The aim of this study was to investigate whether patients with hypertrophic cardiomyopathy (HC) and sleep disordered breathing (SDB) have a higher prevalence of atrial fibrillation (AF) compared to patients with HC without SDB. HC is associated with a high prevalence of AF that contributes to increased morbidity and mortality. SDB is strongly associated with a higher incidence, prevalence, and recurrence of AF in patients without HC. Whether this association also applies to patients with HC is not known. Overnight oximetry was prospectively performed on 91 consecutive patients with echocardiographically confirmed HC. The presence or absence of AF in this population was correlated with the oximetric findings. SDB was associated with a higher prevalence of AF (40% vs 11%, p = 0.005). In addition, SDB was accompanied by significantly increased left atrial volume index (58 ± 19 vs 42 ± 13 ml/m 2 , p = 0.0002). Increasing severity of SDB was correlated with higher AF prevalence and with increase in left atrial volume index. These associations remained significant even after accounting for potential confounders in a multivariate analysis. In conclusion, these findings suggest that the presence and severity of SDB may influence left atrial volume index and the prevalence of AF in patients with HC. SDB may therefore be an important and potentially modifiable cause of morbidity and mortality in this population.
Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HC), with a reported prevalence of approximately 22% and an annual incidence of up to 2% per year. Although the presence of AF in patients with HC is associated with increased mortality, risk for stroke, and severe functional disability, the mechanisms leading to AF in this patient population remain incompletely understood. Sleep disordered breathing (SDB) and particularly its most common type, obstructive sleep apnea, have been associated strongly with increased incidence, prevalence, and recurrence of AF in patients without HC. Whether SDB could also contribute to the occurrence of AF in patients with HC is not known. This question is particularly intriguing because SDB, which may be common in patients with HC, is treatable and as such may provide a strategy to reduce the frequency of AF in this population.
Methods
We studied consecutive patients with HC evaluated at the Mayo Clinic (Rochester, Minnesota). The diagnosis of HC was based on typical clinical, electrocardiographic, and echocardiographic features, with ventricular myocardial hypertrophy occurring in the absence of any other significant cardiac or systemic disease that could explain such hypertrophy. All patients underwent standard clinical evaluations including transthoracic echocardiography, 12-lead electrocardiography, 24-hour Holter monitoring, and a treadmill exercise test. In addition, all patients underwent overnight oximetry; patients who did not undergo overnight oximetry for any reason were excluded. Demographics and clinical data such as age, gender, height, weight, medication use, history of coronary artery disease, diabetes mellitus, hyperlipidemia, hypertension, smoking, and previous surgical septal myectomy or alcohol septal ablation, were prospectively entered into a dedicated database and retrospectively reviewed. Hypertension and hyperlipidemia were considered present if these were stated in the medical record or if the patient was using antihypertensive or lipid-lowering medications, respectively. This study was approved by the Institutional Review Board of the Mayo Clinic.
Overnight oximetry was performed by the Special Pulmonary Evaluation Laboratory. Recorded variables included duration of sleep time, frequency of desaturations (defined as a ≥4% decrease in oxygen saturation from floating baseline), nadir arterial oxygen saturation, and percentage of sleep time with arterial oxygen saturation <90% and <85%. The oxygen desaturation index was defined as total number of desaturations divided by sleep time in hours, according to standard practice. Clinically significant SDB was defined as an oxygen desaturation index >10. In addition, we divided patients by other previously published values of SDB severity and classified them as “no SDB” for an oxygen desaturation index ≤5, “mild SDB” for an oxygen desaturation index of 5 to 15, and “severe SDB” for an oxygen desaturation index >15. Polysomnographic studies were not performed as part of this study. However, previous reports have shown significant correlations between oxygen desaturation index and apnea-hypopnea index.
AF was considered present if any previous AF occurrence was recorded and confirmed on review of the medical record (clinical notes including outside records; International Classification of Diseases, Ninth Revision, coding; and the presence of AF on electrocardiography, echocardiography, or Holter monitoring). Type of AF was classified as paroxysmal if spontaneous resolution occurred within 7 days, persistent if arrhythmia lasted >7 days or required electrical or pharmacologic cardioversion to terminate, and long-standing persistent or permanent if it lasted >1 year. For the purpose of this study, the persistent and permanent types of AF were considered the same.
Two-dimensional and Doppler echocardiography was performed and interpreted at the Mayo Clinic Echocardiographic Laboratory according to standard clinical practice by staff members blinded to this study. Recorded variables included left ventricular ejection fraction, left ventricular mass, left ventricular outflow tract gradient, septal thickness, the presence and severity of mitral valve regurgitation, and diastolic function assessment (E/e′ and E/A ratios). Left atrial volume index was calculated as left atrial volume (biplane area-length method) indexed to body surface area. As noted previously, patients with more than moderate mitral valve regurgitation were excluded. If present, mitral valve regurgitation was qualitatively assigned into 1 of the following categories: none, mild, mild to moderate, and moderate. In our laboratory, these categories would correspond to the following quantification values: mild, effective regurgitant orifice <0.2 mm 2 and regurgitant volume <30 ml; mild to moderate, effective regurgitant orifice 0.2 to 0.28 mm 2 and regurgitant volume 30 to 44 ml; and moderate, effective regurgitant orifice 0.3 to 0.39 mm 2 and regurgitant volume 45 to 59 ml.
Continuous variables are presented as mean ± SD and categorical variables as numbers and percentages. Intragroup comparisons were conducted using Student’s t test for continuous variables and chi-square or Fisher’s exact test as appropriate for nominal variables. Logistic regression analyses were performed to assess for univariate predictors of AF, left atrial volume index, and oxygen desaturation index. Multivariate linear regression was used to explore the independent relations between oxygen desaturation index and AF (adjusting for age, gender, body mass index, hypertension, diabetes mellitus, and history of coronary artery disease) and between oxygen desaturation index and left atrial volume index (adjusting for age, gender, hypertension, mitral valve regurgitation, E/e′ ratio, and left ventricular outflow tract pressure gradient). The oxygen desaturation index was transformed using the base 10 logarithm to achieve a normal distribution. A p value <0.05 was considered significant. All analyses were performed using JMP version 7.0 (SAS Institute Inc., Cary, North Carolina).
Results
From January to August 2008, a total of 91 patients with HC (mean age 52 ± 16 years, 68% men, 43% of the total patients seen) underwent evaluation in the HC clinic and underwent overnight oximetry. Of these, 6 (7%) had previously undergone surgical septal myectomy, and 7 (8%) had previously undergone alcohol septal ablation. Clinically significant SDB (oxygen desaturation index >10) was identified in 30 patients (33%). Baseline clinical characteristics according to the presence or absence of SDB are listed in Table 1 . Patients with and without SDB were similar in terms of distribution of gender, obesity, coronary artery disease, diabetes mellitus, smoking history, and history as well as time since myectomy or septal ablation; subjects with SDB were older and more likely to have histories of treated hypertension. The length of sleep during oximetry studies was similar in patients with and without SDB. As expected, all other measured oximetric parameters were significantly different between patients with and without SDB. Medication use included antiarrhythmic drug therapy in 11 patients (12%), consisting of amiodarone in 8, dofetilide in 2, and sotalol in 1.
| Variable | SDB | p Value | |
|---|---|---|---|
| No (ODI ≤10) (n = 61) | Yes (ODI >10) (n = 30) | ||
| Age (years) | 48 ± 15 | 61 ± 14 | 0.0002 |
| Men | 40 (66%) | 21 (70%) | 0.81 |
| Body mass index (kg/m 2 ) | 32 ± 8 | 31 ± 5 | 0.41 |
| ≤25 | 8 (13%) | 2 (7%) | 0.35 |
| 25–30 | 18 (30%) | 12 (40%) | 0.32 |
| >30 | 35 (57%) | 16 (53%) | 0.84 |
| Coronary artery disease | 6 (10%) | 5 (17%) | 0.50 |
| Diabetes mellitus | 5 (8%) | 4 (13%) | 0.47 |
| Hyperlipidemia | 16 (26%) | 14 (47%) | 0.061 |
| Hypertension | 11 (18%) | 14 (47%) | 0.0060 |
| Previous smoking | 16 (26%) | 5 (17%) | 0.43 |
| Previous heart failure | 1 (2%) | 2 (7%) | 0.25 |
| Previous ventricular septal myectomy/septal ablation | 6 (10%) | 6 (20%) | 0.20 |
| Time since myectomy/septal ablation (years) | 1 ± 2 | 1 ± 2 | 0.44 |
| Atrial fibrillation | 7 (11%) | 12 (40%) | 0.0025 (0.0050 ⁎ ) |
| Type of atrial fibrillation | |||
| Paroxysmal | 6 (10%) | 7 (23%) | 0.11 |
| Persistent/permanent | 1 (2%) | 5 (17%) | 0.0139 |
| Warfarin use | 3 (5%) | 7 (23%) | 0.013 |
| β-blocker use | 37 (62%) | 21 (70%) | 0.49 |
| Calcium channel blocker use | 27 (47%) | 14 (47%) | 0.95 |
| Aspirin use | 12 (20%) | 10 (33%) | 0.19 |
| Antiarrhythmic medication use | 6 (10%) | 5 (17%) | 0.50 |
| Sleep time (hours) | 8.0 ± 1.4 | 8.1 ± 2.0 | 0.73 |
| Mean arterial oxygen saturation (%) | 94 ± 2 | 91 ± 3 | <0.0001 |
| Nadir arterial oxygen saturation (%) | 86 ± 5 | 77 ± 7 | <0.0001 |
| Arterial oxygen saturation <90% (% of sleeping time) | 6 ± 15 | 26 ± 29 | 0.0014 |
| Arterial oxygen saturation <85% (% of sleeping time) | 1 ± 3 | 6 ± 12 | 0.012 |
| Oxygen desaturation index | 3 ± 3 | 20 ± 10 | <0.0001 |
⁎ Adjusted for age, gender, body mass index, hypertension, diabetes mellitus, and history of coronary artery disease.
Echocardiographic results are listed in Table 2 . The mean ejection fraction was 68 ± 8%, and mean septal thickness was 19 ± 6 mm; 3 patients (3%) had septal thicknesses >30 mm. The mean left ventricular outflow tract gradient was 31 ± 37 mm Hg, and 27 patients (30%) had left ventricular outflow tract gradients >36 mm Hg. The mean left ventricular ejection fraction, left ventricular mass, interventricular septal thickness, left ventricular outflow tract gradient, severity of mitral valve regurgitation, and presence of systolic anterior mitral valve motion were similar in patients with and without SDB. One patient had intrinsic mitral valve disease with central coaptation failure resulting in severe mitral valve regurgitation. Although E/A ratio was similar in the 2 groups, patients with SDB had higher estimated left ventricular filling pressures (E/e′ 14 ± 6 vs 20 ± 11, p = 0.042).
| Variable | SDB | p Value | |
|---|---|---|---|
| No (ODI ≤10) (n = 61) | Yes (ODI >10) (n = 29) | ||
| Left ventricular ejection fraction (%) | 68 ± 8 | 67 ± 10 | 0.52 |
| Left ventricular mass (g) | 296 ± 108 | 313 ± 139 | 0.56 |
| Left ventricular outflow tract pressure gradient (mm Hg) | 34 ± 38 | 26 ± 33 | 0.36 |
| Left ventricular outflow tract pressure gradient >36 (mm Hg) | 20 (33%) | 7 (24%) | 0.47 |
| Left atrial length (mm) | 58 ± 9 | 65 ± 9 | 0.0026 |
| Left atrial volume index (ml/m 2 ) | 42 ± 13 | 58 ± 19 | 0.0002 (0.0027 † ) |
| Mitral regurgitation ⁎ | 0.9 ± 0.6 | 1.0 ± 0.6 | 0.37 |
| Interventricular septal thickness (mm) | 18 ± 6 | 18 ± 5 | 0.95 |
| Systolic anterior motion of mitral valve | 33 (54%) | 16 (57%) | 0.82 |
| E/e′ ratio | 14 ± 6 | 20 ± 11 | 0.042 |
| E/A ratio (available from 80 patients [88%]) | 1.3 ± 0.5 | 1.3 ± 0.7 | 0.84 |
⁎ Scoring of mitral regurgitation: 0 = none, 1 = mild, 2 = moderate (severe excluded).
† Adjusted for age, gender, mitral valve regurgitation, E/e′ ratio, left ventricular outflow tract pressure gradient, and hypertension.
Left atrial volume index was significantly higher in patients with SDB compared to those without SDB. After adjusting for age, gender, hypertension, the severity of mitral valve regurgitation, E/e′, and left ventricular outflow tract gradient, SDB remained an independent predictor of increased left atrial volume index (p = 0.0027; Figure 1 ). Linear left atrial volume index was modestly associated with increased oxygen desaturation index (R = 0.32, p = 0.002; Figure 2 ). When including the patient with severe mitral regurgitation in the analysis, the results remained unchanged. Although patients with AF trended toward a stronger association between oxygen desaturation index and left atrial volume index ( Figure 2 ), our study was not powered to fully address this finding.
