- Email: [email protected]
Ventricular septal defect complicating acute myocardial infarction—still an unsolved problem in the invasive treatment era
Cardiovascular Pathology 20 (2011) 93 – 98
Original Article
Ventricular septal defect complicating acute myocardial infarction—still an unsolved problem in the invasive treatment era Anna Ledakowicz-Polak⁎, Łukasz Polak, Marzenna Zielińska Cardiology Clinic, First Department of Cardiology and Cardiosurgery, Medical University of Lodz, Lodz, Poland Received 6 October 2009; received in revised form 19 November 2009; accepted 11 January 2010
Abstract Background: Post-acute myocardial infarction (AMI) ventricular septal defect (VSD) is a rare but catastrophic complication. The aim of study was to delineate the incidence and risk factors of VSD in patients after AMI treated with successful primary percutaneous coronary intervention (pPCI). Methods and results: In the years 2004–2006, a total of 1835 patients with AMI underwent successful pPCI in our hospital. Thirteen patients (0.71%) developed VSD after pPCI. Mean time of occurrence of VSD was 24.46±9.32 h. Patients with VSD had longer time from the AMI onset to pPCI vs. patients without VSD (7.77±2.83 vs. 4.49±4.45, Pb.001). In the VSD group, most of the patients were nonsmokers, had arterial hypertension, and had no previous history of coronary artery disease (CAD). Neither group differed in administered antiplatelet therapy. According to univariate log-regression analysis, the presence of VSD was strongly associated with age N70 years (OR=4.66; P=.007), female gender (OR=5.73; P=.004), anterior infarction (OR=3.86; P=.04), single-vessel CAD (OR=3.74; P=.03), body mass index (BMI) b25 (OR=2.98; P=.04), and left ventricular wall hypertrophy (OR=3.39; P=.03). Conclusions: Our study demonstrated that the incidence of VSD after AMI appears to have declined in patients treated with pPCI. The pathomechanism of VSD in the invasive treatment era is the consequence of several processes and needs further investigation. Advanced age, female gender, anterior infarction, single-vessel CAD, left ventricular wall hypertrophy, and low BMI are strong risk factors of this complication after AMI, which remain invariable over the years. © 2011 Elsevier Inc. All rights reserved. Keywords: Acute myocardial infarction; Ventricular septal defect
1. Introduction Over the past decade, it has been demonstrated that early diagnosis and treatment of acute coronary syndromes improved clinical outcome and shortened the time of hospitalization. The contemporary strategy of this therapy is focused on primary percutaneous coronary intervention (pPCI) of infarct-related artery using balloon angioplasty and stent implantation [1]. Despite these advances ventricular septal defect (VSD) is still a rare but catastrophic mechanical
Funding for this work was provided fully by the authors. The authors do not report any conflict of interest regarding this work. ⁎ Corresponding author. First Department of Cardiology and Cardiosurgery, Sterling University Hospital, Medical University of Lodz, Sterlinga 1/3, 91-425 Lodz, Poland. Tel.: +48 42 6364471; fax: +48 42 6364471. E-mail address: [email protected] (A. Ledakowicz-Polak). 1054-8807/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2010.01.008
complication after acute myocardial infarction (AMI) and it carries an extremely high mortality rate [2–4]. Notwithstanding autopsy studies in the prethrombolytic era revealing the 11% incidence rate of myocardial free wall rupture after AMI, VSD was much less common and occurred at a rate of approximately 1–2% [2,5]. The GUSTO-I trial demonstrated that use of thrombolytic agents seems to have diminished the incidence of VSD to about 0.2% [3]. Several reports demonstrated that pPCI can further reduce the risk of VSD after AMI [4,6,7]. In the prethrombolytic era, VSD occurred most often during the first week after AMI, with a mean time of 3 to 5 days after symptoms onset [2,8,9]. In contrast, most VSDs associated with thrombolytic therapy were diagnosed in the first 24 h after treatment [3,10]. VSD is a serious complication of AMI that generally produces progressive circulatory failure, rapid clinical state deterioration, and almost instantaneous death. Cardiogenic
94
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
shock and severe left ventricular failure are the most important factors determining the outcome. Principal treatment of VSD consists of emergency surgical intervention after rapid stabilization with inotropic agents and, if necessary, the use of intra-aortic balloon counterpulsation [11,12]. In selected patients, percutaneous closure of VSD can be an alternative or a bridge to surgical repair, especially in patients with multi-organ failure or uncertain neurological status [13]. Despite multiple improvements in medical and surgical techniques, both early and long-term prognosis after AMIrelated VSD still remain unsatisfactory. Therefore, the aim of our study was to delineate the incidence and the potential risk factors of VSD in patients with ST-elevation myocardial infarction (STEMI) treated with successful pPCI. Another important objective of the present study was to evaluate the potential pathomechanisms leading to VSD in the invasive treatment era.
2. Material and methods 2.1. Study population The study group comprised 1835 consecutive patients admitted to Sterling University Hospital in Lodz with STEMI during the time period from January 2004 to December 2006 within an emergency treatment scheme. Among this group of patients, 13 developed VSD complicating the AMI course. All patients were treated with angiographically successful pPCI with stent implantation (in majority of them also with abciximab infusion) within 12 h after symptoms onset. The diagnosis of STEMI was confirmed using the contemporary definition of AMI including typical clinical symptoms, ST-segment elevation ≥1 mm in two inferior or lateral leads or ≥2 mm in more than two precordial leads, and a documented elevation of cardiac biomarkers (troponin T, creatinine kinase-MB fraction). All patients underwent extensive diagnostic evaluation to establish the underlying cardiovascular disease and risk factors. VSD was diagnosed by physical examination and 2-D echocardiography with color Doppler function assessing left ventricular systolic function [including ejection fraction (EF)], location and character of VSD (disrupted ventricular septum with left-toright shunt), Doppler pressure gradient, and systolic pulmonary artery pressure. Informed consent was obtained from each patient included, as well as approval of the study protocol from the local ethics committee. 2.2. Statistical analysis In the study, continuous variables are presented as means±S.D. Comparisons between groups were performed using the Whitney–Mann test and χ2 analysis for continuous
and categorical variables, respectively. Univariate logistic regression analysis was used to identify independent predictors of septum rupture in all patients. Statistical significance was assumed at a P value of b.05. 3. Results 3.1. Patients' characteristics regarding both demographic and interview-based data A total of 1835 patients with STEMI treated with angiographically successful pPCI with stent implantation were included in the study. There were 523 (28.5%) women and 1312 (71.5%) men with a mean age of 66.6±11 years. Of those patients, 13 (0.71%) developed VSD in the early period after AMI. Mean time of occurrence of VSD in our group was 24.46±9.32 h. There were no significant differences regarding presence of hypertension and diabetes, and previous history of smoking and coronary artery disease (CAD) between patients with and without VSD. However, in the VSD group most of the patients were nonsmokers (76.9%), had arterial hypertension (76.9%), and had no previous history of CAD (69.2%). Patients with this complication were also significantly older (72.08±9.09 vs. 61.19±11.73, P=.0007) and had lower BMI (21.7±2.52 vs. 27.1±2.96, P=.02). Furthermore, there was evident statistical difference regarding occurrence of female gender among VSD patients when compared to the non-VSD group. Patients' characteristics describing both demographic and interview-based data are summarized in Table 1. 3.2. Patients' characteristics regarding clinical and angiographic data On admission, patients from the VSD group presented remarkably higher heart rate (100.0±16.27 vs. 76.7±16.44, Pb.001) as well as had significantly lower values of both systolic (96.5±20.86 vs. 133.39±27.39, Pb.001) and diastolic blood pressure (60.0±15.28 vs. 81.84±14.34, Pb.001). Taking into account such a low blood pressure, only two patients were treated with angiotensin-converting enzyme inhibitors within the first day of AMI.
Table 1 Demographic and interview-based data of patients with and without VSD
Age Female, n (%) Diabetes Hypertension Smokers BMI (kg/m2) History of CAD, n (%) History of CAD (months)
VSD (+), n=13
VSD (−), n=1822
P
72.08±9.09 9 (69.2) 7 (53.9) 10 (76.9) 3 (23.1) 21.7±2.52 4 (30.8) 8.61±17.8
61.19±11.73 514 (28.2) 583 (32) 926 (50.8) 1020 (56) 27.1±2.96 859 (47.1) 19.9±42.9
.0007 .003 NS NS NS .02 NS NS
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
95
Table 3 Independent predictors of ventricular septal defect Age N70 years Female gender Anterior infarction Single-vessel CAD BMI b25 Left ventricular wall hypertrophy
Fig. 1. The correlation between time from the AMI onset to pPCI and abciximab infusion in VSD (−) and VSD (+) groups.
Additionally, patients with VSD had relatively longer time from the AMI symptoms onset to pPCI compared to the non-VSD group (7.77±2.83 vs. 4.49±4.45, Pb.001). Moreover, patients with this complication evidently more frequently presented with single-vessel CAD than non-VSD patients (69.2% vs. 37.5%, P=.04). In the VSD group, there was also a higher prevalence of anterior AMI observed in comparison to non-VSD patients (76.9% vs. 44.1%, P=.04). Furthermore, the left anterior descending artery was revealed to be significantly more frequent as an infarctrelated artery in patients with a diagnosis of VSD (P=.01). In the VSD group, there was a higher incidence of total occlusion of infarct-related artery than in patients without VSD; however, this observation did not reach statistical significance. Neither group differed in administered antiplatelet therapy (including abciximab infusion). Moreover, in both groups there was no correlation between time from the AMI onset to pPCI and abciximab infusion (Fig. 1).
OR
95% CI
P
4.66 5.73 3.86 3.74 2.98 3.39
1.51–14.34 1.75–18.75 1.06–14.03 1.14–12.3 1.04–9.87 1.13–10.19
.007 .004 .04 .03 .04 .03
In the group of patients with VSD, EF was significantly lower than in patients without such defect (44.5±12.7% vs. 54.2±12.4%, P=.005). Additionally, the left ventricular hypertrophy was remarkably more often detected in the VSD group than in patients without this complication (46.2% vs. 18.4%, P=.03). Considering the incidence of cardiogenic shock, there was significantly higher appearance in individuals with diagnosis of VSD. Patients' characteristics describing clinical and angiographic data are presented in Table 2. 3.3. Thirty-day patient outcome Interventional procedures were performed in seven patients (six cases had emergency cardiosurgical intervention, and one patient underwent percutaneous VSD closure). Patients who were subject to interventional treatment had a 30-day mortality rate of 57.1% (n=4), whereas none of the medically treated individuals survived beyond 30 days. 3.4. Independent predictors of VSD According to results of univariate log-regression analysis, the presence of VSD was strongly associated with age N70 years (OR=4.66; P=.007), female gender (OR=5.73; P=.004), anterior infarction (OR=3.86; P=.04), single-vessel CAD (OR=3.74; P=.03), body mass index (BMI b25) (OR=2.98; P=.04), and left ventricular wall hypertrophy (OR=3.39; P=.03), respectively. Independent determinants of VSD are shown in Table 3.
Table 2 Clinical and angiographic characteristics of patients with and without VSD
Time from AMI onset to pPCI (h) Anterior infarction, n (%) Single vessel CAD LAD, n (%) RCA, n (%) Cx, n (%) LMS, n (%) Total occlusion of infarct-related artery Abciximab therapy EF (%) Left ventricular wall hypertrophy, n (%) Cardiogenic shock, n (%)
VSD (+), n=13
VSD (−), n=1822
P
7.77±2.83 10 (76.9) 9 (69.2) 10 (76.92) 3 (23.08) 0 0 12 (92.3) 7 (53.9) 44.5±12.7 6 (46.2) 9 (69.1)
4.49±4.45 810 (44.1) 684 (37.5) 776 (42.6) 774 (42.4) 262 (14.3) 10 (0.7) 1368 (75.1) 1001 (54.9) 54.2±12.4 336 (18.4) 122 (6.7)
.00002 .04 .04 .01 NS NS NS NS NS .005 .03 .000…
96
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
4. Discussion In spite of the contemporary approach in the treatment of STEMI, it is not possible to avoid all AMI-related complications including VSD. Results of our study confirmed that VSD complicating STEMI is a serious clinical problem with high mortality rate due to cardiogenic shock or prolonged hemodynamic imbalance. It seems that one of the most important risk factor of VSD is time from AMI symptoms onset to the pPCI. The angioplasty performed within 12 h minimizes the extent of myocardial necrosis, thus preserving left ventricular function. Our study demonstrates the incidence and risk factors of VSD in a selected group of patients with STEMI treated with angiographically successful pPCI in a single interventional cardiology center dedicated to the treatment of acute coronary syndromes in a large local area. Results from other studies confirm the concept that early and complete restoration of the infarct-related artery by either thrombolysis or pPCI reduces the incidence of VSD to below 1% [3,6,14]. This is also reflected in our own data where the abovementioned reduction rate reached 0.71%. Additionally, Yip et al. [6] proved that pPCI significantly decreases the risk of AMI-related VSD in comparison to late opening of the infarct-related artery. The important finding in our study is that patients with VSD had relatively longer time from the AMI onset to pPCI compared to the non-VSD group. Taking this data into consideration, further effort in STEMI treatment should be focused on shortening the time between diagnosis and coronary intervention. In our study, mean time of occurrence of VSD was 24.46±9.32 h after AMI onset. Our results are fairly consistent with previous published reports and indicate the trend towards sooner ventricular septal rupture occurrence than in the prethrombolytic era [3,6,15,16]. In the prethrombolytic era. it was reported that VSD formation occurred typically within a median time of 2–5 days after AMI [2,8,9]. More recently, it has been revealed that thrombolytic therapy evidently reduced the time from AMI onset to VSD appearance. Apart from the fact that thrombolytic therapy limits the infarct size, it may also promote hemorrhagic dissection in the myocardium, thus accelerating the onset of the septal rupture [3,17]. Furthermore, it was detected that regional bleeding contributes to accumulation of white blood cells with enhanced metalloproteinase activity, subsequently leading to collagen network damage [18]. The above observations raise questions about potential pathomechanisms leading to early diagnosis of VSD in patients treated with successful pPCI especially due to their simultaneous intensive antiplatelet therapy, including abciximab infusion. Despite the results of other study [19], stating that concomitant administration of glycoprotein IIb/ IIIa may accelerate the occurrence of early ventricular septal rupture most likely due to increased myocardial hemorrhage, our own data is not consistent with this hypothesis.
In our opinion, the pathomechanism of AMI-related VSD in the invasive treatment era is most probably related to rapid restoration of myocardial perfusion. Previous studies revealed that restoration of blood flow after transient ischemia can be associated with dramatic, deleterious events such as arrhythmias, enzyme release, or severe intramyocardial hemorrhage. The above changes were interpreted as manifestations of additional injury coexisting with the process of reperfusion (called “reperfusion injury”) [20]. If successful, the reperfusion accelerates the generation of oxygen free radicals, increases the rate of inflammatory and healing processes, and aggravates the absorption of necrotic tissue by proteolytic enzymes in the infarct area. This, in turn, leads to thinning and softening of the necrotic zone and also to decreased tensile strength of the myocardial fibers [6]. A new view of lethal reperfusion injury revealed that the largest fraction of cardiomyocyte death occurs during the first minutes and hours of the reflow process [20,21]. Therefore reduction of reperfusion injury based on treatments targeting the previously mentioned mechanisms appears to be the next step to minimize the risk of complications after AMI treated with successful pPCI. It is noteworthy in our study that majority of patients with VSD had no previous history of CAD. Additionally, unlike in other studies [2,6,22], in 69% of patients the angiogram revealed single-vessel artery disease with predominance of LAD. Furthermore, in most cases the infarct-related artery was totally occluded. This suggests that the pathophysiology of AMI-related VSD involves sudden, severe ischemia, which, in turn, leads to extensive myocardial necrosis. Moreover, the patients with singlevessel CAD and short history of ischemia rarely develop small natural vessel bypass and collateral circulation. Therefore, AMI in these patients leads to larger heart injury, promoting post-infarction wall weakness with no collateral flow protection. In fact, as demonstrated by other authors [2,3,6,9], we also observed a predominance of anterior AMI in the VSD group. In the VSD group, 78% of patients had a history of arterial hypertension, but the differences in the occurrence of this disease in both study groups were not significant. The hypertension is connected with echocardiographically confirmed left ventricular wall hypertrophy, especially of the septum wall. The changes in myocardium structure during uncontrolled long-lasting hypertension can lead to rupture predisposition after AMI and ischemia [3,6]. The abovementioned findings are most probably due to pathomorphologic changes occurring in the myocardium of individuals with hypertension. Interestingly, the patients in our study who developed VSD had relatively low values of blood pressure on admission. Considering the fact that diastolic blood pressure determines coronary flow, its low values may contribute to a higher extent of myocardial necrosis leading to subsequent occurrence of VSD [23,24].
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
Undoubtedly, the pathomechanism of AMI-related VSD is more complex. According to findings from basic science research, genetic factors may also predispose to cardiac rupture [25]. Furthermore, in the occurrence of this complication the coexistence of several risk factors, which is sometimes unavoidable, plays an important role. The above observation is proved by the interesting result in our study that female gender was the strongest independent predictor of AMI-related VSD. Unfortunately, the mechanism by which female patients have an excess risk for this complication remains unclear. One hypothesis is based on a concept that, in women, the rupture is attributable to more susceptible collagen framework and to differences in the collagen matrix within the infarcted myocardium [26]. Additionally, advanced age has been found to put patients at increased risk for adverse outcomes after AMI [3,6]. In accordance with previous studies, we also proved that old age may be an independent factor of AMI-related VSD. These findings add further information to the hypothesis that aging of the myocardial structure and its changes can promote the risk of septal rupture. Furthermore, the responsiveness of the aged heart to stress is altered with a concomitant attenuation of endogenous protective mechanism, thus increasing vulnerability to injury. The fundamental processes leading to cardiac senescence and to loss of myocardial capacity of self-protection have not been fully understood yet [27]. It is also worth noting that, in our study, patients with VSD had significantly lower BMI values than those without this complication. Our findings are comparable with those of other studies, but it remains uncertain why patients with lower BMI are more likely to experience AMI-related VSD [3,6,28]. It has been reported recently that lean patients who are undergoing PCI are also at increased risk of in-hospital complications and cardiac death. The potential underlying pathomechanism by which low BMI patients have excess of complications and poor outcome after AMI may be related to both the excessive anticoagulation and more frequent presence of severe, noncardiovascular underlying diseases, including cancer or respiratory disorders in lean patients [28]. Nevertheless, the influence of lean body constitution on poor outcome after AMI and the explanation of its potential underlying pathomechanisms need further investigation.
5. Conclusions Our study demonstrated that the incidence of VSD after AMI appears to have declined in patients treated with pPCI. The pathomechanism of VSD in the invasive treatment era is surely the consequence of several processes acting together and needs further investigation. Advanced age, female gender, anterior infarction, single-vessel CAD, left ventricular wall hypertrophy, and low BMI are strong risk factors of this serious complication after AMI, which remain invariable over the years.
97
References [1] Van de W, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909–45. [2] Topaz O, Taylor AL. Interventricular septal rupture complicating acute myocardial infarction: from pathophysiologic features to the role of invasive and noninvasive diagnostic modalities in current management. Am J Med 1992;93:683–8. [3] Crenshaw BS, Granger CB, Birnbaum Y, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. Circulation 2000;101: 27–32. [4] Figueras J, Alcalde O, Barrabes JA, et al. Changes in hospital mortality rates in 425 patients with acute ST-elevation myocardial infarction and cardiac rupture over a 30-year period. Circulation 2008; 118:2783–9. [5] Heitmiller R, Jacobs ML, Daggett WM. Surgical management of postinfarction ventricular septal rupture. Ann Thorac Surg 1986;41: 683–91. [6] Yip HK, Fang CJ, Tsai KT, et al. The potential impact of primary percutaneous coronary intervention on ventricular septal rupture complicating acute myocardial infarction. Chest 2004;125: 1622–8. [7] Moreno R, Lopez-Sendoz J, Garcia E, et al. Primary angioplasty reduces the risk of left ventricular free wall rupture compared with thrombolysis in patients with acute myocardial infarction. J Am Coll Cardiol 2002;39:598–603. [8] Bedynek J, Fenoglio J, McAllister H. Rupture of the interventricular septum as a complication of myocardial infarction. Am Heart J 1979; 97:773–81. [9] Edwards SB, Edward WD, Edwards JE. Ventricular septal rupture complicating acute myocardial infarction: identification of simple and complex types in 53 autopsies hearts. Am J Cardiol 1984;54: 1201–5. [10] Menon V, Webb JG, Hillis LD, et al. Outcome and profile of ventricular septal rupture with cardiogenic shock after myocardial infarction: a report from the SHOCK Trial Registry. J Am Coll Cardiol 2000;36(Suppl A):1110–6. [11] Mantovani V, Mariscalco G, Leva C, Blanzola C, Sala A. Surgical repair of post-infarction ventricular septal defect: 19 years of experience. Int J Cardiol 2006;108:202–6. [12] Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999;34:890–911. [13] Maltais S, Ibrahim R, Basmadjian AJ, et al. Postinfarction ventricular septal defects: towards a new treatment algorithm? Ann Thorac Surg 2009;87:687–93. [14] Simes RJ, Topol EJ, Holmes DR, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation 1995;91: 1923–8. [15] Kamran M, Attari M, Webber G. Ventricular septal defect complicating an acute myocardial infarction. Circulation 2005;112:e337–8. [16] Rhydwen GR, Charman S, Schofield PM. Influence of thrombolytic therapy on the patterns of ventricular septal rupture after acute myocardial infarction. Postgrad Med J 2002;78:408–12. [17] Becker RC, Charlesworth A, Wilcox RG, et al. Cardiac rupture associated with thrombolytic therapy: impact of time to treatment in the Late Assessment of Thrombolytic Efficacy (LATE) study. J Am Coll Cardiol 1995;25:1063–8.
98
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
[18] Gao XM, Xu Q, Kiriazis H, Dart AM, Du XJ. Mouse model of postinfarct ventricular rupture: time course, strain- and gender-dependency, tensile strength, and histopathology. Cardiovasc Res 2005;65:469–77. [19] Arnold JR, Timperley J, Mitchell A, Westaby S, Ormerod O. Ventricular septal rupture following abciximab infusion. Eur J Echocardiogr 2008;9:60–2. [20] Garcia-Dorado D. Myocardial reperfusion injury: a new view. Cardiovasc Res 2004;61:363–4. [21] Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008;88: 581–609. [22] Poulsen SH, Praestholm M, Munk K, Wierup P, Egeblad H, NielsenKudsk JE. Ventricular septal rupture complicating acute myocardial infarction: clinical characteristics and contemporary outcome. Ann Thorac Surg 2008;85:1591–6. [23] Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP, INDANA Project Steering Committee. INdividual Data ANalysis of Antihypertensive intervention. J-Shaped relationship between blood pressure and
[24]
[25]
[26]
[27] [28]
mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 2002;136:438–48. D'Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study. BMJ 1991; 303:385–9. van den Borne SW, Narula J, Voncken JW, et al. Defective intercellular adhesion complex in myocardium predisposes to infarct rupture in humans. J Am Coll Cardiol 2008;51:2184–92. Vakili BA, Kaplan RC, Brown DL. Sex-based differences in early mortality of patients undergoing primary angioplasty for first acute myocardial infarction. Circulation 2001;104:3034–8. Jahangir A, Sagar S, Terzic A. Aging and cardioprotection. J Appl Physiol 2007;103:2120–8. Gruberg L, Weissman NJ, Waksman R, et al. The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox? J Am Coll Cardiol 2002;39: 578–84.
Original Article
Ventricular septal defect complicating acute myocardial infarction—still an unsolved problem in the invasive treatment era Anna Ledakowicz-Polak⁎, Łukasz Polak, Marzenna Zielińska Cardiology Clinic, First Department of Cardiology and Cardiosurgery, Medical University of Lodz, Lodz, Poland Received 6 October 2009; received in revised form 19 November 2009; accepted 11 January 2010
Abstract Background: Post-acute myocardial infarction (AMI) ventricular septal defect (VSD) is a rare but catastrophic complication. The aim of study was to delineate the incidence and risk factors of VSD in patients after AMI treated with successful primary percutaneous coronary intervention (pPCI). Methods and results: In the years 2004–2006, a total of 1835 patients with AMI underwent successful pPCI in our hospital. Thirteen patients (0.71%) developed VSD after pPCI. Mean time of occurrence of VSD was 24.46±9.32 h. Patients with VSD had longer time from the AMI onset to pPCI vs. patients without VSD (7.77±2.83 vs. 4.49±4.45, Pb.001). In the VSD group, most of the patients were nonsmokers, had arterial hypertension, and had no previous history of coronary artery disease (CAD). Neither group differed in administered antiplatelet therapy. According to univariate log-regression analysis, the presence of VSD was strongly associated with age N70 years (OR=4.66; P=.007), female gender (OR=5.73; P=.004), anterior infarction (OR=3.86; P=.04), single-vessel CAD (OR=3.74; P=.03), body mass index (BMI) b25 (OR=2.98; P=.04), and left ventricular wall hypertrophy (OR=3.39; P=.03). Conclusions: Our study demonstrated that the incidence of VSD after AMI appears to have declined in patients treated with pPCI. The pathomechanism of VSD in the invasive treatment era is the consequence of several processes and needs further investigation. Advanced age, female gender, anterior infarction, single-vessel CAD, left ventricular wall hypertrophy, and low BMI are strong risk factors of this complication after AMI, which remain invariable over the years. © 2011 Elsevier Inc. All rights reserved. Keywords: Acute myocardial infarction; Ventricular septal defect
1. Introduction Over the past decade, it has been demonstrated that early diagnosis and treatment of acute coronary syndromes improved clinical outcome and shortened the time of hospitalization. The contemporary strategy of this therapy is focused on primary percutaneous coronary intervention (pPCI) of infarct-related artery using balloon angioplasty and stent implantation [1]. Despite these advances ventricular septal defect (VSD) is still a rare but catastrophic mechanical
Funding for this work was provided fully by the authors. The authors do not report any conflict of interest regarding this work. ⁎ Corresponding author. First Department of Cardiology and Cardiosurgery, Sterling University Hospital, Medical University of Lodz, Sterlinga 1/3, 91-425 Lodz, Poland. Tel.: +48 42 6364471; fax: +48 42 6364471. E-mail address: [email protected] (A. Ledakowicz-Polak). 1054-8807/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2010.01.008
complication after acute myocardial infarction (AMI) and it carries an extremely high mortality rate [2–4]. Notwithstanding autopsy studies in the prethrombolytic era revealing the 11% incidence rate of myocardial free wall rupture after AMI, VSD was much less common and occurred at a rate of approximately 1–2% [2,5]. The GUSTO-I trial demonstrated that use of thrombolytic agents seems to have diminished the incidence of VSD to about 0.2% [3]. Several reports demonstrated that pPCI can further reduce the risk of VSD after AMI [4,6,7]. In the prethrombolytic era, VSD occurred most often during the first week after AMI, with a mean time of 3 to 5 days after symptoms onset [2,8,9]. In contrast, most VSDs associated with thrombolytic therapy were diagnosed in the first 24 h after treatment [3,10]. VSD is a serious complication of AMI that generally produces progressive circulatory failure, rapid clinical state deterioration, and almost instantaneous death. Cardiogenic
94
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
shock and severe left ventricular failure are the most important factors determining the outcome. Principal treatment of VSD consists of emergency surgical intervention after rapid stabilization with inotropic agents and, if necessary, the use of intra-aortic balloon counterpulsation [11,12]. In selected patients, percutaneous closure of VSD can be an alternative or a bridge to surgical repair, especially in patients with multi-organ failure or uncertain neurological status [13]. Despite multiple improvements in medical and surgical techniques, both early and long-term prognosis after AMIrelated VSD still remain unsatisfactory. Therefore, the aim of our study was to delineate the incidence and the potential risk factors of VSD in patients with ST-elevation myocardial infarction (STEMI) treated with successful pPCI. Another important objective of the present study was to evaluate the potential pathomechanisms leading to VSD in the invasive treatment era.
2. Material and methods 2.1. Study population The study group comprised 1835 consecutive patients admitted to Sterling University Hospital in Lodz with STEMI during the time period from January 2004 to December 2006 within an emergency treatment scheme. Among this group of patients, 13 developed VSD complicating the AMI course. All patients were treated with angiographically successful pPCI with stent implantation (in majority of them also with abciximab infusion) within 12 h after symptoms onset. The diagnosis of STEMI was confirmed using the contemporary definition of AMI including typical clinical symptoms, ST-segment elevation ≥1 mm in two inferior or lateral leads or ≥2 mm in more than two precordial leads, and a documented elevation of cardiac biomarkers (troponin T, creatinine kinase-MB fraction). All patients underwent extensive diagnostic evaluation to establish the underlying cardiovascular disease and risk factors. VSD was diagnosed by physical examination and 2-D echocardiography with color Doppler function assessing left ventricular systolic function [including ejection fraction (EF)], location and character of VSD (disrupted ventricular septum with left-toright shunt), Doppler pressure gradient, and systolic pulmonary artery pressure. Informed consent was obtained from each patient included, as well as approval of the study protocol from the local ethics committee. 2.2. Statistical analysis In the study, continuous variables are presented as means±S.D. Comparisons between groups were performed using the Whitney–Mann test and χ2 analysis for continuous
and categorical variables, respectively. Univariate logistic regression analysis was used to identify independent predictors of septum rupture in all patients. Statistical significance was assumed at a P value of b.05. 3. Results 3.1. Patients' characteristics regarding both demographic and interview-based data A total of 1835 patients with STEMI treated with angiographically successful pPCI with stent implantation were included in the study. There were 523 (28.5%) women and 1312 (71.5%) men with a mean age of 66.6±11 years. Of those patients, 13 (0.71%) developed VSD in the early period after AMI. Mean time of occurrence of VSD in our group was 24.46±9.32 h. There were no significant differences regarding presence of hypertension and diabetes, and previous history of smoking and coronary artery disease (CAD) between patients with and without VSD. However, in the VSD group most of the patients were nonsmokers (76.9%), had arterial hypertension (76.9%), and had no previous history of CAD (69.2%). Patients with this complication were also significantly older (72.08±9.09 vs. 61.19±11.73, P=.0007) and had lower BMI (21.7±2.52 vs. 27.1±2.96, P=.02). Furthermore, there was evident statistical difference regarding occurrence of female gender among VSD patients when compared to the non-VSD group. Patients' characteristics describing both demographic and interview-based data are summarized in Table 1. 3.2. Patients' characteristics regarding clinical and angiographic data On admission, patients from the VSD group presented remarkably higher heart rate (100.0±16.27 vs. 76.7±16.44, Pb.001) as well as had significantly lower values of both systolic (96.5±20.86 vs. 133.39±27.39, Pb.001) and diastolic blood pressure (60.0±15.28 vs. 81.84±14.34, Pb.001). Taking into account such a low blood pressure, only two patients were treated with angiotensin-converting enzyme inhibitors within the first day of AMI.
Table 1 Demographic and interview-based data of patients with and without VSD
Age Female, n (%) Diabetes Hypertension Smokers BMI (kg/m2) History of CAD, n (%) History of CAD (months)
VSD (+), n=13
VSD (−), n=1822
P
72.08±9.09 9 (69.2) 7 (53.9) 10 (76.9) 3 (23.1) 21.7±2.52 4 (30.8) 8.61±17.8
61.19±11.73 514 (28.2) 583 (32) 926 (50.8) 1020 (56) 27.1±2.96 859 (47.1) 19.9±42.9
.0007 .003 NS NS NS .02 NS NS
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
95
Table 3 Independent predictors of ventricular septal defect Age N70 years Female gender Anterior infarction Single-vessel CAD BMI b25 Left ventricular wall hypertrophy
Fig. 1. The correlation between time from the AMI onset to pPCI and abciximab infusion in VSD (−) and VSD (+) groups.
Additionally, patients with VSD had relatively longer time from the AMI symptoms onset to pPCI compared to the non-VSD group (7.77±2.83 vs. 4.49±4.45, Pb.001). Moreover, patients with this complication evidently more frequently presented with single-vessel CAD than non-VSD patients (69.2% vs. 37.5%, P=.04). In the VSD group, there was also a higher prevalence of anterior AMI observed in comparison to non-VSD patients (76.9% vs. 44.1%, P=.04). Furthermore, the left anterior descending artery was revealed to be significantly more frequent as an infarctrelated artery in patients with a diagnosis of VSD (P=.01). In the VSD group, there was a higher incidence of total occlusion of infarct-related artery than in patients without VSD; however, this observation did not reach statistical significance. Neither group differed in administered antiplatelet therapy (including abciximab infusion). Moreover, in both groups there was no correlation between time from the AMI onset to pPCI and abciximab infusion (Fig. 1).
OR
95% CI
P
4.66 5.73 3.86 3.74 2.98 3.39
1.51–14.34 1.75–18.75 1.06–14.03 1.14–12.3 1.04–9.87 1.13–10.19
.007 .004 .04 .03 .04 .03
In the group of patients with VSD, EF was significantly lower than in patients without such defect (44.5±12.7% vs. 54.2±12.4%, P=.005). Additionally, the left ventricular hypertrophy was remarkably more often detected in the VSD group than in patients without this complication (46.2% vs. 18.4%, P=.03). Considering the incidence of cardiogenic shock, there was significantly higher appearance in individuals with diagnosis of VSD. Patients' characteristics describing clinical and angiographic data are presented in Table 2. 3.3. Thirty-day patient outcome Interventional procedures were performed in seven patients (six cases had emergency cardiosurgical intervention, and one patient underwent percutaneous VSD closure). Patients who were subject to interventional treatment had a 30-day mortality rate of 57.1% (n=4), whereas none of the medically treated individuals survived beyond 30 days. 3.4. Independent predictors of VSD According to results of univariate log-regression analysis, the presence of VSD was strongly associated with age N70 years (OR=4.66; P=.007), female gender (OR=5.73; P=.004), anterior infarction (OR=3.86; P=.04), single-vessel CAD (OR=3.74; P=.03), body mass index (BMI b25) (OR=2.98; P=.04), and left ventricular wall hypertrophy (OR=3.39; P=.03), respectively. Independent determinants of VSD are shown in Table 3.
Table 2 Clinical and angiographic characteristics of patients with and without VSD
Time from AMI onset to pPCI (h) Anterior infarction, n (%) Single vessel CAD LAD, n (%) RCA, n (%) Cx, n (%) LMS, n (%) Total occlusion of infarct-related artery Abciximab therapy EF (%) Left ventricular wall hypertrophy, n (%) Cardiogenic shock, n (%)
VSD (+), n=13
VSD (−), n=1822
P
7.77±2.83 10 (76.9) 9 (69.2) 10 (76.92) 3 (23.08) 0 0 12 (92.3) 7 (53.9) 44.5±12.7 6 (46.2) 9 (69.1)
4.49±4.45 810 (44.1) 684 (37.5) 776 (42.6) 774 (42.4) 262 (14.3) 10 (0.7) 1368 (75.1) 1001 (54.9) 54.2±12.4 336 (18.4) 122 (6.7)
.00002 .04 .04 .01 NS NS NS NS NS .005 .03 .000…
96
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
4. Discussion In spite of the contemporary approach in the treatment of STEMI, it is not possible to avoid all AMI-related complications including VSD. Results of our study confirmed that VSD complicating STEMI is a serious clinical problem with high mortality rate due to cardiogenic shock or prolonged hemodynamic imbalance. It seems that one of the most important risk factor of VSD is time from AMI symptoms onset to the pPCI. The angioplasty performed within 12 h minimizes the extent of myocardial necrosis, thus preserving left ventricular function. Our study demonstrates the incidence and risk factors of VSD in a selected group of patients with STEMI treated with angiographically successful pPCI in a single interventional cardiology center dedicated to the treatment of acute coronary syndromes in a large local area. Results from other studies confirm the concept that early and complete restoration of the infarct-related artery by either thrombolysis or pPCI reduces the incidence of VSD to below 1% [3,6,14]. This is also reflected in our own data where the abovementioned reduction rate reached 0.71%. Additionally, Yip et al. [6] proved that pPCI significantly decreases the risk of AMI-related VSD in comparison to late opening of the infarct-related artery. The important finding in our study is that patients with VSD had relatively longer time from the AMI onset to pPCI compared to the non-VSD group. Taking this data into consideration, further effort in STEMI treatment should be focused on shortening the time between diagnosis and coronary intervention. In our study, mean time of occurrence of VSD was 24.46±9.32 h after AMI onset. Our results are fairly consistent with previous published reports and indicate the trend towards sooner ventricular septal rupture occurrence than in the prethrombolytic era [3,6,15,16]. In the prethrombolytic era. it was reported that VSD formation occurred typically within a median time of 2–5 days after AMI [2,8,9]. More recently, it has been revealed that thrombolytic therapy evidently reduced the time from AMI onset to VSD appearance. Apart from the fact that thrombolytic therapy limits the infarct size, it may also promote hemorrhagic dissection in the myocardium, thus accelerating the onset of the septal rupture [3,17]. Furthermore, it was detected that regional bleeding contributes to accumulation of white blood cells with enhanced metalloproteinase activity, subsequently leading to collagen network damage [18]. The above observations raise questions about potential pathomechanisms leading to early diagnosis of VSD in patients treated with successful pPCI especially due to their simultaneous intensive antiplatelet therapy, including abciximab infusion. Despite the results of other study [19], stating that concomitant administration of glycoprotein IIb/ IIIa may accelerate the occurrence of early ventricular septal rupture most likely due to increased myocardial hemorrhage, our own data is not consistent with this hypothesis.
In our opinion, the pathomechanism of AMI-related VSD in the invasive treatment era is most probably related to rapid restoration of myocardial perfusion. Previous studies revealed that restoration of blood flow after transient ischemia can be associated with dramatic, deleterious events such as arrhythmias, enzyme release, or severe intramyocardial hemorrhage. The above changes were interpreted as manifestations of additional injury coexisting with the process of reperfusion (called “reperfusion injury”) [20]. If successful, the reperfusion accelerates the generation of oxygen free radicals, increases the rate of inflammatory and healing processes, and aggravates the absorption of necrotic tissue by proteolytic enzymes in the infarct area. This, in turn, leads to thinning and softening of the necrotic zone and also to decreased tensile strength of the myocardial fibers [6]. A new view of lethal reperfusion injury revealed that the largest fraction of cardiomyocyte death occurs during the first minutes and hours of the reflow process [20,21]. Therefore reduction of reperfusion injury based on treatments targeting the previously mentioned mechanisms appears to be the next step to minimize the risk of complications after AMI treated with successful pPCI. It is noteworthy in our study that majority of patients with VSD had no previous history of CAD. Additionally, unlike in other studies [2,6,22], in 69% of patients the angiogram revealed single-vessel artery disease with predominance of LAD. Furthermore, in most cases the infarct-related artery was totally occluded. This suggests that the pathophysiology of AMI-related VSD involves sudden, severe ischemia, which, in turn, leads to extensive myocardial necrosis. Moreover, the patients with singlevessel CAD and short history of ischemia rarely develop small natural vessel bypass and collateral circulation. Therefore, AMI in these patients leads to larger heart injury, promoting post-infarction wall weakness with no collateral flow protection. In fact, as demonstrated by other authors [2,3,6,9], we also observed a predominance of anterior AMI in the VSD group. In the VSD group, 78% of patients had a history of arterial hypertension, but the differences in the occurrence of this disease in both study groups were not significant. The hypertension is connected with echocardiographically confirmed left ventricular wall hypertrophy, especially of the septum wall. The changes in myocardium structure during uncontrolled long-lasting hypertension can lead to rupture predisposition after AMI and ischemia [3,6]. The abovementioned findings are most probably due to pathomorphologic changes occurring in the myocardium of individuals with hypertension. Interestingly, the patients in our study who developed VSD had relatively low values of blood pressure on admission. Considering the fact that diastolic blood pressure determines coronary flow, its low values may contribute to a higher extent of myocardial necrosis leading to subsequent occurrence of VSD [23,24].
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
Undoubtedly, the pathomechanism of AMI-related VSD is more complex. According to findings from basic science research, genetic factors may also predispose to cardiac rupture [25]. Furthermore, in the occurrence of this complication the coexistence of several risk factors, which is sometimes unavoidable, plays an important role. The above observation is proved by the interesting result in our study that female gender was the strongest independent predictor of AMI-related VSD. Unfortunately, the mechanism by which female patients have an excess risk for this complication remains unclear. One hypothesis is based on a concept that, in women, the rupture is attributable to more susceptible collagen framework and to differences in the collagen matrix within the infarcted myocardium [26]. Additionally, advanced age has been found to put patients at increased risk for adverse outcomes after AMI [3,6]. In accordance with previous studies, we also proved that old age may be an independent factor of AMI-related VSD. These findings add further information to the hypothesis that aging of the myocardial structure and its changes can promote the risk of septal rupture. Furthermore, the responsiveness of the aged heart to stress is altered with a concomitant attenuation of endogenous protective mechanism, thus increasing vulnerability to injury. The fundamental processes leading to cardiac senescence and to loss of myocardial capacity of self-protection have not been fully understood yet [27]. It is also worth noting that, in our study, patients with VSD had significantly lower BMI values than those without this complication. Our findings are comparable with those of other studies, but it remains uncertain why patients with lower BMI are more likely to experience AMI-related VSD [3,6,28]. It has been reported recently that lean patients who are undergoing PCI are also at increased risk of in-hospital complications and cardiac death. The potential underlying pathomechanism by which low BMI patients have excess of complications and poor outcome after AMI may be related to both the excessive anticoagulation and more frequent presence of severe, noncardiovascular underlying diseases, including cancer or respiratory disorders in lean patients [28]. Nevertheless, the influence of lean body constitution on poor outcome after AMI and the explanation of its potential underlying pathomechanisms need further investigation.
5. Conclusions Our study demonstrated that the incidence of VSD after AMI appears to have declined in patients treated with pPCI. The pathomechanism of VSD in the invasive treatment era is surely the consequence of several processes acting together and needs further investigation. Advanced age, female gender, anterior infarction, single-vessel CAD, left ventricular wall hypertrophy, and low BMI are strong risk factors of this serious complication after AMI, which remain invariable over the years.
97
References [1] Van de W, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909–45. [2] Topaz O, Taylor AL. Interventricular septal rupture complicating acute myocardial infarction: from pathophysiologic features to the role of invasive and noninvasive diagnostic modalities in current management. Am J Med 1992;93:683–8. [3] Crenshaw BS, Granger CB, Birnbaum Y, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. Circulation 2000;101: 27–32. [4] Figueras J, Alcalde O, Barrabes JA, et al. Changes in hospital mortality rates in 425 patients with acute ST-elevation myocardial infarction and cardiac rupture over a 30-year period. Circulation 2008; 118:2783–9. [5] Heitmiller R, Jacobs ML, Daggett WM. Surgical management of postinfarction ventricular septal rupture. Ann Thorac Surg 1986;41: 683–91. [6] Yip HK, Fang CJ, Tsai KT, et al. The potential impact of primary percutaneous coronary intervention on ventricular septal rupture complicating acute myocardial infarction. Chest 2004;125: 1622–8. [7] Moreno R, Lopez-Sendoz J, Garcia E, et al. Primary angioplasty reduces the risk of left ventricular free wall rupture compared with thrombolysis in patients with acute myocardial infarction. J Am Coll Cardiol 2002;39:598–603. [8] Bedynek J, Fenoglio J, McAllister H. Rupture of the interventricular septum as a complication of myocardial infarction. Am Heart J 1979; 97:773–81. [9] Edwards SB, Edward WD, Edwards JE. Ventricular septal rupture complicating acute myocardial infarction: identification of simple and complex types in 53 autopsies hearts. Am J Cardiol 1984;54: 1201–5. [10] Menon V, Webb JG, Hillis LD, et al. Outcome and profile of ventricular septal rupture with cardiogenic shock after myocardial infarction: a report from the SHOCK Trial Registry. J Am Coll Cardiol 2000;36(Suppl A):1110–6. [11] Mantovani V, Mariscalco G, Leva C, Blanzola C, Sala A. Surgical repair of post-infarction ventricular septal defect: 19 years of experience. Int J Cardiol 2006;108:202–6. [12] Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999;34:890–911. [13] Maltais S, Ibrahim R, Basmadjian AJ, et al. Postinfarction ventricular septal defects: towards a new treatment algorithm? Ann Thorac Surg 2009;87:687–93. [14] Simes RJ, Topol EJ, Holmes DR, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation 1995;91: 1923–8. [15] Kamran M, Attari M, Webber G. Ventricular septal defect complicating an acute myocardial infarction. Circulation 2005;112:e337–8. [16] Rhydwen GR, Charman S, Schofield PM. Influence of thrombolytic therapy on the patterns of ventricular septal rupture after acute myocardial infarction. Postgrad Med J 2002;78:408–12. [17] Becker RC, Charlesworth A, Wilcox RG, et al. Cardiac rupture associated with thrombolytic therapy: impact of time to treatment in the Late Assessment of Thrombolytic Efficacy (LATE) study. J Am Coll Cardiol 1995;25:1063–8.
98
A. Ledakowicz-Polak et al. / Cardiovascular Pathology 20 (2011) 93–98
[18] Gao XM, Xu Q, Kiriazis H, Dart AM, Du XJ. Mouse model of postinfarct ventricular rupture: time course, strain- and gender-dependency, tensile strength, and histopathology. Cardiovasc Res 2005;65:469–77. [19] Arnold JR, Timperley J, Mitchell A, Westaby S, Ormerod O. Ventricular septal rupture following abciximab infusion. Eur J Echocardiogr 2008;9:60–2. [20] Garcia-Dorado D. Myocardial reperfusion injury: a new view. Cardiovasc Res 2004;61:363–4. [21] Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008;88: 581–609. [22] Poulsen SH, Praestholm M, Munk K, Wierup P, Egeblad H, NielsenKudsk JE. Ventricular septal rupture complicating acute myocardial infarction: clinical characteristics and contemporary outcome. Ann Thorac Surg 2008;85:1591–6. [23] Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP, INDANA Project Steering Committee. INdividual Data ANalysis of Antihypertensive intervention. J-Shaped relationship between blood pressure and
[24]
[25]
[26]
[27] [28]
mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 2002;136:438–48. D'Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study. BMJ 1991; 303:385–9. van den Borne SW, Narula J, Voncken JW, et al. Defective intercellular adhesion complex in myocardium predisposes to infarct rupture in humans. J Am Coll Cardiol 2008;51:2184–92. Vakili BA, Kaplan RC, Brown DL. Sex-based differences in early mortality of patients undergoing primary angioplasty for first acute myocardial infarction. Circulation 2001;104:3034–8. Jahangir A, Sagar S, Terzic A. Aging and cardioprotection. J Appl Physiol 2007;103:2120–8. Gruberg L, Weissman NJ, Waksman R, et al. The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox? J Am Coll Cardiol 2002;39: 578–84.