Inflection Point of Ascending Aortic Waveform Is a Powerful Predictor of Restenosis After Percutaneous Transluminal Coronary Angioplasty

Abstract

Background:

Although it was reported that the pulsatility of ascending aortic pressure is closely related to restenosis after percutaneous transluminal coronary angioplasty (PTCA), it is not known whether the reflection period of ascending aortic pressure can predict restenosis after PTCA. The purpose of this study was to evaluate whether reflection in the arterial system can be used to predict restenosis after PTCA.

Methods:

We used the inflection point as the reflection period index and measured the coronary artery diameter, aortic pressure, and inflection time before PTCA. We defined the inflection time as the time interval from the initiation of systolic pressure waveform to the inflection point. We prospectively investigated the effect of inflection time in relation to the subsequent risk of restenosis after PTCA in patients with coronary artery disease.

Results:

Crude cumulative incidence rates of restenosis were 74.1% for the lowest, 33.3% for the middle, and 26.1% for the highest tertile of inflection point levels. After adjustments for age, gender, smoking habits, hypertension, type 2 diabetes, hypercholesterolemia, old myocardial infarction, vessel location, post-minimal lumen diameter, heart rate, and ejection fraction, the odds ratio of restenosis was 6.99 (95% confidence interval, 1.54 to 31.7) for the lowest tertile of the inflection time level compared with the highest tertile level.

Conclusions:

Inflection time is a powerful predictor of restenosis after PTCA.

Inflection time, new predictor, restenosis

We recently reported that the pulsatility index in the proximal arteries is a useful tool to predict the occurrence of restenosis after percutaneous transluminal coronary angioplasty (PTCA),¹ and to diagnose ischemic heart disease² and pulmonary hypertension,³ and found that the analysis of pulmonary arterial reflection is useful in the differential diagnosis of primary pulmonary hypertension and chronic pulmonary thromboembolism.⁴ The analysis is useful to prevent cardiac events from occurring and to treat patients with heart disease. The ascending aortic pressure waveform would provide much more useful information for patients with cardiac diseases. More information, in addition to pulsatility, is easy to diagnose cardiac heart disease and predict the occurrence of restenosis after PTCA. Therefore, we focused on the reflection waveform in the ascending aortic pressure.

As the reflection waveform in the ascending aortic pressure reflects large artery function and systemic arterial stiffness, it is related to the degree of arteriosclerosis and the occurrence of restenosis after PTCA. To determine the reflection wave, we used the inflection time, the time interval from the initiation of systolic pressure waveform to the inflection point.^4,,6 We recently reported that inflection time was associated with an increased risk of coronary heart disease.⁶ Therefore, we hypothesized that although a shorter inflection time would increase the occurrence of restenosis, a longer inflection time would decrease the occurrence of restenosis after PTCA in terms of vascular mechanics. We prospectively investigated the effect of inflection time in relation to the subsequent risk of restenosis after PTCA. Inflection time was associated with restenosis. Although restenosis after PTCA affects mortality and occurrence of cardiac events, analysis of the reflection waveform is a useful tool to reduce mortality and cardiac events.

Methods

Study subjects

The final study consisted of 74 consecutive patients aged from 42 to 82 years, who were admitted to the Ishikiriseiki Hospital between January 1993 and December 1999 for revascularization because of coronary artery disease and were subsequently diagnosed as having stable angina pectoris or silent myocardial ischemia. The enrollment criteria for the study included successful coronary balloon angioplasty, aortic pressure measurements made before angioplasty, and coronary angiography performed 3 months after angioplasty. We excluded 63 patients with acute coronary syndromes, 52 patients treated by adjunctive coronary stent implantation, and 23 patients with chronic renal failure. The protocol was in accordance with our Institutional Guidelines for Human Research, and each patient provided a written statement of informed consent for the diagnostic and therapeutic procedures performed, stating the results could be used for prospective studies.

Measurement of hemodynamic variables

Hemodynamic measurements were made with the patient in the supine position at PTCA. Aortic pressure was measured using a fluid-filled system (5F pigtail catheter) in the ascending aorta. A hard copy was made of the pressure tracing using a chart recorder (Nihon Koden, Surgical Monitoring System, Tokyo, Japan) at a paper speed of 100 mm/sec. We defined the inflection time as the time interval from the initiation of systolic pressure waveform to the inflection point (Fig. 1), and measured the inflection time in patients with and without restenosis. Inflection time was measured by the same experienced observer who was blinded to the clinical status of patients, angiographic data, and follow-up results.

Schematic representations of two different ascending aortic pressure waveform. Inflection time is the time interval between onset of systolic pressure waveform and the inflection point. The left panel is from a patient without restenosis. The right panel is from a patient with restenosis. Inflection time is markedly shorter in patients with restenosis than those without.

Figure 1.

Measurement of angiographic variables

Cardiac catheterization and PTCA were performed according to standard technique. Only conventional balloon angioplasty was allowed for this study. Coronary angiography was performed before and after PTCA and at follow-up 3 months later. Optimal views of the target lesions from all technically suitable angiograms were analyzed using a handheld electronic digital caliper (Mitutoyo Corp., Tokyo, Japan),⁷ and measurements were made of the maximal narrowing of the target lesion and a noninvolved segment. Angiographic measurements were calibrated using the guiding catheter as the reference dimension. The absolute values for the minimal lumen diameter (MLD) and the reference lumen diameter were measured at end-diastole. The PTCA success was defined as achieving a MLD >50% of the reference diameter. The PTCA restenosis was defined as recurrent lumen diameter stenosis >50% on the follow-up angiogram.

Statistical analysis

Values were expressed as mean ± one standard deviation. Categorical variables were compared using the χ² test. Differences in the mean values between the two groups were compared using an unpaired t test. P < .05 was considered statistically significant. Multiple logistic regression analysis was used to evaluate the simultaneous effects of inflection time, age, gender, smoking habits (current smokers or nonsmokers), hypertension (yes or no), type 2 diabetes (yes or no), hypercholesterolemia (yes or no), old myocardial infarction (yes or no), vessel location, post-MLD, heart rate, and ejection fraction. The linear trends in risks were evaluated by entering indicators for each categorical level of exposure, using the median value for each category. We calculated the 95% confidence interval (CI) for each odds ratio (OR), and all P values were two-tailed. Statistical analyses were performed using the SPSS 10.0 software package (SPSS, Inc., Chicago, IL).

Results

Baseline clinical andangiographic characteristics

The baseline clinical characteristics of the study group are summarized in Table 1. Although age, the distribution of gender, the presence of hypertension, diabetes mellitus, previous myocardial infarction or hypercholesterolemia, and smoking status were similar in the two groups, vessel location was significantly different between the two groups. There were no significant differences between patients with and without restenosis in reference lumen diameter, MLD, post-MLD, stenosis rate before PTCA, and ACC/AHA classification. There were no significant differences in heart rate and ejection fraction between the two groups. Although aortic systolic, diastolic, and mean pressures were not different, inflection time was shorter in patients with restenosis than those without restenosis (96.2 ± 29.2 and 118.0 ± 29.9 msec, respectively, P = .002).

Table 1

Baseline characteristics of study patients

	No Restenosis (n = 40)	Restenosis (n = 34)	P
Age (y)	60.3 ± 9.9	64.5 ± 9.6	.070
Male sex (n)	31	28	.605
Hypertension	23	17	.609
Type 2 diabetes	18	11	.311
Hypercholesterolemia	21	15	.549
Current smoker	20	16	.897
Vessel dilated
RCA	13	13
LAD	13	18	.024
LCX	14	3
Old myocardial infarction	19	17	.733
Reference lumen diameter (mm)	2.53 ± 0.42	2.52 ± 0.43	.888
MLD (mm)	0.72 ± 0.39	0.55 ± 0.43	.076
Post-MLD (mm)	1.80 ± 0.45	1.68 ± 0.38	.218
Stenosis rate (%)	76.5 ± 14.1	81.7 ± 14.7	.127
ACC/AHA classification
A, B1	28	21	.462
B2, C	12	13
Heart rate (beats/min)	71.8 ± 11.9	75.1 ± 14.2	.295
Ejection fraction (%)	67.8 ± 13.6	64.5 ± 12.6	.290
Aortic pressure (mm Hg)
Systolic pressure	139 ± 27	141 ± 24	.728
Diastolic pressure	72 ± 13	68 ± 12	.260
Mean pressure	100 ± 16	98 ± 15	.498
Inflection time (msec)	118.0 ± 29.9	96.2 ± 29.2	.002

RCA = right coronary artery; LAD = left anterior descending coronary artery; LCX = left circumflex artery; MLD = minimal lumen diameter; ACC = American College of Cardiology; AHA = American Heart Association.

Values are mean ± SD or No. of patients.

Multivariate analysis ofthe risk for restenosis

To examine whether inflection time was associated with the risk of the restenosis after PTCA in this study population, all patients were classified into tertiles of inflection time level. Inflection time was significantly and negatively associated with restenosis after PTCA. Crude cumulative incidence rates of restenosis were 74.1% for the lowest, 33.3% for the middle, and 26.1% for the highest tertile of inflection time levels. The crude OR of restenosis was 1.24 (95% CI 0.34 to 4.49) among the population of tertile 2 and 8.10 (95% CI 2.28 to 28.8) among those of tertile 1 compared to those of tertile 3 (P = .001 for trend). After adjustment for age, gender, smoking habits, hypertension, diabetes mellitus, hypercholesterolemia, previous myocardial infarction, vessel location, post-MLD, heart rate, and ejection fraction, inflection time was strongly associated with an increased risk of restenosis after PTCA. The multiple-adjusted OR of restenosis after PTCA was 1.02 (95% CI 0.22 to 4.68) for the middle tertile of the inflection time level and 6.99 (95% CI 1.54 to 31.7) for the lowest tertile of the inflection time level compared with the highest tertile.

To further quantify the effect of inflection time on restenosis after PTCA, we modeled inflection time as a continuous variable. The results suggested that the multiple-adjusted OR of restenosis after PTCA was increased by 70% when the inflection time was increased by 20 msec (OR 1.70; 95% CI 1.06 to 2.70).

Discussion

This study showed that inflection time was related to restenosis after PTCA, and reflection waveform in ascending aortic pressure predicts restenosis.

Indexes of reflection waveformin the ascending aortic pressure

Previous investigators demonstrated that the time interval from the initiation of systolic pressure waveform to the inflection point was related to the reflection time derived from the systemic arterial system.^8,9,10 Thus, if the reflection time derived from the systemic arterial system is longer, the inflection point occurs later. In contrast, if the reflection time derived from the systemic arterial system is shorter, the inflection point occurs earlier. Therefore, inflection time, the time interval from the initiation of systolic pressure waveform to the inflection point, is closely related to not only reflection in the arterial system, but also large artery function. Although the inflection time is related to large artery function, it is shorter in stiffened arteries than in the compliant arteries. The fact that the inflection point is detected by high fidelity measurements of arterial pressure waveform makes it impractical in clinical settings. Therefore, we measured the inflection point using a fluid-filled recording system and examined whether the inflection time was correctly defined. The inflection time using the fluid filled recording system was reliable and unchanged by repeated measurements.^4,6

Mechanism by which reflection waveform predicts the occurrence of restenosis after PTCA

Reflection waveform derived from an ascending aortic pressure waveform reveals the stiffness of the systemic arterial system.⁵ When the reflection wave is early and systemic arteries stiffen, the pulse pressure increases and diastolic aortic pressure decreases.¹⁰ Because coronary perfusion primarily occurs during diastole rather than systole, adequate coronary perfusion is very important during diastole.¹¹ In the ascending aorta with stiffening arterial walls, the perfusion pressure and coronary flow during diastole decrease. In contrast, in a compliant ascending aorta, reflection wave is slow, and the perfusion pressure and coronary perfusion during diastole increase. The aorta with early reflection decrease coronary perfusion and increase the restenosis rate, whereas aorta with slow reflection increase coronary perfusion and decrease the restenosis rate after PTCA. Therefore, the inflection time is associated with the occurrence of restenosis after PTCA.

Clinical implications

The ascending aortic pressure waveform reflects the aortic input impedance.¹⁰ Therefore, this study contributes not only to the prevention of restenosis after PTCA, but also to a better understanding of the arterial system.³ We recently showed that ascending aortic pressure waveform analysis focusing on pulsatility enabled the prediction of restenosis after PTCA.¹ These analyses are particularly important for determining therapy, because surgical treatment and new procedures such as directional coronary atherectomy, stenting, or rotablation can be used instead of conventional PTCA.

Study limitations

There are several limitations to this study. First, we analyzed a limited number of patients. To generalize the results of this study, studies involving a large number of patients are essential.

Second, we used a fluid-filled system to record ascending aortic pressure. If we had used a high fidelity pressure transducer, the recorded pressure waveform would have been more accurate. This does not mean, however, that waveform analysis using the fluid-filled recording system is invalid. The fact that we could predict the occurrence of restenosis after PTCA using the fluid-filled system should be interpreted not as a weakness, but as a strength, of the study.

Third, we did not use computerized angiographic analysis. We used handheld electronic digital caliper measurement to determine the percentage of diameter reduction as an index of stenotic severity. Although coronary angiography is precise, electronic digital caliper measurements can estimate the reduction in diameter in a rapid, low-cost way with acceptable accuracy.

We thank Noritsune Aoki for help in the preparation of this article.