Author + information
- Received January 12, 2003
- Revision received February 27, 2003
- Accepted March 20, 2003
- Published online July 16, 2003.
- Kinya Matsubara, MD*,* (, )
- Takashi Nakamura, MD†,
- Toshiro Kuribayashi, MD†,
- Akihiro Azuma, MD† and
- Masao Nakagawa, MD†
- ↵*Reprint requests and correspondence:
Dr. Kinya Matsubara, Department of Medicine, Kyoto Municipal Hospital, Higashitakada-cho 1-2, Mibu, Nakagyou-ku, Kyoto, Japan 604-8845.
Objectives In patients with apical hypertrophic cardiomyopathy (ApHCM), we estimated the severity of cavity obliteration (CO) in the apical potion of the left ventricle and correlated it with various clinical findings including apical aneurysm.
Background Apical hypertrophic cardiomyopathy sometimes develops apical aneurysm. The apical CO is often exhibited in ApHCM along with apical hypertrophy and ischemia. It remains unclear, however, how the CO and others are related to aneurysm.
Methods In 46 patients with ApHCM, we measured CO time on M-mode echocardiography and corrected it by the R-R interval (cCOT). We divided the 46 patients into the following groups: 17 with cCOT ≤200 ms (no/mild CO group); 18 with cCOT >200 to ≤350 ms (moderate CO group); and 11 with cCOT >350 ms (severe CO group). We then compared apical aneurysm, hypertrophy, ischemia, QT interval, and the like between the three groups.
Results The severe CO group exclusively comprised 11 patients having apical aneurysm and paradoxic jet flow. Of the 11 patients, 10 exhibited irreversible defects on exercise single photon emission computed tomography with thallium-201. All with moderate CO showed reversible defects, and none with no/mild CO showed any defects. Left ventricular hypertrophy and the corrected QT interval (QTc) were largest in the severe CO group. There were high correlations between the cCOT, hypertrophy, ischemia, and QTc. Of the 11 patients with severe CO, 6 had nonsustained ventricular tachycardia and 1 had mural thrombus.
Conclusions In ApHCM, sustained CO is an important pathophysiologic condition as well as hypertrophy, ischemia, and prolonged QTc, which are considered jointly related to the development of aneurysm through interactions.
Apical hypertrophic cardiomyopathy (ApHCM) is a relatively rare variant of hypertrophic cardiomyopathy (HCM), characterized by myocardial hypertrophy occurring predominantly in the left ventricular (LV) apical portion, with spade-shaped LV configuration and giant negative T-wave (1,2). Despite its relatively good prognosis (1–6), long-term observations occasionally exhibited gradual progression of cardiac hypertrophy (7,8)and apical aneurysm (8–18).
The ApHCM patients with apical aneurysms showed a higher apical pressure during the systolic phase, which persisted up to the diastolic phase (19,20). Furthermore, it has been demonstrated in HCM (21,22)that mural pressure is high in the portion of cavity obliteration (CO). A high mural pressure may also be caused by the CO and isometric contraction of the apical portion, a contraction pattern characteristic of ApHCM. The high mural pressure may impair myocardial perfusion, leading to myocardial ischemia and replacement fibrosis. Thus, we measured the duration of the CO using M-mode echocardiography and correlated the results with various clinical findings, including myocardial hypertrophy, myocardial ischemia, QT intervals, and apical aneurysm.
Of patients who consulted Kyoto Prefectural University Hospital, Kyoto Municipal Hospital, and Matsushita Memorial Hospital from 1992 to 2001 because of electrocardiographic (ECG) abnormalities or clinical symptoms, 59 patients were diagnosed consecutively as having ApHCM. Of them, we assigned 46 patients to this study, who underwent Holter ECG, echocardiography, exercise single photon emission computed tomography with thallium-201 (201Tl-SPECT), and cardiac catheterization within two weeks. The 46 patients had not been medicated at the time of consultation and were medicated after having all examinations completed. We excluded 13 patients from data analysis: 2 having persistent atrial fibrillation, 1 having coronary stenosis >50%, and 10 undergoing incomplete examinations. One patient with apical aneurysm was excluded for the lack of cardiac catheterization.
Diagnosis of ApHCM
By means of two-dimensional echocardiography, patients were diagnosed as having ApHCM when they had LV hypertrophy of wall thickness ≥15 mm predominantly localized to the LV apex partially or wholly along the circumference, with the ratio of maximal apical wall thickness to basal posterior wall thickness being >1.5 (asymmetric apical hypertrophy).
On the initial record of 12-lead ECG, the longest QT intervals were characteristically obtained from lead V2in most patients with ApHCM. A corrected QT interval (QTc) of >470 ms in male patients and QTc of >480 ms in female patients were regarded as abnormal prolongation. In addition, we measured the maximal voltage of negative T-wave in V3to V6leads and the voltage of S-wave in V1(SV1) and R-wave in V4(RV4) and V5(RV5). Using Holter ECG monitor, we recorded ambulatory ECG for at least 24 h. Nonsustained ventricular tachycardia was defined as at least three consecutive ventricular premature beats of >100 beats/min.
We divided the LV at end diastole into three portions: basal, from mitral annulus to tip of the papillary muscles; mid, entire length of the papillary muscles; and apical, beyond the papillary muscles to the cavity ends. The measurement in each portion was done at its middle.
We used two commercially available echocardiographic instruments, Toshiba SSH 160A (Tokyo, Japan) and Agilent Sonos 2500 (Massachusetts). On M-mode recordings, we measured end-systolic left atrial diameter, end-systolic and end-diastolic diameters of the LV base, and end-diastolic wall thickness of the LV base. On two-dimensional echocardiogram of the short-axis plane, we measured wall area and cavity area of the three portions on three recordings to calculate average wall area/cavity area ratio as relative wall areas (RWA). The maximal apical wall thickness through the circumference was also measured. The ratio of early transmitral flow velocity to atrial flow velocity (E/A ratio) was measured at the level of the mitral valve tip. In addition, we searched for paradoxic jet flow (20)and apical lesions using a transducer, the frequency of which is 5 or 8 MHz.
We recorded M-mode echocardiograms of short-axis images at the middle of the LV apical portion, without being disturbed by aneurysm because it was small if present. We then measured the duration of LV cavity disappearance or CO time, correcting it by R-R intervals as in QTc, and determined the corrected cavity obliteration time (cCOT) by averaging the values in three consecutive cycles. The patients were classified into three groups according to the values of cCOT (Table 1, Fig. 1):
1. No/mild CO group—17 patients with no or mild CO persisting up to the isovolumic diastolic phase (cCOT ≤200 ms);
2. Moderate CO group—18 patients with CO persisting beyond the isovolumic diastolic phase (cCOT >200 to ≤350 ms);
3. Severe CO group—11 patients with CO persisting up to the late diastolic phase (cCOT >350 ms).
In all patients, we performed an exercise tolerance test using a bicycle ergometer according to the standard multistep exercise tolerance protocol, while monitoring blood pressure, heart rate, ECG, and symptoms. At the maximal load of exercise, 111 MBq of thallium was administered intravenously and exercise was continued for 1 min thereafter.
The SPECT images were obtained 10 min after starting the exercise and 3 h later. The short-axis images were obtained from equal thirds of the LV: the base, mid, and apical portion. They were each divided into four segments (septal, anterior, lateral, and posterior regions); thus, the total segment number attained 13, counting the long-axis images of the apical portion or the myocardium beyond the end of the LV cavity.
The severity of thallium perfusion defects was visually evaluated by two independent specialists on the basis of the following four scores: normal = 0, mild = 1, moderate = 2, and severe = 3. The difference between the two examiners was resolved by their consensus. The sum of the scores for all segments was defined to be the defect score. On SPECT images obtained 3 h after exercise, perfusion defects were classified into completely reversible defects and incompletely reversible or fixed defects.
In all the patients, recording of LV pressure curve and left ventriculography were performed to determine LV end-diastolic pressure and ejection fraction and to detect apical wall motion abnormalities, which were then followed by selective coronary arteriography.
Continuous and discrete variables were expressed as mean ± SD and categorical variables as proportions. Continuous, discrete, and categorical variables were compared between the three groups, respectively, by one-way analysis of variance, chi-squared-independence test, and Kruskal-Wallis rank test, which, in the presence of significant differences, were followed by Scheffé, Steel-Dwass, and Tukey multiple comparison tests, respectively, to compare between two groups (no/mild vs. moderate, no/mild vs. severe, moderate vs. severe). Pearson’s correlation coefficients were determined between continuous variables. Spearman’s correlation coefficients by rank were determined between discrete variables and continuous variables. A p value of <0.05 was considered significant.
There were no significant differences in patient age, symptoms, or the history of hypertension between the three groups. The percentage of male patients was only slightly higher in the moderate CO group (Table 1).
SV1+ RV4or RV5did not significantly differ between the three groups. The maximal negative T-wave was significantly greater in the moderate CO group than in two other groups, with no difference between the no/mild CO and severe CO groups. The QTc was largest in the severe CO group, with abnormal prolongation in 1 (6%) patient in the no/mild CO group, in 2 (11%) patients in the moderate CO group, and in 10 (91%) patients in the severe CO group. ST-segment elevation was observed in 7 (64%) patients of the severe CO group but not in the two other groups. Paroxysmal atrial fibrillation was observed in all three groups, with no significant difference in its frequency. Nonsustained ventricular tachycardia was observed in 6 (55%) patients in the severe CO group.
There were no significant differences between the three groups in LV end-diastolic dimension, ventricular septal thickness, posterior wall thickness, left atrial dimension, and E/A ratio. The RWA increased from the mid to apical level of the LV in all three groups. The RWA at the base of the LV did not differ between the three groups, but the RWA at the mid and apical LV differed significantly, becoming greater in ascending order from the no/mild CO group to the severe CO group. Of the 17 patients with no/mild CO, 5 patients with no CO exhibited partial hypertrophy along the circumference of the apical portion. Paradoxic jet flow was exclusively detected in all of the patients with severe CO (Table 1).
Exercise stress 201Tl-SPECT imaging
The double products (i.e., the maximal attained heart rate × blood pressure during exercise) did not significantly differ between the three groups (Table 1). Immediately after exercise, there were perfusion defects in 82 (13.7%) of the total 598 segments: 30 in the vertical apex, 23 in the apical posterior wall, and 17 in the apical anterior wall (Table 2). Severe defects were present in 20 segments: 11 defects in the vertical apex, 7 defects in the apical posterior wall. There were no perfusion defects in the mid or basal level of the LV in any patient.
The defect scores were significantly higher in the severe CO group than in the two other groups (Table 1). Of the total 46 patients, 19 exhibited completely reversible defects (Table 1, Fig. 2), with 18 occupying the whole moderate CO group and 1 belonging to the severe CO group; 10 patients exhibited incompletely reversible (Table 1, Fig. 3) or fixed defects, all belonging to the severe CO group. No patient with no/mild CO had any perfusion defect.
Coronary arteriography did not reveal >50% stenosis in any of the 46 patients. In all patients of the severe CO group, left ventriculography disclosed apical small cavity or ventricular aneurysm during the systolic phase, separated by mid-cavity obliteration from the base of the LV (Table 1, Fig. 3). One of these patients had a mural thrombus in the apical aneurysm. There were no significant differences in the ejection fraction or end-diastolic pressure between the three groups (Table 1).
Correlation coefficients between various parameters
There were high correlations between the cCOT, RWA in the mid and apical portions, defect score, and QTc (Table 3).
Clinical implication of CO and aneurysm formation
It has been reported that myocardial infarction-like findings or aneurysm formation were observed in the apical portion in approximately 10% of ApHCM patients, sometimes associated with severe arrhythmia and cerebral infarction (6,9–13). In our study, apical aneurysm was observed in 12 (20%) of 59 consecutive patients with ApHCM, suggesting that aneurysm formation is not very rare. Of the 11 patients with severe CO and apical aneurysm who were assigned to the data analysis, 7 (64%) had ST-segment elevation, 10 had abnormal QTc, 6 had nonsustained ventricular tachycardia, and 1 had mural thrombus. Aneurysm formation may be an ominous clinical sign in ApHCM.
The patients with no or mild CO displayed mild apical hypertrophy but no sign of myocardial ischemia during exercise. In the patients with moderate CO, apical hypertrophy was moderate and ischemia was reversible. In the patients with severe CO, severe hypertrophy widely extended from the apex to the mid LV, associated with paradoxic jet flow, fixed ischemia, and apical aneurysm. Apical aneurysm was always associated with severe CO but never with mild or moderate CO. The progressive process of hypertrophy and apical aneurysm shown in case reports and long-term studies (6–18)seems similar to the process along the pathologic conditions exhibited by our three patient groups on the basis of the CO severity. It may be clinically meaningful that the cCOT, a simple parameter, is useful in the classification of the severity of ApHCM, linked to pathologic conditions such as hypertrophy, ischemia, aneurysm formation, and in turn, severe arrhythmia or thrombus formation.
Developmental mechanism of apical fibrous lesion
Exercise stress 201Tl-SPECT imaging demonstrated that there were reversible perfusion defects limited to the apical portion in 64% of our patients, suggesting that apical myocardial ischemia occurs frequently in ApHCM. Of the 11 patients with apical pouch or aneurysm, 10 had fixed perfusion defect in the vertical apical segment. Replacement fibrosis may have developed in the apical portion in these patients, as has been confirmed through myocardial biopsy by Akutsu et al. (12).
The CO in HCM set in during early systole and was followed by isometric contraction and high mural pressure of the obliterating portion, which was recorded through the catheter tip enfolded completely in the trabeculae carneae or the apical cavity end (21,22). High pressure in the obliterated cavity began to decline first after the dicrotic notch of the aortic pressure curve, probably owing to impaired relaxation (23), supporting that mural pressure was kept elevated up to the diastolic phase. High pressure was also observed during both the systolic and diastolic phases in the apical cavity, generating paradoxic jet flow (19,20). The CO and high mural pressure will impose an increased pressure load on the apical myocardium, increasing its oxygen demand, and will impair coronary flow through extravascular compression of the coronary artery, leading to chronic myocardial ischemia.
The patients with apical aneurysm had sustained CO, large RWA, and high defect score. There were high correlations between the cCOT, the RWA, and the defect score. It is tempting to speculate as to the causal relationship between the CO, hypertrophy, and ischemia. However, the actual relationships between these factors seem entangled; any of them could be suspected to affect other factors. There seems to be a vicious circle in the natural course of ApHCM, in which the CO, myocardial hypertrophy, and ischemia are involved, making a spiral oriented towards the development of replacement fibrosis of the apical portion.
Prolongation of QTc
There was a good correlation between QTc and cCOT; a delay of relaxation of the apical myocardium should be associated with prolonged CO. Furthermore, QTc was highly correlated with the indexes of cardiac hypertrophy (RWA) and myocardial perfusion abnormality (defect score); apical hypertrophy and ischemia may have led to the prolongation of QTc, as has been reported already (24–27). Delayed relaxation will reduce myocardial perfusion. Thus, prolonged QTc may have also participated in the vicious circle, jointly with the CO, hypertrophy, and ischemia, spiraling towards the aneurysm formation.
Ventricular fibrillation is known to occur sometimes in ApHCM patients (9,28–30)and QT prolongation was frequently observed in our patients with severe CO. This suggests that strict management is required in ApHCM patients showing abnormal QT prolongation and severe CO to prevent ventricular fibrillation, although it is not clear how ventricular fibrillation occurs in them, whether through prolonged QT or through ischemia and fibrous changes of the myocardium, or both.
The limitation in our echocardiographic procedure lies in the difficulty in visualizing apical short-axis images, depending on the technical ability of examiners and patients’ conditions. However, the use of harmonic mode or anatomic M-mode may help to overcome such a limitation. Hemodynamic changes affecting the LV cavity size should influence the CO duration; the medication decreasing afterload or preload will elongate the CO time. These factors need to be taken into account during its measurement.
The present investigation is not a prospective study, and the results could not allow us to reach the conclusion that the cCOT is predictive of aneurysm formation. It remains to be clarified whether the current parameters of clinical severity (i.e., cCOT, hypertrophy, ischemia, and QTc) actually progress or exacerbate in parallel with one another towards the formation of aneurysm as the disease progresses. Furthermore, there may be some patients in whom the progressive process ceases at a relatively early stage.
Wigle and Rakowski (31)discussed a matter of discrimination between midventricular obstruction in HCM and apical cavity obliteration with a small non-obliterated area in ApHCM. Our present patients were selected on the basis of the localization of predominant hypertrophy in the apical portion. During a long lapse of time, however, an apical aneurysm in ApHCM may grow large enough to display systolic hourglass-shaped cavity deformation mimicking midventricular obstruction, but such a large aneurysm was not observed in our patients. On the other hand, midventricular obstruction in HCM, imposing an increased afterload on the myocardium on the apical side, may lead to the growth of apical hypertrophy, becoming similar to ApHCM with a small aneurysm, although there have been no such reports to our knowledge. The issue of discriminating between the two types of cavity separation will be ultimately resolved by prospective studies involving two groups of patients large enough and following them long enough.
Sustained CO in ApHCM is considered an important pathophysiologic condition as well as paradoxic jet flow and may be closely related to the development of apical aneurysm jointly with myocardial hypertrophy, ischemia, and QT prolongation through interactions and in turn, to thrombosis and ventricular fibrillation. Additional prospective studies may suggest that it is predictive of the development of apical aneurysm.
- apical hypertrophic cardiomyopathy
- cavity obliteration time corrected by the R-R interval
- cavity obliteration
- E/A ratio
- ratio of early transmitral flow velocity to atrial flow velocity
- hypertrophic cardiomyopathy
- left ventricle/ventricular
- corrected QT interval
- relative wall area
- thallium single photon emission computed tomography
- Received January 12, 2003.
- Revision received February 27, 2003.
- Accepted March 20, 2003.
- American College of Cardiology Foundation
- Moro E.,
- D’Angelo G.,
- Nicolosi G.L.,
- Mimo D.,
- Zunuttini D.
- Eriksson M.J.,
- Sonnenberg B.,
- Woo A.,
- et al.
- Shikuwa M.,
- Tanioka Y.,
- Nakamura K.,
- et al.
- Ishiwata S.,
- Nishiyama S.,
- Nakanishi S.,
- Seki A.
- Shukuwa M.,
- Omura H.,
- Matsushita T.,
- et al.
- Wilson P.,
- Marks A.,
- Rastegar H.,
- Manolis A.S.,
- Estes M. III.
- Nakamura T.,
- Matsubara K.,
- Furukawa K.,
- et al.
- Criley J.M.,
- Lewis K.B.,
- White R.I.,
- Ross R.S.
- Wigle E.D.,
- Marquis Y.,
- Aucer P.
- Anderson R.S.
- Shawl F.A.,
- Velasco C.E.,
- Goldbaum T.S.,
- Forman M.B.
- Kerr C.R.,
- Hacking A.,
- Henning H.
- Doi Y.L.,
- Hamashige N.,
- Yonezawa Y.,
- et al.
- Wigle E.D.,
- Rakowski H.