Abstract
Conflicting results have been published considering the role of head-up tilt test (HUTT) positivity as a prognostic factor in patients with hypertrophic cardiomyopathy (HCM). The relationship between HCM patients' genotype and their HUTT results has not been previously reported.
The aim of this study was to evaluate patients with HCM and their HUTT results in regard to its value for outcome prediction and to investigate the relation of patients' genotype and their HUTT results.
Seventy-four (51 ± 15 years; 42% women; median follow-up 72 months) HCM patients were divided into two groups based on their HUTT results and were retrospectively analyzed. In 67 (90.5%) subjects included in the analysis, next-generation sequencing-based genomic testing was performed. A composite end point of unexplained syncope, heart failure hospitalization, and death was defined.
A total of 14 patients (18.9%) had positive HUTT (HUTT+), whereas 60 (81.1%) had negative HUTT (HUTT–). Except for the New York Heart Association functional class ( p = 0.01), both groups had similar characteristics. Positive genotype was evenly distributed between the two groups. Composite end point occurred in 5 patients (35.7%) in HUTT+ group versus 14 (23.3%) patients in HUTT– group ( p = 0.33).
We did not find a relationship between HUTT results and long-term outcome. We found no association between HUTT results and genotype.
Keywords: hypertrophic cardiomyopathy, HCM, hypertrophic obstructive cardiomyopathy, HOCM, head-up tilt test, genotype, abnormal baroreflex
Positivity of head-up tilt test (HUTT) has been repeatedly discussed as a possible negative prognostic factor in patients with hypertrophic cardiomyopathy (HCM). 1 2 Due to conflicting results, 3 4 the role of HUTT in risk stratification of HCM patients has not yet been established. In the general population, HUTT is known to identify individuals with a tendency for a vasovagal syncope. 5 Unlike a history of unexplained syncope (which is known to increase the risk of sudden cardiac death (SCD)), 6 7 the value of a history of vasovagal syncope as a prognostic factor is not clear. The relationship between HCM patients' genotype and their HUTT results has not been previously reported.
In this study, we evaluated patients with HCM and their HUTT results in regard to its value for outcome prediction; we also investigated the relationship of patients' genotype and their HUTT results.
Methods
Study Design, Definitions, and Patient Population
This was a retrospective, observational, single-center study design. Since 2007, in our tertiary referral hospital, HUTT has been performed as a part of a screening program for patients with HCM. Eighty-four patients with HUTT protocol were identified. Two study cohorts were then established based on positivity/negativity of the HUTT. Follow-up started at the time of HUTT; patients were followed for a median of 72 months. All patients underwent routine clinical and echocardiographic check-ups at least once a year. The following end points were defined: unexplained syncope, heart failure hospitalization, death from any cause, as well as a composite end point of these events. Information was retrieved from hospital patient records and/or from a phone interview at the end of the follow-up period in May 2018. Ten (11.9%) patients were excluded because of loss to follow-up. The final analysis was performed in 74 patients (51 ± 15 years, 42% women).
The diagnosis of HCM was made by cardiologists based on typical clinical, electrocardiographic, and echocardiographic findings, in the presence of left ventricular wall hypertrophy (wall thickness of ≥15 mm) that could not be explained by a pre-existing cause of increased afterload. 8 9 10 11 HUTT was performed on a mechanically operated tilt table, and restraint belts were placed at waist and knee levels. Fasting subjects were placed in supine position for 15 minutes followed by a 60° tilt for a maximum of 45 minutes. A positive test was defined as an occurrence of impaired consciousness associated with a progressive fall of blood pressure with or without bradycardia as well as asymptomatic systolic blood pressure drop below 85 mm Hg.
In most of the subjects included in this analysis, there was also performed next-generation sequencing-based genomic testing and classification of identified variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. 12 The protocol for the genetic testing has been published previously. 13 Genetic variants categorized into Class IV and V according to ACMG guidelines 12 were considered genotype positive. Analysis including Class III genotypes (those of unknown significance) was also performed.
Statistical Analysis
Student's t -test, Fisher's exact test, and Mann–Whitney U test were used when appropriate. Data were presented as mean ± standard deviation for continuous variables and proportions (percentages) for categorical variables. To assess data distribution, the Shapiro–Wilk test was used. If continuous data showed skewed distribution, Mann–Whitney U test was applied instead of Student's t -test. At baseline, the following clinical and echocardiographic variables with potential impact on outcomes were evaluated in a univariate model: age, sex, New York Heart Association (NYHA) functional class, angina pectoris, a history of an unexplained syncope, a history, as well as a family history of SCD, abnormal blood pressure reaction (ABPR) to exercise, treatment with β-blockers, ejection fraction of the left ventricle, maximum left ventricular wall thickness, left ventricle outflow tract (LVOT) peak gradient, and genotype. The prognostic value of HUTT was analyzed. A Kaplan–Meier graph was used to show event-free survival rates and the differences in survival were assessed using the log-rank test. If more than one event occurred in a single patient, a time-to-first event was used for the analysis. A probability ( p -value) less than 0.05 was considered statistically significant. All presented p -values are two-sided. Microsoft Excel 2010 (Microsoft, Redmond, WA) and statistical software Prism 703 (GraphPad Software Inc., La Jolla, CA) were used.
Results
Out of 74 HCM patients (51 ± 15 years, 42% women), a total of 14 had positive HUTT (HUTT+), whereas 60 (81.1%) were HUTT negative (HUTT–). Baseline clinical and echocardiographic parameters of the two patient cohorts are summarized in Table 1 . Except for NYHA functional class ( p = 0.01), both groups had similar baseline characteristics. Positive genotype was evenly distributed between the two groups. Composite end point occurred in 5 patients (35.7%) in HUTT+ group versus 14 (23.3%) patients in HUTT– group ( p = 0.33) ( Fig. 1 ). None of the presented end points reached statistical significance ( Table 2 ).
Table 1. Clinical and echocardiographic parameters of the two patients' cohorts at baseline.
| HUTT+ ( n = 14) | HUTT– ( n = 60) | p -Value | |
|---|---|---|---|
| Age (Years (mean)) | 56.3 ± 16.0 | 49.8 ± 14.8 | 0.18 |
| Sex (Males (%)) | 42.9 (6) | 61.6 (37) | 0.24 |
| NYHA class (mean) | 2.6 (+/−) 0.72 | 1.85 (+/−) 0.8 | 0.01 |
| Angina class (mean) | 0.8 (+/−) 1.1 | 0.7 (+/−) 1.1 | 0.76 |
| Syncope (%) | 14.3 (2) | 18.3 (11) | 1 |
| SCD (%) | 7.1 (1) | 0 (0) | 0.19 |
| Family history of SCD (%) | 14.3 (2) | 18.3 (11) | 0.32 |
| ABPR (%) | 14.3 (2) | 23.3 (14) | 0.72 |
| Beta-blockers therapy (%) | 78.6 (11) | 50.0 (30) | 0.07 |
| LVEF (%, mean) | 73.2 (+/−) 7.74 | 74.9 (+/−) 6.84 | 0.55 |
| IVS (mm (median)) | 22 | 20 | 0.15 |
| PG (mm Hg (mean)) | 72.1 (+/−) 62.8 | 62.4 (+/−) 43.6 | 0.82 |
| HOCM (%) | 64.3 (9) | 70.0 (42) | 0.75 |
| Genotype + 1 (%) | 21.4 (3) | 23.3 (14) | 1 |
| Genotype + 2 (%) | 42.9 (6) | 52.8 (28) | 1 |
| Follow-up (months (median)) | 70 | 72 | 0.98 |
Abbreviations: ABPR, abnormal blood pressure response during stress test; HOCM, hypertrophic obstructive cardiomyopathy; HUTT, head-up tilt test; IVS, interventricular septum; LVEF, ejection fraction of the left ventricle; NYHA, New York Heart Association; PG, peak gradient; SCD, sudden cardiac death.
Genotype + 1 represents patients with genetic variants categorized into Class IV and V according to ACMG (American College of Medical Genetics and Genomics) guidelines, Genotype + 2 represents patient with genetic variants categorized into Class III, IV, and V according to ACMG guidelines. Genotype typization available in a subgroup of 67 patients.
Fig. 1.
Kaplan–Meier graph of the event-free survival rate of the two study groups. HUTT, head-up tilt test.
Table 2. Clinical outcomes of the two patients' cohorts at the end of follow-up.
| HUTT+ ( n = 14) | HUTT– ( n = 60) | p -Value | |
|---|---|---|---|
| Syncope (%) | 7.1 (1) | 6.7 (4) | 1 |
| HF hospitalization (%) | 7.1 (1) | 8.3 (5) | 1 |
| Death from any cause (%) | 28.6 (4) | 15.0 (9) | 0.25 |
| –SCD (%) | 14.3 (2) | 5.0 (3) | |
| –Heart transplant (%) | 0 (0) | 1.7 (1) | |
| –Appropriate ICD shock (%) | 7.1 (1) | 3.3 (2) | |
| Composite end point (%) | 35.7 (5) | 23.3 (14) | 0.33 |
Abbreviations: HUTT, head-up tilt test; HF, heart failure; ICD, implantable cardioverter-defibrillator; SCD, sudden cardiac death.
Discussion
The principal findings of this study are as follows: (1) The proportion of positive HUTT was lower than in previously published data 5 ; (2) HUTT+ patients did not have a statistically worse outcome than HUTT– patients; and (3) Positive genotype was evenly distributed between the two groups.
The history of unexplained syncope (in particular the nonvasovagal syncope) is an established risk factor of SCD in patients with HCM, 7 14 but the role of vasovagal syncope is not clear. HUTT, known as a method proving individual tendency for vasovagal syncope, has been repeatedly discussed as a possible tool for further specification of this risk 1 3 15 (or universally, of further disease deterioration). A multifactorial mechanism is expected in syncopes of patients with HCM. 16 17
In the recently published European Society of Cardiology Guidelines for the diagnosis and management of syncope, 18 the authors summarized that positivity of HUTT represents a susceptibility to syncopal reaction to different stimuli such as dehydration and supraventricular tachycardia, therefore not limited to vasovagal syncope. This presumption created the rationale for our analysis.
Positive HUTT might be interpreted as a marker of a tendency for hypotension based on vasodepressor reaction to orthostatic stress. 2 The expected pathophysiological mechanism is thought to be an abnormal baroreflex. 17 It has been indirectly measured in patients with ABPR to exercise 19 and in patients with asymptomatic spontaneous blood pressure drop during ambulatory blood pressure monitoring. 3 15 These two characteristics have been more frequently observed in patients at higher risk of SCD. 3 15 20 The abnormal baroreflex is triggered by an extensive activation of the left ventricle mechanoreceptors, leading to a decrease in peripheral vascular resistance. 17 Furthermore, compensatory mechanisms in orthostatic stress (venoconstriction of splanchnic circulation providing for adequate venous return and sufficient increment in heart rate) are attenuated or even absent in the presence of an abnormal baroreflex. 21
The anomalous mechanoreceptor activation is thought to be driven by focal abnormalities in myocardium such as cardiomyocyte disarray or interstitial fibrosis, causing nonhomogeneous wall stress in the left ventricle. 19 Abnormal baroreflex seems to be present inconsistently in patients with HCM in accordance with an accidental, heterogeneous distribution of wall stress in their left ventricle.
To our knowledge, with 74 patients and a median follow-up of 72 months, the analyzed cohort is the largest dataset of patients with HCM and HUTT result. While it could be anticipated that the described pathophysiological mechanism would manifest during the test, the analysis has not yielded statistically significant results. The reason could be poor reproducibility and questionable specificity and sensitivity of HUTT when applied to patients without a history of true vasovagal syncope, 22 23 the analysis has not yielded statistically significant results. Abnormal baroreflex might be one of the mechanisms causing higher SCD risk and therefore worse overall outcome in affected patients with HCM, but HUTT does not help to identify these patients. Identification of ABPR to exercise provides probably a better tool to differentiate such patients.
The only difference in baseline characteristics was a higher NYHA class in HUTT+ patients; this only indicates problematic specificity of the test, especially in patients with advanced disease.
This analysis has some limitations. First, there are some inherent limitations of retrospective observational studies. Second, for a method with such a low specificity and reproducibility, repetitive examinations of patients would be needed for relevant results. Another limitation is the conservative HUTT protocol leading to low overall HUTT positivity in comparison to previously published data. 5 Most of the previously described protocols were potentiated by pharmacological agents. Despite the fact that, to our knowledge, this is the largest cohort of HCM patients with HUTT results, the relatively low number of patients creates the most important limitation of this study.
Conclusions
We did not find a relationship between HUTT results and long-term outcome. We found no association between HUTT results and genotype.
Footnotes
Conflict of Interest None declared.
References
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