Ventricular arterial coupling in patients with stable ischemic heart disease undergoing percutaneous coronary intervention

Journal of military pharmaco-medicine n 0 1-2020 234 VENTRICULAR ARTERIAL COUPLING IN PATIENTS WITH STABLE ISCHEMIC HEART DISEASE UNDERGOING PERCUTANEOUS CORONARY INTERVENTION Pham Vu Thu Ha1; Luong Cong Thuc1; Doan Van De1 SUMMARY Objectives: To investigate the alterations in ventricular arterial coupling (VAC) and its components (Ea, Ees) in patients with stable ischemic heart disease (IHD) after percutaneous coronary intervention (PCI). Subjects and methods: 129 patients with stable IHD (study group) and 40 individuals without IHD (control group) were enrolled. All patients with IHD underwent coronary artery stenting. VAC was calculated using echocardiography single beat method at baseline and 1, 3, 6 months after PCI. Results: At baseline, the median of Ea, Ees and VAC was 2.52 mmHg/ml (IQR: 1.88 - 3.30), 3.87 mmHg/ml (IQR: 2.88 - 4.97) and 0.64 mmHg/ml (IQR: 0.54 - 0.79), respectively. Patients with IHD had significantly lower Ees and higher VAC than those without IHD (p < 0.05). At 3 months and 6 months after PCI, Ees increased dramatically (4.95 mmHg/ml (3.78 - 6.63) vs 5.15 (4.15 - 7.05), respectively, p < 0.05) and VAC decreased signficantly (0.51 mmHg/ml (0.45 - 0.65) vs 0.48 mmHg/ml (0.42 - 0.62), respectively, p < 0.05). In the group of 1-vessel, 2-vessel and 3-vessel lesion, VAC was remarkably lower than at the baseline. There was no association between the changes of VAC after PCI and the number and site of stenting. Conclusion: At baseline, patients with stable IHD had a lower Ees and higher VAC than individuals without stable IHD. At 3 months after PCI, the Ees and VAC decreased drastically. * Keywords: Ischemic heart disease; Percutaneous coronary intervention; Ventricular arterial coupling. INTRODUCTION Stable ischemic heart disease is common in developed countries and tend to increase in developing countries. Recently, PCI has become a modern and effective therapy for coronary artery disease (CAD). However, an optimal revascularization strategy for patients remains controversial. Most patients with stable CAD have no echocardiographic sign of segmental wall motion abnormality as well as disastolic and systolic disorders. The value of a single echocardiographic parameter in the assessment of left ventricular function before and after PCI has been analyzed. The interaction between the left ventricle and arterial system, which was first proposed by Sunagawa et al. and later termed VAC, is now recognized as a key determinant of global cardiovascular performance. VAC is commonly calculated by the ratio of effective arterial elastance 1. 103 Military Hospital Corresponding author: Luong Cong Thuc (lcthuc@gmail.com) Date received: 11/02/2020 Date accepted: 15/02/2020 Journal of military pharmaco-medicine n 0 1-2020 235 (Ea) as a measure of afterload, to left ventricular end-systolic elastance (Ees) as a relatively load independent measure of left ventricular chamber performance. However, understandings about the behaviours of ventricular-arterial coupling in patients with IHD, especially after percutaneous coronary intervention are still limited. Therefore, the aims of our study were: To investigate the VAC in patients with stable IHD and its changes after PCI. SUBJECTS AND METHODS 1. Subjects. - The study group: 129 consecutive patients with stable IHD undergoing coronary angiography were enrolled at the Department of Cardiology, 103 Military Hospital from December 2016 to December 2018. * Selection criteria: Diagnosis of CAD was based upon presence of ≥ 1 angiographically documented coronary stenosis > 50%. * Exclusive criteria: Patients suffered from myocardial infarction, acute coronary syndrome, significant congenital heart disease, valvular heart disease (moderate to severe regurgitation or stenosis), atrial fibrillation, severe infection, hepatic failure, renal failureor no available follow up data. Percutaneous coronary intervention was considered successful when thrombolysis in myocardial infarction (TIMI) grade 3 flow and residual stenosis < 20% were achieved. Coronary angiography was evaluated by an independent interventional cardiologist who was blinded to the patient history, electrocardiogram and echocardiographic data. - The control group: 40 age and gender - matched subjects underwent normal coronary angiography at the time of the study. Exclusion criteria were the same as in the study group. Informed consents were obtained from all participants, and the research protocol was approved by the Institutional Review Board of 103 Military Hospital. 2. Methods. * Study design: Prospective and descriptive study * Study protocol: 12-lead electrocardiogram, echocardiography, blood tests and coronary angiography were obtained from patients. The systolic and diastolic blood pressure were measured at the time of echocardiography. Blood tests were comprised of B-type natriuretic peptide (BNP), fasting blood glucose, creatinine, and a lipid panel were evaluated before PCI. * Echocardiographic study: Echocardiographic examination was performed using the Philips EPIQ 7C with a multi-frequency transducer. Parasternal long- and short-axis views, apical four, three and two-chamber views were used for evaluation of the structure and function of the left ventricle and heart valves. Left ventricle timing intervals were derived from the left ventricle outflow tract flow velocity recorded from the apical five-chamber view using pulsed wave Doppler, with the sample volume positioned about 5 mm proximal to the aortic valve. For each view, three consecutive cardiac cycles were recorded during a short breath-holding. Journal of military pharmaco-medicine n 0 1-2020 236 Standard measurements of cardiac chamber’s dimensions, volumes and wall thickness were obtained during diastole and systole according to the recommendations of the American Society of Echocardiography. Left ventricular ejection fraction was measured using the biplane Simpson’s method. Each patient was kept at rest for at least half an hour before measuring any echo parameter. The first echocardiographic examination was performed within 12 hours prior to PCI. The subsequent echocardiographic examinations were performed at 1 week, 1 month, 3 months, and 6 months after PCI. - Measurement of arterial elastance (Ea): Arterial elastance (Ea) was calculated as the ratio of end-systolic pressure volume to stroke volume (Ea = Pes/SV). Pes was estimated as 0.90 multiplied times systolic blood pressure (SBP) by manual blood pressure cuff at the time of echocardiogram as recommended. Stroke volume was calculated as the results of the left ventricle outflow tract velocity-time integral at apical 5-chamber view with pulsed-wave Doppler) and left ventricle outflow tract cross-sectional area. - Measurement of end - systolic left ventricular elastance (Ees): Ees was determined using a modified single-beat algorithm as previously described by Chen et al. [1]. Ees(sb) = [Pd − (ENd(est)× Ps × 0.9)]/[ENd(est)× SV] ENd(est) = 0.0275 − 0.165 × EF + 0.3656 × (Pd/Ps × 0.9) + 0.515 × ENd(avg) Where EF is the ejection fraction and End(avg) is derived by the following formula. ENd(avg) = 0.35695 - 7.2266 × tNd + 74.249 × tNd2-307.39 × tNd3 + 684.54 × tNd4 - 856.92 × tNd5 + 571.95 × tNd6 - 159.1 × tNd7 tNd: the ratio of pre - ejection period (PEP: R-wave to flow onset) to total systolic period (TSP: R-wave to end-flow) at the onset and the time of termination of flow defined from the aortic Doppler waveform [1]. Once these formulas are implemented on an automatic algorithm, the determination of non-invasive parameters like Ps, Pd, SV, EF, and tNd allows the immediate calculation. - VAC: is then obtained as the ratio of arterial to ventricular elastance (Ea/Ees), which is considered to be the principal determinant of net cardiovascular performance [1]. - Long term follow-up analysis: Patients were followed-up at 1 month, 3 months and 6 months after PCI. Unfavourable events were pre-specified as primary endpoints of death from hospitalization for heart failure, and sudden cardiac death. * Statistical analysis: Continuous variables were expressed as mean and standard deviation in case of symmetrical distribution, or as median and interquartile range in case of asymmetrical distribution. Categorical variables were reported as percentages. The Wilcoxon - Mann - Whitney’s U test or Student’s t-test was used to compare continuous variables; and the Chi-square or Fisher’s exact test for categorical variables. A p-values < 0.05 was considered statistically significant. The SPSS version 23.0 software (SPSS, Chicago, IL, USA) was used for statistical analysis. Journal of military pharmaco-medicine n 0 1-2020 237 RESULTS A total of 129 patients with stable IHD undergoing PCI were included in the study. During the mean follow-up period of 4.7 ± 2.3 months, 24 patients (19.3%) developed cardivascular events, including one death from heart failure and the other 23 cases of severe heart failure requiring hospitalization. 1. Clinical characteristics at baseline The baseline clinical characteristics of the patients in the study and control groups are summarized (table 1). Table 1: Demographic and clinical characteristics of study population. Variables IHD group (n = 129) Control group (n = 40) p Clinical chracteristics Male n (%) 95 (73.6) 22 (55) 0.14 Age (years) 67.75 ± 8.13 65.48 ± 8.16 0.12 BMI (kg/m2) 22.79 ± 3.17 22.38 ± 2.36 0.45 SBP (mmHg) 128.95 ± 17.32 130.13 ± 17.23 0.71 DBP (mmHg) 74.88 ± 9.87 76.75 ± 8.74 0.28 Arterial hypertension n (%) 107 (82.9) 25 (62.5) 0.01 Diabete mellitus 37 (28.7) 9 (22.5) 0.29 Angiographic data LM 8 (6.2) LAD 39 (30.2) LCx 7 (5.4) RCA 13 (10.1) LAD + LCx 13 (10.1) LAD + RCA 17 (13.2) RCA + LCx 10 (7.8) LAD + RCA + LCx 22 (17) Numbers of stents 1 stent 107 (82.9) 2 stent 22 (17.1) BSA: Body surface area, BMI: Body mass index, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, NYHA: New York Heart Association. ACE-I: Angiotensin- converting enzym inhibitor, ARB: Angiotensin-II receptor blocker. Mean age of IHD group was 67.75 ± 8.13, predominantly males (73.6%). Journal of military pharmaco-medicine n 0 1-2020 238 2. Echocardiopgraphic data Ea, Ees and VAC of the study and the control groups measured by echocardiographic single beat method are shown below (table 2). Table 2: Ea, Ees and VAC in patients with stable IHD. Variables IHD group (n = 129) Control group (n = 40) p Ees (mmHg/ml) 3.87 (2.88 - 4.97) 4.38 (3.70 - 5.29) 0.04 Ea (mmHg/ml) 2.52 (1.88 - 3.30) 2.51 (2.05 - 2.96) 0.99 VAC (mmHg/ml) 0.64 (0.54 - 0.79) 0.57 (0.52 - 0.68) 0.02 Data are presented as median (inter-quartile range) Ees: End systolic elastance, Ea: Arterial elastance At baseline, Ea in the study group was similar to that in the control group. Meanwhile, the study group had remarkably lower Ees (3.87 mmHg/ml (2.88 - 4.97)) and higher VAC (0.64 mmHg/ml (0.54 - 0.79)) than those in the control group. 3. Ventricular-arterial coupling after PCI Table 3: Ea, Ees and VAC after PCI. Variables Before PCI (n = 129) After a week (n = 129) After a month (n = 114) After 3 months (n = 102) After 6 months (n = 97) Controls (n = 40) Ea (mmHg/ml) 2.52 (1.88 - 3.3) 2.4 (1.93 - 2.96) 2.45 (1.91 - 2.45) 2.14 (2.14 - 3.53) 2.63 (2.11 - 3.43) 2.51 (2.05 - 2.96) Ees (mmHg/ml) 3.87 (2.88 - 4.96) 3.7 (2.75 - 5.06) 4.3 (3.1 - 5.97)*# 4.95 (3.78 - 6.63)*# 5.15 (4.15 - 7.05)*# 4.38 (3.70 - 5.29) VAC 0.64 (0.54 - 0.79) 0.63 (0.51 - 0.75) 0.60 (0.5 - 0.74) 0.51 (0.45 - 0.65)*# 0.48 (0.42 - 0.62)*# 0.57 (0.52 - 0.68) Data were presented as median (inter quartile range); *: p < 0.05 compared with baseline. # p < 0.05 compared with the control After PCI, Ees was significantly improved at 1, 3, and 6 months and VAC was significantly reduced after 3 and 6 months. Journal of military pharmaco-medicine n 0 1-2020 239 Table 4: VAC after PCI and the numbers of stents. 1 stent (n = 107) 2 stent (n = 22) p Before PCI 0.63 (0.54 - 0.79) 0.65 (0.52 - 0.89) 0.9 After 7 days 0.64 (0.51 - 0.76) 0.61 (0.53 - 0.77) 0.92 After 1 month 0.61 (0.5 - 0.75) 0.55 (0.49 - 0.68) 0.2 After 3 months 0.51 (0.46 - 0.66) * 0.49 (0.45 - 0.54) * 0.35 After 6 months 0.48 (0.42 - 0.62) * 0.51 (0.42 - 0.60) * 0.81 p 0.0001 0.028 * p < 0.05 compared with before PCI. There was no significiant difference in VAC between 1 - stent and 2 - stent group. Table 5: VAC after PCI and the site of stenting. Position VAC LAD (n = 58) LCx (n = 23) RCA (n = 43) p Before PCI 0.64 (0.53 - 0.83) 0.67 (0.57 - 0.75) 0.62 (0.54 - 0.77) 0.8 After 7 days 0.64 (0.52 - 0.8) 0.66 (0.57 - 0.73) 0.60 (0.5 - 0.75) 0.5 After 1 month 0.61 (0.53 - 0.69) 0.64 (0.47 - 0.78) 0.6 (0.50 - 0.74) 0.97 After 3 months 0.50* (0.46 - 0.66) 0.52 * (0.47 - 0.67) 0.50 * (0.46 - 0.66) 0.69 After 6 months 0.48 * (0.4 - 0.64) 0.53 * (0.43 - 0.65) 0.49 * (0.42 - 0.6) 0.6 p 0.0001 0.29 0.0001 * p < 0.05 compared with before PCI. Journal of military pharmaco-medicine n 0 1-2020 240 DISCUSSION To the best of our knowledge, this is the first study to investigate the effects of PCI on VAC. VAC, a key determinant of cardiovascular performance, is reliably estimated by the Ea/Ees ratio. Experimental models have shown that left ventricle maximal work is delivered when the Ea/Ees ratio is nearly unity, while maximal ventricular efficiency occurs when the Ea/Ees ratio approximates 0.5. Ees has been reported to decrease in patients with CAD. In addition, neurohormonal activation in this condition may produce vasoconstriction and tarchycardia, leading to increase in Ea. As such, the Ea/Ees ratio or VAC may increase in CAD. Ees represents the stiffness and contraction of the left ventricle. In the present study, Ees in the study group was lower, but Ea was not different from that in the control group, leading to significantly higher VAC in the study group. Antonini et al. (2009) also showed a remarkable decrease in Ees and increase in VAC in patients with history of myocardial infarction [2]. Similarly, Mathieu et al. (2010), in a canine model of myocardial infarction, showed that Ees after myocardial infarction obtained from invasive measurements significantly decreased, as well as the Ees/Ea ratio (1.4 ± 0.2 vs 0.6 ± 0.1, respectively, p < 0.001). It is noted that Ea reported in the invasive experiments was higher than that in our study. It is likely because our patients received optimal medical treatment [3]. Our data showed a significant increase in Ees and decrease in VAC after PCI, especially at 3-month and 6-month follow-up. Data from elective PCI for stable angina showed an upward and rightward shift of the pressure-volume loop during temporary ischemia, and immediate return to baseline after reperfusion, suggesting that primary PCI may result in improvement of left ventricle compliance [4]. Trambaiolo et al. (2019) recently reported that VAC decreased substantially after PCI (1.74 ± 0.8 vs 1.24 ± 0.09, respectively, p = 0.021). Systolic cardiac function, as represented by EF, SV, and wall motion were also improved after PCI (WMSI) [5]. PCI combined with optimal medical treatment may help improve the left ventricular contraction and VAC, resulting in more effective cardiovascular performance. The follow-up was 4.7 ± 2.3 months, VAC in the 1-vessel, 2-vessel or 3-vessel group significantly decreased after 3 - 6 months of revascularization. This proved that the coupling of the cardiovascular was better after PCI. Kass showed that the myocardial ischemia was affected by the coupling. Furthermore, such coupling influenced myocardial perfusion by elevating the proportion of coronary flow during the systolic time period. The myocardial ischemia impacted ventricle and arterial stiffness and caused to increase end diastolic pressure, decreased systolic and diastolic function. Remmelink did not recognize the markedly increased Ea/Ees compared with the baseline. Perhaps, measuring VAC by invasive method was so early that the parameters had not changed yet [6]. Journal of military pharmaco-medicine n 0 1-2020 241 VAC was not different between one - stent and two - stent group but VAC of each group improved better than before PCI, especially after 3 - 6 months. This proved that the coupling of the cardiovascular was better after stenting. After intervention, all these conditions may be resolved, leading to the decrease in ventricular and arterial stiffness and improvement of ventricular-arterial coupling. Our data at baseline, 1, 3 and 6 months after PCI showed that VAC was not affected by the location of stenting. In each site of stenting, VAC improved remarkably at 3 months and 6 months after PCI compared with baseline. A study by Rememlink et al. (2009) showed that regional left ventricular function is similar after stenting LAD or RCA [7]. There are several mechanisms responsible for myocardial damage in patients with stable CAD, including reduced coronary flow, chronic ischemia, small vessel microembolization, and endothelial dysfunction. However, the average territorial longitudinal strain and the ventricular stiffness for LAD, LCX, and RCA were not different before and after PCI. In all the study subjects, GLS after PCI (global longitudinal strain) values were significantly higher than before PCI [8]. In this study, after PCI GLS values were significantly higher [8]. This data suggest that PCI may improve not only left ventricle function but also the VAC and regardless of stenting site. CONCLUSION In conclusion, left VAC obtained from echocardiography increased significantly in patients with stable IHD. Percutaneous coronary intervention led to improvement of VAC, regardless of the number of stent used and sites of intervention. VAC may be used as a assessment tool for the improvement in patients with CAD. REFERENCES 1. Chen C.H., Fetics B., Nevo E., et al. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol. 2001, 38 (7), pp. 2028- 2034. 2. 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Effects of mechanical left ventricular unloading by impella on left ventricular dynamics in high-risk and primary percutaneous coronary intervention patients. Catheterization and Cardiovascular Interventions. 2010, 75, pp.187-194. 7. Remmelink Maurice, Robbert J. de Winter et al. The effect of repeated ischemic periods on left ventricular dynamics during percutaneous coronary intervention in cardiac hemodynamics in PCI: Effects of ischemia, reperfusion and mechanical support, Amsterdam, University of Amsterdam. 2009, pp.26-32. 8. Sikora-Frac M., Zaborska B. et al. Improvement of left ventricular function after percutaneous coronary intervention in patients with stable coronary artery disease and preserved ejection fraction: Impact of diabetes mellitus. Cardiology Journal. 2019.