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- What this Study Adds
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Hypertrophic cardiomyopathy (HCM) is a genetic disease of the cardiac sarcomere characterized by progressive, usually asymmetrical, wall thickening and left ventricular hypertrophy, impaired contractility and diastolic dysfunction of the left ventricle, with imminent development of heart failure [1-5]. An unexpected drop of blood pressure during exercise, and neurological symptoms, such as repetitive fainting, dizziness or blurred vision, are found with progression of the disease. Patients with HCM are at increased risk of mortality from several causes, such as serious ventricular arrhythmia leading to sudden cardiac death, progression of heart failure or stroke [1-5].
An impaired sympathetic–parasympathetic balance is frequently involved in the pathogenesis of HCM. An increased adrenergic drive is believed to be a potential stimulus for left ventricular hypertrophy, a variety of the symptoms and premature death in HCM patients [2, 3, 6-14].
Blockers of β-adrenergic receptors, called also β-blockers, belong to the first-line pharmacological treatment in HCM patients, mainly because of their strong negative inotropic effect on the myocardium, reduction in ventricular stiffness, improvement of ventricular relaxation, slowing of the heart rate with increased time for diastolic filling, and a reduced excitability [2, 3, 15, 16]. These drugs have proven beneficial effects in HCM patients with angina or dyspnoea on effort, particularly when associated with left ventricular outflow tract (LVOT) obstruction, and are often used as an antiarrhythmic treatment of ventricular arrhythmias [1-3, 6-8, 16]. Although nondihydropyridine calcium channel antagonists, i.e. verapamil and diltiazem, are an alternative to the β-blocker approach in the treatment of HCM [3, 16], mainly in patients without LVOT obstruction, the evidence for their use in HCM patients is not as strong as for β-blockers. In contrast to calcium channel antagonists, β-blockers, by blocking β-adrenergic receptors, produce a number of autonomic effects in different groups of patients, such as those with hypertension, stable coronary artery disease or heart failure, including reduction of sympathetic influences or improvement of vagal effects on the heart [17-21]. However, similar data on the autonomic function of the cardiovascular system in HCM patients treated or not with β-blockers are missing.
The aim of this observational study was to compare the autonomic modulation of the heart rate between consecutive HCM patients, treated or untreated with β-blockers, and healthy subjects. Heart rate variability (HRV), baroreflex sensitivity (BRS) and baroreflex delay, i.e. delay in a change in heart rate after blood pressure alteration, were used as indirect and non-invasive indices of the autonomic control of the cardiovascular system.
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In this study, we have observed no difference in HRV and baroreflex sensitivity between HCM patients treated and untreated with β-blockers, as well as between the HCM patients and control subjects. However, baroreflex delay is significantly prolonged in untreated HCM patients compared both with HCM individuals on β-blockers and with healthy participants. The duration of baroreflex delay in HCM patients on β-blocker therapy is not significantly different from that in healthy volunteers. In other words, HCM patients treated with β-blockers present with a normalized delay of baroreflex. This seems to be a novel, previously unreported effect of these drugs.
The autonomic regulation in HCM patients has been studied by various means, including measurement of circulating catecholamines, myocardial norepinephrine content, myocardial norepinephrine spillover or norepinephrine reuptake by sympathetic nerves [13, 14, 31, 32]. It has even been reported that HCM patients have a reduced myocardial β-adrenergic receptor density  compared with healthy people. Looking beyond catecholamines, such non-invasive functional methods as HRV and arterial or cardiopulmonary baroreflex function analysis have also been used in HCM patients, showing not only the sympathetic agitation but also vagal withdrawal in this disease [12, 33-37].
While HRV is believed to represent mainly the vagal tonic influence on the heart, baroreflex function is a good approach for the evaluation of the reflex autonomic modulation of the whole cardiovascular system [24, 38, 39]. Few papers report on the function of the cardiopulmonary or arterial baroreflex in HCM patients [36, 37]. Usually, it is shown that the autonomic control of the heart is mediated by changes in blood pressure in the main or pulmonary circulation in HCM patients. An alternative hypothesis is that due to abnormal local wall strains the mechanoreceptors of the hypertrophied left ventricle may present an exaggerated response to some stimuli, e.g. exertion, and lead to some of the changes in the autonomic activity [9, 36, 37, 40].
In our study, we have analysed total HRV by means of the standard deviation of the duration of all pulse intervals and, additionally, with the use of spectral HRV analysis (Table 2) . There were no significant differences in HRV between the studied HCM groups, or between them and the healthy group. Also, we have not observed any significant difference in the resting spontaneous BRS  between the HCM patients and the healthy people, or between HCM patients with or without β-blockers. It should be mentioned, however, that baroreflex sensitivity characterizes only the magnitude of the cardiac cycle change in response to a change in blood pressure. In contrast, the baroreflex delay is an index that quantifies the latency of the heart response to a change in autonomic modulation secondary to an alteration in blood pressure [26-29, 41]. In other words, baroreflex sensitivity describes the amount of response of the heart to a change in blood pressure, whereas baroreflex delay represents the dynamicity of this process.
It has been shown that baroreflex delay increases after atropine-induced vagal blockade, i.e. the conditions in which the vagally mediated control of sinus node activity are stopped, while the sympathetic effects become unopposed [29, 41]. Westerhof et al.  have also observed that the baroreflex delay is prolonged during head-up tilting, and the magnitude of this prolongation depends both on the duration of the tilting and the tilting angle. Head-up tilting is a physiological challenge accompanied by fast, persistent vagal withdrawal and sympathetic agitation [29, 41-43]. These studies clearly show that the baroreflex delay is a sensitive marker of changes in the sympathetic activity [29, 41, 43].
To the best of our knowledge, the baroreflex delay has never before been analysed in HCM patients, and thus reporting on the delay in these patients is one of the novelties of this study. We have observed that the baroreflex delay in HCM patients without β-blockers is significantly longer, by ∼0.8 s, than in healthy people. This suggests that the dynamicity of the whole baroreflex arc between arterial baroreceptors loaded or unloaded by any change in systolic blood pressure (afferent part of this reflex) and the evoked sinus node response in the form of an altered duration of the cardiac cycle is postponed (efferent part of the reflex). This finding is no longer surprising if we connect the following two aforementioned aspects: (i) the adrenergic predominance in HCM patients compared with healthy people [13, 14, 31-37]; and (ii) the change in the baroreflex delay elicited by changes in the sympathetic and parasympathetic activity [29, 41]. Taking into account both these aspects, it starts to become obvious that the increased adrenergic drive in HCM patients must increase the baroreflex delay in them.
The observed prolongation of the baroreflex delay is due to the untreated adrenergic effects in HCM patients without β-blockers. This situation seems to be treatable and reversible, because the baroreflex delay in HCM patients on β-blockers is approximately 0.5 s shorter than in HCM patients without these drugs, and it becomes comparably long as in healthy people. The shorter and normalized baroreflex delay in HCM patients on β-blockers is another novelty of our study, because a similar effect has not been studied or demonstrated before.
β-Blockers represent the mainstay of the most contemporary pharmacological therapy in HCM patients, because they reduce symptoms by a number of potential mechanisms (e.g. strong negative inotropic effects, improvement of ventricular filling and reduction in heart rate, oxygen consumption and angina pain) [3, 6, 16]. Our additional statistical analysis shows that only β-blockers influence baroreflex delay, and their effect is independent of age and gender in HCM patients. Most probably, it is also independent of the remaining pharmacological treatment in our patients. If so, a natural consequence of our findings are questions about the mechanisms of the observed beneficial effects of β-blockers on the baroreflex delay in HCM patients, and whether such an effect might be predicted or expected?
Regarding the mechanisms of action of β-blockers, we need to refer to the aforementioned effect of catecholamines, i.e. the downregulation of myocardial β-adrenergic receptors in HCM patients [1-3, 6-8, 16]. If we consider β-blockers, these drugs reduce or completely prevent the influence of catecholamines on β-adrenergic receptors within the cardiovascular system in different diseases, including HCM. It has been observed that the use of β-blockers in patients with heart failure due to dilated cardiomyopathy was associated with upregulation of the density of myocardial β-adrenergic receptors . Although a similar study in HCM has not yet been performed, we may assume that these drugs can induce similar adaptation of the adrenergic system. It is thus plausible that in HCM patients receiving long-term treatment with β-blockers (in our study, metoprolol or bisoprolol for at least 6 months), there was sufficient time for such upregulation of the β-adrenergic receptors to take place. A higher density of receptors usually requires less agonist to induce a comparable effect than during conditions in which the receptor density is lower. This might provide new conditions for the sympathetic–parasympathetic balance and improve the dynamicity for the blood pressure–heart rate interactions, i.e. shortening the prolonged baroreflex delay. However, this explanation is based not only on the results from other studies but also on some extrapolations of these results and it therefore remains only a speculation.
The answer to the question of whether the observed effect of β-blocker on baroreflex delay might be expected or not is not so obvious. On the one hand, β-blockers directly slow down the rate of spontaneous depolarization of the sinus node; therefore, the later response of the sinus node to a change in blood pressure with a further prolongation of the already longer baroreflex delay might be expected. Of our HCM patients, those on β-blockers had a slightly longer mean resting pulse interval of 983 ms (i.e. a heart rate of 61 beats min−1) than patients without β-blockers, whose pulse interval was 908 ms (or a heart rate of 66 beats min−1). These mean pulse intervals did not differ significantly between both HCM groups (Table 2), whereas their baroreflex delays were significantly different. For this reason, it is probably not the effect of β-blockers on the heart rate that is responsible for our findings. Another potential explanation is the beneficial action of β-blockers on the sympathetic–parasympathetic balance. The β-blocker-induced shift of this balance towards the restoration of vagal control over the heart might increase the dynamicity of such control. It has been reported that vagal effects on the sinus node take no more than 0.3–0.5 s in the resting supine position, and that this time is prolonged during sympathetic stimulation triggered by head-up tilt (to ∼0.9 s) or atropine blockade (to >1.2 s) . If HCM without β-blockade translates into more adrenergic activity and HCM with β-blockers means less sympathetic tone, then the above argument seems to be in agreement with the expectation that β-blockers shorten the baroreflex delay.
There is one additional aspect of our study which requires another explanation. The HCM patients on β-blocker therapy had a significantly increased LVM, LVMI and left ventricular ejection fraction compared with HCM patients who were not treated with β-blockers. These findings might be explained by the incidence of the obstruction of the LVOT in HCM patients with or without β-blockers. In the group of 19 HCM patients without β-blockers, there were only four patients with the LVOT obstruction. In contrast, in the group of 32 HCM patients treated with β-blockers, nearly half of them (15 cases) presented with LVOT obstruction (Table 1). Although the proportion test did not show any statistical difference in the incidence of LVOT obstruction, its presence is always associated with much greater left ventricular hypertrophy, with more increased LVM and LVMI and with more dynamic myocardial contraction, shown here by the higher ejection fraction [1-3, 7, 8].
Limitations of the study must be recognized. First, only indirect measures for the evaluation of autonomic modulation of the cardiovascular system were applied. However, various methods for HRV and baroreflex function are commonly used, both in research and in clinical practice [24, 39, 45-49]. A second limitation is the use of a spontaneous method for baroreflex function and not, for example, phenylephrine or nitroprusside challenges. However, with HCM patients even short-lasting but dramatic changes in afterload and preload can cause serious clinical problems (e.g. arrhythmia, angina or syncope). This raises both safety and ethical issues, for which reason we have decided not to perform phenylephrine/nitroprusside tests. We are also aware that the use of eight parameters in a multivariate linear regression model for baroreflex delay with only 51 HCM patients may raise some questions about the reliability of the results. We used this analysis only as an exploratory data-mining tool to look for new ideas and suggestions for future and larger studies. Finally, we have limited detailed considerations of the various mechanisms leading to sympathetic–parasympathetic imbalance in HCM patients, because they would only be speculative and far beyond the scope of this paper.
In summary, we have observed that the baroreflex delay is longer in HCM patients untreated with β-blockers in comparison to both HCM patients on β-blocker therapy and healthy subjects. This prolongation of the delay may suggest a change in the dynamicity of the sinus node response to a change in blood pressure caused by an increased sympathetic predominance in HCM patients. We have also observed that this delay is normalized in HCM patients who are treated with β-blockers, and that the reduction in the baroreflex delay caused by β-blockers is independent of the age and gender of the patient. As this study appears to provide the first analysis of baroreflex delay in HCM patients, we believe that our results add important information regarding the pathomechanisms of HCM. Furthermore, we believe that the reported effect of β-blockers on baroreflex delay in HCM patients provides some new insights into the mechanisms of action of these medications in HCM patients.
We are aware, however, that more extensive clinical studies in HCM patients are needed to explore the clinical value of baroreflex delay and the effects of other treatment options (e.g. calcium antagonists, septal myotomy or alcohol ablation, or coil embolization of the septal coronary arteries [3, 16]) on the autonomic regulation of the cardiovascular system.