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Antti Saraste

Publications and source records attributed to Antti Saraste.

18 recordsLinked to original sources
PubMed2006

Cardiomyocyte apoptosis is related to left ventricular dysfunction and remodelling in dilated cardiomyopathy, but is not affected by growth hormone treatment.

BACKGROUND AND AIMS: Cardiomyocyte apoptosis (CA) is a common feature of end-stage heart failure. We examined whether CA is associated with cardiac dysfunction and remodelling in heart failure due to dilated cardiomyopathy and studied the effect of human growth hormone (hGH) on CA. METHODS AND RESULTS: We studied 38 patients, included in a phase III multi-center, randomised, double-blind and placebo-controlled trial of biosynthetic hGH treatment in dilated cardiomyopathy, at baseline and after 14 weeks treatment. Twenty-six patients received hGH and 12 received placebo. CA was quantified in endomyocardial biopsies using the TUNEL assay. CA correlated with left ventricular size (r=0.43, p=0.007). Compared to patients with CA below the median of 0.53%, patients with CA above the median had significantly larger left ventricular volumes and lower ejection fractions (EF) by echocardiography (median (interquartile range)) 200 ml (84) vs. 257 ml (134) and 27% (11) vs. 23% (9). Expression of the Fas receptor was associated with a high rate of CA. hGH treatment significantly increased serum IGF-1 levels, but it had no effect on CA or cardiac structure and function. CONCLUSION: CA is related to left ventricular enlargement and dysfunction in dilated cardiomyopathy. CA is not affected by short-term treatment with hGH.

Apoptosis↗
PubMed2006

Cardiomyocyte apoptosis and duration of aortic clamping in pig model of open heart surgery.

OBJECTIVE: Apoptotic cardiomyocyte death is induced during open heart surgery, but its determinants are poorly understood. Prolonged aortic clamping time is associated with adverse clinical outcomes. The purpose of this study was to determine whether occurrence of cardiomyocyte apoptosis is related to the duration of aortic clamping in experimental pig model of cardiac surgery with cardiopulmonary bypass. METHODS: The pigs (mean weight 29 +/- 1 kg) were randomly divided to undergo cardioplegic arrest for 60 (n = 4) or 90 (n = 4) min followed by reperfusion period of 120 min. Control group (n = 5) was connected to cardiopulmonary bypass for 120 min without cardioplegic arrest. Cardiomyocyte apoptosis was detected (TUNEL assay and immunohistochemical staining of active caspase-3) in left ventricular tissue samples obtained before ischemia and after the ischemia-reperfusion period. RESULTS: Apoptotic cardiomyocytes were found in all samples obtained after cardioplegic arrest and cardiopulmonary bypass alone with the TUNEL assay. The amount of apoptosis after the 120 min of cardiopulmonary bypass alone in the control group was 0.006 +/- 0.001%. Compared with this, cardiomyocyte apoptosis was increased after cardioplegic arrest. After 60 min of aortic cross-clamp the amount of apoptosis was 0.019 +/- 0.004% (p = 0.031). After 90 min of aortic cross-clamp the amount was 0.042 +/- 0.005% (p < 0.001) being significantly higher than after 60 min (p = 0.001). Aortic cross-clamp of 90 min also resulted in a detectable increase in caspase-3 activation when compared with controls. CONCLUSIONS: The occurrence of cardiomyocyte apoptosis increases with prolonged aortic clamping time during open heart surgery.

Animals↗
PubMed2006

Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study.

The objective of this study was to apply transthoracic Doppler echocardiography (TTDE) in mice to study coronary flow reserve (CFR), an index of coronary microvascular function, in mild and severe forms of experimental viral myocarditis. Regarding methodology, BALB/c mice were infected with cardiotropic coxsackieviruses causing either a mild (Nancy strain) or a severe (Woodruff strain) myocarditis. Left ventricular dimensions, fractional shortening, and CFR (ratio of left coronary artery flow velocity during maximal adenosine-induced vasodilatation to rest) were measured by TTDE before infection and again 1 or 2 wk after infection. As a result, the resting flow velocity did not change after infection. In contrast, CFR reduced significantly 1 wk after infection with either virus variant [from 2.5 (SD 0.3) to 1.4 (SD 0.1) in severe and from 2.4 (SD 0.4) to 2.1 (SD 0.3) in mild myocarditis], being significantly lower in the severe than mild myocarditis. CFR remained low in severe myocarditis 2 wk after infection. Fractional shortening decreased to the same levels 1 wk after infection with either virus variant [from 0.54 (SD 0.02) to 0.43 (SD 0.03) in severe and from 0.51 (SD 0.03) to 0.44 (SD 0.02) in mild myocarditis, P < 0.05]. However, 2 wk after infection, mice with severe myocarditis had enlarged left ventricles and lower fractional shortening [0.31 (SD 0.03)] than mice with mild myocarditis [0.47 (SD 0.02), P < 0.01]. In conclusion, CFR measured with TTDE is reduced in coxsackievirus myocarditis in mice. Low CFR is associated with progressive heart failure, indicating that dysfunction of coronary microcirculation is a determinant of poor outcome in viral myocarditis.

Animals↗
PubMed2006

Comparison of MRI and positron emission tomography for measuring myocardial perfusion reserve in healthy humans.

Myocardial perfusion reserve (MPR, defined as the ratio of the maximum myocardial blood flow (MBF) to the baseline) is an indicator of coronary artery disease and myocardial microvascular abnormalities. First-pass contrast-enhanced magnetic resonance imaging (CE-MRI) using gadolinium (Gd)-DTPA as a contrast agent (CA) has been used to assess MPR. Tracer kinetic models based on compartmental analysis of the CA uptake have been developed to provide quantitative measures of MBF by MRI. To study the accuracy of Gd-DTPA first-pass MRI and kinetic modeling for quantitative analysis of myocardial perfusion and MPR during dipyridamole infusion, we conducted a comparison with positron emission tomography (PET) in 18 healthy males (age = 40 +/- 14 years). Five planes were acquired at every second heartbeat with a 1.5T scanner using a saturation recovery turboFLASH sequence. A perfusion-related parameter, the unidirectional influx constant (Ki), was computed in three coronary artery territories. There was a significant correlation for both dipyridamole-induced flow (0.70, P = 0.001) and MPR (0.48, P = 0.04) between MRI and PET. However, we noticed that MRI provided lower MPR values compared to PET (2.5 +/- 1.0 vs. 4.3 +/- 1.8). We conclude that MRI supplemented with tracer kinetic modeling can be used to quantify myocardial perfusion.

Adult↗
PubMed2005

Cytomegalovirus infection of the heart is common in patients with fatal myocarditis.

BACKGROUND: Although enteroviruses and adenoviruses are considered to be the leading causes of the usually mild clinical myocarditis, little is known about the etiology of severe or fatal myocarditis. METHODS: We collected all available clinical records and myocardial autopsy samples for patients who had myocarditis recorded as the underlying cause of death in Finland during the period of 1970-1998. Findings for all available patients (20 men and 20 women; median age, 49 years) with myocarditis that fulfilled the Dallas criteria and who had sufficient data were included in the study. Twelve subjects who had died accidentally served as control subjects. Polymerase chain reaction (PCR) and in situ hybridization assays were used for detection of viral genomes (adenovirus, cytomegalovirus, enterovirus, human herpesvirus 6, influenza A and B viruses, parvovirus B19, and rhinovirus) in heart samples. RESULTS: Viral nucleic acids were found in the hearts of 17 patients (43%), including cytomegalovirus (15 patients), parvovirus B19 (4 patients), enterovirus (1 patient), and human herpesvirus 6 (1 patient). In 4 patients, cytomegalovirus DNA was found in addition to parvovirus B19 or enterovirus genomes. No adenoviruses, rhinoviruses, or influenza viruses were detected in this study of fatal myocarditis. In 67% of the patients for whom PCR was positive for cytomegalovirus, in situ hybridization revealed viral DNA in cardiomyocytes. Only 1 of these patients was immunocompromised. In the control group, only human herpesvirus 6 (1 subject) and parvovirus B19 (1 subject) DNA were detected. CONCLUSIONS: In this population-based study, cytomegalovirus was found to be the most common specific finding in immunocompetent patients with fatal myocarditis. This may have important clinical implications for the treatment of severe acute myocarditis.

Adolescent↗
PubMed2005

Cardiomyocyte apoptosis after antegrade and retrograde cardioplegia.

BACKGROUND: Retrograde cardioplegia alone is often used in aortic valve and aortic root surgery. Due to the differences in venous anatomy between the right and the left side of the heart, retrograde cardioplegia is associated with incomplete protection of the right side. Since some apoptotic cardiomyocyte death is inevitable during an open heart surgery, we compared the extent of cardiomyocyte apoptosis in the left and right ventricles after antegrade and retrograde cardioplegia in a pig ischemia-reperfusion model. METHODS: Pigs (n = 16, mean weight 30 kg) were openly assigned into the groups of antegrade and retrograde cardioplegia. After aortic cross-clamping, 500 mL of cold crystalloid (modified St Thomas) cardioplegia was administered into the ascending aorta or the coronary sinus. Aortic cross-clamp time was 30 minutes. Cardiomyocyte apoptosis was measured using the terminal transferase mediated ddUTP nick end-labeling (TUNEL) assay and immunohistochemical (IHC) staining for active caspase-3 in myocardial biopsies obtained before ischemia and after 90 minutes of reperfusion. RESULTS: Apoptotic cardiomyocytes were significantly increased after ischemia-reperfusion as shown by both the TUNEL assay and caspase-3 activation. In the right ventricle, retrograde cardioplegia was associated with a 3.4-fold higher amount (TUNEL assay) of apoptotic cardiomyocytes as compared with antegrade cardioplegia (0.107% vs 0.032%, p < 0.05). A similar difference was also found in the left ventricle, although at a lower level (0.027% vs 0.012%, p < 0.05). CONCLUSIONS: Increased apoptotic death of cardiomyocytes after retrograde cardioplegia as compared with the antegrade procedure implicates that retrograde cardioplegia alone provides inferior cardioprotection against irreversible ischemia-reperfusion injury both in the right and the left ventricle.

Animals↗
PubMed2005

Transthoracic Doppler echocardiography as a noninvasive tool to assess coronary artery stenoses--a comparison with quantitative coronary angiography.

We prospectively tested the diagnostic accuracy of Doppler transthoracic echocardiography in detection of coronary artery stenoses throughout the main coronary arterial tree. In all, 84 patients referred for diagnostic quantitative coronary angiography were studied. Coronary artery stenosis was identified with color Doppler as local spot of turbulence, and local flow velocity was measured using pulsed wave Doppler. Angiography showed significant stenoses (diameter reduction > 50%) in 33 patients. An abnormal maximal-to-prestenotic blood flow velocity ratio greater than 2.0 in subtotal stenoses, or the detection of collateral blood flow in the absence of normal antegrade flow in the case of total occlusion (N = 6), resulted in overall sensitivity of 82% and specificity of 92%. The sensitivity and specificity were, respectively, 73% and 92% for left anterior descending coronary artery, 63% and 96% for right coronary artery, and 38% and 99% for left circumflex coronary artery stenoses. Transthoracic echocardiography is a promising noninvasive technique to diagnose significant coronary artery stenoses.

Coronary Angiography↗
PubMed2005

Diagnosis and presentation of fatal myocarditis.

The clinical presentation of myocarditis is highly variable, and histopathology is thus considered to be the cornerstone of diagnosis. We studied how accurately myocarditis was diagnosed in a series of routine autopsies and how fatal myocarditis presents clinically. All death certificates with myocarditis recorded as the underlying cause of death in Finland in 1970 to 1998 were collected retrospectively (N = 639). All cases with cardiac autopsy samples and clinical data available (n = 142; median age, 51 years) were included in this study. The cardiac samples were reexamined for the presence of myocarditis by 3 experienced independent pathologists using the Dallas criteria. The clinical data were evaluated for the presenting signs and symptoms of myocarditis. Histopathologic reanalysis showed that only 32% of the 142 subjects met the Dallas criteria for myocarditis (75% of pediatric and 28% of adult patients, P = .001). Clinicians had suspected myocarditis in only one third of the hospitalized Dallas-positive patients. Dallas-positive patients presented more often with features of myocardial infarction (26% versus 9%, P = .026) or heart failure (35% versus 10%, P = .001) than Dallas-negative subjects. The signs and symptoms of infectious disease were also more common in Dallas-positive patients (61% versus 23%, P < .001). In contrast, Dallas-negative subjects died suddenly or were found dead more frequently (68% versus 39%, P = .004). The most evident cause of death in the Dallas-negative subjects was ischemic heart disease (n = 78, 55% of all cases). Our study provides evidence that myocarditis is overdiagnosed on routine autopsies, particularly in patients who have died suddenly or are found dead. Fatal myocarditis appears to present equally often as heart failure, sudden death, or mimicking myocardial infarction.

Adolescent↗
PubMed2004

Apoptotic cardiomyocyte death in fatal myocarditis.

Acute myocarditis is often a self-limited process with a good outcome. Experimental animal studies have found that cardiomyocyte apoptosis occurs in severe forms of myocarditis. We studied whether cardiomyocyte apoptosis plays a role in the development of fatal acute human myocarditis. Myocardial autopsy samples from subjects who died of acute myocarditis in Finland between 1970 and 1998 were studied. Thirty-three of these cases(16 men and 17 women; 45 +/- 6 years old) were randomly selected for this study. All cases fulfilled the histopathologic Dallas criteria for myocarditis. Eight subjects who had died accidentally served as controls. Apoptotic DNA fragmentation (terminal transferase-mediated DNA nick end labeling) and activation of caspase-3 (immunohistochemistry) were detected. The mode of death was determined retrospectively from all available clinical data. In fatal myocarditis, large amounts of cardiomyocytes showed apoptotic DNA fragmentation or contained active caspase-3 (2.0 +/- 0.3% and 2.8 +/- 0.4%, respectively). In the controls, few apoptotic cardiomyocytes were found (0.008 +/- 0.003% by terminal transferase-mediated DNA nick end labeling and 0.009 +/- 0.003% by detection of active caspase-3, p <0.001 vs myocarditis). The amount of apoptosis did not correlate with the age or gender of the cases, recognized viral etiology, histologic features, or duration of disease. However, more apoptotic cardiomyocytes were detected in the subjects who had myocarditis and had died of heart failure (n = 18) than in those who had myocarditis and died suddenly of cardiac arrest (n = 15; 2.6 +/- 0.4% vs 1.1 +/- 0.2%, p <0.001). In conclusion, cardiomyocyte apoptosis is a common mechanism of myocardial damage in severe acute human myocarditis. Moreover, higher rates of cardiomyocyte apoptosis are associated with the development of fatal heart failure in acute myocarditis.

Analysis of Variance↗
PubMed2004

Cardioprotective effects of vasopeptidase inhibition vs. angiotensin type 1-receptor blockade in spontaneously hypertensive rats on a high salt diet.

The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.

Aldosterone↗
PubMed2003

Coronary artery diameter can be assessed reliably with transthoracic echocardiography.

We studied whether diameters of coronary arteries can be measured accurately with the use of transthoracic echocardiography (TTE). By knowing the anatomic diameter of the coronary artery together with coronary flow velocity it is possible to measure coronary flow volume more precisely by TTE. However, the suitability of TTE for measurement of diameters of all main epicardial coronary arteries has not been systematically validated. We measured the diameters of the left main (LM), left anterior descending (LAD), left circumflex (LCX), and right coronary arteries (RCA) with the use of TTE [manual two-dimensional (2D), color-Doppler, and automated 2D analysis] in 30 patients who had normal coronary anatomy. We compared these diameters to those measured with quantitative coronary angiography (QCA). We could measure diameters of LM, LAD, LCX, and RCA by TTE in up to 37%, 63%, 7%, and 60% of patients, respectively. The overall correlation coefficients between TTE and QCA measurements were 0.83 (P < 0.01) with manual 2D analysis, 0.82 (P < 0.01) with automated 2D analysis, and 0.94 (P < 0.01) with a color-Doppler-based analysis. Interobserver variability of TTE measurements was low (coefficient of variation 5.4 +/- 4.6-7.5 +/- 8.8%). TTE is an accurate method to evaluate coronary artery diameter in patients with healthy coronary arteries.

Aged↗
PubMed2003

Cardiomyocyte apoptosis and ischemic preconditioning in open heart operations.

BACKGROUND: The aim of the present study was to ascertain the percentage of left apical myocardial apoptosis in three-vessel coronary artery bypass grafting patients quantitatively and the impact of ischemic preconditioning. METHODS: Twenty-one patients with three-vessel disease who had elective coronary artery bypass grafting were randomized in a ratio of 2:1 to ischemic preconditioning (n = 14) or a control group (n = 7). The ischemic preconditioning protocol was established by two cycles of ascending aorta occlusion for 2 minutes followed by 3 minutes of reperfusion. Myocardial samples from the apex of the left ventricle were taken using a Tru-Cut needle before aortic cross-clamping and immediately after declamping. The percentage of apoptosis was analyzed by TUNEL methods. Data on hemodynamics and biochemical markers were collected. RESULTS: Low levels of myocardial apoptosis were found before the operation (0.01% +/- 0.00%). During the early reperfusion period, the percentage of myocardial apoptotic cells significantly increased (0.15% +/- 0.05%, p = 0.008). Ischemic preconditioning significantly improved cardiac index and right ventricular ejection fraction recovery after the operation (p = 0.036 and 0.001 respectively, repeated measure) but had no effect on myocardial apoptosis before and after the operation (0.01 +/- 0.00 versus 0.01 +/- 0.00, p = 0.658 and 0.12% +/- 0.04% versus 0.23% +/- 0.14%, p = 0.302). CONCLUSIONS: Cardioplegic myocardial ischemia during open heart operation was associated with induction of cardiomyocyte apoptosis in humans. Attenuation of postoperative cardiac dysfunction by ischemic preconditioning appeared to be independent of apoptosis.

Aged↗
PubMed2003

Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction.

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Expression of heme oxygenase-1 in response to myocardial infarction in rats.

Heme oxygenase-1 (HO-1) is a heat shock protein catalysing the degradation of heme to yield biliverdin, carbon monoxide and iron. Several recent studies have proposed the stress-inducible HO-1 to participate in cellular protection also in the heart. We, therefore, examined the expression and localization of HO-1 in a rat experimental myocardial infarction model. Male Wistar rats were subjected to left anterior coronary artery ligation or sham-operation and sacrificed at 1 day, 1 week and 4 weeks after ligation. The expression of HO-1 mRNA was assessed by real-time quantitative RT-PCR and the localization of HO-1 protein by immunoconfocal microscopy. At day 1, HO-1 mRNA was increased 3.9-fold in the peri-infarct border area vs sham-operated hearts (P<0.001) and 2.9-fold vs remote areas of the same hearts (P<0.001). At 1 week, HO-1 mRNA levels remained significantly higher (5-fold) in the peri-infarct border area than in sham-operated hearts (P<0.001). In addition, HO-1 mRNA transiently increased 1.6-fold in the remote non-infarcted myocardium vs sham operated hearts (P<0.05). HO-1 mRNA returned to basal levels by 4 weeks. The increase in HO-1 mRNA was accompanied by increased immunoreactivity of HO-1 protein in the vascular walls throughout the myocardium, and in the cardiomyocytes and fibroblast-like cells of the peri-infarct border areas. Cardiomyocytes showed immunoreactivity at the intercalated disc area, and in the sarcoplasmic reticulum as indicated by the striated pattern of staining. The results suggest that the induction of HO-1 may have an important role in the heart during the first days after myocardial infarction.

Animals↗
PubMed2002

Soluble tumor necrosis factor receptor levels identify a subgroup of heart failure patients with increased cardiomyocyte apoptosis.

BACKGROUND: We studied whether the presence of cardiomyocyte apoptosis (CA) in explanted failing hearts is related to previous exposure to the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). METHODS: Serum levels of TNF-alpha and its soluble type two receptors (sTNFRII) were measured with ELISAs in 15 cardiac transplant recipients. CA was quantified with TUNEL assay in the explanted failing hearts and autopsy samples from six normal hearts. RESULTS: The number of CA was significantly higher in explanted failing hearts than in normal hearts (0.041% vs. 0.007%, p<0.01). In heart failure patients, serum TNF-alpha was highly variable and did not correlate with CA. In contrast, serum sTNFRII showed a significant correlation (Pearson's r=0.74, p=0.002) with the amount of CA in explanted hearts. sTNFRII level >4500 pg/ml identified seven patients with 2.7 times higher percentage of CA than the other heart failure patients. CONCLUSION: Increased levels of sTNFRII identify a heart failure patient subgroup with high CA activity.

Apoptosis↗
PubMed2002

Cardiomyocyte apoptosis after antiviral WIN 54954 treatment in murine coxsackievirus B3 myocarditis.

OBJECTIVE: Cardiomyocyte apoptosis (CA) is known to occur in experimental coxsackievirus B3 (CVB3) myocarditis. However, the mechanisms of CA induction are not well known. In this study we investigate the role of direct viral induction of CA in CVB3 myocarditis. DESIGN: A/J mice were infected with the Woodruff strain of CVB3 and treated with WIN 54954 for 5 days thereafter. WIN 54954, a compound that inhibits early events of picornavirus infection, is known to dramatically reduce mortality in murine CVB3 myocarditis without abrogating systemic or myocardial inflammation. Presence of viral RNA (in situ hybridization), CA (TUNEL method) and histopathology were studied in transverse ventricular sections at day 7 post infection (n = 8 treated and n = 8 non-treated). RESULTS: The proportion of cardiomyocytes containing viral RNA was 89% lower in WIN 54954 treated mice when compared with non-treated mice (0.29 +/- 0.56% vs 2.76 +/- 1.65%, p = 0.003). Treatment also reduced the amount of CA by 52% compared with non-treated mice (0.20 +/- 0.06% vs 0.42 +/- 0.06%, p < 0.001). The reduction of CA by WIN treatment did not result in any increase of necrosis, in fact treatment reduced the area of necrotic lesions by 77% (2.51 +/- 1.64% vs 11.10 +/- 8.76%, p = 0.028). CONCLUSION: Taking the results of the reduced CA, necrosis and viral RNA with no effect on inflammation into account, our findings suggest the importance of direct viral effect in cardiomyocyte damage by both apoptosis and necrosis in CVB3 myocarditis.

Animals↗
PubMedDate not supplied

Cardiomyocyte apoptosis in experimental coxsackievirus B3 myocarditis.

INTRODUCTION: Viruses are known to induce apoptosis in their host cells. We studied whether cardiomyocyte apoptosis occurs upon coxsackievirus B3 (CVB3) infection and whether virus-associated apoptosis plays a role in the pathogenesis of experimental myocarditis. METHODS: BALB/c mice were infected with two variants of CVB3 causing either mild or severe myocarditis. Myocardial and serum samples were collected from Day 1 to Day 14 after virus inoculation. Apoptosis was detected in myocardial tissue sections using the terminal transferase-mediated DNA nick end labelling (TUNEL) assay and staining of active caspase 3, and compared with the presence of infectious CVB3 and viral proteins in cardiomyocytes. RESULTS: Compared with the noninfected control mice, infection with either CVB3 variant resulted in significantly increased cardiomyocyte apoptosis, which peaked on Day 5 after infection. At this time, the average percentages of apoptotic cardiomyocytes were 0.17% (SD 0.04; P=.03) and 0.77% (SD 0.11; P<.01) in mild and severe disease forms, respectively. The amount of apoptosis correlated with titers of infectious CVB3 in the heart muscle. Viral proteins were detected in the TUNEL-positive cells by immunohistochemistry. In the late stages of disease, apoptosis, together with inflammatory infiltrates persisted only in the severe disease form. CONCLUSIONS: CVB3-associated myocardial damage involves cardiomyocyte apoptosis. In the early stages of the disease, it appears to be triggered by viral replication in the cardiomyocytes.

Animals↗