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Heart 2000;83:511–517
Abnormal cardiopulmonary exercise variables inasymptomatic relatives of patients with dilatedcardiomyopathy who have left ventricularenlargement N G Mahon, S Sharma, P M Elliott, M K Baig, M W Norman, S Barbeyto,W J McKenna Abstract
Background—Left ventricular enlargement with normal systolic function is common in asymp-
tomatic relatives of patients with familial dilated cardiomyopathy, many of whom progress to
overt dilated cardiomyopathy at follow up.
Objective—To examine maximal and submaximal gas exchange variables of cardiopulmonary
exercise testing in asymptomatic relatives with left ventricular enlargement.
Design and setting—Controlled evaluation of metabolic exercise performance of patients with
dilated cardiomyopathy and asymptomatic relatives with left ventricular enlargement identified
through prospective family screening in a cardiomyopathy outpatient clinic.
Methods—23 relatives with left ventricular enlargement, 33 normal controls, 29 patients with
dilated cardiomyopathy, and 10 elite athletes with echocardiographic criteria of left ventricular
enlargement (“physiological” enlargement) underwent symptom limited upright cycle ergometry
using a ramp protocol.
Results—Peak oxygen consumption (pVO ; mean (SD)) was significantly reduced in relatives
with left ventricular enlargement (78 (16.3)%) v normal controls (96%, p < 0.01) and athletes(152%, p < 0.001), but was higher than in patients with dilated cardiomyopathy (69%, p < 0.01).
pVO was less than 80% of predicted in 75% of patients, 58% of relatives, 22% of controls, and none of the athletes. Oxygen pulse (pVO /heart rate) was less than 80% of predicted in 69% of patients, 35% of relatives, 6% of controls, and none of the athletes. The slope of minute ventila-tion v CO production ( VE/ VCO ) was > 30 in 68% of patients, 50% of relatives, and in none of the controls or athletes. Anaerobic threshold, occurring in relatives at 37 (14)% of thepredicted VO , was higher than in the patients (32%, p < 0.01) and lower than in the controls (45%, p < 0.05) or in the athletes (55%, p < 0.001).
Conclusions—Maximal and submaximal cardiopulmonary exercise test variables are abnormal
in asymptomatic relatives with left ventricular enlargement, in spite of normal systolic function.
This provides further evidence that left ventricular enlargement represents subclinical disease in
relatives of patients with dilated cardiomyopathy. Metabolic exercise testing can complement
echocardiography in identifying relatives at risk for the development of dilated cardiomyopathy.
(Heart 2000;83:511–517)
Keywords: cardiomyopathy; exercise; diagnosis Idiopathic dilated cardiomyopathy usually de- cific antibodies, as well as raised circulating velops insidiously and is often advanced at the isoforms.5 A recent three year follow up study patients referred to hospital is poor, with a 25–30% one year mortality and a 50% five year develops in 27% of patients with left ventricu- mortality.1 The ability to identify early disease would be a significant advance in the current Patients with dilated cardiomyopathy have Department of
management of this disease and facilitate stud- abnormal maximal and submaximal responses Cardiological
to cardiopulmonary exercise testing,7 involving Sciences, St George’s
Hospital Medical
School, Cranmer
dilated cardiomyopathy has identified a subset hypothesised that asymptomatic left ventricu- Terrace, London
of relatives who have left ventricular enlarge- lar enlargement in the relatives of such patients SW17 ORE, UK
ment (defined as a left ventricular diastolic cardiopulmonary exercise capacity, in contrast predicted for age and body surface area2 in the to cardiopulmonary performance in individu- presence of normal systolic function, and in the als with physiological left ventricular enlarge- absence of an underlying cause such as hyper- ment caused by athletic training. Our aim in tension or athletic training.3 4) Left ventricular this study was thus to examine maximal and enlargement in a relative of a patient with dilated cardiomyopathy may be a marker of exercise testing in those relatives of cardiomy- early or mild disease. Relatives with left opathy patients found to have left ventricular ventricular enlargement have a higher than expected prevalence of circulating heart spe- patients with overt dilated cardiomyopathy, normal controls, and athletes with “physiologi- underwent clinical assessment, 12 lead ECG, cal” dilatation of the left ventricle as a result of EXERCISEAll patients and controls were fasted for two hours before exercise testing. Exercise was per- formed in the upright position on a Sensor- Twenty three consecutive asymptomatic rela- tives with left ventricular enlargement, from 19 families attending a tertiary referral centre protocol ranging from 10–15 watts/min (se- lected to ensure adequate stress and avoid pre- went metabolic exercise testing. They were mature fatigue) in a quiet air conditioned room with an average temperature of 21°C and full dilated cardiomyopathy being followed up dur- resuscitation facilities. Each test was super- ing the same period. Evaluation of asympto- vised by an experienced cardiologist, nurse, matic relatives was performed with local ethics committee approval and has been described in Before the test all patients underwent a three detail elsewhere.6 Left ventricular enlargement minute practice run at zero work rate. A respi- was defined as an unexplained left ventricular ratory exchange ratio below 0.85 was required before starting the test. Simultaneous breath by than 112% of predicted in the presence of a breath gas exchange analysis was performed shortening fraction of greater than 25%.6 using a dedicated Sensormedics metabolic cart Predicted left ventricular end diastolic dimen- sion (LVEDDc) was calculated according to Linda, California, USA). Respiratory gas was sampled continuously from a mouthpiece and LVEDDc = [45.3 × BSA0.3] − [0.03 × age] transducer for oxygen and a 2900 MMC non- dispersive infrared sensor for carbon dioxide.
The signals underwent analogue to digital con- version for the calculation of oxygen consump- diomyopathy was defined according to World Health Organization criteria9; in addition, all (VCO ) using an established technique.11 Meas- patients with dilated cardiomyopathy had an urements included VO (l/min), VCO (l/min), LVEDD of > 112% of predicted, with a short- minute ventilation (VE), heart rate (beats/ ening fraction of < 25%. Patients with coron- min), work rate (WR; watts), and respiratory ary disease, hypertension, valvar disease, or a quotient. Graphs of VO v VCO to calculate regular alcohol intake of > 21 units/week in calculate aerobic work eYciency, VE v VO , excluded. All relatives with left ventricular oxygen pulse v VO , and heart rate v VO were enlargement filled in a questionnaire about generated by an IBM computer (Sensormedics Vmax/Vision software) using on line gasexchange data from the metabolic cart, each variable being plotted at 10 second intervals.
Forty five volunteers with a normal 12 lead Signals from a 12 lead ECG were displayed bolic exercise testing under identical condi- tions. All volunteers were required to fill in a (Marquette Electronics Inc, Milwaukee, Wis- questionnaire about their daily physical activ- consin, USA). Blood pressure was measured by ity. Individuals performing more than two auscultation at the brachial artery at one hours of organised physical training a week minute intervals during exercise and for the first three minutes after exercise, using a fulfilled echocardiographic criteria for leftventricular enlargement were also evaluated.
An elite athlete was defined as an individual who had attained a suYciently high standard The peak oxygen consumption (pVO ), defined in his or her sport to compete at international as the highest oxygen consumption achieved during exercise, was calculated by measuringthe mean of the highest values over the last 10 seconds of exercise. To allow for age, body size, All subjects underwent conventional two di- and sex diVerences,12 results were expressed as a percentage of the predicted maximum oxygen weeks before the exercise test. End diastolic consumption (VO max), which was calculated and end systolic diameters were measured from using established nomograms based on age, the short axis views at the level of the tips of the sex, height, and weight.13–15 Values below 80% mitral valve leaflets, and shortening fraction fall below established 95% confidence limits was derived from these measurements.10 All and were considered abnormal.16 The anaero- echocardiograms were analysed blind to the bic threshold was calculated non-invasively clinical diagnosis. All patients with dilated car- using the V slope method17 and expressed as a diomyopathy and left ventricular enlargement percentage of the predicted VO max. Values Metabolic exercise in left ventricular enlargement under 40% were considered abnormal.18 The per cent of athletes, 69% of patients with oxygen pulse (O pulse) was calculated as the dilated cardiomyopathy, 60% of relatives with quotient of the pVO and peak heart rate. Values were expressed as a percentage of the maxi- was 26 (12.2) years in athletes (range 15–54), formulae for predicted VO max and predicted 46 (12.6) years in patients (19–70), 32 (12.6) maximum heart rate.19 Values below 80% of years in relatives (17–62), and 34 (12.8) years predicted were considered abnormal. Values in controls (15–66). Two relatives with left above 80% were regarded as normal provided ventricular enlargement who undertook more the individual had achieved a maximum heart than two hours of structured physical activity a rate of at least 80%. The work rate (WR) in watts at peak exercise was determined andexpressed as a percentage of the predicted maximum work rate calculated according to Baseline echocardiographic data for all four LVEDD% in relatives with left ventricular Expired volume v expired CO was plotted enlargement was 118.4 (5). This did not diVer graphically, and the relation ( VE/ VCO ) was significantly from LVEDD% of either athletes calculated as the slope below the point of or patients with dilated cardiomyopathy, but anaerobic threshold. The normal gradient of the slope is 26–30.22 A respiratory quotient of (p < 0.001). Fractional shortening (FS) in relatives with left ventricular enlargement was 31 (4.4)%; this was lower than in normal con- excluded from the study. Six patients with trols (37 (5.3)%, p < 0.001) and higher than in dilated cardiomyopathy and two relatives with the patients (17 (4.4)%, p < 0.001).
left ventricular enlargement were excluded onthis basis.
Statistical analysis was performed using SPSS Most of the patients with dilated cardiomyopa- for Windows (SPSS Inc, Chicago, Illinois, USA). All variables were tested for normality of (NYHA) functional class I (10 (36)%) or II (16 (54)%); three patients (10%) were in class III.
The patients were all symptomatic at presenta- dent’s t test, analysis of variance, tion. All of them were on angiotensin convert- Mann–Whitney U test, Kruskall–Wallis test, ing enzyme inhibitors, 45% were on diuretics, and bivariate correlation tests were used where appropriate. A value of p < 0.05 was consid- ered significant. Metabolic and echocardio- angiotensin II antagonists. All the relatives graphic results were expressed as absolute values and as percentages of predicted values to minimise diVerences resulting from age and sex Nineteen of the patients with cardiomyopa- disparities. Results are expressed as mean thy (66%) were in sinus rhythm and 10 (34%) had atrial fibrillation; six (20%) had left axisdeviation on the ECG, and five (17%) had left bundle branch block. Non-sustained ventricu- lar tachycardia (three or more ventricular exercise testing without complication. Seventy ectopic beats at a rate of > 120 beats/min) was Echocardiographic and metabolic exercise data (all groups) *Comparison with LVE group.
†Per cent of normal standard.
AT, anaerobic threshold (% of predicted VO max); DCM, dilated cardiomyopathy; FS, fractional shortening; HRmax, maximum heart rate; LVE, left ventricular enlargement; LVEDD, left ventricular end diastolic dimension; O pulse, quotient of pVO and peak heart rate; pVO , peak oxygen consumption; PET CO pressure of end tidal carbon dioxide; RQ, respiratory quotient; VE, minute ventilation.
documented at initial assessment in 11 (39%) of the patients. The asymptomatic subjects with left ventricular enlargement were all in controls (45%, p = 0.02) or the athletes (55%, sinus rhythm. The relatives with left ventricular p < 0.001). Anaerobic threshold occurred at less than 40% of the predicted VO max in 75% of the patients, 65% of the relatives, 22% of the controls, and none of the athletes (table 2).
Metabolic exercise variables are shown for allfour groups in table 1. Maximum heart rate (per cent predicted) in the relatives did not dif- fer significantly from controls or athletes but was higher than in the patients (92 (9.8)% v 89 When all 103 subjects were analysed together, (15)%, p = 0.02). Relatives achieved 83 (20)% modest correlations were observed between of their predicted maximum work rate v 63% fractional shortening and O pulse (r = 0.49, (p < 0.004) in the patients, 104% (p = 0.001)in normal controls, and 156% (p < 0.001) in athletes. Similar significant diVerences wereobserved when absolute values (beats/min andwatts respectively) were analysed (table 1).
The results are shown in fig 1. Oxygen pulse inthe relatives was 89 (17)% of predicted, whichwas lower than that observed in normalcontrols (167%, p < 0.001), and higher than in the patients (70%, p < 0.01). O pulse was less than 80% of predicted in 69% of the patients,in 35% of the relatives, in 6% of the controls,and in none of the athletes (table 2). One patient and one relative had an O pulse that Boxplot of oxygen pulse values for each group, showing median, quartiles, and 95th centiles. Dashed line because of a low maximum heart rate. In 40% represents 80% of predicted oxygen pulse. of the patients and 46% of the relatives theoxygen pulse did not increase in the expected parabolic pattern23 but began to plateau belowthe anaerobic threshold. In these patients,heart rate increased more rapidly at the point offlattening.
Peak oxygen uptakeThe results are shown in fig 2. pVO significantly reduced in the relatives (78 (16.3)%) compared with the normal controls (96%, p < 0.01) and the athletes (152%,p < 0.001), and was higher than in the patients(69%, p < 0.01). Similar significant diVerences were observed when absolute values in ml/kg/ min were analysed (table 1). Peak oxygen con- Boxplot of p VO per cent predicted for each group, showing median, quartiles, and 95th centiles. Dashed patients, in 58% of the relatives, in 22% of the line represents 80% of predicted p VO . controls, and in none of the athletes (table 2).
The results are shown in fig 3. The slope of theminute ventilation as a function of VCO below creased in the patients, with a mean value of 34 in controls and at the upper limit of normal in the relatives. Sixty eight per cent of the patientsand 50% of the relatives had a slope of > 30. No normal controls and no ath-letes had a value above 30 (table 2).
The results are shown in fig 4. Anaerobic threshold occurred at a mean of 37 (14)% of showing median, quartiles, and 95th centiles. Dashed line the predicted VO max in the relatives, which represents the normal slope of 30. Metabolic exercise in left ventricular enlargement Prevalence of abnormal results within each group including changes in peripheral blood flow,ratios of type I to type II muscle fibres, and mitochondrial density, which are observed in patients with dilated cardiomyopathy and heart failure25 26—may also occur in left ventricular enlargement. However, as arteriovenous oxy- gen diVerence is generally increased in heart failure in spite of the changes described above, a reduction in the relatives is unlikely.
*Per cent predicted.
AT, anaerobic threshold; DCM, dilated cardiomyopathy; HRmax, maximum heart rate; LVE, left ventricular enlarge- ment; O pulse, quotient of pVO and peak heart rate; pVO , peak oxygen consumption; VE, minute ventilation.
possibility of peripheral mechanisms for re-duced exercise performance in relatives with (r = −0.49, p < 0.001), maximum VCO was normal in the relatives, 46% had a threshold (r = 0.42, p < 0.001), NYHA class documented in patients with congestive car- (r = −0.50, p < 0.001), and WR% (r = 0.53, diac failure,27–29 but the mechanisms of this p < 0.001). LVEDD% correlated poorly with increased ventilatory response are controver- metabolic measurements, even when athletes sial. Ventilation–perfusion mismatch reflecting increased pulmonary dead space caused bypulmonary vascular abnormalities has been Discussion
proposed.30 This is supported by the finding The results show that asymptomatic relatives of that end tidal CO was normal in all patients in patients with dilated cardiomyopathy, and who this study. However, relatives with left ventricu- also have left ventricular enlargement, have lar enlargement who do not have heart failure significantly abnormal cardiopulmonary exer- are unlikely to have pulmonary vascular abnor- cise test results. This adds to the serological and immunological evidence that left ventricu- involved include augmented chemosensitiv- lar enlargement represents early disease in ity,31 an enhanced ergoreflex causing direct some individuals. While the mechanisms of stimulation of ventilation by muscle activity,32 abnormal responses remain speculative, this and reduced ability to increase gas transfer on study suggests that both cardiac and peripheral exercise.33 Similar reflexes may be involved in the regulation of peripheral blood flow andcould be responsible for the abnormal oxygen Although baseline systolic function was normal suggests that asymptomatic relatives may not in the relatives, analysis of the oxygen pulse only be developing subtle cardiac abnormali- pattern suggests that abnormalities of cardio- ties but also have more widespread changes aVecting cardiovascular performance.
caused by impaired augmentation of systolicfunction in response to exercise. Oxygen pulse is the product of stroke volume and arteriov- enous oxygen diVerence.16 The peak oxygen The contrast between results obtained in the relatives and in the athletes reinforces the view relatives. In 46% of the relatives (compared that left ventricular enlargement in relatives is with 40% of the patients) the oxygen pulse an indicator of underlying pathology. Left ven- started to plateau with increasing work rate tricular enlargement in athletes is common and instead of rising in its normal parabolic represents a normal physiological response to fashion. One possible mechanism for an early intensive physical training. Of 515 elite athletes plateau of oxygen pulse is the failure of stroke evaluated at this institution, 32% had echocar- volume to increase. In patients with dilated cardiomyopathy and left ventricular enlarge- ment who had abnormally flat oxygen pulse consumption observed in athletes with left responses, the plateau occurred at or shortly ventricular enlargement who underwent car- after the anaerobic threshold. This phenom- diopulmonary exercise testing suggests that it is enon has previously been described in patients not the ventricular enlargement per se that is with hypertrophic cardiomyopathy23 and may responsible for the cardiopulmonary abnor- malities observed in the relatives, and further- metabolic acidaemia because of a depressed more that metabolic exercise testing may be a useful method of distinguishing physiologicalfrom pathological left ventricular enlargement.
PERIPHERAL MECHANISMSAn alternative explanation for the reduced pVO and oxygen pulse in the relatives would be The definition of left ventricular enlargement a reduction in arteriovenous oxygen diVerence as “enlargement with normal systolic function” in these individuals. Alterations that could should be qualified by the recognition that while systolic function is within normal limits in these patients it is lower than in normal con- 1 Diaz RA, Obasohan O, Oakley CM. Prediction of outcome Br Heart J 1987;58:393–9.
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3 Michels VV, Moll PP, Miller FA, et al. The frequency of evidence of a decline in systolic function, which familial dilated cardiomyopathy in a series of patients with nonetheless remains within normal limits, such idiopathic dilated cardiomyopathy. N Engl J Med 1992;326:
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We gratefully acknowledge the assistance of Mary Gould, Carol 31 Chua TP, Clark AL, Amadi AA, et al. Relation between Page, and Brian Mist. Sanjay Sharma and Mark W Norman chemosensitivity and the ventilatory response to exercise in were supported by British Heart Foundation junior fellowships.
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Mid-ventricular HOCM with apical asynergy A 45 year old woman presented with recurrent was sparing of the basal septum and the apex episodes of rapid non-sustained palpitations was not hypertrophied but rather thinned, and associated dizziness. She had no significant asynergic, and aneursymal (fig 1). No throm- medical history or family history of cardiac disease. Examination revealed a soft systolic abnormalities were present. Colour Doppler murmur. ECG showed sinus rhythm with left revealed a turbulent jet in both systole and ventricular hypertrophy on voltage criteria and early diastole with flow from apex to base.
inferolateral T wave changes. Transthoracic echocardiography demonstrated the unusual systolic flow away from the transducer (apical finding of mid-ventricular hypertrophic ob- four chamber position), then mid-ventricular structive cardiomyopathy with systolic cavity cavity obstruction with no flow, followed by a obliteration at the papillary muscle level and an high early diastolic velocity (4 m/s) and flow associated intracavity velocity of 4 m/s. There from apex to base concurrent with the mitralinflow E wave. This paradoxical early diastolicflow is thought to represent blood trapped inthe apical cavity in systole, which subsequentlyleaves ventricular obstruction is no longer present.
Several patterns of hypertrophic cardiomy- opathy (HCM) have now been clearly defined.
The apical variant constitutes 25% of all HCMin the Japanese population, but only 1–2% ofthe HCM cases in non-Japanese patients. Mid-ventricular HCM with apical asynergy is some-what less common. In the largest publishedreport to date, a Japanese team reported anincidence of concealed apical aneurysm with Apical two chamber view demonstrating mid-ventricular cavity obliteration of approxi- mid-ventricular obstruction and an apical aneurysm. mately 1.5% of all HCM cases. The incidencein non-Japanese patients is yet to be clarified.
The importance of this variant is its associationwith ventricular arrhythmias and systemicembolism, the latter occurring in 30% ofpatients. Identification of the paradoxical earlydiastolic flow from apex to base can be a Department of
marker of a sequestered apical chamber in Cardiology, King’s
patients with cavity obliteration, particularly College Hospital,
when the apical cavity cannot readily be delin- Denmark Hill, London
eated by cross sectional echocardiography.
SE5 9RS, UK
J C Cooke
Following the echocardiographic findings in this patient, a 24 hour Holter monitor was per- formed and revealed self limiting runs ofsupraventricular tachycardia along with ven- Continuous wave Doppler trace from an apical tricular couplets, but no ventricular tachycar- four chamber position revealing the mid-ventricular dia. Her palpitations are now controlled on obstruction with cessation of flow followed by paradoxical

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