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CLINICAL STUDY: HEART FAILURE

Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure

Antonio Abbate, MD^*,*, Giuseppe G. L. Biondi-Zoccai, MD^*, Rossana Bussani, MD, Aldo Dobrina, MD, Debora Camilot, MD, Florinda Feroce, MD, Raffaele Rossiello, MD, Feliciano Baldi, MD, Furio Silvestri, MD, Luigi M. Biasucci, MD, FACC^* and Alfonso Baldi, MD

^* Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
Department of Pathologic Anatomy, University of Trieste, Trieste, Italy
Department of Physiology and Pathology, University of Trieste, Trieste, Italy
Department of Biochemistry and Biophysics "F. Cedrangolo", Section of Pathologic Anatomy, Second University of Naples, Naples, Italy

Manuscript received July 2, 2002; revised manuscript received November 1, 2002, accepted November 19, 2002.

^* Reprint requests and correspondence: Dr. Antonio Abbate, Catholic University of Rome, Institute of Cardiology, Largo A. Gemelli, 8, Rome, RM 00168, Italy.
abbatea{at}yahoo.com

	Abstract

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OBJECTIVES: The purpose of this study was to evaluate a potential correlation between apoptotic rate (AR), post-infarction left ventricular (LV) remodeling, and clinical characteristics in subjects who died late (10 days) after an acute myocardial infarction (AMI) with evidence of persistent occlusion of the infarct-related artery at autopsy.

BACKGROUND: Apoptosis contributes to myocardiocyte loss in cardiac disease and may have a pathophysiologic role in post-infarction LV remodeling.

METHODS: The AR was calculated at the site of infarction and in remote unaffected LV regions, using co-localization of in situ end labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3, in 14 subjects who died within two months after AMI. Correlation between AR and clinical characteristics such as age, site of AMI, transmural extension, multivessel coronary disease, and signs and/or symptoms of heart failure (HF), at the time of initial hospitalization for AMI or subsequently before death, was assessed using non-parametric statistical tests. Parameters of LV remodeling including diameters, free wall thickness, diameter-to-wall-thickness ratio, and mass were measured at gross examination at autopsy. Values are expressed as median (interquartile range).

RESULTS: Among clinical variables, early symptomatic post-infarction HF (9 cases, 64%) was associated with nearly fourfold increased AR at the site of infarction (26.2% [24.5% to 28.8%] vs. 6.4% [1.9% to 13.3%], p = 0.001). Moreover, AR both at the site of infarction and in unaffected regions was significantly correlated with parameters of progressive LV remodeling (p < 0.05).

CONCLUSIONS: Our data show that in patients dying 10 days after AMI, myocardial apoptosis is strongly associated with and may be a major determinant of unfavorable LV remodeling and early symptomatic post-infarction HF.

Abbreviations and Acronyms   AEC   3-amino-9-ethylcarbazide   AMI   acute myocardial infarction   AR   apoptotic rate   DNA   deoxyribonucleic acid   HF   heart failure   IRA   infarct-related artery   LV   left ventricle/ventricular   PCNA   proliferating cell nuclear antigen   TUNEL   terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling

The goal of this study was to evaluate the potential correlation between AR at the time of death (both at the site of infarction and in unaffected LV areas), clinical characteristics of the subjects in the days preceding death (including the occurrence of signs or symptoms of HF), and macroscopic signs of LV remodeling in subjects dying late (10 to 62 days) after AMI, all with persistent occlusion of the infarct-related artery (IRA) occlusion (as IRA status may itself influence AR) (16).

	Methods

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We selected, at routine postmortem examination, 14 subjects according to the following inclusion criteria: 1) death due to nontraumatic cause, occurring 10 to 62 days after an AMI; 2) persistent occlusion of the IRA documented at postmortem examination; and 3) no clinical or pathologic evidence of re-infarction. We collected data on initial hospitalization for AMI in all cases. Site of infarction, IRA, initial treatment (including fibrinolytic treatment for ST-segment elevation AMI), and past medical history were obtained from clinical charts. Clinical and laboratory data regarding the days preceding death were available in all cases. Re-infarction was excluded on the basis of clinical, laboratory, and pathology data. Patients were considered to be suffering from symptomatic HF if one or more of the following signs, symptoms, or clinical characteristics had been present in the days before death: dyspnea at rest (not due to concomitant pulmonary or musculoskeletal disorders) associated with jugular venous distension, third heart sound and/or pulmonary rales, peripheral edema, elevated pulmonary wedge pressure and/or central venous pressure, reduced cardiac output, need of intravenous inotropic support and significant (>4.5 kg) decrease in weight after diuretic use (Stages C or D and New York Heart Association functional class IV according to American College of Cardiology/American Heart Association guidelines for the evaluation and management of HF [17]). Treatment by insulin or oral antidiabetic agents was used to define diabetics.

Pathology.   Gross examination of the hearts was performed to measure various LV parameters, to define the infarcted area, and to confirm total IRA occlusion. Cardiac diameters were calculated at the atrioventricular section, and LV free wall thickness was measured at the median third of the unaffected free wall (usually the posterior wall). Infarcts were defined as large infarcts if an area of transmural necrosis involving more than one LV wall (approximately 30% of the circumference) was found at pathology. Left ventricular hypertrophy was defined as LV wall thickness 15 mm in unaffected LV regions. A transverse diameter-to-free wall thickness 9 was used to define LV dilation. The combination of hypertrophy and dilation was defined as eccentric hypertrophy. Pulmonary, liver, and/or renal congestion and signs of renal and/or intestinal hypoperfusion were considered pathologic evidence of HF as indirect signs of chronic congestive state and circulatory failure (4,18).

Tissue specimens were obtained at sites of infarction (Fig. 1A) and in unaffected regions of the LV remote from the infarcted area. Specimens were fixed in 10% paraformaldehyde. In situ end labeling of deoxyribonucleic acid (DNA) fragmentation terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) was performed using the Apoptag kit (Oncor, Gaithersburg, Maryland), according to the supplier’s instructions (Fig. 1B). For immunohistochemistry, the sections already treated for the TUNEL assay were heated and then incubated with antibodies against muscle actin (mouse monoclonal anti-human actin HHF35 from Dako, Carpinteria, California; dilution 1:50) and caspase-3 (rabbit polyclonal anti-human caspase-3 from Upstate Biotechnology, Lake Placid, New York; dilution 1:100) and visualized by the streptavidin-biotin system (Dako), using either 3-amino-9-ethylcarbazide (AEC) or diaminobenzidine as the final chromogen (Figs. 1C and 1D). Myocardiocytes were defined as apoptotic if co-localization of markers of DNA fragmentation (TUNEL) and caspase-3 was evident (Fig. 1D), according to the fact that high immunohistochemical expression of caspase-3 detected with the antibody used in this study is present in myocardiocytes undergoing apoptosis, co-localizes with TUNEL-positive myocardiocytes, and corresponds mostly to increased expression of its activated form (9,19,20). The AR was expressed as the ratio of the number of myocardiocytes co-expressing TUNEL and caspase-3 positivity on nucleated cells per field (250x). Muscle actin-negative cells as well as myocardiocytes co-expressing TUNEL positivity and specific staining for markers of DNA synthesis (proliferating cell nuclear antigen [PCNA]) (using mouse monoclonal anti-human PCNA PC10 antibody from Dako, dilution 1:100) and/or markers of transcription activity (ribonucleic acid splicing factor SC-35) (using mouse monoclonal anti SC-35 from Sigma, Milan, Italy; dilution 1:200) were not included in the cell count. TUNEL-negative/caspase-3-positive cells, although likely to be cells committed to apoptosis, were not considered to be apoptotic because caspase-3 activation may represent a reversible step in the apoptotic cascade (6). Suitable negative and positive controls for TUNEL and caspase-3 were performed, as defined elsewhere (9). Briefly, controls for TUNEL were performed as indicated by the supplier (using a normal female rodent mammary gland 3 to 5 days after weaning of rat pups for positive control and sham staining leaving out active terminal deoxynucleotidyl transferase but including proteinase K digestion to control for nonspecific incorporation of nucleotides or for nonspecific binding of enzyme-conjugate). A human lymph node was used as a control for activated caspase-3 (strong immunoreactivity was evident in the apoptotic-prone germinal center B-lymphocytes of the lymph node and not in the mantle zone). Moreover, negative controls indicating the non-interference of TUNEL and secondary antibodies were performed by leaving out the primary antibodies (actin, caspase-3, PCNA and SC-35 respectively).

View larger version (156K): [in this window] [in a new window]   Figure 1 Characterization of apoptotic myocardiocytes. (A) Hematoxylin/van Gieson stain. Site of recent infarction: reparative fibrosis, newly sprouted vessels, and granulation tissue (original magnification x500). (B) In situ end labeling of deoxyribonucleic acid (TUNEL) staining. Region of the left ventricle at the site of infarction: TUNEL-positive nuclei (brown) are evident (original magnification x500; 3-amino-9-ethylcarbazide [AEC], lightly counterstained with hematoxylin). (C) Double staining: nuclear staining for TUNEL and cytoplasmic staining for muscle actin. TUNEL-positive cells (brown nuclear staining) co-express cytoplasmic muscle actin (original magnification x600; AEC, lightly counterstained with hematoxylin). (D) Double staining: nuclear staining for TUNEL and cytoplasmic staining for caspase-3 (original magnification x600; AEC, lightly counterstained with hematoxylin).

	Results

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Clinical data.   Clinical characteristics of the patients are shown in Table 1. In particular, median time to death post AMI was 16 days. All patients had non-cardiac comorbidities at the time of death, which variably contributed to the outcome (i.e., upper and lower gastrointestinal bleeding, severe anemia, pulmonary infective infiltrates, stroke). Three patients (21%) died during the initial hospital admission (at day 10); the others were discharged from the hospital and subsequently readmitted before death. Seven patients had an anterior AMI, and four received fibrinolysis at the time of initial AMI. Nine patients (64%) had a diagnosis of HF at the time of initial hospitalization for AMI or subsequently before death, and five patients died late after AMI without clinical evidence of HF. None of the subjects had clinical or pathologic evidence of reinfarction (Table 1).

View larger version (17K): [in this window] [in a new window]   Figure 2 Myocardial apoptosis in subjects with early symptomatic post-infarction heart failure. Apoptotic rate at the site of the infarction was increased nearly fourfold in subjects with symptomatic heart failure at the time of initial hospitalization for acute myocardial infarction or subsequently before death versus the remaining subjects (26.2% [24.5% to 28.8%] vs. 6.4% [1.9% to 13.3%], p = 0.001). Column height = median value; vertical bar = interquartile range.

Apoptosis and cardiac remodeling.   Analysis of correlation between apoptosis and macroscopic signs of LV remodeling revealed a statistically significant link between AR at both sites (infarction and remote unaffected site) and macroscopic signs of cardiac remodeling (LV transverse and longitudinal diameters, free wall thickness, diameter-to-wall thickness ratio, and mass) (Table 2, Fig. 3).

View larger version (22K): [in this window] [in a new window]   Figure 3 Correlations between macroscopic signs of post-infarction left ventricular (LV) remodeling and apoptotic rate (AR) at the site of acute myocardial infarction and in remote unaffected LV regions. Correlation between AR at the site of infarction and LV longitudinal (A) and transverse (B) diameter, free wall thickness (C), transverse diameter-to-free wall thickness (D), and cardiac weight (E). Correlation between AR in remote regions and the same LV macroscopic parameters (F to L), respectively. Black and white dots represent subjects with (filled squares) and without (empty squares) early symptomatic post-infarction heart failure, respectively.

View larger version (23K): [in this window] [in a new window]   Figure 4 Myocardial apoptosis in progressive left ventricular (LV) remodeling. Increasing apoptotic rate (AR) in infarct (A) and remote sites (B) in progressive unfavorable LV remodeling. Column height = median value; vertical bar = interquartile range. p = 0.050 at Kruskal-Wallis three-way test for A, and p = 0.11 for B. No statistically significant differences were found comparing the three groups separately at Mann-Whitney, Bonferroni adjusted, two-way U test. *p = 0.014 for cases with compensatory hypertrophy (AR of 3.2% [0.5 to 12.0]) versus the other two groups characterized by LV dilation combined (AR of 26.0% [22.6 to 28.7]) (at Mann-Whitney U test). **p = 0.050 for cases with end-stage dilation (AR of 0.9% [0.7 to 1.1]) versus the other two groups with LV hypertrophy combined (AR of 0.4% [0.3 to 0.7]) (at Mann-Whitney U test).

	Discussion

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Saraste et al. (21) have shown that patients with more severe HF and rapid clinical progression had higher AR at the time of transplantation versus patients with slower progression. This correlation between AR and disease progression in dilated cardiomyopathy has been recently prospectively validated in a study by Metzger et al. (22) in patients undergoing partial ventriculectomy.

The association between apoptosis and unfavorable prognosis may be, at least in part, explained by a causal role of myocardiocyte apoptosis in the pathophysiology of progressive cardiac remodeling leading to cardiac and circulatory failure. Indeed, there is in our data a statistically relevant correlation between AR and gross parameters of LV remodeling, as LV cavity size. The latter is considered a strong independent clinical prognostic factor (23) and a potential surrogate end point for prognosis in patients with HF (24).

Moreover, AR correlated not only with macroscopic signs assessed at pathology but also with the signs and symptoms of decompensated HF before death. Interestingly, the occurrence of these features does not appear irrelevant in the clinical assessment of patients with HF, because it is associated with increased mortality independently from other clinical variables (such as LV ejection fraction) (25–28). Although speculative, it is possible that enhanced apoptosis may be responsible for a more rapid disease progression in patients showing unfavorable cardiac remodeling and symptomatic HF. It has been suggested that the peripheral circulation, more than cardiac performance, is responsible for the development of symptoms (29). In fact, it is difficult from morphologic examination of the heart to differentiate a damaged but compensated heart from one that is failing. This may suggest that peripheral neurohormonal rearrangements may be associated with more pronounced clinical presentation and may be responsible, at least in part, for progressive deterioration of HF (30).

Initial phases of cardiac remodeling are often characterized by compensatory cardiac and non-cardiac mechanisms. Left ventricular hypertrophy of the surviving portions of the heart is considered an initially effective compensatory phenomenon (3), characterized by a low-grade apoptosis and a more favorable prognosis when compared with LV dilation. Apoptosis may play a role in the transition from compensated concentric hypertrophy to decompensated eccentric hypertrophy (31–33).

Increased plasma norepinephrine levels are part of the peripheral neurohormonal rearrangements (30). Interestingly, they are associated with a worse prognosis (34), whereas treatment with beta-blockers favorably affects prognosis in patients with HF (35). Of note, beta₁-receptor agonism is associated with myocardiocyte apoptosis in vitro (36), and treatment with metoprolol significantly reduces myocardiocyte apoptosis in an experimental HF model in dogs (15). The same effects appears to be exerted by angiotensin II (34,37), whereas angiotensin-converting enzyme inhibitors modulate the unfavorable neurohormonal rearrangements (34), cardiac remodeling (38), and apoptosis (14) and improve symptoms and prognosis in HF.

Therefore, two forms of apoptosis appear to affect the course of post-infarction remodeling, both leading to unfavorable LV remodeling and symptomatic HF: ischemia-driven apoptosis at the site of recent infarction (7–10,13–15,21), and load-dependent or receptor-dependent apoptosis at sites remote from the ischemic area (11,32,33,36,37,39). An early article by Gottlieb et al. (40), being the first study to evaluate apoptosis in the ischemic heart, reported an increased AR in an ischemia-reperfusion model, suggesting that apoptosis was associated with reperfusion more than with hypoxia alone and supporting the concept that completion of the apoptotic cascade depends on the available energetic levels (6). However, subsequent studies have completed this scenario by showing that, although reperfusion after myocardial ischemia accelerates apoptosis in the non-salvageable myocardiocytes, reperfusion is also associated with a significantly lower total number of cells undergoing apoptosis, supporting an overall beneficial effect by reperfusion (41). Caspase-3 activation represents one of the terminal phases of the apoptotic cascade, thus representing a potential target for anti-apoptotic therapy. Although initial experimental studies using caspase inhibitors in animal models showed interesting results, clinical trials using such inhibitors are still ongoing (42).

Most studies investigating apoptosis in vivo or ex vivo, including the present study, however, suffer from the major drawback of selection bias. Indeed, the evaluation of subjects dying 10 to 62 days after AMI may have led to the selection of a group of patients with more adverse prognosis and extremely elevated AR, in comparison to the great majority of cases surviving several weeks and months after AMI. These considerations may explain the differences in AR in our samples when compared with animal models or with models of end-stage HF in patients undergoing cardiac transplantation, even if both of these models may suffer from inverse selection bias (6). As discussed by Sam et al. (11), the evaluation in animal models of only those individuals surviving until the established temporal end point for sacrifice may have led to underestimation of AR, as nearly 65% of the animals died spontaneously beforehand and therefore were not analyzed (11). Similarly, analysis of the hearts explanted from patients undergoing cardiac transplantation (12,21) may have not been able to assess AR in those patients with more severe HF who did not survive long enough to receive a cardiac transplant. In vivo validation of our data will therefore be necessary, and it would be extremely useful also to assess whether patients with increased myocardial apoptosis may be identified early through determination of clinical characteristics (such as signs of HF), of levels of plasma markers (such as soluble tumor necrosis factor receptors [43]), and/or of apoptosis-targeted molecular imaging such as myocardial perfusion scan using marked annexin V (44).

Conclusions.   Results in our data show that in patients with AMI dying 10 to 62 days after the infarction with persistent IRA occlusion at the time of death, apoptosis is strongly associated with, and may be a major determinant for developing, unfavorable LV remodeling and early symptomatic HF. A direct cause–effect link, however, cannot be assumed by our data, and further studies are required to define the precise mechanisms and impact of apoptosis on ischemic LV dysfunction, as well as potential applications in the development of improved diagnostic and therapeutic measures. Given the small sample size, the borderline statistical significance in some of the analyses performed, the possible confounding factors, and the unknown duration of the apoptotic cascade in human myocardiocytes, mechanistic and causal connections should be cautiously drawn.

	Acknowledgments

 
The authors wish to thank Dr. Di Trocchio Vera (University of Roma-Tre, Rome, Italy) for her editorial assistance with the manuscript and the illustrations.

	References

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