CLINICAL STUDY
Utility of metabolic exercise testing in distinguishing hypertrophic cardiomyopathy from physiologic left ventricular hypertrophy in athletes
Sanjay Sharma, BSc, MRCPa*,
Perry M. Elliott, MRCPa*,
Greg Whyte, PhD*,
Niall Mahon, MD, MRCP(I)a*,
Mohan S. Virdee, MRCPa*,
Brian Mist, PhDa* and
William J. McKenna, FRCP, FACC, FESCa*
a St. George’s Hospital Medical School, London, United Kingdom
* University of Wolverhampton, Walsall Campus, Walsall, United Kingdom
Manuscript received July 29, 1999;
revised manuscript received February 22, 2000,
accepted April 11, 2000.
Reprint requests and correspondence: Dr. Sanjay Sharma, Department of Cardiological Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom
ssharma21{at}hotmail.com
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Abstract
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OBJECTIVES
This study evaluated the role of metabolic (cardiopulmonary gas exchange) exercise testing in differentiating physiologic LVH in athletes from HCM.
BACKGROUND
Regular intensive training may cause mild increases in left ventricular wall thickness (LVWT). Although the degree of left ventricular hypertrophy (LVH) is typically less than that seen in hypertrophic cardiomyopathy (HCM), genetic studies have shown that a substantial minority of patients with HCM have an LVWT in the same range. The differentiation of physiologic and pathologic LVH in this "gray zone" can be problematic using echocardiography and electrocardiography alone.
METHODS
Eight athletic men with genetically proven HCM and mild LVH (13.9 ± 1.1 mm) and eight elite male athletes matched for age, size and LVWT (13.4 ± 0.9 mm) underwent symptom limited metabolic exercise stress testing. Peak oxygen consumption (pVO2), anaerobic threshold, oxygen pulse and respiratory exchange ratios were measured in both groups and compared with those observed in 12 elite and 12 recreational age- and size-matched athletes without LVH.
RESULTS
Elite athletes with LVH had significantly greater pVO2 (66.2 ± 4.1 ml/kg/min vs. 34.3 ± 4.1 ml/kg/min; p < 0.0001), anaerobic threshold (61.6 ± 1.8% of the predicted maximum VO2 vs. 41.4 ± 4.9% of the predicted maximum VO2; p < 0.001) and oxygen pulse (27.1 ± 3.2 ml/beat vs. 14.3 ± 1.8 ml/beat; p < 0.0001) than individuals with HCM. A pVO2 >50 ml/kg/min or >20% above the predicted maximum VO2 differentiated athlete’s heart from HCM.
CONCLUSIONS
Metabolic exercise testing facilitates the differentiation between physiologic LVH and HCM in individuals in the "gray zone."
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Abbreviations and Acronyms
| | AT | = anaerobic threshold | | A-V | = systemic arteriovenous oxygen difference | | BP | = blood pressure | | ECG | = electrocardiogram | | HCM | = hypertrophic cardiomyopathy | | HR | = heart rate | | LV | = left ventricular | | LVH | = left ventricular hypertrophy | | LVWT | = left ventricular wall thickness | | O2P | = oxygen pulse | | pVO2 | = peak oxygen consumption | | RER | = respiratory exchange ratio | | SV | = stroke volume | | VCO2 | = carbon dioxide production | | VO2 | = oxygen consumption | | VO2 max | = maximal oxygen consumption |
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Hypertrophic cardiomyopathy (HCM) is the most common cause of exercise related sudden cardiac death in athletes (1–5). The identification of HCM in athletes can be problematic because some athletes develop substantial physiologic left ventricular hypertrophy (LVH) (13 mm to 16 mm) during intense physical training (6–10). Although the degree of LVH in athletes is typically less than that observed in HCM (11), genetic studies have revealed that a substantial minority of patients with HCM have a wall thickness in the same range as athletic competitors. Such individuals are often asymptomatic and participate in competitive sports but remain at risk for sudden death (12–14).
At present, routine genetic testing is not a practical method for differentiating physiologic from pathologic LVH. Several echocardiographic and electrocardiographic features can help to distinguish between HCM and physiologic LVH in athletes, but, inevitably, a small number of individuals fall into a "gray zone" (15) where differentiation between the two entities using echocardiography and electrocardiogram (ECG) alone may be problematic. Recent studies have shown that the majority of individuals with HCM have abnormal cardiopulmonary indexes during symptom limited metabolic exercise testing (16). The aim of this study was to determine whether metabolic exercise testing assists in the differentiation of HCM with mild hypertrophy and physiologic hypertrophy in individuals participating in regular sports.
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Methods
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Subjects.
Active HCM patients with mild hypertrophy
Between 1995 and 1999, ongoing research in the molecular genetics of HCM at St. George’s Hospital Medical School, U.K., led to the identification of 26 young adults with mild LVH (<16 mm) secondary to a sarcomeric protein gene mutation. Of these, eight individuals had sufficient characteristics to simulate the "gray zone," (i.e., male gender, complete absence of cardiovascular symptoms, athletic by nature [arbitrarily defined as participating in organized physical activity for at least 5 h per week]), a LVWT of 13 mm to 16 mm, absence of resting left ventricular (LV) outflow obstruction or systolic anterior motion of the mitral valve, normal LV cavity size and normal resting Doppler indexes of diastolic function (E value of 71 ± 14 cm/s, a value of 38 ± 6 cm/s and E/A of 2.1 ± 0.6) (17). Six individuals had mutations in the troponin gene, and two had mutations in the beta myosin heavy chain gene. Five played competitive sport at regional level (soccer n = 3, badminton n = 1, handball n = 1); two were army cadets who had trained intensely for over two years, and one cycled over 10 miles daily and played several recreational sports (Table 1). All selected individuals were exercised for risk stratification purposes and were not in a medically enforced detrained state at the time of the study. None of the individuals with HCM was on any form of regular medication.
Highly trained athletes with LVH
Eight hundred highly trained male Caucasian athletes underwent 12-lead ECG and two-dimensional echocardiography during peak competitive seasons between 1996 and 1999 as part of an ongoing cardiovascular evaluation program. Athletes were recruited from the British premier soccer and rugby leagues, British Lawn Tennis Association, national swimming, rowing, cycling and triathlete squads and the 1996 world championships in squash. Eight of 800 athletes (1%) had a left ventricular wall thickness (LVWT) >12 mm and participated in predominantly endurance sports at the national level (Table 2). None had a family history of HCM or premature sudden cardiac death. The parents and at least one sibling of each elite athlete with LVH underwent clinical evaluation with a 12-lead ECG and two-dimensional echocardiography using methods described elsewhere (11,18,19). All relatives had a normal ECG and two-dimensional echocardiogram.
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Table 2 Echocardiographic and Cardiopulmonary Gas Exchange Characteristic in Elite Athletes With Left Ventricular Hypertrophy
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Controls.
Elite athletes without LVH
Twelve elite age- and size-matched athletes without LVH (LVWT <12 mm) were selected from the ongoing screening program as described above. The athletes were selected from the same sporting disciplines as those of athletes with LVH. All athletes were asymptomatic and had participated at national levels within six months before the evaluation.
Recreational athletes
The recreational athlete group comprised 12 age- and size-matched healthy male volunteers with a normal 12-lead ECG and two-dimensional echocardiogram who participated in organized physical activity for at least 5 h per week. Five played soccer, two rugby, three squash, and two cycled daily. All were asymptomatic; none was on any form of medication, and none had a family history of cardiovascular disease or premature sudden cardiac death.
Metabolic (cardiopulmonary) exercise.
All subjects and controls fasted for at least 4 h before the exercise test. Exercise was performed in an upright position with a Sensormedics ergometrics 800 S cycle ergometer (Bilthoven, the Netherlands) using a ramp protocol (20) of 25 W/min in recreational athletes and individuals with HCM and 30 W/min in elite athletes in a quiet air-conditioned room with an average temperature of 21° C and full resuscitation facilities. Before the test, the exercise procedure was explained, and all subjects underwent a 3 min familiarization test at zero work load. All patients had a respiratory exchange ratio (RER) <0.85 before commencing the test. Patients were instructed to pedal at a speed of between 60 and 70 revolutions per min. Pedal speed was displayed so that the subjects could clearly observe their cadence rates and make adjustments accordingly? Subjects were encouraged to exercise to the point of exhaustion. Breath-by-breath gas exchange analysis was performed using a dedicated Sensormedics metabolic cart (V Max 29 Console, Sensormedics,). Respiratory gas was sampled continuously from a mouthpiece and analyzed using a 1111D/000 paramagnetic transducer for oxygen and a 2900 MMC nondispersive infrared sensor for carbon dioxide. The signals underwent analogue to digital conversion for the calculation of oxygen consumption (VO2) and carbon dioxide output (VCO2) by an established technique (21,22). A printout of VO2 (l/min), VCO2 (l/min), heart rate (HR) (beats per min), work rate (W) and RER was obtained and averaged at 10 s intervals to obtain smooth graphical representation. Graphs of VCO2 versus VO2 were used to estimate anaerobic threshold (AT). Signals from a 12-lead ECG were displayed continuously and recorded at 2 min intervals using a Marquette Max 1 electrocardiographic recorder (Marquette Electronics Inc., Milwaukee, Wisconsin). Blood pressure (BP) was measured by auscultation at the brachial artery at 1 min intervals during exercise and at 30 s intervals for the first 5 min after cessation of exercise using a mercury sphygmomanometer. An abnormal BP response was defined either as an increase in exercise systolic BP throughout the exercise test of <20 mm Hg, compared with resting values, or an initial increase in systolic BP >20 mm Hg with a subsequent fall by peak exercise of >20 mm Hg, compared with the peak value, or a continuous decrease in systolic BP throughout the test of >20 mm Hg, compared with the baseline BP (23). Tests were supervised by an experienced cardiologist, senior nurse and senior technician.
The following calculations were made: - Peak oxygen consumption (pVO2) was defined as the highest oxygen consumption achieved during exercise. This was the highest measured VO2 value over the last 10 s of exercise. Data were presented as absolute values (l/min) and normalized for body weight (ml/kg/min). The predicted maximal oxygen consumption (VO2 max) was calculated using established equations based on age and gender (24,25). The normalized value was then expressed as a percentage of the predicted maximum value. Values <83% were considered abnormal because they fell below previously established 95% confidence limits (26).
- Anaerobic threshold is the VO2 above which aerobic energy production is supplemented by anaerobic mechanisms and is reflected by an increase in lactate and lactate/pyruvate ratio in the muscle and arterial blood (26). This was estimated noninvasively by plotting VCO2 versus VO2 ("V slope method") (27). The AT was expressed as a percentage of the predicted VO2 max. Values <42% were considered abnormal (28).
- Oxygen pulse (O2P) is the quotient of the VO2 to heart rate (HR) (equation 1). It is the product of stroke volume (SV) and the systemic arteriovenous oxygen difference (A-V) O2 (equation 2).
 | (1) |
 | (2) |
Values were expressed as a percentage of the maximum predicted O2P calculated from equation 1 using established formulae for predicted VO2 max (24,25) and predicted maximum heart rate (28,29). Values >83% were regarded as normal if the individual had achieved a maximal heart rate of at least 80% to exclude chronotropic incompetence, because this is associated with falsely high readings.
Statistical analysis.
All values are expressed as the mean ± 1 standard deviation. Comparisons between groups were performed using a univariate analysis of variance test with post hoc (Bonferroni) analyses to identify intergroup differences. A p value <0.05 was considered significant.
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Results
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Subject and control demographics.
The demographics of athletes and individuals with HCM are shown in Table 3.
Metabolic exercise.
All individuals in the study exercised to exhaustion and stopped due to fatigue. All individuals achieved an HR within two standard deviations of the predicted maximum HR and an RER >1.1, indicating sufficient metabolic stress. There was no significant difference in the maximal HR or peak RER between any of the groups in the study (Table 3). No individual experienced cardiovascular symptoms during exercise. No individual had cardiac arrhythmia. One athlete with HCM (Patient 6; Table 1) had planar ST segment depression  2 mm from the resting ECG. The BP responses to exercise (i.e., the difference between resting and peak systolic BPs) were normal in all individuals in the study and did not differ significantly between different groups (Table 3).
Metabolic parameters in elite athletes, recreational athletes and individuals with HCM.
There were no significant differences in cardiopulmonary parameters between elite athletes with and without LVH. Elite athletes with and without LVH had a greater pVO2, AT and O2P than recreational athletes and individuals with HCM (p < 0.0001) (Table 3). Recreational athletes had a greater pVO2 than individuals with HCM. There was no overlap in the distribution of any cardiopulmonary parameter when comparing elite athletes with recreational athletes or individuals with HCM (Fig. 1). All athletes with LVH had a pVO2 >58 ml/kg/min or >46% above the predicted maximum VO2, AT 60% of the predicted VO2 max and O2P >20 ml/beat. A pVO2 >50 ml/kg/min or >20% of the predicted maximum value, AT >55 ml/kg and an O2P >20 ml/beat clearly distinguished athletes with LVH from individuals with HCM (Tables 1 and 2).
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Figure 1 Box plot showing the distribution of pVO2 values in elite athletes with and without LVH, recreational athletes and individuals with HCM. The horizontal bars (in ascending order) represent the 10th, 25th, 50th, 75th, and 90th percentiles. The round circles below and above the bars represent the number of points below the 10th and 90th percentile, respectively, in each group. HCM = hypertrophic cardiomyopathy; LVH = left ventricular hypertrophy; pVO2 = peak oxygen consumption.
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Left ventricular end diastolic diameter and LV inflow velocities in elite athletes, recreational athletes and individuals with HCM.
There was no significant difference in LV cavity size between elite athletes with and without LVH (56 ± 3 mm and 56 ± 2 mm, respectively) or between individuals with HCM and recreational athletes (50 ± 1.5 mm and 51 ± 1 mm, respectively). Elite athletes with LVH had a significantly greater LV cavity size than individuals with HCM (p < 0.001). After individual correction of LV cavity size for age and body surface area using Henry’s regression equations (30), the LV cavity size exceeded the predicted upper range in six of eight elite athletes with LVH but was within normal limits in all individuals with HCM.
There was no significant difference in resting LV inflow velocities (E wave, A wave and E/A ratio) between elite athletes with and without LVH, recreational athletes or individuals with HCM (Table 4).
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Table 4 Resting Diastolic Indexes in Individuals with HCM, Elite Athletes With and Without LVH and Recreational Athletes
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Discussion
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This study takes advantage of highly selected and well characterized subjects to examine exercise responses in the elite athlete and morphologically mild HCM. The study demonstrates that metabolic exercise testing can be used to differentiate physiologic hypertrophy in elite athletes from HCM with mild hypertrophy. Conventional measurements during exercise tests that do not utilize gas exchange measurements (HR and BP responses) would not have helped distinguish between the two entities, and ST segment analysis would have assisted in the diagnosis of pathologic LVH in only one case.
The "gray zone.".
Between 1% and 2% of elite athletes have an LVWT of 13 to 16 mm (10). Although the presence of a wall thickness outside these ranges suggests the diagnosis of HCM, some patients with the disease have mild hypertrophy within the same range as that observed in highly trained athletes. It is this overlap that constitutes the "gray zone" between physiologic LVH in athletes and morphologically mild HCM. A number of clinical, electrocardiographic and echocardiographic features can assist in the identification of HCM in an athlete in these circumstances. Hypertrophic cardiomyopathy is more likely in the presence of a positive family history of HCM in a first degree relative, echocardiographic demonstration of a small LV cavity dimension (11,31), large left atrial diameter (31), abnormal diastolic filling patterns (32,33) and the presence of pathological Q waves and ST and T wave abnormalities on the ECG (34,35). Conversely, an enlarged LV cavity in association with mild LVH is indicative of physiologic adaptation to intensive training rather than HCM (10). In a small minority of individuals, these distinguishing features are absent. Regression of LVH after detraining is a definitive method for differentiating physiologic from pathologic LVH (36); however, most athletes are reluctant to detrain, because it may jeopardize fitness and team selection. All individuals with LVH in this study fell into the "gray zone" with respect to the LVWT. Although six of the eight elite athletes with LVH had an enlarged LV cavity dimension (>55 mm) suggesting physiologic LVH (15), the remaining 10 individuals with LVH had normal LV cavity dimensions. In these 10 individuals, reliance on LV dimension would have failed to differentiate between an athlete’s heart and HCM in the absence of a genetic diagnosis.
Utility of metabolic (cardiopulmonary) exercise to differentiate pathologic and physiologic LVH.
Cardiopulmonary exercise testing is a safe and clinically useful technique for assessing exercise capacity in patients with HCM. Several studies have demonstrated that pVO2 is abnormal in the majority of patients with HCM, including those with mild or no symptoms (37–41). Metabolic exercise testing is also used to assess fitness in athletes, and studies published to date indicate that pVO2 values in elite athletes usually range between 55 and 70 ml/kg/min and exceed predicted maximum values by as much as 50%. Such athletes also have a high AT and O2P. This study demonstrated a separation in pVO2 (Fig. 1), AT and O2P between elite athletes with physiological LVH and patients with HCM and mild LVH. A pVO2 >50 ml/kg/min or >20% above the predicted VO2 max, an AT >55% of the predicted VO2 max and an O2P >20 ml/beat would discriminate physiologic LVH from HCM. The cut-off cardiopulmonary gas exchange values selected are 10% greater than the highest values achieved by athletic individuals with HCM, to allow for the limited number of patients studied, but are still considerably lower than values achieved by elite athletes. Experience of cardiopulmonary exercise testing in 740 HCM patients in our laboratory using a cycle-ergometer has yet to identify an individual with HCM achieving values greater than these.
Mechanisms of increased cardiopulmonary parameters in athletes.
The pVO2 is determined by peak cardiac output and the A-V. Athletes attain high pVO2 values through large increases in cardiac output and greater widening of the A-V during exercise. The increase in cardiac output is predominantly due to augmentation of SV, whereas the increase in the A-V is due to the enhanced oxidative capacity within the exercising muscle, resulting from a high cellular mitochondrial concentration (42,43). In contrast, most individuals with HCM have impaired LV filling during exercise, which prevents the augmentation of SV required to achieve a high cardiac output on exercise (44). There is also evidence that some patients with beta-myosin heavy chain mutations (45,46) have low mitochondrial density in skeletal muscle that may contribute to a low oxygen uptake (16). Analysis of the oxygen pulse profile (product of SV and A-V) provides evidence for the mechanisms responsible for the higher pVO2 in athletes. In this study the O2P was higher throughout exercise in elite athletes with LVH compared with athletes with HCM (Fig. 2), indicating a superior SV and A-V from the beginning to the end of exercise and confirming the physiological differences between the two entities outlined above. The higher AT in elite athletes compared with individuals with HCM in this study can be explained by superior oxygen delivery to exercising muscle and highly efficient oxygen extraction by skeletal muscle to promote aerobic metabolism for prolonged exercise. It could be argued that some of the differences in cardiopulmonary parameters between athletes and HCM related to relative differences in fitness. However, individuals with HCM also had lower cardiopulmonary parameters than recreational athletes (who do not develop LVH and would not constitute the "gray zone") indicating that even highly active individuals with HCM have an intrinsic defect in cardiopulmonary response, which prevents an appropriate increase in cardiac output and/or widening of the A-V during exercise.
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Figure 2 Oxygen pulse profiles in an athlete with LVH (athlete 5) and an individual with HCM (patient 7). HCM = hypertrophic cardiomyopathy; LVH = left ventricular hypertrophy; O2 = oxygen.
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Clinical implications.
The differentiation between physiologic and pathologic LVH in an athletic individual may represent an important and difficult clinical problem. Decisions based on 12-lead ECG and echocardiography alone may be prone to error, resulting in the loss of livelihood or the death of an individual. When faced with an asymptomatic athletic individual with mild LVH without an obvious family history of HCM and nondiagnostic ECG abnormalities, a pVO2 >50 ml/kg/min or >20% above the predicted maximum value permits reassurance of the individual. Similarly, an O2 pulse >20 ml/beat and an AT >55% of the predicted VO2 max appear to be indicators of physiological adaptation rather than HCM.
Study limitations.
Genetic testing was not performed in elite athletes with LVH, because of the impracticalities associated with the genetic heterogeneity of the condition. However, the possibility of familial HCM in elite athletes with HCM was minimized by the demonstration of a normal 12-lead ECG and echocardiograms in both parents and at least one sibling. The number of elite athletes with LVH and individuals with genetically proven HCM studied was small due to the low prevalence (1%) of LVH >12 mm in athletes and genetically proven individuals with HCM who fulfill criteria for the "gray zone." Nevertheless, the study is of clinical relevance because it identifies a relatively simple, noninvasive method of making a definitive diagnosis in athletes in the "gray zone."
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Acknowledgments
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The authors wish to thank Ms. Shaughan Dickie and Ms. Annie O’Donoghue for their important support and assistance.
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Footnotes
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Dr. Sanjay Sharma is supported by a fellowship award from the British Heart Foundation.
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References
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S. Basavarajaiah, A. Boraita, G. Whyte, M. Wilson, L. Carby, A. Shah, and S. Sharma
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S. Basavarajaiah, M. Wilson, G. Whyte, A. Shah, W. McKenna, and S. Sharma
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S. Basavarajaiah, A. Shah, and S. Sharma
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Heart,
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B. J. Maron and A. Pelliccia
The Heart of Trained Athletes: Cardiac Remodeling and the Risks of Sports, Including Sudden Death
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S Basavarajaiah, M Wilson, S Junagde, G Jackson, G Whyte, S Sharma, and W O Roberts
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A Anastasakis, C Kotsiopoulou, A Rigopoulos, A Theopistou, N Protonotarios, D Panagiotakos, N Mammalis, and C Stefanadis
Similarities in the profile of cardiopulmonary exercise testing between patients with hypertrophic cardiomyopathy and strength athletes
Heart,
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A. Pelliccia, R. Fagard, H. H. Bjornstad, A. Anastassakis, E. Arbustini, D. Assanelli, A. Biffi, M. Borjesson, F. Carre, D. Corrado, et al.
Recommendations for competitive sports participation in athletes with cardiovascular disease: A consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology
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D. L. King, L. El-Khoury Coffin, and M. S. Maurer
Myocardial contraction fraction: a volumetric index of myocardial shortening by freehand three-dimensional echocardiography
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D J R Hildick-Smith and L M Shapiro
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Abstract
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