Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile-obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 ± 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement ≥20% of myocardial mass (23 [30%] vs 19 [18%] labile-obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum ≥3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.
Novel imaging technologies have indicated that characteristics unrelated to outflow hemodynamics but related to the primary myopathy, such as fibrosis by imaging, microvascular ischemia, and abnormal myocardial mechanics, are highly prevalent in hypertrophic cardiomyopathy (HC) and may be important arbiters of outcomes. Therefore, nonobstructive hemodynamics alone may not always confer low risk, a viewpoint corroborated by several anecdotal examples in our large-volume practice. Moreover, previously published outcome studies did not separate nonobstructive (resting and provoked gradients <30 mm Hg) and labile-obstructive (resting <30 mm Hg; provoked ≥30 mm Hg) variants, as is the current clinical practice. Therefore, it is additionally unclear if there are differences in outcomes between nonobstructive versus labile-obstructive HC phenotypes not evident in existing published reports since both these groups were combined.
Methods
This study was approved by the institutional review board. A total of 344 patients were recruited at their first visit to the Johns Hopkins Hypertrophic Cardiomyopathy Center from 2005 to 2013 if they fulfilled previously used diagnostic criteria for HC, which primarily was a maximal septal wall thickness ≥15 mm in the absence of other cardiac or systemic disease that may produce a similar degree of left ventricular (LV) hypertrophy, and 293 of them were followed for a mean of 3.3 ± 3.6 years. Patients with a previous myectomy or alcohol septal ablation were excluded. Clinical information was collected as previously described. We compared clinical features and outcomes within the 3 HC subgroups.
Sustained ventricular tachycardia (VT), ventricular fibrillation (VF), appropriate implantable cardioverter defibrillator (ICD) discharge, heart failure worsening (defined as New York Heart Association (NYHA) class worsening to class III or IV), and death were recorded by reviewing Holter and exercise electrocardiographic tracings, ICD interrogation reports, and clinical visit notes. Appropriate ICD discharges were defined as documented VT or VF events at heart rate ≥180betas/min. Sudden cardiac death (SCD) risk was assessed by noting nonsustained ventricular tachycardia (NSVT), unexplained syncope of non-neurocardiogenic origin, previous VT/VF, family history of SCD, septum ≥3 cm, and abnormal blood pressure response.
Echocardiography was performed using a GE Vivid 7 ultrasound machine (GE Ultrasound, Milwaukee, Wisconsin) using a standard clinical protocol. Conventional measurements were performed as previously published. Systolic anterior movement of the mitral valve was defined as absent, incomplete (no contact with the septum), and complete (contact between leaflet and septum). LV outflow tract (LVOT) gradients were measured before and immediately after a symptom-limited exercise test, and patients were classified into nonobstructive (<30 mm Hg at rest and exercise), labile-obstructive (<30 mm Hg at rest and ≥30 mm Hg with exercise), and obstructive (≥30 mm Hg at rest).
Cardiac magnetic resonance imaging was performed on a 1.5T system (MAGNETOM Avanto; Siemens Healthcare, Erlangen, Germany), as described previously, with contrast, gadopentetate dimeglumine at 0.2 mmol/kg (Magnevist; Bayer Schering, Berlin, Germany). Late gadolinium enhancement (LGE) images were assessed in short-axis view with validated software (QMASS 7.4; Medis, Leiden, The Netherlands) by an experienced reader (C.C.V). Endocardial and epicardial borders were manually traced in each slice, and the myocardium was divided into 16 segments starting from the anterior insertion point of the right ventricle. A region of interest was placed in an area of normal appearing nulled myocardium, typically the basal lateral wall. Pixels with signal intensity >6 standard deviations greater than the mean of normal myocardium were considered abnormal. The extent of LGE was expressed as a percentage of total LV myocardial mass.
Patients with angina ≥3 months despite optimal medical therapy were referred for positron emission tomography (PET) scanning and were imaged using a GE Discovery VCT PET/CT system. Regional myocardial perfusion was assessed using a same day rest/stress protocol as described previously. Attenuation-corrected PET images were reconstructed by an iterative algorithm with postprocessing filtering and static data sets analyzed using CardIQ Physio (GE Healthcare). Regional myocardial perfusion was semiquantitatively assessed from the reoriented images on different cardiac planes (short, horizontal, and vertical long axes) using the standard 17 American Heart Association segmentation, 5-point visual score method. The summed stress score (SSS) and summed rest score (SRS) consisted of the summation score of the 17 LV segments during vasodilator stress and rest perfusion imaging. The summed difference score (SDS) consisted of the difference between SSS and SRS. An SDS ≥2 was considered abnormal in this study.
Data were analyzed using STATA software version 13 (StataCorp LP, College Station, Texas). Continuous variables are presented as mean ± standard deviation and categorical variables as the total number and percentage. Comparison of variables across groups was performed using analysis of variance and the chi-square or Fisher’s exact test as appropriate. Statistical significance was set at p <0.05. We used Kaplan–Meier procedure to estimate the survival function for each category of HC. We then used a log-rank test to determine whether there was a significant difference in the 3 survival functions. A Cox proportional multivariate hazard model was built to control for potential confounders.
Results
Clinical and echocardiographic characteristics of the study population, which included 96 nonobstructive (33%), 114 labile-obstructive (39%), and 83 obstructive patients (28%), are summarized in Tables 1 and 2 . Obstructive patients were older and had more dyspnea at presentation, whereas gender distribution, co-morbidity profiles, and body mass index did not differ among groups. Family history of HC, history of VT/VF, NSVT, and ICD in place were more common in nonobstructive patients ( Table 1 ). Maximum septal wall thickness and LV ejection fraction were similar among groups. Obstructive patients had a greater E/e’ ratio and a larger left atrial diameter ( Table 2 ).
| Variable | Non-Obstructive (n=96) | Labile-Obstructive (n=114) | Obstructive (n=83) | Total (n=293) | p-value | |
|---|---|---|---|---|---|---|
| Length of follow-up (years) | 3.5±3.8 | 3.2±3.5 | 2.8±3.2 | 3.3±3.6 | 0.5 | |
| Age (years) | 49±15 | 50±15 | 55±13 | 51±15 | 0.01 | |
| Male | 60 (63%) | 83 (73%) | 51 (61%) | 194 (66%) | 0.2 | |
| Body Mass Index (kg/m 2 ) | 29.4±5.7 | 29.7±5.3 | 30.4±6.0 | 29.8±5.7 | 0.5 | |
| NYHA | I | 64 (67%) | 71 (62%) | 30 (36%) | 165 (56%) | <0.001 |
| II | 24 (25%) | 24 (21%) | 37 (45%) | 85 (29%) | ||
| III | 8 (8%) | 19 (17%) | 16 (19%) | 43 (15%) | ||
| Angina pectoris | 33 (34%) | 46 (40%) | 37 (45%) | 116 (40%) | 0.4 | |
| Syncope | 17 (18%) | 25 (22%) | 14 (17%) | 56 (19%) | 0.6 | |
| Ventricular tachycardia/fibrillation | 10 (10%) | 0 (0%) | 1 (1%) | 11 (4%) | <0.001 | |
| Non-sustained ventricular tachycardia | 18 (19%) | 9 (8%) | 8 (10%) | 35 (12%) | 0.047 | |
| Atrial Fibrillation | 17 (18%) | 9 (8%) | 8 (10%) | 34 (12%) | 0.08 | |
| Implantable Cardioverter Defibrillator | 18 (19%) | 6 (5%) | 9 (11%) | 33 (11%) | 0.009 | |
| Family History | ||||||
| Hypertrophic Cardiomyopathy | 29 (31%) | 16 (15%) | 10 (12%) | 55 (19%) | 0.003 | |
| Sudden cardiac death | 26 (27%) | 28 (26%) | 19 (23%) | 73 (25%) | 0.8 | |
| Sudden cardiac death risk factors | 1.4±1.1 | 1.2±1.0 | 1.4±1.0 | 1.3±1.0 | 0.2 | |
| Medications | ||||||
| β-blocker | 68 (71%) | 77 (68%) | 67 (81%) | 212 (73%) | 0.1 | |
| Disopyramide | 0 (0%) | 6 (5%) | 5 (6%) | 11 (4%) | 0.06 | |
| Ca-blocker | 13 (14%) | 28 (25%) | 25 (30%) | 66 (23%) | 0.02 | |
| Variables | Non-Obstructive | Labile-Obstructive | Obstructive | Total | p-value | |
|---|---|---|---|---|---|---|
| Max wall thickness (cm) | 2.0±0.5 | 2.0±0.5 | 2.2±0.5 | 2.1±0.5 | 0.1 | |
| Left atrium (cm) | 4.0±0.7 | 4.1±0.7 | 4.5±0.7 | 4.2±0.7 | <0.001 | |
| Ejection fraction (%) | 63±10 | 64±8 | 65±9 | 64±9 | 0.2 | |
| E/A | 1.4±0.8 | 1.3±0.5 | 1.3±0.7 | 1.3±0.6 | 0.4 | |
| E/e’ | 16±9 | 17±9 | 24±13 | 19±11 | <0.001 | |
| Left ventricular outflow tract gradient at rest (mmHg) | 8±4 | 15±7 | 58±25 | 25±26 | <0.001 | |
| Left ventricular outflow tract gradient at stress (mmHg) | 18±6 | 69±42 | 111±40 | 64±50 | <0.001 | |
| Systolic anterior motion of mitral valve | No | 41 (43%) | 31 (27%) | 2 (2%) | 74 (25%) | <0.001 |
| Incomplete | 54 (57%) | 68 (60%) | 44 (53%) | 166 (57%) | ||
| Complete | 0 (0%) | 15 (13%) | 37 (45%) | 52 (18%) | ||
| Exercise time (seconds) | 552±195 | 573±224 | 486±184 | 545±206 | 0.04 | |
| Exercise capacity (METs) | 10.7±3.6 | 10.6±4.4 | 8.0±3.5 | 9.9±4.1 | <0.001 | |
| Heart rate at rest (beats/min) | 66±13 | 63±14 | 65±12 | 65±13 | 0.2 | |
| Systolic blood pressure at rest (mmHg) | 128±19 | 134±17 | 131±18 | 131±18 | 0.05 | |
| Diastolic blood pressure at rest (mmHg) | 77±12 | 78±11 | 74±11 | 76±11 | 0.05 | |
| Heart rate at stress (beats/min) | 147±27 | 147±28 | 135±26 | 143±27 | 0.004 | |
| Systolic blood pressure at stress (mmHg) | 166±30 | 167±34 | 147±34 | 161±34 | <0.001 | |
| Diastolic blood pressure at stress (mmHg) | 82±17 | 84±17 | 75±17 | 81±18 | 0.002 | |
| Age-predicted heart rate (%) | 86.1±14.5 | 86.7±14.3 | 81.2±14.1 | 84.9±14.5 | 0.02 | |
LGE images were available in 77 nonobstructive, 105 labile-obstructive, and 72 obstructive patients (87% of the original sample), with clinical and echocardiographic characteristics comparable to those of the original groups. Presence of LGE was similar between groups (nonobstructive: 51 [66%] vs labile-obstructive: 64 [61%] vs obstructive: 49 [68%], p = 0.6). However, extent of LGE was greater in nonobstructive (nonobstructive: 21 ± 16% vs labile-obstructive: 11 ± 12% vs obstructive: 12 ± 10%, p = 0.002), and a larger proportion of nonobstructive patients carried a high LGE burden (≥20% myocardial mass; nonobstructive: 23 [30%] vs labile-obstructive: 19 [18%] vs obstructive: 8 [11%], p = 0.01; Figure 1 ).
A subset of 83 patients (34 nonobstructive, 28 labile-obstructive, and 21 obstructive) underwent ammonia PET scanning. Fewer labile-obstructive patients had SDS ≥2, indicating a lower extent of regional perfusion abnormalities (nonobstructive: 28 [82%] vs labile-obstructive: 15 [54%] vs obstructive: 16 [76%], p = 0.04; Figure 1 ).
We noted 60 events (36 VT/VF including 30 ICD discharges, 12 heart failure worsening, and 2 deaths) in the 293 patients during follow-up. Follow-up time and the mean number of SCD risk factors did not differ among groups ( Table 1 ).
Kaplan–Meier ( Figure 2 ) and univariate Cox regression analysis indicated nonobstructive patients were at significantly greater risk of VT/VF during follow-up compared to labile-obstructive (p = 0.03, Table 3 ). Adjusting for age, gender, and the established SCD risk factors (syncope, family history of SCD, abnormal blood pressure response, septal thickness ≥3 cm), nonobstructive patients remained significantly at greater risk than labile-obstructive (p = 0.04; Table 3 ). History of NSVT, family history of HC, NYHA functional class, presence or extent of LGE, CFR, and SDS by PET, ejection fraction, left atrial diameter, septal thickness, E/e’ ratio, and LVOT gradients at rest or exercise were not associated with a greater risk of VT/VF in univariate analysis. A greater proportion of nonobstructive patients experienced a VT/VF at follow-up when compared to labile-obstructive (9.4% vs 1.8%, p = 0.01). A similar trend was noted when compared to the obstructive group (9.4% vs 3.6%, p = 0.1; Figure 3 ).
| Unadjusted Hazard Ratio (95% CI) | p-value | Adjusted Hazard Ratio ∗ (95% CI) | p-value | |
|---|---|---|---|---|
| HC group | ||||
| Non-Obstructive | 1.0 | – | 1.0 | – |
| Labile-Obstructive | 0.18 (0.04-0.84) | 0.03 | 0.2 (0.04-0.98) | 0.04 |
| Obstructive | 0.45 (0.12-1.66) | 0.23 | 0.5 (0.11-2.02) | 0.31 |
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