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PubMed1989

Prognosis in hypertrophic cardiomyopathy--echocardiographic follow-up and histopathological study.

In 30 consecutive hypertrophic cardiomyopathy (HCM) patients who eventually died and 50 who survived, morphologic and functional changes in the heart during a follow-up period of an average of 3.9 years were echocardiographically evaluated. Echocardiographic indices were compared among 5 groups of patients with HCM, consisting of 4 groups of patients who eventually died (SD: 17 patients who suffered sudden death, ED: 4 who died of embolism, HF: 4 who died of congestive heart failure, NC: 5 who died of a noncardiac event) and 1 group of patients who survived with nondilated left ventricle (S: 50 patients). These indices at the last evaluation before death were compared with histopathological findings of left ventricles in 12 autopsied patients. At the initial evaluation ED and HF patients had a larger left ventricular end-diastolic dimension (LVDd), and HF patients had a smaller percent fractional shortening (%FS) and a slower normalized rapid filling rate (nRFR: mean rapid filling rate/LVEDV) than S patients, but these indices showed no differences between SD and S patients. During follow-up, no echocardiographic indices changed in S patients, but LVDd was increased and %FS and nRFR were decreased in SD and HF patients. Mean myocyte diameter and % area of disarray showed no differences among the 4 death groups. However, compared with NC, the other 3 groups, especially HF, had larger % area of massive fibrosis. The % area of massive fibrosis was correlated with LVDd (r = 0.80, p less than 0.005), %FS (r = -0.64, p less than 0.05), and nRFR (r = -0.95, p less than 0.001) at the last evaluation. These results suggested that echocardiographic follow-up was useful in predicting the progression of the myocardial lesion and the prognosis of HCM.

Adolescent↗
PubMed2001

Diabetes related cardiomyopathy time dependent echocardiographic evaluation in an experimental rat model.

Type I diabetes is associated with a unique form of cardiomyopathy in the absence of atherosclerosis. The mechanisms involved in this phenomenon are not defined, but in humans this is associated with initial diastolic dysfunction followed by altered contractile performance. A relevant animal model would provide opportunities for mechanistic studies and experimental therapeutics, but none have been previously established for this unique form of cardiac pathophysiology, particularly with respect to clinically relevant and time-dependent diastolic and systolic assessments. Here we tested the hypothesis that the streptozotocin rat model mimics human phenomena with respect to time-dependent diastolic and systolic performance deficits, and investigated a role for cardiac hypertrophy and/or fibrosis. Streptozotocin was dosed 65 mg/kg i.p. and cardiac performance was assessed longitudinally for 56 days using noninvasive echocardiographic techniques. Significant hyperglycemia was detected within 3 days and remained elevated throughout the study (p<0.05). Significant reductions in HR and diastolic performance (transmitral flow velocities and slopes) were observed within 3 days relative to age matched controls, and these reductions progressed throughout the 56 day study. In contrast, statistically significant systolic dysfunction (LV fractional shortening, cardiac output) and LV dilation were detected only after 35 days. Increases in LV size and/or extent of fibrosis were not observed at any time. These results demonstrate the value of echocardiographic methods for time-dependent diastolic and systolic assessments in rodent models. Furthermore, diastolic dysfunction precedes contractile abnormalities in the streptozotocin model, similar to events that occur in humans.

Analysis of Variance↗
PubMed2006

Relation between flow reserve capacity of penetrating intramyocardial coronary arteries and myocardial fibrosis in hypertension: study using transthoracic Doppler echocardiography.

OBJECTIVE: The purpose of this study was to compare coronary flow reserve (CFR) capacity of penetrating intramyocardial coronary artery (PICA) using transthoracic Doppler echocardiography and biochemical marker of myocardial fibrosis in hypertension (HTN). METHODS: In 58 patients (male:female ratio = 31:27; mean age 47 +/- 9 years) with chest pain and normal coronary angiogram findings, the width of color Doppler signal and peak diastolic velocity of PICA flow were measured in the myocardium just beneath the apical impulse window using transthoracic Doppler echocardiography. PICA-CFR and PICA-width ratio were calculated as the ratio of hyperemic to baseline peak diastolic velocity and as the ratio of hyperemic to baseline width after the adenosine infusion (140 mug/kg/min), respectively. Serum carboxy-terminal propeptide of procollagen type I, as a biochemical marker, was measured and patients were divided into 3 groups: 19 with HTN and PICA-CFR less than 2.0 (group A); 23 with HTN and PICA-CFR of 2.0 or more (group B); and 16 who were normotensive with PICA-CFR of 2.0 or more (group C). RESULTS: Baseline peak diastolic velocity for group A was higher than the other two groups (P < .005 vs groups B and C). PICA-width ratio was higher than the other two groups (P < .005 vs groups B and C). Serum propeptide of type I was 137.1 +/- 16.6 ng/mL in group A, 96.2 +/- 13.7 ng/mL in group B, and 78.8 +/- 11.2 ng/mL in group C (P < .0001 vs group B and group C). PICA-CFR was closely related to serum propeptide of type I (P < .001, r = -0.723). CONCLUSION: The impaired PICA-CFR is related to myocardial fibrosis in patients with HTN, chest pain, and normal coronary angiogram results.

Coronary Artery Disease↗
PubMed1997

[Temporary mechanical left heart support. Recovery of heart function in patients with end-stage idiopathic dilated cardiomyopathy].

BACKGROUND: Implantation of a mechanical cardiac support system (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. Our experience now includes 13 patients who have been "weaned" from MCSS and we report about the overall results of this treatment as well as the effects of ventricular unloading on cardiac function, anti-beta 1-adrenoceptor-autoantibody (A-beta 1-AAB) level and the degree of myocardial fibrosis. METHODS: 13 patients with non-ischemic IDC who had been admitted here in cardiogenic shock (CI < 1.61.min-1.m2, left ventricular ejection fraction [LVEF] < 16% and left ventricular internal diameter in diastole [LVIDd] > 68 mm) and who all tested positive for A-beta 1-AABs were implanted with an uni-(12 patients) or a biventricular (1 patient) mechanical assist device. Echocardiographic evaluation and A-beta 1-AAB-level-monitoring was routinely performed after implantation and explantation of the MCSS and the degree of myocardial fibrosis was assessed at the time of implantation and after explantation. RESULTS: During a mean duration of mechanical support of 236 +/- 201 days (range: 30 to 794 days), LV-EF improved to a mean of 46% and LVIDd decreased to a mean value of 56 mm in these 13 patients. A-beta 1-AABs decreased and disappeared 11.7 weeks after implantation of the device and did not reincrease thereafter. The highly pathologic degree of fibrosis at the time of implantation diminished to normal values about 1 year after explantation. One patient died of anesthesiologic complications and another patient shortly presented with a new episode of cardiac insufficiency 6 months after explantation. He was implanted again with an univentricular assist device was successfully transplanted 3 weeks later. Mean observation period of the remaining 11 patients now amounts to 12.6 +/- 9.77 (range: 3 to 26) months after explantation of the device--as of May, 31, 1997--with a cumulative observation period of 139 patient months. CONCLUSION: Temporary implantation of a MCSS may normalize cardiac function in selected patients with IDC. The striking degree of myocardial fibrosis can reduce to normal values after explantation of the device. A-beta 1-AABs disappear during ventricular unloading and do not increase thereafter. "Weaning" from mechanical device may constitute an alternative treatment to cardiac transplantation in selected patients.

Adult↗
PubMedDate not supplied

Ethanol ingestion on allylamine-induced experimental subendocardial fibrosis.

Effects of ethanol ingestion on allylamine-induced subendocardial fibrosis of the myocardium and intimal hyperplasia of the intramyocardial coronary artery were investigated in male Wistar rats. The toxic effect of allylamine is ascribed to acrolein produced from allylamine by benzylamine oxidase. Animals were forced to drink allylamine solution for 12 weeks. Incidence and size of subendocardial fibrosis were examined, and the lesions of the intramyocardial artery were scrutinized. Effects of ethanol on the systemic blood pressure and benzylamine oxidase activity were investigated in another experiment. Treatment with allylamine resulted in subendocardial fibrosis (size = 4.2%) in 4 of 12 rats. The incidence of fibrosis was increased (up to 6/12) and the area of fibrosis was augmented (to 6.8%) in animals additionally treated with epinephrine. The lesions in the intramyocardial vasculature were also augmented. Ethanol ingestion reduced allylamine-induced subendocardial fibrosis and intramyocardial coronary lesions. The effects were significant in animals additionally treated with epinephrine. Systemic blood pressure and benzylamine oxidase activity were not significantly affected by allylamine or by ethanol. The vasodilatory effect of ethanol may have prevented the development of microvascular spasm induced by allylamine.

Alcohol Drinking↗
PubMed2006

Effect of Angiotensin II Type 1 receptor blocker on cardiac angiotensin-converting enzyme and chymase-like activities, and cardiac fibrosis in cardiomyopathic hamsters.

It has been reported that cardiac chymase has an effect on cardiac fibrosis through the Angiotensin (Ang) II formation and an Ang II-independent mechanism. In the present study, Ang II type 1 (AT1) receptor blocker (candesartan cilexetil) was administered to dilated cardiomyopathic (DCM; Bio TO2) hamsters for 4 weeks to study the effect of AT1 receptor blocker on cardiac chymase-like activity and cardiac fibrosis. Echocardiography, histological examination, and assessment of cardiac angiotensin-converting enzyme (ACE)/chymase-like activities were conducted. Hamsters showed cardiac dysfunction due to increased left ventricular dimensions and decreased ventricular wall thickness, significant increase in cardiac chymase-like activity, and fibrosis. This result indicates that the cardiac chymase-like activity is responsible for cardiac fibrosis. When candesartan cilexetil was administered to Bio TO2 hamsters, cardiac chymase-like activity increased significantly, whereas cardiac fibrosis decreased significantly. Cardiac ACE and chymase-like activities were unchanged in non-DCM hamsters with candesartan cilexetil. This suggests that the cardiac Ang II formation mechanism was stimulated by suppressing the effect of cardiac Ang II, and cardiac chymase-like activity could be increased. Moreover, this mechanism may be more highly activated if cardiac Ang II is activated in the heart. In conclusion, we demonstrated that AT1 receptor blocker reduced cardiac fibrosis, although cardiac chymase-like activity increased. Because the Ang II-forming pathway and the effect of chymase in hamsters is similar to that in dogs, the results of the present study may supplement the available information for dogs.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1992

[The value of ACE inhibitors in heart failure (mechanism of action)].

ACE-inhibitors improve symptoms and prognosis in patients with heart failure. The V-Heft II trial has demonstrated that the beneficial effect of these agents is superior to unspecific vasodilators. Besides sustained arterial and venous vasodilation the inhibition of the neurohumoral axis is thought to play an important role. Angiotensin II and catecholamines not only exert vasoconstrictor effects, but might also contribute to vascular and myocardial growth. Thus, it may not be surprising that the beneficial effects of ACE inhibitors in heart failure only emerge during long-term therapy rather than after short-term administration. It has been shown that these agents improve blood flow to skeletal muscle during exercise after chronic therapy (not acutely), and there is some preliminary evidence that improvement of endothelial function might be involved in this effect, i.e., by reducing the degradation of bradykinin, an endothelial vasodilator. ACE inhibitors reduce LV hypertrophy, an important risk factor for cardiovascular disease and prognosis. Moreover, there is experimental evidence that ACE inhibitors can prevent and even reverse interstitial fibrosis in the left ventricle. Although the plasma renin activity may be normal in patients with chronic heart failure, recent data using polymerase chain reaction indicate that the tissue cardiac renin angiotensin system is activated in the failing human heart as assessed by measurements of angiotensin converting enzyme mRNA and angiotensinogen mRNA which may be an important target for ACE-inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy.

The cardioprotective properties of carvedilol (a vasodilating beta-adrenoceptor blocking agent) were studied in a rat model of dilated cardiomyopathy induced by autoimmune myocarditis. Twenty-eight days after immunization, surviving Lewis rats (32/43=74%) were divided into three groups to be given 2 mg kg(-1) day(-1) (Group-C2, n=10) or 20 mg kg(-1) day(-1) (Group-C20, n=10) of carvedilol, or vehicle (0.5% methylcellulose, Group-V, n=12). After oral administration for 2 months, body weight, heart weight (HW), heart rate (HR), rat alpha-atrial natriuretic peptide (r-ANP) in blood, central venous pressure (CVP), mean blood pressure (mean BP), peak left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), +/-dP dt(-1) and area of myocardial fibrosis were measured. Values were compared with those for normal Lewis rats (Group-N, n=10). Two out of 12 (17%) rats in Group-V died from day 28 to day 42 after immunization. No rat died in Groups-C2, -C20 and -N. Although the CVP, mean BP, LVP and +/-dP dt(-1) did not differ among the three groups, the HW, HR and r-ANP in Group-C2 (1.14+/-0.03, 339+/-16 and 135+/-31) and Group-C20 (1.23+/-0.04, 305+/-8 and 156+/-24) were significantly lower than those in Group-V (1.36+/-0.04 g, 389+/-9 beats min(-1) and 375+/-31 pg ml(-1), respectively). The LVEDP in Group-C2 was significantly lower than that in Group-V (7.4+/-1.4 and 12.2+/-1.2 mmHg, respectively, P<0. 05). The area of myocardial fibrosis in Group-C2 was smaller than that in Group-V (12+/-1 and 31+/-2%, P<0.01). These results indicate that a low dose of carvedilol has beneficial effects on dilated cardiomyopathy.

Animals↗
PubMed2001

Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure.

BACKGROUND: Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF). METHODS AND RESULTS: Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg. kg(-1). d(-1). VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing-induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1+/-0.4 to 1.9+/-0.2 ms/mm, P<0.05), atrial fibrosis (from 11.9+/-1.1% to 7.5+/-0.4%, P<0.01), and mean AF duration (from 651+/-164 to 218+/-75 seconds, P<0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion. CONCLUSIONS: CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.

Angiotensin II↗
PubMed2005

NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology.

Chronic heart failure, secondary to left ventricular hypertrophy or myocardial infarction, is a condition with increasing morbidity and mortality. Although the mechanisms underlying the development and progression of this condition remain a subject of intense interest, there is now growing evidence that redox-sensitive pathways play an important role. This article focuses on the involvement of reactive oxygen species derived from a family of superoxide-generating enzymes, termed NADPH oxidases (NOXs), in the pathophysiology of ventricular hypertrophy, the accompanying interstitial fibrosis and subsequent heart failure. In particular, the apparent ability of the different NADPH oxidase isoforms to define the response of a cell to a range of physiological and pathophysiological stimuli is reviewed. If confirmed, these data would suggest that independently targeting different members of the NOX family may hold the potential for therapeutic intervention in the treatment of cardiac disease.

Cardiomyopathy, Hypertrophic↗
PubMed1995

Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR.

BACKGROUND: Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease. METHODS AND RESULTS: Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy. CONCLUSIONS: After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.

Aging↗
PubMed1995

Late sudden deaths after repair of tetralogy of Fallot. Electrocardiographic findings associated with survival.

Of 141 hospital survivors after intracardiac repair of tetralogy of Fallot, eight died suddenly 6-23 years later. Compared with the other 133 patients, these eight were older at operation, with higher post-repair systolic right ventricular pressure and more often complete atrioventricular block; ventricular arrhythmia was diagnosed before death in three cases. In follow-up totalling 2255 patient years, the linearized rate of sudden death was 0.35%/year. The instantaneous risk of sudden death showed continuous increase with the length of follow-up. Of 80 survivors electrocardiographically evaluated 13-26 (median 20) years postoperatively, none had complete block, but 79 had complete right bundle branch block, including seven with left anterior hemiblock. Ventricular extrasystoles were recorded in 1% at rest, in 34% during exercise and in 83% during 24-hour ambulatory monitoring, with Lown Grade > or = II in 27%. Old age and possibly presence of fibrosis and/or fibroelastosis in right ventricular outflow Lown Grade. A patient with Lown grade III died suddenly 2 years after our follow-up. Old age at repair thus was associated with increased risk of late sudden death and with frequent ventricular arrhythmia in long-term survivors.

Adolescent↗
PubMed1987

[Neoplastic form of chronic erythromyelosis (erythrosarcoma) with eosinophilia and cardiac lesions].

The paper is concerned with a case history of a 24-year old man suffering from chronic erythromyelosis with erythrokaryocytic metaplasia of the peripheral lymph nodes, bone marrow, spleen, liver, heart and lungs. The hypereosinophilic syndrome and endocardial fibrosis caused diagnostic difficulties. A short-term effect after injection of the plasma from a patient with erythrocytic aplasia containing antierythroblastic antibodies was obtained, tumor tissue mass reduced. Later on courses of CAMP-therapy were initiated. The progression of disease resulted in the patient's death in 2 years.

Adult↗
PubMed1981

Cardiac biopsy of Kawasaki disease.

Two hundred one patients (138 boys, 63 girls), 1 month to 11 years old, with Kawasaki disease underwent coronary angiography, ultrasonic tomography, myocardial imaging, and biopsy of right ventricular myocardium. Aneurysms of epicardial coronary arteries, mostly left, occurred in 26 cases (12.9%). Degeneration and proliferation of endothelium, edema, scarring, and fibrosis, slight to moderate, involved the tunicae of intramural small vessels in all cases. These changes tended to abate with time. The basic lesion of Kawasaki disease, round-cell myocarditis and fibrosis, involved all cases and persisted. Disarrangement, abnormal branching, disarray, and hypertrophy of myocytes correlated significantly with myocarditis, but not with epimural or intramural coronary angitis. As a consequence of the myocardial changes, it is suggested that some cases may terminate as myocardiopathy. Scoring criteria for vascular and myocardial changes in biopsy specimens are included.

Biopsy↗
PubMed1995

Local regulation of extracellular matrix structure.

The extracellular matrix (ECM) is composed of various collagens, glycosaminoglycans, and elastin bathed by a tissue fluid found throughout the interstitial space. It is this substratum in which fibroblasts and macrophages normally reside, where fibroblast phenotypic transformation occurs, and into which inflammatory cells migrate when called upon during tissue repair. Many diseases, expressed in an organ-specific manner, require organ-specific ECM remodeling. Regulation of fibrillary type I collagen synthesis, whose disproportionate (relative to degradation) accumulation is characteristic of the tissue fibrosis that adversely alters organ function, is therefore of considerable importance. Emerging evidence implicates angiotensin converting enzyme (ACE), found in fibroblast-like cells, and ACE-related peptides, angiotensin II and bradykinin, in serving important regulatory functions that influence wound healing and thereby ECM structure in health and disease. The heart and its collagen matrix have been targeted for discussion in this brief review.

Animals↗
PubMed2006

Myocyte-restricted focal adhesion kinase deletion attenuates pressure overload-induced hypertrophy.

Focal adhesion kinase (FAK) is a ubiquitously expressed cytoplasmic tyrosine kinase strongly activated by integrins and neurohumoral factors. Previous studies have shown that cardiac FAK activity is enhanced by hypertrophic stimuli before the onset of overt hypertrophy. Herein, we report that conditional deletion of FAK from the myocardium of adult mice did not affect basal cardiac performance, myocyte viability, or myofibrillar architecture. However, deletion of FAK abolished the increase in left ventricular posterior wall thickness, myocyte cross-sectional area, and hypertrophy-associated atrial natriuretic factor induction following pressure overload. Myocyte-restricted deletion of FAK attenuated the initial wave of extracellular signal-regulated kinase activation and cFos expression induced by adrenergic agonists and biomechanical stress. In addition, we found that persistent challenge of mice with myocyte-restricted FAK inactivation leads to enhanced cardiac fibrosis and cardiac dysfunction in comparison to challenged genetic controls. These studies show that loss of FAK impairs normal compensatory hypertrophic remodeling without a concomitant increase in apoptosis in response to cardiac pressure overload and highlight the possibility that FAK activation may be a common requirement for the initiation of this compensatory response.

Animals↗
PubMed1991

Long-term pulmonary hypertension produced by cigarette smoking is associated with subendocardial fibrosis and inflammation of the right ventricle: a morphometric analysis in the guinea pig model.

We have developed a guinea pig model of cigarette smoking induced lung disease, whereby animals exposed for several months to cigarette smoke develop emphysematous lung destruction as well as mild pulmonary hypertension with increased muscularization of the arterioles. To ascertain whether the animals with pulmonary hypertension had structural alterations of the right ventricle, we morphologically determined the volume proportion of inflammatory cells, fibrosis, and muscle cytoplasm and nuclei, and compared these values to those of age matched animals not exposed to smoke. We found that there was a significantly increased volume proportion of both fibrous tissue and inflammatory cells in the subendocardial myocardium after 12 months of cigarette smoke exposure, but not after 3 or 6 months. Since the degree of pulmonary hypertension, and the weight of the right ventricle were similar at the 3 time periods, we conclude that the inflammatory cell infiltrate and fibrosis in the subendocardial myocardium are manifestations of long term pulmonary hypertension, rather than any indication of co-existant damage to the myocardium as a result of the smoke exposure. These features would be compatible with the "right ventricular hypothesis" of Morrison (8) for the development of cor pulmonale, with the pathological changes seen as a result of a dysequilibrium between oxygen supply and demand in the right ventricle.

Animals↗
PubMed2002

Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction.

Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF ( approximately 1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII ( approximately 1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX(-/-) mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.

Animals↗