Clinical and Experimental Hypertension
ISSN: 1064-1963 (Print) 1525-6006 (Online) Journal homepage: http://www.tandfonline.com/loi/iceh20
Left ventricular hypertrophy on long-term cardiovascular outcomes in patients with STelevation myocardial infarction Jin-Sun Park, Jeong-Sook Shin, You-Hong Lee, Kyoung-Woo Seo, Byoung-Joo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk & Joon-Han Shin To cite this article: Jin-Sun Park, Jeong-Sook Shin, You-Hong Lee, Kyoung-Woo Seo, ByoungJoo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk & Joon-Han Shin (2015): Left ventricular hypertrophy on long-term cardiovascular outcomes in patients with ST-elevation myocardial infarction, Clinical and Experimental Hypertension, DOI: 10.3109/10641963.2015.1047943 To link to this article: http://dx.doi.org/10.3109/10641963.2015.1047943
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Date: 05 November 2015, At: 16:23
http://tandfonline.com/iceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, Early Online: 1–6 ! 2015 Taylor & Francis Group, LLC DOI: 10.3109/10641963.2015.1047943
Left ventricular hypertrophy on long-term cardiovascular outcomes in patients with ST-elevation myocardial infarction Jin-Sun Park, Jeong-Sook Shin, You-Hong Lee, Kyoung-Woo Seo, Byoung-Joo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk, and Joon-Han Shin
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Department of Cardiology, Ajou University School of Medicine, Suwon, Korea
Abstract
Keywords
Background: Left ventricular hypertrophy (LVH) had been associated with increased adverse cardiovascular events in hypertensive patients. Prognostic significance of LVH in patients with ST-elevation myocardial infarction (STEMI) is not established. This study aimed to investigate prognostic impact of LVH on the patients with STEMI. Methods: We analyzed the data and clinical outcomes of 30-day survivors with STEMI who underwent successful coronary intervention from 2003 to 2009. Definition of LVH was LV mass index (LVMI) 4115 g/m2 in male and 495 g/m2 in female. Patients were classified into a LVH group and a non-LVH group. Occurrence of major adverse cardiovascular events (MACE; death, recurrent MI, target vessel revascularization (TVR)) within 5 years was evaluated. Results: We enrolled 418 patients and mean follow-up duration was 43 ± 17 months. Two hundred and fourteen patients (51%) had LVH. The survival of the patients with LVH was significantly worse than the patients without LVH (log-rank p ¼ 0.024). In a multivariate regression model, the presence of LVH was independently associated with increased risk for all-cause mortality (OR, 2.37; 95% CI, 1.096– 5.123, p ¼ 0.028). When the end points were analyzed based on LVH severity, all-cause mortality was significantly correlated with LVH severity (p ¼ 0.011). The severe LVH was independently associated with increased risk for all-cause mortality (OR, 5.110; 95% CI, 1.454–17.9, p ¼ 0.001). Conclusion: LVH was associated with increased rate of adverse clinical outcomes in 30-day survivors after STEMI, who underwent successful coronary intervention.
Left ventricular hypertrophy, myocardial infarction, prognosis History Received 7 February 2015 Revised 19 March 2015 Accepted 27 March 2015 Published online 6 July 2015
Background
Methods
Left ventricular hypertrophy (LVH) has been known as an independent predictor of adverse cardiovascular events in various etiologies (1–3). As hypertrophied myocardium is associated with a diastolic dysfunction (4), impaired LV performance (5,6) and arrhythmia (7,8), the differences of LV geometry are closely related with the prevalence of cardiovascular events. Most of the large scale studies were evaluated especially in hypertensive patients. In hypertensive patients, identifying LVH is considered important for stratification of cardiovascular risk (9). Prognostic significance of LVH in patients with ST-elevation myocardial infarction (STEMI) is not yet established. It might be reasonable to assume the structural changes accompanied by LVH could have adverse effect on both the infarct zone and the non-infarct zone with time. After STEMI, the clinical adverse effect of LVH has not been evaluated in these selected patients. This study aimed to investigate prognostic impact of LVH in patients with STEMI.
We consecutively enrolled 30-day survivors after STEMI, who underwent successful revascularization. Successful revascularization was defined as thrombolysis in myocardial infarction trial (TIMI) grade 3 flow and 530% residual stenosis in the infarct related artery after primary percutaneous coronary intervention (PCI). The medical records of all patients were retrospectively reviewed. This study was approved by the Ajou University Hospital Institutional Review Board (approval number: AJIRB-MED-MDB-13312). We excluded patients from the study if they had history of prior revascularization. We also excluded patients if the LV dysfunction was caused by any of the following: predisposing cardiomyopathy, severe valvular heart disease including symptomatic aortic stenosis, more than moderate aortic and mitral regurgitation. Transthoracic echocardiography was performed within 48 h of primary PCI. Left ventricular mass (LVM) was calculated according to Devereux’s formula (10), using linear measurements derived from two-dimensional echocardiography (11): LVM ¼ 0:8 f1:04 ½ðLV internal diastolic diameter þ posterior wall thickness in diastole
Correspondence: Joon-Han Shin, MD, Department of Cardiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 443-380, Korea. E-mail: [email protected]
þ septal wall thickness in diastoleÞ3 ðLV internal diastolic diameterÞ3 g þ 0:6g
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The LVM was indexed to body surface area. Definition of LVH was LV mass index (LVMI) 4115 g/m2 in male and 495 g/m2 in female based on the American Society of Echocardiography’s guidelines (11). All patients were divided into two groups according to the presence of LVH: a non-LVH group and a LVH group. To calculate LV ejection fraction, the biplane method of disks (modified Simpson’s rule), using standard 4- and 2-chamber apical views, was used (11). The end point of the present study was major adverse cardiac events (MACEs) within 5 years, including death, recurrent myocardial infarction (MI), target vessel revascularization (TVR) and hospitalization due to heart failure (HF). Recurrent myocardial infarction was defined according to the universal definition of MI (12). The TVR was defined as clinically indicated percutaneous or surgical revascularization of the index vessel during follow-up. At 5 years after index STEMI, follow-up data were obtained by reviewing medical records and/or telephone interview with patients. SPSS 13.0 statistical software package (SPSS, Chicago, IL) was used for all calculations. Data are shown as the mean ± standard deviation for continuous variables and as numbers and percentages for categorical variables. Data were compared using unpaired Student’s t test for continuous variables and Pearson’s chi-square test for categorical variables. Event-free survival analysis for patients in these groups was performed using the Kaplan–Meier method, and the differences between groups were assessed by the log-rank test. Multiple logistic regression analysis was performed to assess independent factors associated with MACEs. The parameters indicating LVH of patients were compared by MACEs, controlling for additional well-known predictors of MACEs. The clinical outcomes were also analyzed based on LVH severity. The severity of LVH was defined based on the American Society of Echocardiography’s guidelines (11). The severity of LVH was defined as following: mild LVH as LVMI 116–131 g/m2 in male and 96–108 g/m2 in female, moderate LVH as 132–148 g/m2 in male and 109–121 g/m2 in female and severe LVH as 149 g/m2 in male and 122 g/m2 in female. Multivariate logistic regression analysis was performed to assess the effect of LVH severity on clinical outcomes. Null hypotheses of no difference were rejected if p values were 50.05.
Results From 2003 to 2009, totally 418 patients (347 males, 56 ± 12 years) were enrolled. Mean LVMI of the 418 patients was 115 ± 30 g/m2. Baseline LVMI showed normal distribution. Two hundred and fourteen patients (51%) had LVH (170 males, 58 ± 12 year-old). In the LVH group, mean LVMI of males was 139 ± 24 g/m2 and that of females was 130 ± 29 g/m2. In the non-LVH group, mean LVMI of males was 94 ± 13 g/m2 and that of females was 81 ± 14 g/m2. Patients with LVH were older (58 ± 12 vs. 55 ± 11 year-old, p ¼ 0.005), had more history of hypertension and cerebrovascular accident (46 vs. 29%; p50.001 and 5 vs.1%; p ¼ 0.021, respectively) than the patients without LVH. The laboratory findings did not show any significant difference at index STEMI. There was no significant statistical difference in medical treatments between the two groups (Table 1).
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Angiographic and procedural data are listed in Table 2. Left anterior descending coronary artery disease was more common in patients with LVH (61 vs. 48%, p ¼ 0.008). Procedural type was similar in both groups. Drug eluting stents were most commonly implanted in these groups. The results of echocardiographic findings according to the groups are listed in Table 3. The parameters indicating LV chamber size, such as LV end diastolic dimension and LV end diastolic volume index, were significantly larger in the LVH group (52 ± 4 vs. 48 ± 5 mm, p ¼ 0.003, 55 ± 13 vs. 50 ± 11 mL/m2, p ¼ 0.015). The LV systolic function measured by ejection fraction in the LVH group was significantly reduced (51 ± 10 vs. 54 ± 10%, p ¼ 0.004). The regional LV function measured wall motion score index was also significantly worsened in the LVH group (1.57 ± 0.34 vs. 1.46 ± 0.32, p ¼ 0.005). Patients were followed up for 43 ± 17 months after index STEMI. The MACEs occurred in 70 patients (17%). Of 418 patients, 32 patients died (8%), 14 patients experienced recurrent MI (3%), 5 patients were readmitted with HF (1%) and 29 patients needed TVR (7%). Totally 158 (38%) patients were readmitted during follow-up. Of 158 patients, 60 patients were readmitted with non-cardiovascular reasons and the others were readmitted with cardiovascular reasons including MACEs, stroke (2 patients), peripheral arterial occlusive disease (1 patient) and aortic dissection (1 patient). In LVH group, more MACEs occurred (21 vs. 13%, p ¼ 0.036) and more patients died (11 vs. 4%, p ¼ 0.017). Among all-cause
Table 1. Baseline clinical characteristics.
Variables Age (year-old) Men, n (%) BMI (kg/m2) BSA (m2) Medical history Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Previous CVA, n (%) Smoking, n (%) eGFR (ml/min/1.73m2) LDL cholesterol (mg/dl) hs-CRP (mg/L) Killip class Killip class 3, n (%) Killip class 4, n (%) Medication at discharge Beta-blocker, n (%) RAS blocker, n (%) ACE inhibitor, n (%) ARB, n (%) CCB, n (%) statin, n (%) SBP at discharge (mmHg) DBP at discharge (mmHg)
Non-LVH group (n ¼ 204)
LVH group (n ¼ 214)
p Value
55 ± 11 177 (87) 24 ± 3 1.8 ± 0.2
58 ± 12 170 (79) 25 ± 3 1.7 ± 0.2
0.005 0.051 0.187 0.137
59 (29) 40 (20) 24 (12) 2 (1) 140 (69) 84 ± 24 107 ± 33 0.83 ± 1.81
99 (46) 50 (23) 15 (7) 11 (5) 129 (60) 80 ± 30 103 ± 36 1.7 ± 3.88
50.001 0.405 0.129 0.021 0.083 0.121 0.197 0.066
11 (5) 4 (2)
7 (3) 9 (4)
0.340 0.261
147 (72) 197 (97) 150 (74) 47 (23) 28 (14) 169 (83) 118 ± 16 71 ± 10
163 (76) 202 (94) 141 (66) 61 (29) 31 (15) 162 (76) 119 ± 16 72 ± 11
0.372 0.284 0.108 0.266 0.889 0.091 0.473 0.478
LVH, left ventricular hypertrophy; BMI, body mass index; BSA, body surface area; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; hs-CRP, high sensitivity C-reactive protein; RAS, renin-angiotensin system; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; SBP, systolic blood pressure; DBP, diastolic blood pressure.
Left ventricular hypertrophy and prognosis
DOI: 10.3109/10641963.2015.1047943
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mortality, there were 6 cardiac deaths (2 vs. 1%, p ¼ 0.373) and 6 non-cardiac deaths (2 vs. 1%, p ¼ 0.373). Although the other 20 deaths with unknown causes were suspected of sudden cardiac deaths, it was not confirmed by autopsy. Rates of recurrent MI, HF and TVR were not significantly different between the groups. In a multivariate regression model, the presence of LVH was independently associated with increased risk for all-cause mortality (p ¼ 0.028, Table 4). Event-free survival curves of patients according to LVH are reported in Figure 1. The event-free survival curves for freedom of MACE were not significantly different between the groups (log-rank p ¼ 0.232). The survival of patients with
Table 2. Baseline angiographic characteristics. Non-LVH group (n ¼ 204)
Variables Culprit lesion LAD, n (%) LCX, n (%) RCA, n (%) LM, n (%) Coronary Artery Disease 1 Vessel disease, n (%) 2 Vessel disease, n (%) 3 Vessel disease, n (%) PCI Thrombectomy only, n (%) POBA, n (%) BMS, n (%) DES, n (%)
98 16 88 2
(48) (8) (43) (1)
95 (47) 66 (32) 43 (21) 3 3 16 184
(2) (2) (8) (90)
LVH group (n ¼ 214) 131 13 68 1
p Value
(61) (6) (32) (0.5)
0.008 0.565 0.02 0.615
99 (46) 79 (37) 36 (17)
1.000 0.356 0.317
1 4 26 185
(0.5) (2) (12) (86)
0.362 1.000 0.192 0.287
LVH, left ventricular hypertrophy; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; LM, left main artery; PCI, primary coronary intervention; POBA, plain old balloon angioplasty; BMS, bare metal stent; DES, drug eluting stent.
Table 3. Baseline echocardiographic characteristics.
Variables
Non-LVH group (n ¼ 204)
LVH group (n ¼ 214)
p Value
LVEDD (mm) LVESD (mm) IVST (mm) PWT (mm) RWT LVEDV (mL) LVESV (mL) LVEDVI (mL/m2) LVESVI (mL/m2) LVEF (%) LV mass (g) LVMI (g/m2) WMSI
48 ± 5 32 ± 9 10 ± 2 10 ± 1 0.41 ± 0.09 88 ± 19 44 ± 14 50 ± 11 25 ± 8 54 ± 10 162 ± 30 92 ± 14 1.46 ± 0.32
52 ± 4 34 ± 6 12 ± 2 12 ± 2 0.47 ± 0.08 95 ± 27 50 ± 28 55 ± 13 29 ± 9 51 ± 10 241 ± 53 137 ± 25 1.57 ± 0.34
0.003 5 0.001 5 0.001 5 0.001 5 0.001 0.08 0.043 0.015 0.016 0.004 5 0.001 5 0.001 0.005
LVH, left ventricular hypertrophy; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; IVST, interventricular septal thickness at end diastole; PWT, posterior wall thickness at end diastole; RWT, relative wall thickness; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVEDVI, left ventricular end diastolic volume index; LVESVI, left ventricular end systolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; WMSI, wall motion score index.
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LVH was significantly worse than patients without LVH (log-rank p ¼ 0.024). The parameters indicating LVH of patients were compared between the groups by all-cause mortality, in addition to the well-known predictors of MACEs. In the regression model, variables were age, gender, hypertension, diabetes mellitus, previous cerebrovascular accident, smoking, anterior MI, wall motion score index, ejection fraction, LVMI, LV end systolic volume index and relative wall thickness. By multivariate logistic regression, age (odds ratio [OR], 1.086; 95% confidence interval [CI], 1.038–1.135; p50.001), smoking (OR, 3.032; 95% CI, 1.072–8.572, p ¼ 0.044), LVMI (OR, 1.023; 95% CI, 1.009–1.038, p50.001) and LV end systolic volume index (OR, 1.112; 95% CI, 1.043–1.186, p ¼ 0.002) were independent predictors for all-cause mortality. When the end points were analyzed based on LVH severity, all-cause mortality was significantly correlated with LVH severity (p ¼ 0.011, Figure 2). In a multivariate regression model, the severe LVH was independently associated with increased risk for all-cause mortality (OR, 5.110; 95% CI, 1.454–17.9, p ¼ 0.001, Figure 3).
Discussion The present study demonstrated the close relationship between LVH and increased rate of adverse clinical outcomes in patients with STEMI who underwent successful PCI. Survivors of a first STEMI face a substantial risk of further cardiovascular events. Accompanied by greater use of PCI and recommended medication, there have been significant decreases in in-hospital and 30-day mortality rates after STEMI (13). Even in the reperfusion era, risk stratification after AMI remains important (14). It is well-known that prognosis after AMI is predominantly influenced by severity of LV systolic dysfunction, presence of residual myocardial ischemia and extent of electrical instability (15). In the patients surviving acute events, these predictors are still valid. After the concept of early intervention in patients with STEMI, the number of patients with severe LV dysfunction, residual myocardial ischemia or lethal arrhythmia, have significantly decreased. Owing to early intervention, none of the patients have moderate or severe LV dysfunction in the present study. Although statistical difference was observed in the systolic function between groups, ejection fraction was not independent predictor for all-cause mortality in the present study. Thus, additional predictors after STEMI should be evaluated for improving survival in the clinical practice. In the present study, we demonstrated that LVH was associated Table 4. Multivariate logistic regression analysis of the presence of left ventricular hypertrophy for adverse outcomes. Variables MACEs All-cause mortality Recurrent MI HF TVR
Hazard ratio (95% CI) 1.60 2.37 0.498 1.61 1.193
(0.923–2.75) (1.096–5.123) (1.166–1.489) (0.991–2.615) (0.574–2.481)
p Value 0.094 0.028 0.212 0.055 0.636
MACEs, major adverse cardiovascular events; MI, myocardial infarction; HF, heart failure; TVR, target vessel revascularization; CI, confidence interval.
J.-S. Park et al.
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Figure 1. Kaplan–Meier survival curves for free of adverse outcomes in the left ventricular hypertrophy (LVH) group and the non-LVH group. MACEs, major adverse cardiovascular events; LVH, left ventricular hypertrophy; MI, myocardial infarction.
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DOI: 10.3109/10641963.2015.1047943
Left ventricular hypertrophy and prognosis
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Figure 2. Comparisons of clinical outcomes based on the severity of left ventricular hypertrophy. MACEs, major adverse cardiovascular events; MI, myocardial infarction; HF, heart failure; TVR, target vessel revascularization.
Figure 3. Multivariate logistic regression analysis for all-cause mortality. LVH, left ventricular hypertrophy; CI, confidence interval.
with adverse long-term outcomes in the 30-day survivors after STEMI. Although we could not find any relationship between LVH and occurrences of recurrent MI or readmission with HF due to low rates of recurrent MI and readmission with HF resulting from relatively good LV function and complete revascularization of the study population, LVH was independent predictor for all-cause mortality. Increased LVM results from volume and pressure overloads, or a combination of both (16). After STEMI, the acute loss of myocardium results in an abrupt increase in loading conditions that induce acute LV remodeling. Myocyte necrosis and the resultant increase in loading conditions initiate and subsequently modulate reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar (17). Chronically increased hemodynamic load could induce progressive interstitial fibrosis accounting for abnormal myocardial stiffness and ultimately ventricular dysfunction (18,19). The change of the complex fibrillar structure could induce early contractile dysfunction. In our previous study, we demonstrated, using the speckle tracking imaging, that the myocardial fibrotic process may affect the early contractile dysfunction of LV even in patients with normal EF (20). In the patients with LVH, the myocardial structural and functional alterations beyond EF representing
LV systolic function might affect the adverse long-term clinical outcomes in 30-day survivors after STEMI. Perivascular fibrosis with medial thickening of the intramyocardial coronary arteries is associated with LVH (18,19). Anatomic changes in the intramyocardial coronary arteries trigger an increase in the vascular resistance, which reduces the coronary flow reserve resulting in the inability to meet myocardial oxygen demands (21,22). Since LVH is associated with alterations of myocardial perfusion with a reduction of coronary flow reserve and vascular remodeling, residual myocardial ischemia could be present in patients with LVH even after restoration of epicardial coronary artery perfusion with successful reperfusion therapy. As more myocardial oxygen demand is present in severe LVH, severity of LVH was related with all-cause mortality in the present study. Arrhythmogenesis could be another possible mechanism. The increased risk of sudden cardiac death in the patients with LVH is thought to be due to malignant ventricular arrhythmia because of an increased frequency and complexity of ventricular ectopy and the increased vulnerability to inducible of arrhythmia (23). The electrical vulnerability resulting from LVH might also contribute to increased rates of cardiovascular events in the 30-day survivors after STEMI.
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There are several limitations to the present study. First, echocardiographic measuring LVM using linear measurements has potential limitations, based on the assumption that the LV is represented by a prolate ellipse (10). Although geometric deformation of LV was not considered, LVM obtained with this method has been well validated (11). Owing to the simplicity and the ease of the technique, echocardiographic measuring LVM using linear measurements was used in most of the previous large-scale clinical studies (1–3). Second, in the acute stage of STEMI, acute interstitial myocardial edema could be present (24). The calculated LVM might reflect both acute and chronic LV remodeling in the present study. The role of acute and chronic remodeling might be different in clinical outcomes. In present study, distinguish of acute and chronic LV remodeling was impossible due to technical limitation of echocardiography. Irrespective of acute or chronic remodeling, we evaluated the clinical impact of the LVH itself. To minimize this error, we enrolled patients who underwent echocardiography within 48 h of primary PCI. Third, we examined the prognostic significance of LVH only at baseline and did not evaluate the impact of their serial changes. The progression or regression of LVH might affect the clinical outcomes. Further studies would be needed to demonstrate the impact of change in LVH. Fourth, we failed to demonstrate the statistical difference between mild LVH and moderate LVH in all-cause mortality. Owing to uneven distribution of the study population, patients with moderate LVH were relatively small in the present study. As the severe LVH was independently associated with increased risk for all-cause mortality compared with the mild and moderate LVH, there might be LVH severity-dependent correlation with all-cause mortality. In the present study, LVH was associated with adverse clinical outcomes, especially all-cause mortality in patients with STEMI who underwent successful coronary intervention. Severity of LVH affected all-cause mortality, even after adjusting for other risk factors. Our findings suggest that baseline LVM could help to assess the prognosis of the patients with STEMI and a more intensive treatment might be needed for patients with LVH.
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Declaration of interest 20.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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ISSN: 1064-1963 (Print) 1525-6006 (Online) Journal homepage: http://www.tandfonline.com/loi/iceh20
Left ventricular hypertrophy on long-term cardiovascular outcomes in patients with STelevation myocardial infarction Jin-Sun Park, Jeong-Sook Shin, You-Hong Lee, Kyoung-Woo Seo, Byoung-Joo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk & Joon-Han Shin To cite this article: Jin-Sun Park, Jeong-Sook Shin, You-Hong Lee, Kyoung-Woo Seo, ByoungJoo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk & Joon-Han Shin (2015): Left ventricular hypertrophy on long-term cardiovascular outcomes in patients with ST-elevation myocardial infarction, Clinical and Experimental Hypertension, DOI: 10.3109/10641963.2015.1047943 To link to this article: http://dx.doi.org/10.3109/10641963.2015.1047943
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Date: 05 November 2015, At: 16:23
http://tandfonline.com/iceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, Early Online: 1–6 ! 2015 Taylor & Francis Group, LLC DOI: 10.3109/10641963.2015.1047943
Left ventricular hypertrophy on long-term cardiovascular outcomes in patients with ST-elevation myocardial infarction Jin-Sun Park, Jeong-Sook Shin, You-Hong Lee, Kyoung-Woo Seo, Byoung-Joo Choi, So-Yeon Choi, Myeong-Ho Yoon, Gyo-Seung Hwang, Seung-Jea Tahk, and Joon-Han Shin
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Department of Cardiology, Ajou University School of Medicine, Suwon, Korea
Abstract
Keywords
Background: Left ventricular hypertrophy (LVH) had been associated with increased adverse cardiovascular events in hypertensive patients. Prognostic significance of LVH in patients with ST-elevation myocardial infarction (STEMI) is not established. This study aimed to investigate prognostic impact of LVH on the patients with STEMI. Methods: We analyzed the data and clinical outcomes of 30-day survivors with STEMI who underwent successful coronary intervention from 2003 to 2009. Definition of LVH was LV mass index (LVMI) 4115 g/m2 in male and 495 g/m2 in female. Patients were classified into a LVH group and a non-LVH group. Occurrence of major adverse cardiovascular events (MACE; death, recurrent MI, target vessel revascularization (TVR)) within 5 years was evaluated. Results: We enrolled 418 patients and mean follow-up duration was 43 ± 17 months. Two hundred and fourteen patients (51%) had LVH. The survival of the patients with LVH was significantly worse than the patients without LVH (log-rank p ¼ 0.024). In a multivariate regression model, the presence of LVH was independently associated with increased risk for all-cause mortality (OR, 2.37; 95% CI, 1.096– 5.123, p ¼ 0.028). When the end points were analyzed based on LVH severity, all-cause mortality was significantly correlated with LVH severity (p ¼ 0.011). The severe LVH was independently associated with increased risk for all-cause mortality (OR, 5.110; 95% CI, 1.454–17.9, p ¼ 0.001). Conclusion: LVH was associated with increased rate of adverse clinical outcomes in 30-day survivors after STEMI, who underwent successful coronary intervention.
Left ventricular hypertrophy, myocardial infarction, prognosis History Received 7 February 2015 Revised 19 March 2015 Accepted 27 March 2015 Published online 6 July 2015
Background
Methods
Left ventricular hypertrophy (LVH) has been known as an independent predictor of adverse cardiovascular events in various etiologies (1–3). As hypertrophied myocardium is associated with a diastolic dysfunction (4), impaired LV performance (5,6) and arrhythmia (7,8), the differences of LV geometry are closely related with the prevalence of cardiovascular events. Most of the large scale studies were evaluated especially in hypertensive patients. In hypertensive patients, identifying LVH is considered important for stratification of cardiovascular risk (9). Prognostic significance of LVH in patients with ST-elevation myocardial infarction (STEMI) is not yet established. It might be reasonable to assume the structural changes accompanied by LVH could have adverse effect on both the infarct zone and the non-infarct zone with time. After STEMI, the clinical adverse effect of LVH has not been evaluated in these selected patients. This study aimed to investigate prognostic impact of LVH in patients with STEMI.
We consecutively enrolled 30-day survivors after STEMI, who underwent successful revascularization. Successful revascularization was defined as thrombolysis in myocardial infarction trial (TIMI) grade 3 flow and 530% residual stenosis in the infarct related artery after primary percutaneous coronary intervention (PCI). The medical records of all patients were retrospectively reviewed. This study was approved by the Ajou University Hospital Institutional Review Board (approval number: AJIRB-MED-MDB-13312). We excluded patients from the study if they had history of prior revascularization. We also excluded patients if the LV dysfunction was caused by any of the following: predisposing cardiomyopathy, severe valvular heart disease including symptomatic aortic stenosis, more than moderate aortic and mitral regurgitation. Transthoracic echocardiography was performed within 48 h of primary PCI. Left ventricular mass (LVM) was calculated according to Devereux’s formula (10), using linear measurements derived from two-dimensional echocardiography (11): LVM ¼ 0:8 f1:04 ½ðLV internal diastolic diameter þ posterior wall thickness in diastole
Correspondence: Joon-Han Shin, MD, Department of Cardiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 443-380, Korea. E-mail: [email protected]
þ septal wall thickness in diastoleÞ3 ðLV internal diastolic diameterÞ3 g þ 0:6g
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The LVM was indexed to body surface area. Definition of LVH was LV mass index (LVMI) 4115 g/m2 in male and 495 g/m2 in female based on the American Society of Echocardiography’s guidelines (11). All patients were divided into two groups according to the presence of LVH: a non-LVH group and a LVH group. To calculate LV ejection fraction, the biplane method of disks (modified Simpson’s rule), using standard 4- and 2-chamber apical views, was used (11). The end point of the present study was major adverse cardiac events (MACEs) within 5 years, including death, recurrent myocardial infarction (MI), target vessel revascularization (TVR) and hospitalization due to heart failure (HF). Recurrent myocardial infarction was defined according to the universal definition of MI (12). The TVR was defined as clinically indicated percutaneous or surgical revascularization of the index vessel during follow-up. At 5 years after index STEMI, follow-up data were obtained by reviewing medical records and/or telephone interview with patients. SPSS 13.0 statistical software package (SPSS, Chicago, IL) was used for all calculations. Data are shown as the mean ± standard deviation for continuous variables and as numbers and percentages for categorical variables. Data were compared using unpaired Student’s t test for continuous variables and Pearson’s chi-square test for categorical variables. Event-free survival analysis for patients in these groups was performed using the Kaplan–Meier method, and the differences between groups were assessed by the log-rank test. Multiple logistic regression analysis was performed to assess independent factors associated with MACEs. The parameters indicating LVH of patients were compared by MACEs, controlling for additional well-known predictors of MACEs. The clinical outcomes were also analyzed based on LVH severity. The severity of LVH was defined based on the American Society of Echocardiography’s guidelines (11). The severity of LVH was defined as following: mild LVH as LVMI 116–131 g/m2 in male and 96–108 g/m2 in female, moderate LVH as 132–148 g/m2 in male and 109–121 g/m2 in female and severe LVH as 149 g/m2 in male and 122 g/m2 in female. Multivariate logistic regression analysis was performed to assess the effect of LVH severity on clinical outcomes. Null hypotheses of no difference were rejected if p values were 50.05.
Results From 2003 to 2009, totally 418 patients (347 males, 56 ± 12 years) were enrolled. Mean LVMI of the 418 patients was 115 ± 30 g/m2. Baseline LVMI showed normal distribution. Two hundred and fourteen patients (51%) had LVH (170 males, 58 ± 12 year-old). In the LVH group, mean LVMI of males was 139 ± 24 g/m2 and that of females was 130 ± 29 g/m2. In the non-LVH group, mean LVMI of males was 94 ± 13 g/m2 and that of females was 81 ± 14 g/m2. Patients with LVH were older (58 ± 12 vs. 55 ± 11 year-old, p ¼ 0.005), had more history of hypertension and cerebrovascular accident (46 vs. 29%; p50.001 and 5 vs.1%; p ¼ 0.021, respectively) than the patients without LVH. The laboratory findings did not show any significant difference at index STEMI. There was no significant statistical difference in medical treatments between the two groups (Table 1).
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Angiographic and procedural data are listed in Table 2. Left anterior descending coronary artery disease was more common in patients with LVH (61 vs. 48%, p ¼ 0.008). Procedural type was similar in both groups. Drug eluting stents were most commonly implanted in these groups. The results of echocardiographic findings according to the groups are listed in Table 3. The parameters indicating LV chamber size, such as LV end diastolic dimension and LV end diastolic volume index, were significantly larger in the LVH group (52 ± 4 vs. 48 ± 5 mm, p ¼ 0.003, 55 ± 13 vs. 50 ± 11 mL/m2, p ¼ 0.015). The LV systolic function measured by ejection fraction in the LVH group was significantly reduced (51 ± 10 vs. 54 ± 10%, p ¼ 0.004). The regional LV function measured wall motion score index was also significantly worsened in the LVH group (1.57 ± 0.34 vs. 1.46 ± 0.32, p ¼ 0.005). Patients were followed up for 43 ± 17 months after index STEMI. The MACEs occurred in 70 patients (17%). Of 418 patients, 32 patients died (8%), 14 patients experienced recurrent MI (3%), 5 patients were readmitted with HF (1%) and 29 patients needed TVR (7%). Totally 158 (38%) patients were readmitted during follow-up. Of 158 patients, 60 patients were readmitted with non-cardiovascular reasons and the others were readmitted with cardiovascular reasons including MACEs, stroke (2 patients), peripheral arterial occlusive disease (1 patient) and aortic dissection (1 patient). In LVH group, more MACEs occurred (21 vs. 13%, p ¼ 0.036) and more patients died (11 vs. 4%, p ¼ 0.017). Among all-cause
Table 1. Baseline clinical characteristics.
Variables Age (year-old) Men, n (%) BMI (kg/m2) BSA (m2) Medical history Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Previous CVA, n (%) Smoking, n (%) eGFR (ml/min/1.73m2) LDL cholesterol (mg/dl) hs-CRP (mg/L) Killip class Killip class 3, n (%) Killip class 4, n (%) Medication at discharge Beta-blocker, n (%) RAS blocker, n (%) ACE inhibitor, n (%) ARB, n (%) CCB, n (%) statin, n (%) SBP at discharge (mmHg) DBP at discharge (mmHg)
Non-LVH group (n ¼ 204)
LVH group (n ¼ 214)
p Value
55 ± 11 177 (87) 24 ± 3 1.8 ± 0.2
58 ± 12 170 (79) 25 ± 3 1.7 ± 0.2
0.005 0.051 0.187 0.137
59 (29) 40 (20) 24 (12) 2 (1) 140 (69) 84 ± 24 107 ± 33 0.83 ± 1.81
99 (46) 50 (23) 15 (7) 11 (5) 129 (60) 80 ± 30 103 ± 36 1.7 ± 3.88
50.001 0.405 0.129 0.021 0.083 0.121 0.197 0.066
11 (5) 4 (2)
7 (3) 9 (4)
0.340 0.261
147 (72) 197 (97) 150 (74) 47 (23) 28 (14) 169 (83) 118 ± 16 71 ± 10
163 (76) 202 (94) 141 (66) 61 (29) 31 (15) 162 (76) 119 ± 16 72 ± 11
0.372 0.284 0.108 0.266 0.889 0.091 0.473 0.478
LVH, left ventricular hypertrophy; BMI, body mass index; BSA, body surface area; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; hs-CRP, high sensitivity C-reactive protein; RAS, renin-angiotensin system; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; SBP, systolic blood pressure; DBP, diastolic blood pressure.
Left ventricular hypertrophy and prognosis
DOI: 10.3109/10641963.2015.1047943
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mortality, there were 6 cardiac deaths (2 vs. 1%, p ¼ 0.373) and 6 non-cardiac deaths (2 vs. 1%, p ¼ 0.373). Although the other 20 deaths with unknown causes were suspected of sudden cardiac deaths, it was not confirmed by autopsy. Rates of recurrent MI, HF and TVR were not significantly different between the groups. In a multivariate regression model, the presence of LVH was independently associated with increased risk for all-cause mortality (p ¼ 0.028, Table 4). Event-free survival curves of patients according to LVH are reported in Figure 1. The event-free survival curves for freedom of MACE were not significantly different between the groups (log-rank p ¼ 0.232). The survival of patients with
Table 2. Baseline angiographic characteristics. Non-LVH group (n ¼ 204)
Variables Culprit lesion LAD, n (%) LCX, n (%) RCA, n (%) LM, n (%) Coronary Artery Disease 1 Vessel disease, n (%) 2 Vessel disease, n (%) 3 Vessel disease, n (%) PCI Thrombectomy only, n (%) POBA, n (%) BMS, n (%) DES, n (%)
98 16 88 2
(48) (8) (43) (1)
95 (47) 66 (32) 43 (21) 3 3 16 184
(2) (2) (8) (90)
LVH group (n ¼ 214) 131 13 68 1
p Value
(61) (6) (32) (0.5)
0.008 0.565 0.02 0.615
99 (46) 79 (37) 36 (17)
1.000 0.356 0.317
1 4 26 185
(0.5) (2) (12) (86)
0.362 1.000 0.192 0.287
LVH, left ventricular hypertrophy; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; LM, left main artery; PCI, primary coronary intervention; POBA, plain old balloon angioplasty; BMS, bare metal stent; DES, drug eluting stent.
Table 3. Baseline echocardiographic characteristics.
Variables
Non-LVH group (n ¼ 204)
LVH group (n ¼ 214)
p Value
LVEDD (mm) LVESD (mm) IVST (mm) PWT (mm) RWT LVEDV (mL) LVESV (mL) LVEDVI (mL/m2) LVESVI (mL/m2) LVEF (%) LV mass (g) LVMI (g/m2) WMSI
48 ± 5 32 ± 9 10 ± 2 10 ± 1 0.41 ± 0.09 88 ± 19 44 ± 14 50 ± 11 25 ± 8 54 ± 10 162 ± 30 92 ± 14 1.46 ± 0.32
52 ± 4 34 ± 6 12 ± 2 12 ± 2 0.47 ± 0.08 95 ± 27 50 ± 28 55 ± 13 29 ± 9 51 ± 10 241 ± 53 137 ± 25 1.57 ± 0.34
0.003 5 0.001 5 0.001 5 0.001 5 0.001 0.08 0.043 0.015 0.016 0.004 5 0.001 5 0.001 0.005
LVH, left ventricular hypertrophy; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; IVST, interventricular septal thickness at end diastole; PWT, posterior wall thickness at end diastole; RWT, relative wall thickness; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVEDVI, left ventricular end diastolic volume index; LVESVI, left ventricular end systolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; WMSI, wall motion score index.
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LVH was significantly worse than patients without LVH (log-rank p ¼ 0.024). The parameters indicating LVH of patients were compared between the groups by all-cause mortality, in addition to the well-known predictors of MACEs. In the regression model, variables were age, gender, hypertension, diabetes mellitus, previous cerebrovascular accident, smoking, anterior MI, wall motion score index, ejection fraction, LVMI, LV end systolic volume index and relative wall thickness. By multivariate logistic regression, age (odds ratio [OR], 1.086; 95% confidence interval [CI], 1.038–1.135; p50.001), smoking (OR, 3.032; 95% CI, 1.072–8.572, p ¼ 0.044), LVMI (OR, 1.023; 95% CI, 1.009–1.038, p50.001) and LV end systolic volume index (OR, 1.112; 95% CI, 1.043–1.186, p ¼ 0.002) were independent predictors for all-cause mortality. When the end points were analyzed based on LVH severity, all-cause mortality was significantly correlated with LVH severity (p ¼ 0.011, Figure 2). In a multivariate regression model, the severe LVH was independently associated with increased risk for all-cause mortality (OR, 5.110; 95% CI, 1.454–17.9, p ¼ 0.001, Figure 3).
Discussion The present study demonstrated the close relationship between LVH and increased rate of adverse clinical outcomes in patients with STEMI who underwent successful PCI. Survivors of a first STEMI face a substantial risk of further cardiovascular events. Accompanied by greater use of PCI and recommended medication, there have been significant decreases in in-hospital and 30-day mortality rates after STEMI (13). Even in the reperfusion era, risk stratification after AMI remains important (14). It is well-known that prognosis after AMI is predominantly influenced by severity of LV systolic dysfunction, presence of residual myocardial ischemia and extent of electrical instability (15). In the patients surviving acute events, these predictors are still valid. After the concept of early intervention in patients with STEMI, the number of patients with severe LV dysfunction, residual myocardial ischemia or lethal arrhythmia, have significantly decreased. Owing to early intervention, none of the patients have moderate or severe LV dysfunction in the present study. Although statistical difference was observed in the systolic function between groups, ejection fraction was not independent predictor for all-cause mortality in the present study. Thus, additional predictors after STEMI should be evaluated for improving survival in the clinical practice. In the present study, we demonstrated that LVH was associated Table 4. Multivariate logistic regression analysis of the presence of left ventricular hypertrophy for adverse outcomes. Variables MACEs All-cause mortality Recurrent MI HF TVR
Hazard ratio (95% CI) 1.60 2.37 0.498 1.61 1.193
(0.923–2.75) (1.096–5.123) (1.166–1.489) (0.991–2.615) (0.574–2.481)
p Value 0.094 0.028 0.212 0.055 0.636
MACEs, major adverse cardiovascular events; MI, myocardial infarction; HF, heart failure; TVR, target vessel revascularization; CI, confidence interval.
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Figure 1. Kaplan–Meier survival curves for free of adverse outcomes in the left ventricular hypertrophy (LVH) group and the non-LVH group. MACEs, major adverse cardiovascular events; LVH, left ventricular hypertrophy; MI, myocardial infarction.
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DOI: 10.3109/10641963.2015.1047943
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Figure 2. Comparisons of clinical outcomes based on the severity of left ventricular hypertrophy. MACEs, major adverse cardiovascular events; MI, myocardial infarction; HF, heart failure; TVR, target vessel revascularization.
Figure 3. Multivariate logistic regression analysis for all-cause mortality. LVH, left ventricular hypertrophy; CI, confidence interval.
with adverse long-term outcomes in the 30-day survivors after STEMI. Although we could not find any relationship between LVH and occurrences of recurrent MI or readmission with HF due to low rates of recurrent MI and readmission with HF resulting from relatively good LV function and complete revascularization of the study population, LVH was independent predictor for all-cause mortality. Increased LVM results from volume and pressure overloads, or a combination of both (16). After STEMI, the acute loss of myocardium results in an abrupt increase in loading conditions that induce acute LV remodeling. Myocyte necrosis and the resultant increase in loading conditions initiate and subsequently modulate reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar (17). Chronically increased hemodynamic load could induce progressive interstitial fibrosis accounting for abnormal myocardial stiffness and ultimately ventricular dysfunction (18,19). The change of the complex fibrillar structure could induce early contractile dysfunction. In our previous study, we demonstrated, using the speckle tracking imaging, that the myocardial fibrotic process may affect the early contractile dysfunction of LV even in patients with normal EF (20). In the patients with LVH, the myocardial structural and functional alterations beyond EF representing
LV systolic function might affect the adverse long-term clinical outcomes in 30-day survivors after STEMI. Perivascular fibrosis with medial thickening of the intramyocardial coronary arteries is associated with LVH (18,19). Anatomic changes in the intramyocardial coronary arteries trigger an increase in the vascular resistance, which reduces the coronary flow reserve resulting in the inability to meet myocardial oxygen demands (21,22). Since LVH is associated with alterations of myocardial perfusion with a reduction of coronary flow reserve and vascular remodeling, residual myocardial ischemia could be present in patients with LVH even after restoration of epicardial coronary artery perfusion with successful reperfusion therapy. As more myocardial oxygen demand is present in severe LVH, severity of LVH was related with all-cause mortality in the present study. Arrhythmogenesis could be another possible mechanism. The increased risk of sudden cardiac death in the patients with LVH is thought to be due to malignant ventricular arrhythmia because of an increased frequency and complexity of ventricular ectopy and the increased vulnerability to inducible of arrhythmia (23). The electrical vulnerability resulting from LVH might also contribute to increased rates of cardiovascular events in the 30-day survivors after STEMI.
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There are several limitations to the present study. First, echocardiographic measuring LVM using linear measurements has potential limitations, based on the assumption that the LV is represented by a prolate ellipse (10). Although geometric deformation of LV was not considered, LVM obtained with this method has been well validated (11). Owing to the simplicity and the ease of the technique, echocardiographic measuring LVM using linear measurements was used in most of the previous large-scale clinical studies (1–3). Second, in the acute stage of STEMI, acute interstitial myocardial edema could be present (24). The calculated LVM might reflect both acute and chronic LV remodeling in the present study. The role of acute and chronic remodeling might be different in clinical outcomes. In present study, distinguish of acute and chronic LV remodeling was impossible due to technical limitation of echocardiography. Irrespective of acute or chronic remodeling, we evaluated the clinical impact of the LVH itself. To minimize this error, we enrolled patients who underwent echocardiography within 48 h of primary PCI. Third, we examined the prognostic significance of LVH only at baseline and did not evaluate the impact of their serial changes. The progression or regression of LVH might affect the clinical outcomes. Further studies would be needed to demonstrate the impact of change in LVH. Fourth, we failed to demonstrate the statistical difference between mild LVH and moderate LVH in all-cause mortality. Owing to uneven distribution of the study population, patients with moderate LVH were relatively small in the present study. As the severe LVH was independently associated with increased risk for all-cause mortality compared with the mild and moderate LVH, there might be LVH severity-dependent correlation with all-cause mortality. In the present study, LVH was associated with adverse clinical outcomes, especially all-cause mortality in patients with STEMI who underwent successful coronary intervention. Severity of LVH affected all-cause mortality, even after adjusting for other risk factors. Our findings suggest that baseline LVM could help to assess the prognosis of the patients with STEMI and a more intensive treatment might be needed for patients with LVH.
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Declaration of interest 20.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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