Journal of the American College of Cardiology Vol. 35, No. 2, by the American College of Cardiology ISSN /00/$20.

Journal of the American College of Cardiology Vol. 35, No. 2, 2000 2000 by the American College of Cardiology ISSN 0735-1097/00/$20.00 Published by Elsevier Science Inc. PII S0735-1097(99)00577-X Persistent ST Segment Deression in Precordial Leads V5 V6 After Q-Wave Anterior Wall Myocardial Infarction Is Associated With Restrictive Physiology of the Left Ventricle Myocardial Infarction Abid Assali, MD, Samuel Sclarovsky, MD, Itzhak Herz, MD, Mordechai Vaturi, MD, Irit Gilad, PHD, Alejandro Solodky, MD, Nili Zafrir, MD, Yehuda Adler, MD, Alex Sagie, MD, Yochai Birnbaum, MD, David Hasdai, MD Tel Aviv, Israel OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS To examine the relationshi between the ersistence of ST segment deression in leads V5 V6 after Q-wave anterior wall myocardial infarction (MI) and the filling attern of the left ventricle (LV). Precordial ST segment deression redominantly in leads V5 V6 is associated with increased in-hosital morbidity and mortality after acute myocardial ischemia, erhas due to reduced diastolic distensibility of the LV. We rosectively studied 19 atients after Q-wave anterior wall MI ( 6 months). All atients underwent 12-lead ECG recording, symtom-limited treadmill exercise testing with single hoton emission comuted tomograhy thallium-201 imaging, transthoracic Doler echocardiograhy, cardiac catheterization and measurement of circulating atrial natriuretic etide (ANP) and brain natriuretic etide (BNP) levels. Patients were classified based on the resence of ST segment deression in leads V5 V6: ST segment deression 0.1 mv ; ST segment deression 0.1 mv. Patients in had greater LV end diastolic ressures (32.4 6.5 mm Hg vs. 14.8 6.1 mm Hg; 0.0001), higher lasma ANP (44.4 47.1 g/ml vs. 10.7 14 g/ml; 0.04) and BNP levels (89.4 62.7 g/ml vs. 23.6 33.1 g/ml; 0.01), greater left atrium area (20.6 3.1 cm 2 vs. 17.8 2.4 cm 2 ; 0.05), lower eak atrial (A), higher early (E) mitral inflow velocities, a higher E/A ratio and a lower deceleration time (167 44 ms vs. 220 40 ms; 0.05). Lung thallium utake during exercise was more common in Grou II (78% vs. 10%, 0.04). Persistent ST segment deression in leads V5 V6 in survivors of Q-wave anterior wall MI is associated with increased LV filling ressure and a restrictive LV filling attern. (J Am Coll Cardiol 2000;35:352 7) 2000 by the American College of Cardiology Several studies have demonstrated that atients with recordial ST segment deression after acute myocardial infarction (AMI) have larger infarcts, greater incidence of recurrent ischemia, worse left ventricular ejection fraction (LVEF) and a higher rate of adverse clinical events, including greater mortality (1 3). Willems et al. (4) reorted that recordial ST segment deression also ortends imortant rognostic information during anterior wall AMI, reflecting both greater infarct size and higher in-hosital mortality. Persistent ST segment deression before discharge is also an From the Deartment of Cardiology, Rabin Medical Center, Beilinson Camus, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscrit received December 9, 1998; revised manuscrit received Setember 10, 1999, acceted October 27, 1999. indeendent risk factor for increased mortality and morbidity after AMI treated with thrombolytic theray (5 7). Most of these rior studies have not differentiated among the various atterns of recordial ST segment deression. The imortance of the location of redominant recordial ST segment deression, however, has been emhasized by several recent studies. ST segment deression redominantly in left recordial leads (V4 V6) in atients after inferior wall AMI was associated with increased in-hosital mortality, resumably due to diffuse ischemia associated with concomitant coronary artery disease articularly involving the left anterior descending coronary artery (8 10). Sclarovsky et al. (11) also reviously reorted that atients with unstable angina ectoris and ST segment deression redominantly in leads V4 V6 (in the absence of tachycardia) had severe coronary artery disease, often with left main

JACC Vol. 35, No. 2, 2000 February 2000:352 7 Assali et al. Persistent ST Deression and Restrictive Physiology 353 Abbreviations and Acronyms A eak atrial velocity ACE angiotensin converting enzyme AMI acute myocardial infarction ANP atrial natriuretic etide BNP brain natriuretic etide DT decceleration time E eak inflow early velocity E/A ratio of E and A FS fractional shortening LV left ventricle or ventricular LVEDP left ventricular end diastolic ressure LVEF left ventricular ejection fraction MI myocardial infarction SPECT single hoton emission comuted tomograhy coronary artery involvement, and a oor rognosis when they develoed AMI (12). The athohysiology behind these observations is not clear. Recently we ostulated that ST segment deression redominantly in leads V4 V6 during acute inferior wall myocardial infarction (MI) is reflective of transient diffuse ischemia, causing reduced diastolic distensibility of the left ventricle (LV) (13) and increased secretion of atrial natriuretic etide (ANP) (14). The rimary objective of this study was to examine the hyothesis that there is a relationshi between ersistent ST segment deression in the recordial leads V5 V6 in atients with revious Q-wave anterior wall MI and the filling attern of the LV. METHODS Patients. We rosectively studied 19 consecutive atients 6 months after Q-wave acute anterior MI (athological Q-wave in leads V1 to V3 and abnormal wall motion in the anterior wall as detected by echocardiograhy) with functional class 1 or 2 and taking angiotensin enzyme converting (ACE) inhibitors. We excluded atients with another infarction other than the index infarction, chronic renal failure (serum creatinine level 1.5 mg%), valvular heart disease or cardiomyoathy, severe LV dysfunction (LVEF 25%), cor ulmonale, LV hyertrohy or interventricular conduction defects (left bundle branch block, left anterior fascicular block, left osterior fascicular block or right bundle branch block). Study rotocol. The following rotocol was aroved by the local institutional review board. After informed consent was obtained, each atient underwent the following tests: 12-lead ECG recording, symtom-limited treadmill exercise testing using the Bruce or modified Bruce rotocol with single hoton emission comuted tomograhic (SPECT) thallium-201 imaging, transthoracic two-dimensional and Doler echocardiograhy and left ventriculograhy and coronary angiograhy using the Judkin s technique via the Figure 1. Reresentative electrocardiograms of atient with revious anterior wall MI with (uer anel) and without (lower anel) significant recordial ST segment deression in leads V5 V6. femoral artery. Blood samles were also drawn from the antecubital vein in the suine osition after an overnight fast for the measurement of lasma ANP and brain natriuretic etide (BNP) levels. Electrocardiograhic analysis. The ECG recordings were analyzed by two indeendent investigators blinded to the results of other tests. All ECG recordings had abnormal Q-wave in leads V1 to V3. Patients were further classified into two grous based on the resence of ST segment deression in recordial leads V5 V6, as reviously described (13,14). Briefly, the degree of ST segment deression was determined in all leads (measured manually to the nearest 0.05 mv, 0.06 s after the J oint). For each atient the sum of the ST segment deression was calculated. Patients were classified as if the sum of ST segment deression in leads V5 V6 was 0.1 mv and if the sum of ST segment deression was 0.1 mv in leads V5 V6 (Fig. 1). Echocardiograhy. M-mode and two-dimensional echocardiograhy, sectral ulsed-wave and color Doler studies were obtained (by an exerienced oerator blinded to the results of other tests) using a Hewlett-Packard (Andover, Massachusetts) hased array sector scanner with a 2.5 MHz transducer (77020A). M-mode measurements were derived from imaging two-dimensional arasternal short-axis views and included end diastolic and end systolic LV cavity diameter at the mitral and midventricular level. Setal and osterior wall thickness were obtained from the short axis view at the mitral level. Left ventricular inflow velocities were obtained by ulsed-wave Doler echocardiograhy, by lacing the samle volume at the level of the mitral leaflet tis and at midventricle, 3 cm into the LV, from the aical four-chamber view. Measurements included the following arameters from the mitral flow velocity sectrum (average of five beats): eak inflow early (E) and eak atrial (A) velocities (cm/s), as well as their ratio E/A and the deceleration time (DT) of the early wave (ms). SPECT thallium-201 imaging. All atients underwent SPECT thallium-201 imaging during symtom-limited treadmill exercise testing using the Bruce or modified Bruce rotocol (15). At eak exercise, a dose of 3 mci of thallium-201 was injected intravenously, and SPECT im-

354 Assali et al. JACC Vol. 35, No. 2, 2000 Persistent ST Deression and Restrictive Physiology February 2000:352 7 aging was erformed. Rest SPECT images were obtained 4 h after exercise. If fixed defects were detected, reinjection was also erformed at 24 h. The SPECT images were analyzed for fixed or reversible abnormalities, findings suggestive of multivessel abnormality and increased lung thallium utake. Hemodynamic assessment and coronary angiograhy. Systemic blood ressure and LV end diastolic ressure (LVEDP) were measured during cardiac catheterization but before coronary angiograhy. Coronary angiograhy was erformed using 5 6F catheters. The severity of coronary artery stenosis was visually assessed by two blinded investigators using orthogonal views. Single lane left ventriculograhy was erformed in the right anterior oblique view. All rocedures were erformed using nonionic contrast media. Measurement of lasma ANP and BNP levels. Blood samles were taken from the antecubital vein in the suine osition after an overnight fast. The samle was transferred immediately into chilled glass tubes containing disodium ethylenediamine tetraacetic acid (1 mg/ml) and arotinin (500 units/ml) and centrifuged immediately at 4 C, and the lasma was frozen and stored at 80 C until assayed. Atrial natriuretic etide and BNP were determined using direct immunoradiometric kits (Shionora & Co., Ltd., Osaka, Jaan and urchased from Cis Bio International, France). The kits (16) are highly sensitive and emloy two different monoclonal antibodies that recognize the C-terminal region and the ring structure of ANP and BNP, resectively. The first antibody is bound to the solidified bead, which is incubated with the hormone, and the second I (125) monoclonal antibody is added to form a sandwich comlex. After incubation the beads are washed to remove unbound radioiodinated antibody. A direct ositive correlation is obtained between hormone concentration (2.5 2,000 g/ml for both hormones) and radioactivity measured by gamma counter. Statistical analysis. All continuous data are exressed as mean SD unless otherwise indicated. Comarisons of arameters between two grous were made by the Fisher exact test or the unaired Student t test. Correlation coefficients between hemodynamic, Doler and lasma ANP and BNP levels were calculated by Pearson linear regression analysis. P 0.05 was considered statistically significant. RESULTS The clinical and demograhic features of the atient oulation are resented in Table 1. No difference between grous was found in relation to age, medications, coronary artery risk factors and history of revascularization rocedures. The mean ST segment deression (for leads V5 and V6 together) in was 0.34 0.14 mv, as comared with 0.013 0.019 mv for ( 0.0001). Systemic blood ressure, LVEDP and LVEF are resented in Table 2. Systemic blood ressure and LVEF were Table 1. Clinical Characteristics of Patients According to ECG Pattern Men/women 9/1 8/1 Age (years) 60 12.3 62.0 12.5 Years ost MI 4.4 3.0 3.5 2.0 Prior coronary byass surgery 2 (20%) 2 (22%) Prior PTCA 8 (80%) 7 (78%) Hyertension 4 (40%) 3 (33%) Diabetes mellitus 4 (40%) 3 (33%) Nitrate 5 (50%) 5 (56%) Asirin 10 (100%) 9 (100%) Diuretic 5 (50%) 4 (44%) ST segment deression 0.1 mv in leads V5 V6; ST segment deression 0.1 mv in leads V5 V6. PTCA ercutaneous transluminal coronary angiolasty. similar in both grous. The LVEDP was significantly higher in comared with (32.4 6.5 mm Hg vs. 14.8 6.1 mm Hg; 0.0001). There was a ositive correlation between the sum of ST segment deression and the LVEDP (r 0.65; 0.003). The left anterior descending coronary artery was occluded without distal erfusion in 2 (22%) atients in, as comared with none of the atients in. In the remaining atients in, the distal vessel received native collateral circulation in two atients, circulation via an arterial graft in two atients and antegrade flow in three atients. In, the distal vessel received native collateral circulation in three atients, circulation via an arterial graft in two atients and antegrade flow in five atients. None of the atients in either grou had mitral regurgitation grade 2, and four atients in each grou had mitral regurgitation 2. The lasma ANP and BNP levels of the two grous are also resented in Table 2. Patients in had significantly higher lasma ANP (44.4 47.1 g/ml vs. 10.7 14 g/ml; 0.04) and BNP levels (89.4 Table 2. Hemodynamic, Left Ventricle Function, ANP and BNP Data of the Two Grous According to ECG Pattern Systemic SBP 130 20 137 17 NS (mm Hg) Systemic DBP 78 5 82 9 NS (mm Hg) LVEF* (%) 46.8 14.1 43 13.8 NS LVEDP (mm Hg) 14.8 6.1 32.4 6.5 0.0001 ANP (g/ml) 10.7 14 44.4 47.1 0.04 BNP (g/ml) 23.6 33.1 89.4 62.7 0.01 ANP atrial natriuretic etide; BNP brain natriuretic etide; DBP diastolic blood ressure; LVEDP left ventricular end-diastolic ressure; LVEF left ventricular ejection fraction; SBP systolic blood ressure. *Measured during cardiac catheterization.

JACC Vol. 35, No. 2, 2000 February 2000:352 7 Assali et al. Persistent ST Deression and Restrictive Physiology 355 Table 3. Two-Dimensional Echocardiograhic Data According to ECG Pattern LV-EDD (mm) 56.1 6.5 51.6 9.1 NS LV-ESD (mm) 38.6 6.5 36.1 11.4 NS IVS (mm) 9.6 1.06 10.0 2.0 NS PWT (mm) 10.4 1.07 10.3 2.0 NS LA diameter (mm) 36.6 2.4 41.2 3.8 0.007 LA area (cm 2 ) 17.8 2.4 20.6 3.1 0.05 LV-FS (%) 30.0 8.6 31.0 11.8 NS EDD end-diastolic diameter; ESD end-systolic diameter; FS fractional shortening; IVS interventricular setum thickness; LA left atrium; LV left ventricle; PWT osterior wall thickness. 62.7 g/ml vs. 23.6 33.1 g/ml; 0.01) than atients in. We observed a ositive correlation between the sum of ST deression in leads V5 V6 and lasma BNP levels (r 0.63; 0.004) but not with ANP levels. The two-dimensional echocardiograhic data are resented in Table 3. The LV end diastolic and systolic diameters were similar in both grous. No significant difference was found in the thickness of the LV (interventricular setum and osterior wall). The LV systolic function as measured by two-dimensional echocardiograhic [LV fractional shortening (FS)] was also not significantly different. The diameter of the left atrium, however, was significantly higher in than in (4.12 0.38 cm vs. 3.66 0.24 cm; 0.007). Similarly, the left atrium area was found to be bigger in comared with (20.6 3.1 cm 2 vs. 17.8 2.4 cm 2 ; 0.05). We found a significant correlation between the sum of ST deression in leads V5 V6 and the left atrium diameter (r 0.51, 0.03). The transmitral Doler measurements are resented in Table 4. Patients in had significantly lower A, higher E and a higher E/A ratio comared with atients in. Decceleration time was lower in (167 44 ms vs. 220 40 ms; 0.05). Five of the nine atients in had a DT of less than 160 ms (as comared with 2 of 10 in, 0.17) and five of nine atients had an E/A ratio greater than 1.1 (as comared with 1 of 10 in, 0.06). We found a significant correlation Table 4. Transmitral Doler Variables in Patients Groued According to ECG Pattern E (cm/s) 50 18.5 75 32.6 0.03 A (cm/s) 104 42.5 71 14.5 0.05 E/A ratio 0.55 0.38 1.11 0.82 0.05 DT (ms) 220 40 167 44 0.05 s exressed as median SD. A eak flow velocity during atrial contraction; DT deceleration time of early mitral flow; E eak flow velocity during early diastole. between the sum of ST deression in leads V5 V6 and the transmitral Doler flow arameter E (r 0.53, 0.02) and borderline with A (r 0.43, 0.07) and the E/A ratio (r 0.43, 0.07). A correlation was found between ANP lasma levels and the transmitral Doler flow arameters E (r 0.62, 0.004), A (r 0.43, 0.07) and E/A ratio (r 0.62, 0.005). Exercise testing. The exercise data are shown in Table 5. There were no differences between the two grous in exercise duration, eak heart rate, eak systolic blood ressure and the rate-ressure roduct. Patients in had more angina and dysnea during exercise, but these differences were not significant. Seventy-eight ercent of the atients in had increased lung thallium utake during exercise comared with 10% in ( 0.04). DISCUSSION Acute MI causes comlex alterations in LV structure and function. In this study several measures were used to assess LV function of atients with revious Q-wave anterior wall MI according to the attern of ST segment deression in leads V5 V6. This study demonstrates that ersistent ST segment deression in leads V5 V6 in atients with revious Q-wave anterior wall AMI is associated with 1) increased LVEDP, 2) restrictive diastolic mitral flow attern, 3) larger left atrium diameter and area, 4) increased lung thallium utake during symtom-limited treadmill exercise testing, and 5) and increased lasma levels of ANP and BNP. Relation between ST segment deression and LVEDP. Our data indicate that atients with ersistent ST segment deression in leads V5 V6 had higher LVEDP comared with those without. We found that the LVEDP can be redicted by the magnitude of ST segment deression in these leads, with a significant direct correlation. The similar systolic function is suggestive of a redominantly diastolic abnormality. This is also suorted by the finding of Doler variables of the mitral diastolic flow and larger left atrium found by two-dimensional echocardiograhy, which are also suggestive of a restrictive filling attern. Hasdai et al. (13) reviously reorted that ST segment deression redominantly in leads V4 V6 during the acute hase of inferior MI is reflective of diffuse ischemia due to extensive coronary artery disease with reduced diastolic distensibility and increased LVEDP. This can also be learned from the work of Grossman et al. (17) and of Dwyer (18), demonstrating that atrial acing in ischemic atients results in significant ST segment deression in leads V4 V6 and an increase in LVEDP, as oosed to lack of ECG changes and a decline in LVEDP in nonischemic subjects. Relation between ST segment deression and the filling attern of the LV. During the ast decade, several studies have related the Doler mitral flow velocity attern to LV and ulmonary caillary wedge ressure recording. Three

356 Assali et al. JACC Vol. 35, No. 2, 2000 Persistent ST Deression and Restrictive Physiology February 2000:352 7 Table 5. Exercise Treadmill Data During Symtom-Limited Treadmill Exercise Testing According to ECG Pattern Exercise duration (min) 6.8 2.2 6.5 3.7 NS Peak heart rate (beats/min) 149 12 133 18 NS Peak systolic blood ressure (mm Hg) 168 17 173 12 NS Rate-ressure roduct (mm Hg beats 24,858 1,889 22,794 2,793 NS min 1 ) Angina during exercise 0 (0%) 4 (44%) 0.055 Dysnea during exercise 0 (0%) 3 (33%) NS Increased lung thallium utake 1 (10%) 7 (78%) 0.04 abnormal atterns have been described and correlated with hemodynamic findings (19,20). One of these atterns, the restrictive attern, is characterized by increased early filling (E), reduced atrial filling (A), increased E/A ratio and short DT of early filling. Recently, the restrictive attern was found to be the best redictor of cardiac death after AMI (21,22). In our study, we demonstrated that atients with revious Q-wave anterior wall MI with ersistent ST segment deression in leads V5 V6 have a Doler mitral flow velocity attern that is consistent with restrictive hysiology. They have increased early filling (E), reduced atrial filling (A), higher E/A ratio and shorter DT of early filling. Both myocardial relaxation and comliance are affected by ischemia. Abnormal myocardial relaxation and decreased LV comliance have been described in the subacute hase of AMI (23). It aears that while all the infarctions in our cohort had evidence of diastolic dysfunction, atients in demonstrated a more severe diastolic dysfunction characterized by restrictive hysiology. The chronic diffuse subendocardial ischemia due to elevated LVEDP in atients with revious Q-wave anterior wall MI with ersistent ST segment deression in leads V5 V6 may be the cause for this restrictive attern of filling. Our study, as others (21,22), demonstrates that atients with restrictive filling hysiology also have more functional imairment (more angina, dysnea and lung thallium utake during exercise). Relation between ST segment deression and the natriuretic etides. Atrial natriuretic etide and BNP are two of the major etides in the natriuretic family with a similar ability to romote natriuresis and diueresis, inhibit the renin-angiotensin-aldosterone axis and cause vasodilation. Brain natriuretic etide may be the suerior rognosticator for risk stratification after AMI indeendent of LVEF (24). The mechanism for the release of ANP and BNP remain uncertain. Disease states associated with increased ulmonary caillary wedge ressure and increased atrial stretch are associated with increased secretion of ANP from the atrium (24). Unlike ANP, BNP is synthesized in and secreted rimarily from the LV in resonse to increased myocardial stretch, suggesting that BNP may be a more secific indicator of ventricular athology (25). Measurement of both these etides may be a suerior, noninvasive way to stratify risk in ost-mi atients, because high levels of these etide in the lasma are associated with higher risk to develo symtomatic heart failure and death (24,25). In a revious study (14) we demonstrated that atients with acute inferior wall MI and recordial ST segment deression redominantly in leads V4 V6 had higher ANP levels than atients without ST segment deression or atients with ST segment deression redominantly in leads V1 V3. This finding was also associated with increased in-hosital mortality. In this study we found that atients with revious Q-wave anterior wall MI who had ersistent ST segment deression in leads V5 V6 had higher levels of both ANP and BNP, which correlated with the sum of the ST segment deression in these leads and the magnitude of the LVEDP. Since this grou of atients had similar LVEF as the grou without ersistent ST segment deression in the recordial leads V5 V6, we assume that these finding are best exlained by the elevated LVEDP and the restrictive filling attern of the LV. Clinical imlications. Because a restrictive LV filling attern is a useful indicator of function and rognosis, it is of great ractical value to identify atients likely to have this filling attern by a simle and noninvasive method. This study demonstrates that ersistent ST segment deression in leads V5 V6 among atients who have survived Q-wave anterior wall AMI accurately identifies a subgrou of atients with high LV filling ressure and restrictive LV filling attern. This ECG requires less exertise to obtain and interret than other available techniques and, thus, may be more readily imlemented. Study limitations. These results are affected by the selection criteria of the oulation. By including only survivors of Q-wave anterior wall AMI 6 months, atients with a worse rognosis who died before were not studied. Thus, our results cannot be generalized to the whole oulation immediately after AMI. Second, we did not measure the isovolumic relaxation time, which is robably the most sensitive of the Doler indexes in detecting imaired

JACC Vol. 35, No. 2, 2000 February 2000:352 7 Assali et al. Persistent ST Deression and Restrictive Physiology 357 relaxation (26) or the flow velocity attern in the ulmonary veins that correlates with the LVEDP better than the mitral Doler variables (27). In our study we analyzed only the mitral flow velocity rofile, which is more standardized, easy to obtain in all atients and extensively used in the noninvasive assessment of LV filling abnormalities. Conclusions. This study demonstrates that ersistence of ST segment deression in leads V5 V6 in a subgrou of atients who have survived Q-wave anterior wall AMI is associated with high LV filling ressure and a restrictive LV filling attern. Rerint requests and corresondence: Dr. David Hasdai, Deartment of Cardiology, Rabin Medical Center (Beilinson Camus), Petah Tiqva, 49100, Israel. E-mail: dhasdai@ost.tau.ac.il. REFERENCES 1. Haltky MA, Califf RM, Lee KL, Pryor DB, Wagner GS, Rosati RA. 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