Changes in Phasic Coronary Blood Flow Velocity Profile and Relative Coronary Flow Reserve in Patients With Hypertrophic Obstructive Cardiomyopathy
Background In this study, we both investigated coronary flow velocity in hypertrophic obstructive cardiomyopathy (HOCM) and tested the hypothesis of differing coronary flow reserve (CFR) of coronary arteries perfusing left ventricular regions with nonuniform myocardial hypertrophy by measuring the relative CFR.
Methods and Results Coronary flow velocity was assessed in left anterior descending coronary (LAD) and left circumflex (LCx) arteries in 18 patients with HOCM and marked hypertrophy only in the ventricular septum, in 13 patients without obstruction (HCM), and in 9 age- and sex-matched normal subjects at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 μg/kg per minute). Relative CFR was estimated as the ratio between absolute CFR of the LAD and absolute CFR of the LCx (LAD/LCxCF). At the peak of rapid atrial pacing and during dobutamine stress, LAD/LCxCF was reversed in HOCM patients (from 1.25±0.11 to 0.82±0.07 and 0.79±0.06, respectively), whereas it remained unchanged in control subjects (from 1.0±0.1 to 1.0±0.05 and 1.0±0.05, respectively; P<.001). In HCM patients, LAD/LCxCF at rest was 1.10±0.11, whereas during rapid atrial pacing and dobutamine stress, it was 0.92±0.08 and 0.90±0.09, respectively. Relative CFR was 0.62±0.05 in HOCM patients and 1.05±0.05 (P<.001) in normal subjects. There was an inverse correlation between relative CFR and peak systolic outflow tract gradient (r2=.74, P<.001).
Conclusions Regional distribution of hypertrophy in some patients with HOCM resulted in regional impairment of coronary flow. Relative CFR can be used to estimate regional disturbances of coronary flow and may help in patient selection for new interventional therapeutic techniques.
As in patients with aortic valve disease,1 2 patients with HOCM develop evidence of myocardial ischemia, despite the presence of normal coronary arteries, as a consequence of alterations in relevant coronary flow dynamics. The phasic coronary flow characteristics that have been demonstrated in patients with HOCM3 4 5 include the development of an early systolic retrograde component, a reduced systolic component, and an increased diastolic component. Patients with HOCM have regional distribution of hypertrophy, and CFV characteristics of a coronary artery reflect mainly regional changes in coronary flow dynamics in the explored area.
Relative CFR was proposed by Gould et al6 and shown to be relatively independent of physiological conditions such as aortic pressure and heart rate. Thus, in patients with HOCM and a regional distribution of hypertrophy predominantly in the interventricular septum, relative CFR could be estimated as the ratio between absolute CFR of the LAD (ACFRLAD) and absolute CFR of the LCx (ACFRLCx).
The purpose of the present study was to investigate the phasic characteristics of CFV in conscious patients with HOCM under conditions of rest and, more importantly, during different loading conditions that may (dobutamine stress) or may not (rapid atrial pacing) change left ventricular outflow tract gradient. Furthermore, in an effort to shed more light onto the pathophysiology of coronary circulation in patients with HOCM, we measured CFR during intracoronary papaverine administration. Finally, to test the hypothesis of differing CFR values for coronary arteries perfusing left ventricular regions with nonuniform myocardial hypertrophy, we measured the relative CFR.
The study cohort consisted of 18 nonconsecutive patients with typical echocardiographic Doppler findings7 8 (10 men and 8 women) who were prospectively selected from patients undergoing cardiac catheterization for HOCM. Their mean age was 46.3±7.4 years (range, 32 to 61 years). Inclusion criteria were (1) a hypertrophic nondilated left ventricle (ventricular septum thickness, ≥15 mm) with marked hypertrophy only in the ventricular septum, (2) a basal interventricular pressure gradient of 30 mm Hg recorded in the left ventricular outflow tract, (3) normal coronary arteries at angiography, and (4) no underlying cardiac or systemic disease. A control group of 9 age- and sex-matched patients with normal 12-lead ECGs as well as echocardiographic Doppler and coronary angiographic findings (5 men and 4 women; mean age, 45.1±8.2 years) investigated in our hospital for atypical chest pain underwent the same study protocol. An additional group of 13 age- and sex-matched patients with HCM was also studied as a control group intermediate between normal subjects and those with HOCM. The inclusion criteria for the HCM group were the same as in the HOCM group apart from no basal interventricular pressure gradient in the left ventricular outflow tract.
The research protocol was approved by the Ethics Committee of the Institutional Review Board of the Department of Cardiology, Hippokration Athens University Hospital. All patients gave informed written consent for participation in the study.
A complete transthoracic echocardiographic examination was used in the evaluation of HOCM and HCM in all patients with a Hewlett-Packard ultrasound system (Sonos 1500) connected to a 2.5-MHz external probe. The two-dimensional study was used to identify and quantify morphological features of the left ventricle. Patients with asymmetrical septal hypertrophy of the left ventricle only were included in the HOCM group. The criterion for the diagnosis of asymmetrical septal hypertrophy was the finding of a thickened septum that was ≥1.5 times the thickness of the posterior wall when measured in diastole just before atrial systole. Mitral flow velocity was recorded with pulsed Doppler by locating the sample in the tips of the mitral valve leaflets imaged in a four-chamber view. Abnormal diastolic function was demonstrated in all patients through evaluation of the isovolumetric relaxation time, which was measured from aortic valve closure to mitral valve opening; the peak flow velocity of early and late diastolic filling (E and A waves); and E/A ratio. Doppler color flow imaging revealed mitral regurgitation with the appearance of turbulent flow in the left ventricular outflow tract.
After all patients were premedicated with diazepam (5 mg IM), right and left diagnostic catheterization, including coronary angiography, was performed. The protocol was similar to that used in previous studies.9 10 11 Selective coronary angiography and left ventriculography were performed by Judkins technique. The left and right coronary arteries were imaged in multiple views, including craniocaudal projections. Coronary artery stenosis was considered significant if the lumen diameter was narrowed by ≥30%. The studies were evaluated by two observers in a blinded manner. All patients received 10 000 U of intravenous heparin before coronary angiography and 5000 U each hour during the procedure.
CFV was assessed using an intracoronary Doppler catheter.12 A 7F coronary guiding catheter was positioned at the left coronary artery ostium, and a 0.010-in coronary angioplasty guide wire was advanced first into the LAD and later into the LCx. A high-quality signal of blood flow velocity was displayed with a 2.5F Millar 20-MHz Doppler velocimeter (model DC-101) along with instantaneous ECG and continuous aortic root pressure recordings on a multichannel recorder. CFV was measured in the proximal LAD and then in the proximal LCx. Before the Doppler catheter was placed in the guiding catheter, the mean and phasic Doppler flow velocity recordings were zeroed and calibrated from an internally set 0 to 100 cm/s signal for full-scale deflection, as is our usual practice during CFV measurements.1 In the LCx, recordings were repeated after Millar Doppler velocimeter was transferred from the LAD into the LCx, where measurements of CFV were repeated. We then recorded a rest CFV pattern and aortic pressure. Phasic coronary flow patterns were recorded at paper speeds of 25, 50, and 100 mm/s, and the averaged peak CFV was obtained.
A 7F Millar micromanometer catheter was then advanced into the left ventricle via the left femoral sheath over a guide wire, and pressures were recorded from the left ventricular apex. Arterial pressure was recorded simultaneously from the 7F coronary guiding catheter positioned at the left coronary artery, with a fluid-filled pressure transducer zeroed to the midchest level. Simultaneous pressures were recorded in the left ventricle via the Millar catheter and the aorta via the guiding catheter.
To induce hemodynamic stress, rapid right atrial pacing and graded intravenous dobutamine infusion were used sequentially. An intracoronary bolus of 12 mg papaverine was injected through the guiding catheter to measure coronary vasodilator reserve. The procedure was repeated in both the LAD and LCx. All these interventions were done at steady state and after the CFV variables returned to baseline for ≥5 minutes.
We commenced an atrial rapid pacing stress test. The pacing rate was started at 90 bpm and increased by 20 bpm every 3 minutes until a final pacing rate of 130 bpm was reached. Doppler CFV of both LAD and LCx, ECG, and aortic pressure were recorded at the end of each pacing.
After the hemodynamic and CFV data had returned to baseline, dobutamine was administered through a peripheral intravenous line with an infusion pump system in graded doses, starting at a rate of 5 μg/kg per minute and increasing the dose by 5 μg/kg per minute every 5 min to a maximum of 20 μg/kg per minute. Hemodynamic and CFV measurements were continuously monitored and recorded at the end of the 5-minute equilibration period at each dobutamine dose. The end points for atrial pacing and intravenous dobutamine were prespecified and included heart rate of 130 bpm; increase in left ventricular end-diastolic pressure of >10 mm Hg; and development of significant arrhythmias, angina, dyspnea, or other intolerable symptoms.
Doppler Flow Velocity Studies
The Doppler catheter was placed in the center of the vessel coaxial to the lumen sequentially in the LAD and LCx with care taken to place the catheter away from side branches. Every effort was made to acquire a reliable signal along with ECG and pressure tracings. The Doppler catheter position was frequently viewed by fluoroscopy to check its position. All data were recorded on a Honeywell multichannel strip-chart recorder. The area under the CFV curve was quantified by computerized planimetry. Systole was defined from the beginning of the left pressure upstroke to the dicrotic notch of the aortic pressure, and diastole was defined as the remainder of the cardiac cycle. Absolute CFR was calculated as the ratio of mean CFV at peak papaverine-induced hyperemia to mean resting CFV. The ratio between ACFRLAD and ACFRLCx was calculated as the relative CFR. Coronary flow was taken as the product of the mean CFV times the CSA of the proximal LAD and LCx. CSA was determined at end diastole just distal to the Doppler velocity catheter tip from a single angiographic view, assuming a circular cross section, as follows: CSA=(D/2)2, where D represents the vessel diameter. Coronary arteriography to measure LAD and LCx diameter was performed after a single bolus injection of 8 mL of low osmolarity contrast medium, at rest, and at maximal hyperemia during rapid atrial pacing and after dobutamine infusion. Maximal vessel diameters measured during these interventions were assumed to be the vessel diameters during papaverine infusion.
All data are expressed as mean±SD. Repeated measures ANOVA (randomized block two-way ANOVA without replication) was used to compare the study data obtained at rest, at peak atrial pacing–induced tachycardia, and at peak intravenous dobutamine infusion. When results of ANOVA were significant, the Bonferroni inequality was used to isolate the individual significant differences. The χ2 test was used to compare qualitative data. Statistical correlations between relative CFR and hemodynamic parameters were made by linear regression analysis. Statistical significance was defined as P<.05.
Clinical and echocardiographic characteristics of the study population are presented in Table 1⇓. Control subjects had a significantly thinner interventricular septum and a lower ventricular septum/posterior wall ratio. Furthermore, diastolic dysfunction in HOCM and HCM patients was indicated by the significantly prolonged isovolumetric relaxation time and the inversed E/A ratio from the transmitral valve blood flow.
Hemodynamic data obtained in the study are summarized in Table 2⇓.
Resting end-diastolic left ventricular pressure indicated impaired left ventricular diastolic function in patients with HOCM, which deteriorated at peak rapid atrial pacing. In contrast, dobutamine improved left ventricular end-diastolic pressure. Systolic blood pressure declined slightly in patients during pacing-induced tachycardia or dobutamine infusion, whereas it increased in normal subjects. The peak outflow tract gradient significantly decreased at peak rapid atrial pacing and dramatically increased after dobutamine due to the dynamic nature of outflow tract obstruction. Rapid atrial pacing and dobutamine infusion induced left ventricular outflow tract gradient in 4 patients with HCM (31%).
Hemodynamic and CFV changes returned to baseline 5 minutes after pacing and 15 minutes after dobutamine infusion interruption.
In all patients in our study, phasic CFV wave forms in the proximal LAD and LCx showed a predominantly diastolic pattern; the same occurred in control subjects (Tables 3 to 5⇓⇓⇓). A systolic retrograde (negative) CFV wave was recorded in early systole (around the point of the peak transvalvular pressure difference), in LAD, in all patients with HOCM, in 4 patients with HCM, and in none of the control subjects. In LCx, there was no or only a very small retrograde CFV, and changes were trivial during hemodynamic interventions. In patients, coronary flow at rest was increased in LAD compared with in LCx, with a LAD/LCx ratio of >1, whereas in control subjects, coronary flow was equal in the two vessels, with a LAD/LCx coronary flow ratio of 1. This was the result of a greater diastolic coronary flow component in LAD than in LCx, whereas systolic coronary flow was decreased in LAD compared with LCx.
At the peak of rapid atrial pacing, coronary flow significantly increased in both LAD and LCx, but the increases in LCx were significantly larger than those in LAD (Fig 1⇓). This difference was mainly due to the systolic coronary flow in LCx, which was 10 times greater than that in LAD. In contrast, controls showed equal increases in coronary flow in the two vessels during rapid atrial pacing. Finally, systolic retrograde CFV significantly increased in LAD.
Dobutamine stress resulted in significant increases in diastolic coronary flow in LAD and LCx, but systolic CFV was impressively reversed and a negative wave was detected in LAD, whereas systolic CFV in LCx showed a positive response with a significant increase similar to that in normal subjects. Consequently, the mean coronary flow in patients with HOCM between LAD and LCx was reversed with a LAD/LCx ratio of <1.
Absolute and Relative CFR
The intracoronary injection of papaverine significantly increased the mean CFV in patients and control subjects in both arteries, but CFR was lower in patients with HOCM and HCM than in normal subjects, although CFR in LCx was nearer the CFR detected in controls than the CFR in LAD. Thus, relative CFR was <1 in HOCM and HCM patients and it was nearly 1 in normal subjects. The relative CFR in HCM patients was between the values of relative CFR in HOCM patients and control subjects; that means that although LAD received more blood than LCx at rest, CFR in LAD was lower than in LCx. Furthermore, rapid atrial pacing and dobutamine stress resulted in an increase in diastolic coronary flow in both LAD and LCx, with predominance of LCx. Systolic coronary flow decreased in LAD but increased in LCx. In control subjects, hemodynamic interventions resulted in increased systolic and diastolic CFV in both LAD and LCx. There was an inverse correlation between relative CFR and peak systolic outflow tract gradient (r2=.74, P<.001) (Fig 2⇓). In addition, the LAD/LCx ratio of coronary flow was closely related to peak systolic outflow tract gradient at rest (r2=.62, P<.001), which held true during rapid atrial pacing (r2=.63, P<.001) and dobutamine infusion (r2=.63, P<.001) (Fig 3⇓).
Coronary CSA Measurements
At rest, the measured CSA of the LAD was lower in controls (8.65±1.74 mm2) than in patients (12.11 ±2.8474 mm2, P<.05). The same was true for the CSA of the LCx (controls, 7.45±1.56 mm2; patients, 11.21±2.22 mm2; P<.05). In both groups, CSA measured at peak atrial pacing tachycardia (controls: LAD, 9.01±0.92 mm2; LCx, 8.11±1.05 mm2; patients: LAD, 12.85±2.41 mm2; LCx, 12.03±1.85 mm2) and at peak dobutamine stress (controls: LAD, 9.25±1.24 mm2; LCx, 8.25±1.32 mm2; patients: LAD, 12.97±2.56 mm2; LCx, 12.28±2.03 mm2) was significantly higher compared with the resting measurements (P<.05).
In this study, we measured CFV and CSA of two vessels, the LAD and LCx, in patients with HOCM, and we calculated coronary flow. Similar studies8 have been reported, but LCx CFV was not measured, and intracoronary Doppler catheters were not used. Thus, the study did not provide an assessment of the relation of coronary flow in the LAD, the main artery perfusing the intraventricular septum, with that in the LCx, which is not involved in the perfusion of the myocardium with marked hypertrophy. It is reasonable to think that the hypertrophic myocardium located in the intraventricular septum caused increased oxygen demand, resulting in vasodilation, which in response reduces the coronary flow reserve. Furthermore, patients without obstruction showed a pattern of coronary blood flow and CFR of the responsible artery perfusing the hypertrophic myocardium intermediate between that of normal subjects and that of patients with HOCM.
Indeed, we clearly detected that in patients with hypertrophic cardiomyopathy, CFR was significantly reduced compared with that in the control group. Similar findings were reported in a group of patients with hypertrophic cardiomyopathy evaluated by means of thermodilution assessment of coronary sinus blood flow.13 Furthermore, we showed that within the pathological left ventricle, there were regions perfused by the LCx that were not involved in the impaired vasodilatory effect of hypertrophic myocardium, at least not to the extent that this happened in LAD. We used the relative CFR with the assumption that the LAD was the vessel associated with the asymmetrical septal hypertrophy and the LCx was the vessel with relatively normal distribution. This index was reduced in patients with HOCM, indicating that impaired coronary flow is rather regional and “asymmetrical.”
We recently studied1 alterations of diastolic CFV pattern in the proximal LAD of patients with significant pure aortic valve stenosis and have showed that they were closely correlated to concomitant changes in hemodynamic parameters. Systolic retrograde coronary flow is present at rest and increases during conditions of stress in relation to the increase in transvalvular pressure gradient. In our HOCM group, systolic coronary flow was reduced in all patients, and a prominent reversed coronary flow was observed. Hemodynamic interventions resulted in a further increase of the negative retrograde systolic wave, which finally produced a reduction in coronary flow in the LAD, whereas coronary flow increased in LCx. This in turn may reduce septal contractility and represent a compensatory mechanism that is trying to reduce the outflow tract gradient. Recently, Sigwart14 described a catheter-based technique that produced a localized septal infarct and resulted in reduction in the septum in HOCM; this technique is based on the idea that systolic and diastolic myocardial function of selected areas of the left ventricle can be selectively suppressed by ischemia and that intracavity pressure gradients in HOCM diminish greatly when the septal is ischemic.
The increased ratio of LAD/LCx coronary flow at rest in patients with marked asymmetrical hypertrophy indicates that LAD takes the major portion of left artery blood supply but that its reserve function is highly reduced. Thus, these patients could be possible candidates for the Sigwart ablation of the septal artery technique.
Despite the great care that was taken in the assessment of stable and undisturbed CFV, some potential limitations must be considered. The older zero-crossing technique is able to measure CFV; its changes are closely correlated with changes in coronary flow. On the other hand, the Doppler angioplasty guide wire with a 12-MHz Doppler transducer lacks some of the limitations inherent in the older technique.15 Results of this study suggest that regional impairment of CF is related to regional distribution of hypertrophy. However, these conclusions cannot be extrapolated to the general population of patients with HOCM, particularly because patients with marked hypertrophy of regions of the left ventricle other than the intraventricular were not included in the study. The absence of an additional bolus injection of contrast medium during papaverine-induced hyperemia and the assumption of equal diameters of LAD and LCx at maximal hyperemia after dobutamine or rapid atrial pacing may lead to underestimation of real coronary flow during papaverine administration. However, because the same assumption of vessel diameter measurements was used in all subjects, it is reasonable to assume that this method is valid for comparisons between patients and control subjects and between different vessels in the same subject.
In conclusion, regional distribution of hypertrophy in some patients with HOCM resulted in regional impairment of coronary flow. Patients with HCM and without occlusion may represent an intermediate group of moderate hypertrophy. In some of these patients, a dynamic obstruction occurred, resulting in deterioration in CFR. Relative CFR can be used to estimate regional disturbances of coronary flow and may help in patient selection for new interventional therapeutic techniques.
Selected Abbreviations and Acronyms
|CFR||=||coronary flow reserve|
|CFV||=||coronary flow velocity|
|HCM||=||hypertrophic cardiomyopathy without obstruction|
|HOCM||=||hypertrophic obstructive cardiomyopathy|
|LAD||=||left anterior descending coronary artery|
|LCx||=||left circumflex artery|
- Received October 24, 1996.
- Revision received February 10, 1997.
- Accepted February 13, 1997.
- Copyright © 1997 by American Heart Association
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