DISSECTING FUNCTIONAL IMPAIRMENT IN HYPERTROPHIC CARDIOMYOPATHY BY DYNAMIC ASSESSMENT OF DIASTOLIC RESERVE AND OUTFLOW OBSTRUCTION:
A COMBINED CARDIOPULMONARY-ECHOCARDIOGRAPHIC STUDY
Federica Rea ,Elisabetta Zacharaa, Andrea Avellaa, Pasquale Barattaa, Michele di Maurob, Massimo Uguccionia, Iacopo Olivottoc
aCardiology Division, Cardiac Arrhythmia Center and Cardiomyopathies Unit, St.Camillo-Forlanini Hospital, Rome, Italy. bCardiology, University of L’Aquila, Italy. cReferral Center for Cardiomyopathies,Careggi University Hospital Florence, Italy
Running title: Diastolic reserve and VO2 max in HCM
Corresponding Author: Federica Re, MD, Cardiology Division, Cardiac Arrhythmia Center and Cardiomyopathies Unit, St.Camillo-Forlanini Hospital, Via Portuense 332, 00149 Rome, Italy.
Tel/fax: +39-06-58704539
E-mail address: re.federica77@gmail.com
ABSTRACT
Background: Exercise limitation in patients with hypertrophic cardiomyopathy (HCM) is often attributed to left ventricular outflow tract (LVOT) obstruction and diastolic impairment. However, these features assessed at rest fail to predict performance. In order to evaluate their variations and interplay during effort in HCM, we performed real-time echocardiographic assessment of diastolic function and outflow obstruction during cardiopulmonary test (CPX).
Methods: We included 197 consecutive HCM patients (mean age 45±15 years, 129 males), undergoing CPX. Mitral inflow, annular velocities and diastolic dysfunction (DD) grade were measured at baseline and at peak exercise. Oxygen consumption (VO2 max) values < 75% of maximum predicted were considered abnormal.
Results: One hundred-seven patients (54%) had DD grade II-III at rest (Rest DD), whereas 40 (20%) showed preserved diastolic function (grade 0/I) both at rest and on effort (No DD). The remaining 50 patients (25%) had a grade 0/I pattern at rest but exhibited impaired diastolic reserve on exercise (Latent DD). Latent DD was associated with higher prevalence of patients with VO2 <75% in both the non-obstructive and the latent-obstructive group: at multivariate regression analysis, left atrium volume index, LV obstruction at rest and rest or latent DD were significantly associated with lower peak VO2 .When rest-obstructive patients were excluded from the analysis, rest- or latent DD were the only determinants of exercise impairment (latent-obstructive, OR 8.9; 95% CI 1.5-18.8; p=0.012; non-obstructive, OR 2.2; 95% CI 1.0 -5.8; p=0.03)
Conclusion: Latent impairment in diastolic reserve is a major determinant of exercise intolerance in HCM. Comprehensive assessment of outflow obstruction and diastolic reserve during cardiopulmonary test represents an important adjunct to clinical management.
Most patients with hypertrophic cardiomyopathy (HCM) show reduced exercise tolerance.1,2,3 In patients with resting left ventricular outflow tract (LVOT) obstruction, this is considered a direct consequence of impedance to flow and mitral regurgitation.4-7 In non-obstructive patients, however, the pathophysiology is less clear and diastolic dysfunction (DD) has historically been advocated to explain exertional symptoms. A relationship between DDat rest and exercise capacity has been proposed by several authors.8-11 However, worsening of LV filling during exercise has not been convincingly assessed. In addition, a substantial proportion of HCM patients who are non-obstructive at rest develop dynamic obstruction on effort, thus complicating the pathophysiologic picture of exercise limitation.12
Ultimately, a complex scenario emerges in which DD and obstruction, both resting or provocable, variably combine to create a number of different HCM subsets. Unless the whole spectrum is taken into account, it is impossible to extrapolate the impact of DD on exercise capacity – a potentially relevant issue, as dissection of these clinical subsets is key to emerging treatment strategies, based on precise knowledge of mechanisms involved in the genesis of symptoms. In the present study, we therefore aimed to provide a comprehensive evaluation of exercise tolerance in HCM patients by simultaneous, dynamic assessment of diastolic function and outflow obstruction with echocardiographic monitoring during cardiopulmonary test (CPX). The role of exercise-related changes in LV filling parameters and latent DD (i.e. not evident in resting conditions) with regard to symptoms and exercise limitation was specifically assessed.
METHODS Study population
The study included one hundred and ninety-seven consecutive outpatients with HCM (mean age 45±15 years, 129 males) referred to our tertiary referral center for noninvasive functional evaluation; of these, 110 (56%) were in New York Heart Association (NYHA) functional class I, 81 (41%) in class II and 6 (3%) in class III. Diagnosis of HCM was based on the demonstration of a hypertrophied (wall thickness ≥15 mm), non-dilated LV in the absence of other cardiac or systemic diseases capable of producing a similar degree of hypertrophy. Our institutional review board authorized use of this database according to the principles outlined in the Declaration of Helsinki. Cardioactive medications were withdrawn at least 72 hours before the test with exception of amiodarone. Patients were excluded if they were in permanent atrial fibrillation (AF) or were unable to exercise due to advanced age or heart failure symptoms resulting from the “end-stage” phase of HCM with systolic dysfunction (LVEF <50%) or if they had a prior history of septal myectomy or alcohol septal ablation. Patients with prior documentation of ventricular tachyarrhythmias on effort or exertional syncope were also excluded.
Baseline (Rest) Echocardiography
Standard echocardiographic studies were performed under basal conditions with a commercially available instrument (VIVID 9 GE Medical System, Oslo Norway). Magnitude and distribution of LV hypertrophy were assessed as previously described.13-15 From the apical view, LV volume, LV ejection fraction (LVEF) and left atrial (LA) volume were measured using biplane Simpson’s rule method.16 Peak instantaneous LVOT gradient was measured at rest, in the supine and in the upright positions, with continuous-wave Doppler interrogation directly parallel to the LVOT in the apical five chamber view. Peak gradients were derived using the modified Bernoulli equation. Resting LVOT obstruction was considered present in the presence of a peak pressure gradient ≥ 30 mmHg at baseline or during Valsalva manouvre.
Pulsed-wave Doppler recordings of transmitral flow were obtained at the mitral leaflet tips from the apical four chamber view to assess E wave, peak late diastolic transmitral velocity and deceleration time (DT). Peak early diastolic mitral annular velocity obtained by pulsed-wave tissue Doppler technique were measured, and e’ septal, e’ lateral and e’ average velocities, E/e’septal, E/e’ lateral and E/e’ average were calculated.
Diastolic dysfunction was categorized using the criteria recommended in the 2009 American Society of Echocardiography guidelines.17 Normal diastolic function included subjects with septal e’ ≥ 8 cm/s, lateral e’ ≥ 10 cm/s, and LA index volume < 34 ml/m2. Mild DD (grade I) was classified as a mitral E/A ratio < 0.8, DT > 200 msec, or average E/e’ ratio ≤ 8 . Moderate DD (grade II) was classified as a mitral E/A ratio of 0.8 to 1.5, DT of 160 to 200 msec and average E/e’ ratio of 9 to 12. Severe DD (grade III) was characterized by restrictive filling with mitral E/A ratio ≥ 2, DT < 160 msec, and average E/e’ ratio > 13 or septal E/e’ ratio ≥ 15 and lateral E/e’ ratio > 12.18 Subjects were required to meet two Doppler criteria for moderate or severe DD to be so classified. Mitral regurgitation was evaluated with semiquantitative method and graded as following: none or trivial (0), mild (1), moderate (2), and severe (3).19
Exercise echocardiography and cardiopulmonary test
After the baseline echocardiogram was obtained, symptom-limited CPX was performed on a bicycle ergometer in the upright position. To facilitate simultaneous echocardiographic assessment, we limited the ramp steep to a maximum of 10 watts per minute. All patients were encouraged to perform to exhaustion. Oxygen saturation monitoring was performed by pulse oximetry. Twelve-lead ECG, blood pressure and heart rate were recorded at rest and at each exercise step. An abnormal blood pressure response was defined by either a failure of systolic blood pressure to rise > 20 mm Hg or any fall in systolic blood pressure during exercise.20
Cardiopulmonary variables, oxygen uptake (VO2 ml/min) and carbon dioxide production (CO2 ml/min), were continuously measured with breath-by-breath analysis. Anaerobic threshold (AT) was determined by the analysis of ventilatory equivalents. Exercise was considered adequate if the respiratory gas exchange ratio (RER) exceeded the value of 1.0. Peak oxygen uptake (peak VO2) was defined as the highest VO2 level achieved during the final 30 seconds of the exercise test. The peak VO2 was expressed both as an absolute value relative to body weight (ml/kg/min) and as a percentage of the maximum predicted value (peak VO2%). Values <75 % of the maximum predicted value for age, gender and height were considered abnormal.21
During exercise transthoracic echocardiographic monitoring was performed with assessment of LVOT velocities every two minutes. Immediately after each gradient was recorded, the degree of systolic anterior motion of the mitral valve (SAM) and mitral regurgitation were assessed in the apical and/or parasternal long-axis views. SAM was graded semiquantitatively from 2-dimensional images or derived from M-mode recordings using a previously described grading system.22 At the end of exercise, patients were immediately placed in the left lateral decubitus position and LVOT velocities and diastolic function were recorded every minute for five minutes. Peak Doppler parameters considered in the analysis were those measured immediately post-exercise in the left lateral decubitus position.
Based on echocardiographic assessment of LVOT velocities, 3 main profiles were defined: “non-obstructive” (absence of obstruction at rest and during exercise or recovery), “latent-obstructive” (evidence of obstruction during exercise or recovery) and “rest-obstructive” (overt obstruction at rest).1
Diastolic reserve was assessed in terms of exertional change in diastolic profile. Impaired diastolic reserve was defined as new occurrence or worsening of DD with respect to baseline. Patients were classified with regard to DD grade as: Rest DD (grade II/III at rest), Latent DD (grade 0/I at rest but II/III on effort) and No DD (grade 0/I at rest and on effort).
Data were digitally stored and measurements were made at completion of each study. All echocardiograms were performed by a single expert operator (FR); the following intra-observer variability (tested using digital archiving images) was 3.7% for the assessment of LVOT gradient, 5.8% for mitral regurgitation, 7.4% for E/e’ septal and 8.7% for E/e’ lateral.
Statistical analysis
Continuous variables are reported as mean and standard deviation, in case of normally-distributed variables, or as median and quartiles, in case of non-normally distributed variables. Normality of distribution was assessed by the Kolmogorov-Smirnov test. Categorical variables are expressed as count and percentages. Continuous variables were compared by t test, Mann-Whitney U test or ANOVA as appropriate. Categorical data were compared using the χ2 test.
Multivariable logistic regression with the backward stepwise method (using an entry p value < 0.2) was performed to identify covariates associated with functional impairment, defined as VO2 max < 75%. Bootstrapping in 1000 samples
was used to validate the models. The area under curve was calculated to evaluate the predictive power of the final model. All P are two-sided and considered significant at < 0.05. Analyses were performed using SPSS version 18.0 (SPSS, IBM, Chicago, US).
RESULTS
Identification of HCM profiles and baseline related to obstruction
Clinical, demographic, echocardiographic and metabolic characteristics of the 197 HCM patients, compared with 40 healthy volunteers, are reported in Table 1. As expected, HCM patients showed impaired functional capacity and diastolic function compared to the controls. One hundred-eight patients (55%) had neither LVOT obstruction at rest nor during exercise or recovery (non-obstructive profile). In 48 patients (24%) obstruction was absent at rest but occurred on exercise (latent-obstructive profile). The remaining 41 patients (21%) showed significant LVOT obstruction at rest (rest-obstructive profile). ANOVA comparison of the 3 HCM profiles showed unequal distribution for several variables; however, post-hoc comparison showed a significant difference only between non-obstructive and rest-obstructive patients, the latter being more symptomatic (Tables 2-3). Moreover rest-obstructive patients, compared to other groups, had a greater prevalence of high-grade DD at rest, as confirmed by larger LA volume index and higher E/e’ ratio at rest and during exercise.
Cardiopulmonary test results
There were no complications during exercise. Compared with healthy volunters, HCM patients achieved lower peak VO2 values (20 ± 6 vs 28 ± 7 ml/kg/min; p<0.001) with an abnormal exercise tolerance (peak VO2 < 75% predicted
value) observed in 142 patients (72%). (Tables 1-3)
Diastolic dysfunction at rest and during exercise
E, e’ septal and e’ lateral wave velocities progressively increased during exercise in healthy subjects, consistent with the expected , normal diastolic reserve (Figure 1). This however was not the case in HCM patients, in whom such increment was markedly reduced and the E/e’ ratio increased (Figures 2-3). One hundred-seven patients (54%) had DD grade II/III at rest (Rest DD), whereas 40 (20%) showed preserved diastolic function (grade 0/I) both at rest and on effort (No DD). The remaining 50 patients (25%), mainly belonging to the non obstructive group, had a grade 0/I pattern at rest but exhibited impaired diastolic reserve on exercise, reflected by unfavourable changes in diastolic profile
compared to baseline. Of these 50 patients, the majority (n=36) had grade II DD at peak of exercise, whereas the remaining 14 patients had grade III. Patients with obstruction at rest showed a more severe profile of DD at rest and on exercise compared to non-obstructive and latent-obstructive patients, as reflected by lower values of septal and lateral velocities and higher value of mean E/e’(p < 0.01).
At peak of exercise only 6 of the 197 patients (0.3 %) had an increase in mitral regurgitation grade from mild to moderate: all were in the latent-obstructive group (Table 2).
Interrelation of DD and LVOT obstruction
Combining obstructive and diastolic features, different functional profiles were obtained. In the non-obstructive group, peak VO2 was lower in patients with Rest DD and Latent DD than in those with No DD, who performed significantly
better. In the latent-obstructive group, no significant differences in VO2 existed among the three diastolic profiles,
although patients with No DD trended towards higher VO2 peak values (Figure 4). Rest-obstructive patients (with the
exception of a single patient) all presented rest or latent DD. The worst functional profile (VO2 peak 58% of predicted
value) was observed in patients combining rest DD and rest obstruction (Figure 4), comprising the highest proportion with VO2 peak < 75% of predicted value (Figure 5). Conversely, the best functional profile was observed in
non-obstructive patients with No DD (VO2 peak 74% of predicted value).
Of note, latent DD was more often associated with impaired exercise tolerance (peak VO2 <75% of maximum predicted value) than resting DD in both the non-obstructive and the latent-obstructive groups (Figure 5).
At multivariate regression analysis, LA volume index, LV obstruction at rest and resting or latent DD were significantly associated with lower VO2 peak values (Table 4). When the rest-obstructive group was excluded from the analysis, rest or latent DD were the only determinants of exercise impairment (latent-obstructive OR 8.9; 95% CI 1.5 to 18.8, p = 0.012; non-obstructive OR 2.2; 95% CI 1.0 to 5.8, p = 0.030) (Table 5).
DISCUSSION
By combining simultaneous echocardiography and cardiopulmonary testing, the present study provided a comprehensive and dynamic evaluation of HCM pathophysiology during exercise. We identified six unique patient subsets based on the interplay of DD and outflow obstruction – both defined as resting, exercise-induced or absent. Our results shed light on the mechanisms of exercise limitation (and potential treatment targets), with particular regard to the previously unresolved subset of patients who are non-obstructive at rest. Of note, most of the 197 study patients (72%) showed some degree of functional impairment compared to healthy controls. Consistent with earlier literature,1-9 this
finding confirms the high prevalence of exercise limitation in HCM individuals, even when they report themselves as being asymptomatic because of long-term adaptation to their condition.
In healthy subjects, the velocities of E, e’ septal and e’ lateral waves progressively increased during exercise, consistent with the expected, normal diastolic reserve.23 In HCM patients, however, such increment was clearly blunted during effort, independent of the resting diastolic profile present at baseline. Overall, 88% of our patients had DD of sufficient degree during exercise to cause functional limitation and symptoms. In about half, however (41%), this was not predictable based on their favourable diastolic profile at rest. Our findings are consistent with previous reports highlighting the low predictive value of resting diastolic parameters with regard to functional capacity in HCM patients,9,11,24 while limited data are available regarding exertional variations in diastolic parameters. Recently, an abnormal diastolic reserve has been documented by means of longitudinal diastolic functional reserve index (DFRI) derived from tissue Doppler measurements in small HCM cohorts.25-27
Based on our findings, latent impairment in diastolic reserve emerges as a major determinant of exercise intolerance in HCM, calling for systematic evaluation of LV filling properties during exercise. Latent DD was in fact associated with worse functional capacity in our patients, compared with resting DD. While the reasons for this apparent paradox are unclear, it may be hypothesized that patients who develop/worsen DD on effort may adapt less well that those who cope with it full-time. In other words, this aspect might reflect a sort of acute diastolic stress that leads to maladaptation to exercise. This concept finds support in the literature based on other disease models. 28,29
In HCM patients with normal or only mildly impaired diastolic function at rest, a clinically relevant impairment of diastolic reserve should be sought during exercise testing and the information should be integrated with simultaneous assessment of dynamic obstruction at the subaortic and/or midventricular level. Exercise echocardiography combined with the accuracy of CPX evaluation provides the best of possible worlds with regard to functional assessment of individual HCM patients, not only with regard to clinical staging,30 but also in the light of emerging therapeutic
strategies.31 Indeed, dynamic assessment of diastolic function should ideally become part of routine protocols in the
same manner as that of provocable gradients.12 This concept is particularly relevant to patients who are truly
non-obstructive (i.e. not latent-non-obstructive) and may affect management in at least two ways: the first is to stimulate increase surveillance (eg by serial biomarker evaluation) in order to detect evidence of disease progression warranting advanced therapeutic options even in the presence of preserved systolic function.32 Unfortunately, HCM patients are often
referred late for cardiac transplantation because of falsely reassuring values of LVEF.33 The second implication derives
from the possibility that novel pharmacological treatment under investigation might have a direct benefit on myocardial relaxation in HCM.34 Unless latent DD is identified by functional assessment, an indication to these therapies might be
Resting obstruction has been previously associated with impaired metabolic exercise capacity and increased risk of heart failure-related complications and death.2,35,36 Patients with resting obstruction in the present study were characterized by marked functional impairment with lower VO2 peak values and more advanced DD compared to the
non-obstructive and latent-obstructive groups (p <0.01). This was reflected by higher E/e’ ratio values and larger LA volume index. Thus, resting obstruction and DD appear closely interrelated, and probably part of an adverse process leading from afterload mismatch to regional anisotropy of relaxation and impaired LV filling.37,38 Obstruction is also associated with greater LV thickness and may worsen coronary microvascular dysfunction.39,40 Indeed, the relationship between obstruction and DD is so strict, that only one resting-obstructive patient had mild or no diastolic impairment during exercise. Whether relief of obstruction by surgical myectomy or alcohol septal ablation leads to significant improvement in diastolic parameters is still unresolved, in view of the frequent conduction disturbances produced by such procedures (left and right bundle branch block, respectively), which per se may impair diastole and thus represent a major confounder.
CONCLUSIONS
Dynamic obstruction and DD may produce different grades of functional limitation in HCM patients. At one end of the functional spectrum are rest-obstructive patients, presenting with marked DD, large LA volume index and elevated filling pressures: these individuals generally have severe functional limitation and adverse outcome. At the other end are those who are truly non-obstructive (at rest and during effort) and have no or mild DD, characterized by preserved exercise capacity and favourable clinical course. Between these two extremes, intermediate profiles are characterized by variable interplay of obstruction and impaired diastolic reserve, as well as variable outcome. A comprehensive assessment of outflow obstruction and diastolic reserve during CPX test represents the best strategy to gauge the relative importance of each pathophysiological component, assess disease progression and choose the best available treatment.
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Figure legend
Figure 1. Transmitral flow and tissue Doppler velocity at rest and after exercise in healthy subject with normal diastolic reserve. Panel A-B: transmitral flow pattern. Panel C-D: septal annulus tissue Doppler velocities. Panel E-F: lateral annulus tissue Doppler velocities
Figure 2. Transmitral flow and tissue Doppler velocity at rest and after exercise in HCM patient with impaired diastolic reserve. Panel A-B: transmitral flow pattern. Panel C-D: septal annulus tissue Doppler velocities. Panel E-F: lateral annulus tissue Doppler velocities
Figure 3. E/e’ mean values at rest and peak exercise between HCM patients (red line) and healthy subjects (blu line )
Figure 4. Functional profiles in HCM patients subsets (circles are mild outliners, little asterisks are extreme outliners)
Figure 5. Prevalence of patients with oxygen consumption <75% of maximum predicted value in HCM patients subsets
Table 1
Demographic, clinical, echocardiographic and metabolic data Study population 197 Healthy controls 40 p Age 45 ± 15 46 ± 14 0.746 Gender (F/M) 68/129 11/29 0.391 BSA(m2) 1.87 ± 0.22 1.85 ± 0.25 0.234 HR (beats/minute) 80 ± 18 75 ± 18 0.099 Mx LV thickness (mm) 20.1 ± 5.5 8.3 ± 1.0 <0.001 LVEDD (mm) 48.5 ± 3.0 46.8 ± 5.9 0.007 LVESD (mm) 22.6 ± 2.1 26.3 ± 2.6 <0.001 E-wave (cm/s) 70.7 ± 18.9 74.5 ± 18.4 0.266 A-wave (cm/s) 70.3 ± 22.3 66.9 ± 26.9 0.396 E/A ratio 1.12 ± 0.50 1.22 ± 0.60 0.247 DTE (msec) 214 ± 52 203 ± 48 0.240 e’ septal (cm/s) 7.0 ± 3.2 10.8 ± 3.1 <0.001 e’ lateral (cm/s) 9.6 ± 4.0 13.1 ± 4.1 <0.001 e’ average (cm/s) 8.0 ± 3.1 12.2 ± 3.5 <0.001 E/e’ septal 12.9 ± 6.2 8.8 ± 3.7 <0.001 E/e’ lateral 8.4 ± 3.7 6.3 ± 1.7 <0.001 E/e’ average 9.8 ± 4.0 7.6 ± 2.5 <0.001 LAi (ml/m2) 28.9 ± 9.0 22.8 ± 2.8 <0.001 EF (%) 67.7 ± 8.0 62.1 ± 5.3 <0.001 NYHA f.class* <0.001 I 110 n.a. II 81 n.a. III 6 n.a. MR grade 0.347 0 129 35 1 52 5 2 10 0 3 6 0
VO2 peak (ml/kg/min) 20 ± 6 28 ± 7 <0.001 VO2 peak % 64 ± 13 92 ± 11 <0.001
Legend: M = male, F = female, BSA = body surface area, NYHA f.class = New York Heart Association functional class, n.a. = not applicable, Mx LV thickness = maximal left ventricular wall thickness, EF = ejection fraction, LAi = left atrium volume index, MR = mitral regurgitation, E-wave = Doppler E wave, A-wave = Doppler A wave, DTE = deceleration time, e’ = tissue Doppler e’ wave.
Table 2
Baseline characteristics of the study poulation subsubgroups Non-obstructive
108 Latent-obstructive48 Rest-obstructive41 P value
Age 43
±
15 45±
14 50±
16 0.053 Gender (F/M) 36/72 34/14 18/23 0.331 BSA (m2) 1.83±
0.22 1.95±
0.21* 1.86±
0.21 0.007 HR (beats/minute) 81±
20 79±
12 79±
16 0.783 E-wave (cm/s) 67.5±
17.6 72.6±
19.5 77.1±
20.3 * 0.016 A-wave (cm/s) 64.1±
19.9 74.7±
23.2 * 81.5±
22.0 * <0.001 E/A ratio 1.16±
0.47 1.10±
0.55 1.05±
0.52 0.431 DTE (msec) 205.7±
43.2 222.9±
62.9 227.6±
59.5*§ 0.033 e’ septal (cm/s) 7.0±
3.1 6.2±
3.1 4.6±
1.9 *§ <0.001 e’ lateral (cm/s) 10.3±
4.2 9.7±
3.7 7.6±
3.1 *§ <0.001 e’ average (cm/s) 8.7±
3.4 8.0±
2.5 6.1±
2.2 *§ <0.001 E/e’ septal 10.7±
3.6 12.6±
4.2 18.9±
9.1 *§ <0.001 E/e’ lateral 7.2±
2.2 8.2±
3.0 11.7±
5.4 *§ <0.001 E/e’ average 8.4±
2.1 9.6±
3.0 13.9±
5.8 *§ <0.001 LVOT ∆P (mmHg) 8.2±
3.1 15.9±
10.0 45.5±
15.8 *§ <0.001 LAi (ml/m2) 26.8±
8.1 26.9±
5.9 36.9±
10.2 *§ <0.001 EF (%) 66.6±
9.2 67.2±
5.9 70.9±
7.2* 0.017 NYHA f.class * *§ <0.001 I 82 24 4 II 26 24 31 III 0 0 6 MR grade *§ <0.001 0 84 31 14 1 21 13 18 2 3 3 4 3 0 1 5 LVDD grade *§ <0.001 0 38 8 1 1 25 12 6 2 45 27 22 3 0 1 12 *p <0.05 vs non-obstructive § p<0.05 vs latent-obstructiveTable 3
Exercise parameters of the Study Population Overall 197 Non-obstructive 108 Latent-obstructive 48 Rest-obstructive 41 p E-wave (cm/s) 100.2 ± 24.9 100.3 ± 23.0 98.3 ± 26.6 106 ± 27.6 0.326 A-wave (cm/s) 97.3 ± 30.8 93.8 ± 30.2 98.1 ± 23.3 107.9 ± 37.4* 0.045 E/A ratio 1.14 ± 0.54 1.19 ± 0.57 1.04 ± 0.38 1.13 ± 0.61 0.302 DTE (msec) 168.3 ± 59.4 176.5± 41.7 186.3 ± 42.8 125.6 ± 89.8 *§ <0.001
Peak e’ septal (cm/s) 8.6 ± 3.5 9.5 ± 3.6 8.1 ± 2.8 6.8 ± 3.2 * <0.001
Peak e’ lateral (cm/s) 11.9 ± 4.0 12.8 ± 4.1 11.7 ± 3.6 9.9 ± 3.3 * 0.001
Peak e’ average (cm/s) 10.3 ± 3.3 11.2 ± 3.4 9.9 ± 2.7 8.3 ± 3.1 *§ 0.001
Peak E/e’ septal 13.3 ± 5.7 11.6 ± 4.2 12.9 ± 4.4 17.9 ± 7.4 *§ 0.001
Peak E/e’ lateral 9.2 ± 3.0 8.3 ± 2.3 9.1 ± 3.4 11.4 ± 3.2 *§ 0.001
Peak E/e’ average 10.5 ± 3.4 9.4 ± 2.4 10.3 ± 3.2 13.7 ± 4.0 *§ 0.001
Peak LVOT ∆P (mmHg) 41.5 ± 32.9 18.0 ± 5.4 57.2 ± 23.2 84.9 ± 30.0 *§ 0.001 LVDD grade Rest DD 44 28 35 None DD 31 9 0 Latent DD 33 12 5 HR peak (beats/min) 131 ± 23 134 ± 24 134 ± 21 119 ± 19 *§ 0.001
HR max predicted (beats/minute) 161 ± 20 162 ± 19 163 ± 18 156 ± 20 0.164 % of max predicted HR 82 ± 16 84 ± 16 83 ± 22 77 ± 10* 0.035
AP increase < 20 mmhg 20 (10%) 10 (9%) 3 (6%) 7 (17%) 0.215
VO2/HR 13.8 ± 3.5 13.1 ± 3.4 15.4 ± 3.6* 13.7 ± 3.4 <0.001
VO2 peak (ml) 2293 ±724 2288 ± 761 2431 ± 708 2141 ± 618 0.169
VO2 peak (ml/kg/min) 20 ± 6 21± 7 20 ± 6 16 ± 4 *§ <0.001
% of max predicted VO2 64 ± 13 69 ± 12 70 ± 13 58 ± 13 *§ <0.001
Peak VO2 < 75% of predicted VO2 142 (72%) 76 (70%) 30 (62%) 36 (88%)*§ 0.025
VE/VCO2 26 ± 6 25 ± 6 26 ± 4 28 ± 7 * 0.034
AT (ml) 14 ± 8 15 ± 9 14 ± 9 11 ± 7 0.060
RER 1.1 ± 0.7 1.0 ± 0.2 1.0 ± 0.2 1.3 ± 0.5 0.145
VE (l/min) 41 ± 16 40 ± 16 44 ± 17 39 ± 13 0.273
Exercise duration (min) 10 ± 3 10 ± 3 10 ± 3 8 ± 3 *§ 0.002
Watts 98 ± 33 102 ± 34 107 ± 33 77 ± 22 *§ <0.001
*p <0.05 vs non-obstructive § p<0.05 vs latent-obstructive
Legend: % of predicted HR = percentage of maximum predicted HR at peak of exercise; VE/VCO2 = ventilation/carbon dioxide slope; AT = anaerobic threshold; AP increase = exertional arterial pressure increase; RER = respiratory exchange ratio. All reported peak Doppler parameters were measured immediately post-exercise in the left lateral decubitus position.
Binary logistic regression analysis assessing the predictors of peak VO2 <75% of predicted value in the overall HCM cohort Multivariate (p-OR) 95% CI OBS/DD (grade 1-8)* 0.036 1.084 1.033-1.258 LA volume index 0.004 1,027 1.009-1.046
* 1= no OBS no DD; 2= no OBS latent DD; 3 = no OBS rest DD; 4= latent OBS no DD; 5= latent OBS latent DD; 6= latent OBS rest DD; 7= rest OBS latent DD; 8= rest OBS rest DD
Table 5.
Binary logistic regression: target end-point peak VO2 max <75% of predicted value in subgroups
Multivariate (p-OR) 95% CI Rest-obstructive Latent DD/rest DD 0.012 7.200 1.385 - 16.412 Non-obstructive Latent DD/rest DD 0.030 2.260 1.012 - 5.801 Latent-obstructive Latent DD/rest DD 0.012 8.909 1.596 - 18.812
