercising. Doctors can prescribe simple, individualised exercise programmes to adhere to the medication side effects. If patients are still symptomatic, doctors will pivot to a drug known as non-dihydropyridine calcium channel blockers. The channel blockers prevent calcium ions from entering the heart muscle, which softens the stiff tissue and improves left ventricular diastolic function. 

The dosage that works for one patient may not work for another patient, since the specific effects can vary from person to person. For current medications, guidelines recommend titrating the medicine based on effectiveness or the maximum dose the patient can tolerate, rather than using one identical dose for every patient (Thomas & Johnson, 2020). This is important because too much beta blockade can cause excessive slowing of the heart, low blood pressure, dizziness and weakness, while too little of a dosage may not provide enough symptom relief. Because of this, there is not one “optimal” dosage that works for every patient. Doctors generally need to adjust the dosage based on the person’s blood pressure, heart rate, symptoms and how well they tolerate medicine. Genetic differences in drug metabolism can further complicate treatment, as two patients with identical dosages may result in varied levels of concentration in their bodies (Bjerregaard et al., 2026). Research on beta-blocker pharmacogenetics has shown that variations in genes involved in drug metabolism and beta-adrenergic receptors can contribute to differences in treatment response (Cleveland Clinic, 2024). 

Another serious but uncommon concern involves patients with an undiagnosed adrenal gland tumour called pheochromocytoma. These tumours can release large amounts of adrenaline and catecholamine, or other similar hormones, into the body. (Johns Hopkins Medicine, 2026). If a beta blocker is given before the excessive amounts of adrenaline are controlled, blocking the beta receptors can leave the alpha-receptors unopposed. This is known as unopposed alpha stimulation and can cause several blood vessel constrictions to occur and an increase in blood pressure. This situation is not a typical reaction experienced by most patients, but it demonstrates why doctors need to consider patients’ previous medical concerns before starting beta blockers.  

Beta blockers can also cause chronotropic incompetence, also described as “frozen heart”. This does not mean the heart stops responding, but rather the heart cannot increase its rate when doing strenuous activity. Normally, adrenaline causes the heart to beat faster and contract more strongly during physical activity (Griffith, 2025). Beta blockers reduce this response, causing patients to feel more fatigued, unusually tired, out of breath and short of breath during exercise. This can especially be difficult for patients with HCM since the disease itself can already cause exercise intolerance. Therefore, while lowering the heart rate can be beneficial for controlling the symptoms, lowering it too much can negatively impact a person’s ability to exercise and perform daily tasks. 

Another risk of beta blockers is that they can sometimes mask warning signs of hypoglycaemia. When blood sugar becomes too low, the body releases more adrenaline, which can cause symptoms like rapid heart beat, shaking and anxiety. Beta blockers can reduce some of these adrenergic responses, causing patients to not release their blood sugar. Although beta blockers do not automatically cause neuroglycopenic shock, severe untreated hypoglycemia can eventually cause neuroglycopenic symptoms, such as difficulty concentrating, unusual behaviour, seizure and loss of consciousness. This makes monitoring especially important for patients who are at risk for hypoglycaemia. 

Finally, beta blockers can contribute to vasoconstriction and worsening of Raynaud’s phenomenon in susceptible patients. Raynaud’s phenomenon occurs when tiny blood vessels, usually in the fingers or toes, undergo excessive vasospasm (Tervi, 2024). The affected areas can go cold, numb, painful or change color. The risk is higher with beta blockers that also affect beta-2 receptors because those receptors are in charge of managing blood relaxation in certain muscle groups. If beta receptor blockade increases the tendency towards vasoconstriction, patients who already experience Raynaud’s might have worse symptoms. This is another example of how the same medication can have different effects depending on the patient’s individual characteristics and other health conditions.

Overall, these risks and limitations demonstrate why beta blockers cannot be viewed as a medication that will produce the exact same result in every patient. Beta blocker type, dosage, genetics, drug metabolism, receptor activity, underlying health conditions and individual sensitivity all play a key role in the effects of the medication. Research shows that differences in patients’ genes can contribute to different beta blocker responses, therefore proving that biological differences between people can affect how the medication works. Genetic differences in the adrenergic receptors could also influence cardiovascular outcomes and the response to beta-blocker therapy. Ultimately, if beta blockers do not work for one patient, it does not mean that the drug is ineffective as a whole. Instead, doctors need to adjust dosage, type or consider another treatment based on the patient’s symptoms and response. The individualised approach helps explain why beta blockers can produce effective results for some, while others may experience unwanted effects and limited benefits.

Discussion

The evidence presented in this paper suggests that variation in clinical response and tolerability to beta-blocker therapy among patients with HCM is caused by multiple factors rather than a single cause. No single factor can fully explain why the same treatment can produce extremely varying results. Instead, differences in cardiac physiology, HCM phenotype, symptom severity, beta-blocker type and dosage, genetic variation and potentially other environmental factors appear to interact with one another. 

LVOTO is an important physiological factor because beta-blockers reduce both heart rate and myocardial contractility, which in turn decrease the LVOT gradient and improve diastolic filling. However, LVOTO varies between patients and can occur at rest or only after provocation. Furthermore, a reduction in LVOT obstruction does not automatically result in improved exercise capacity. In the metoprolol trial, LVOT gradients and stroke volume improved, but measurements like peak oxygen consumption and exercise capacity did not significantly change. This shows that differences in cardiac physiology may be a large contributor to the variable clinical responses in HCM patients, but solely basing it on this evidence may overlook differences between how the patients actually experience the treatment. 

Genetic variation provides a second mechanism for treatment variability by affecting both the drug’s target and metabolism. The ADRB1 gene demonstrates that some genotypes were associated with different responses. In particular, the Ser49Gly polymorphism provided substantially varying results, whereas the Arg389Gly did not produce meaningful differences between genotypes. Similarly, CYP2D6 variation alters the metabolism of metoprolol. Poor metabolisers generally experienced greater exposure and stronger reductions in heart rate and blood pressure. At times, the beta blockers became overly effective and created abnormally low heart rates, making the treatment intolerable. However, these findings do not establish genetics as the exclusive factor; instead, genetics is one of many contributors. 

HCM phenotype and symptom severity further complicate the response to beta-blocker therapy. Patients with obstructive and non-obstructive disease have different cardiac physiology, while phenotypes like classic HCM and adverse remodelling mean there are different levels of cardiac dysfunction and functional limitation. This means the same reduction in heart rate or contractility will be more beneficial to some patients due to variable phenotypes and symptoms. Increasing beta blockade is also limited by the patient’s ability to tolerate symptoms like fatigue, dizziness and exercise intolerance, which occur as heart rate decreases excessively with the drug. 

Diet represents a potentially important environmental factor, but the evidence is considerably less conclusive. The Western diet mouse study demonstrated greater cardiac dysfunction in mice, suggesting environmental factors may be significant when considering cardiac diseases. However, this study did not investigate the usage of beta blockers or their effectiveness and tolerability in patients. Therefore, dietary factors cannot currently be considered a reliable determinant in the response to beta blockers in human HCM. 

Overall, the evidence supports a different future for beta-blocker therapy: the use of an individualised approach which evaluates both physiological and clinical outcomes and considers the patient’s phenotype, symptoms, tolerance and genetic characteristics. Future research should focus on larger human studies that examine all of these factors together, rather than individually. This could ultimately improve the personalisation of beta-blocker selection and dosing for patients with HCM. Furthermore, the genetic findings also highlight the potential for a different direction in HCM treatment. Researchers are beginning to investigate gene therapies such as CRISPR-based gene editing and gene silencing approaches. These approaches could correct or reduce the effects of the specific genetic defects that are related to HCM. These approaches represent a major paradigm change in treatment techniques and have vast potential for curative options. Additionally, researchers are exploring targeted treatments that specifically target the underlying molecular defects of HCM. This expansion would reflect a more thorough and accurate insight into the pathophysiology of hypertrophic cardiomyopathy. Furthermore, researchers are exploring whether carefully prescribed moderate-intensity exercise may be safe and useful for HCM patients. This necessitates highly tailored risk assessments and collaborative decision making to increase quality of life and reframe patient activity standards (Dupont, 2025).

Conclusion

The evidence indicates that variation in clinical response and tolerability to beta-blocker therapy among patients with hypertrophic cardiomyopathy is explained by a combination of physiological, genetic, pharmacological and environmental factors rather than a single cause. 

Differences in left ventricular outflow tract obstruction and the HCM phenotype can influence how effectively beta blockers improve cardiac functions and symptoms, while factors such as dosage, beta-blocker type and individual health conditions can affect tolerability and the occurrence of adverse effects. Genetic variation also contributes to this variability, with the ADRB1 gene potentially affecting the drug’s target receptor and the CYP2D6 gene influencing the metabolism and concentration of drugs such as metoprolol. Additionally, evidence from animal research suggests that metabolic and dietary factors may modify the severity of HCM, although their direct influence on beta-blocker response in humans remains uncertain. 

Therefore, the difference in beta-blocker response among HCM patients can be understood as a result of interactions between the patient’s cardiac characteristics, genetics, drug metabolism, how often treatment is given and other biological factors. This understanding supports an individualised approach to treatment, where beta-blocker type and dosage are adjusted depending on the patient’s symptoms, physiological response and overall tolerance compared to applying the same treatment strategy to every patient. However, further human research is required to satisfy an understanding of the contribution of factors such as diet and to determine how genetic and physiological differences can be used to more accurately predict treatment response and tolerability.

Bjerregaard, L., Dybro, A.M., Saaby, L., Poulsen, S.H., Rasmussen, T.B. and Jensen, M.S.K. (2026). Beta-blocker (bisoprolol) vs calcium-channel blocker (verapamil) in nonobstructive hypertrophic cardiomyopathy. JACC, 87(8), pp.1063–1083.

Cleveland Clinic. (2024). Chronotropic incompetence (CI): Symptoms & causes. Cleveland Clinic [online]. <https://my.clevelandclinic.org/health/diseases/chronotropic-incompetence>

Curran, L., de Marvao, A., Inglese, P., McGurk, K.A., Schiratti, P.-R., Clement, A., Zheng, S.L., Li, S., Pua, C.J., Shah, M., Jafari, M., Theotokis, P., Buchan, R.J., Jurgens, S.J., Raphael, C.E., Baksi, A.J., Pantazis, A., Halliday, B.P., Pennell, D.J., Bai, W., Chin, C.W.L., Tadros, R., Bezzina, C.R., Watkins, H., Cook, S.A., Prasad, S.K., Ware, J.S. and O’Regan, D.P. (2023). Genotype-phenotype taxonomy of hypertrophic cardiomyopathy. Circulation: Genomic and Precision Medicine, 16(6).

Dupont, I. (2025) HCM: Advancements in diagnosis, treatment and future, HILARIS [online]. <https://www.hilarispublisher.com/open-access/hcm-advancements-in-diagnosis-treatment-and-future-115360.html>

Dybro, A.M., Rasmussen, T.B., Nielsen, R.R., Andersen, M.J., Jensen, M.K. and Poulsen, S.H. (2021). Randomized trial of metoprolol in patients with obstructive hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 78(25), pp.2505–2517.

Frishman, W.H. (2003). Beta-adrenergic blockers. Circulation, 107(18).

Hypertrophic Cardiomyopathy Association (2024). Beta Blockers – What they do & when they’re used in HCM. Hypertrophic Cardiomyopathy Association [online]. <https://www.4hcm.org/beta-blocker>

Lu, D.-Y., Hailesealassie, B., Ventoulis, I., Liu, H., Liang, H.-Y., Nowbar, A., Pozios, I., Canepa, M., Cresswell, K., Luo, H.-C., Abraham, M.R. and Abraham, T.P. (2017). Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy. International Journal of Cardiology, 243, pp.290–295.

Mathai, S. and Williams, L. (2022). Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy and the impact of mavacamten. Therapeutic Advances in Chronic Disease, 13, 204062232211360.

Meloche, M., Khazaka, M., Kassem, I., Barhdadi, A., Dubé, M.P. and Denus, S. (2020). CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta‐analysis. British Journal of Clinical Pharmacology, 86(6), pp.1015–1033.

Nollet, E.E., Algül, S., Goebel, M., Schlossarek, S., van der Wel, N.N., Jans, J.J.M., van de Wiel, M.A., Knol, J.C., Pham, T.V., Piersma, S.R., de Goeij-de Haas, R., Hermans, J., van Klinken, J.B., van Weeghel, M., Houtkooper, R.H., Carrier, L., Jimenez, C.R., Kuster, D.W.D. and van der Velden, J. (2023). Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in mice: A two-hit model of hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology Plus, 6, 100050.

Ommen, S.R., Ho, C.Y., Asif, I.M., Balaji, S., Burke, M.A., Day, S.M., Dearani, J.A., Epps, K.C., Evanovich, L., Ferrari, V.A., Joglar, J.A., Khan, S.S., Kim, J.J., Kittleson, M.M., Chayakrit Krittanawong, Martinez, M.W., Mital, S., Naidu, S.S., Saberi, S., Semsarian, C., Times, S. and Cynthia Burstein Waldman (2024). 2024 AHA/ACC/AMSSM/hrs/paces/SCMR guideline for the management of hypertrophic cardiomyopathy: A report of the American Heart Association/American College of Cardiology Joint Committee on clinical practice guidelines. Circulation, 149(23).

Penn Medicine (2025). Hypertrophic Cardiomyopathy. Penn Medicine [online]. <https://www.pennmedicine.org/conditions/hypertrophic-cardiomyopathy>

Pucci, G., Ranalli, M.G., Battista, F. and Schillaci, G. (2016). Effects of β-Blockers With and Without Vasodilating Properties on Central Blood Pressure. Hypertension, 67(2), pp.316–324.

Raimoglou, D. (2024). Structural and functional impact of adrenoceptor Beta-1 gene polymorphism in patients with hypertrophic cardiomyopathy and response to beta-blocker therapy. The Anatolian Journal of Cardiology, pp.150–157.

Smith, A.J., Magaret, A., Bowles, L., Anderson, T., Panchal, J. and Walters, B. (2025). Beta blockers and hypertrophic obstructive cardiomyopathy: A systematic review and meta-analysis. Open Heart, 12(2), e003460-e003460.

Soler, R., Méndez, C., Rodríguez, E., Barriales, R., Ochoa, J.P. and Monserrat, L. (2018). Phenotypes of hypertrophic cardiomyopathy. An illustrative review of MRI findings. Insights into Imaging, 9(6), pp.1007–1020.

Tervi, A. Ramste, M., Abner, E., Cheng, P., Lane, J.M., Maher, M., Valliere, J., Lammi, V., Satu Strausz, Juha Riikonen, Nguyen, T., Martyn, G.E., Sheth, M.U., Xia, F., Mauro Lago Docampo, Gu, W., Esko, T., Saxena, R., Matti Pirinen, Aarno Palotie, Samuli Ripatti, Nasa Sinnott-Armstrong, Daly, M., Engreitz, J.M., Rabinovitch, M., Heckman, C.A., Quertermous, T., Jones, S.E. and Ollila, H.M. (2024). Genetic and functional analysis of Raynaud’s syndrome implicates loci in vasculature and immunity. Cell Genomics, 100630.

Thomas, C.D. and Johnson, J.A. (2020). Pharmacogenetic factors affecting β-blocker metabolism and response. Expert Opinion on Drug Metabolism & Toxicology, 16(10), pp.953–964.

Van der Velden, J., Tocchetti, C.G., Varricchi, G., Anna Monica Bianco, Sequeira, V., Hilfiker-Kleiner, D., Hamdani, N., Leite-Moreira, A.F., Mayr, M., Inês Falcão-Pires, Thum, T., Dawson, D., Jean-Luc Balligand and Heymans, S. (2018). Metabolic changes in hypertrophic cardiomyopathies: Scientific update from the working group of myocardial function of the European Society of Cardiology. Cardiovascular Research, 114(10), pp.1273–1280.

Vilcant, V. and Hai, O. (2022). Left ventricular outflow tract obstruction, National Library of Medicine [online]. <https://www.ncbi.nlm.nih.gov/books/NBK470446/>

Weissler-Snir, A., Rakowski, H. and Meyer, M. (2023). Beta-blockers in non-obstructive hypertrophic cardiomyopathy: Time to ease the heart rate restriction? European Heart Journal, 44(37), pp.3655–3657.