Am J Physiol Heart Circ Physiol 291: H871-H875, 2006.
First published February 24, 2006; doi:10.1152/ajpheart.01375.2005
0363-6135/06 $8.00
Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study
Antti Saraste,1,2,*
Ville Kytö,2,3,*
Markku Saraste,1
Tytti Vuorinen,4
Jaakko Hartiala,1 and
Pekka Saukko5
Departments of 1Clinical Physiology and 2Medicine, Turku University Central Hospital; and Departments of 3Anatomy, 4Virology, and 5Forensic Medicine, University of Turku, Turku, Finland
Submitted 27 December 2005
; accepted in final form 22 February 2006
 |
ABSTRACT
|
|---|
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.
coronary microcirculation; coxsackievirus B3; fractional shortening; left coronary artery
VIRAL MYOCARDITIS IS USUALLY a mild disease, but sometimes it leads to irreversible myocardial injury, heart failure, and dilated cardiomyopathy (6). In addition to myocyte necrosis, structural damage of myocardial microcirculation, such as obstruction and luminal narrowing, has been observed in acute viral myocarditis in mice (4, 14, 20). Moreover, intracoronary guide wire measurements in patients with myocarditis and inflammatory cardiomyopathy have demonstrated that both inflammation and viral infection can cause endothelial dysfunction (12, 22). It has been hypothesized that dysfunction of coronary microcirculation resulting in focal ischemia-reperfusion contributes to myocardial injury in viral myocarditis (5, 15). However, the relationship between microvascular dysfunction and development of heart failure in myocarditis remains unknown.
Transthoracic Doppler echocardiography (TTDE) has been validated as a noninvasive tool to study coronary artery flow velocity and coronary flow reserve (CFR) in humans (2, 11, 17, 18). Reduced CFR, a ratio of coronary flow velocity during maximal vasodilatation with adenosine to baseline, indicates the presence of either a flow-limiting coronary artery stenosis or dysfunction of coronary microcirculation (10, 23). Recently, TTDE has been applied to study CFR in mice with atherosclerosis (7, 24).
To explore the role of dysfunction of coronary microcirculation in the course of viral myocarditis, we applied TTDE to measure CFR in mice and compared it with left ventricular systolic function in mice infected with coxsackievirus B3 (CVB3) variants causing either mild or severe forms of myocarditis.
|
MATERIALS AND METHODS
|
|---|
Experimental model.
Thirty adolescent 5- to 7-wk-old male BALB/c mice from the Animal Center of the University of Turku were infected intraperitoneally with 2 x 104 plaque-forming units of two myocarditic variants of CVB3. We characterized the time courses of viral infection and myocarditis in this model in detail previously (1, 16). Ten mice were infected with the Nancy variant of CVB3 that causes mild myocarditis that is nonlethal. Twenty mice were infected with the Woodruff variant that causes severe myocarditis associated with high mortality. The local animal ethic committee approved the study, and the investigation conforms with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996).
Study protocol.
All mice were studied by TTDE before infection. Five randomly chosen mice infected with either Nancy or Woodruff variants were studied again by TTDE 1 and 2 wk after infection. TTDE was performed with an Acuson Sequoia (Siemens Acuson, Mountain View, CA) and a 15-MHz linear transducer (15L8). Images were stored in a digital image archive (Kinet DX, Acuson Siemens) and analyzed later so that the observers were blinded to study groups and time points. All measurements were calculated as means of three cardiac cycles. Before TTDE, mice were fully anesthetized with ketamine (60 mg/kg) and diazepam (10 mg/kg), given intraperitoneally. The chest was mechanically shaved, mice were kept in the supine position, and normothermia was maintained with the use of a heating pad, a thermoregulating lamp, and a rectal thermometer. ECG leads were attached to extremities, and ECG was displayed in real time. Adenosine (0.5 mg/ml; ITEM Development, Stocksund, Sweden) was infused intravenously via tail vein with an infusion pump at the rate of 0.32 mg·kg–1·min–1. Infusion was continued for a minimum of 2 min to ascertain that the maximum effect was achieved. A dose-response study comparing adenosine infusion rates (0.16, 0.32, and 0.64 mg·kg–1·min–1) was carried out in six noninfected mice to ascertain that the effective dosage was used. Mice were euthanized after TTDE using CO2. The heart was excised, and transverse sections of the heart from the midventricular level were fixed in neutral buffered formaldehyde and embedded in paraffin for histological analysis.
M-mode echocardiography.
Left ventricular dimensions and fractional shortening (FS) were measured in short-axis M-mode images of the left ventricle obtained at the level of mitral valve leaflet tips as previously described (8, 21). Coefficients of variation (CVs) for repeated measurements of FS by the same and by two independent analyzers were 0.07.
Doppler echocardiography.
CFR was calculated as the ratio of peak diastolic flow velocity in the left coronary artery (LCA) during maximal vasodilatation induced by adenosine to resting flow velocity. Flow in the descending LCA was localized, and its course was followed under color Doppler mapping in the anterior wall of the left ventricle using modified long-axis views. The blood flow velocity spectrum in the middle LCA was then recorded by using pulsed-wave Doppler, both at rest and during adenosine infusion to measure diastolic flow velocities. Sample volume was kept as small as possible. Ultrasound beam and flow were aligned as parallel as possible. Angle correction was not used. CV for repeated measurements of flow velocities from archived flow velocity profiles of six mice by the same and two independent analyzers were 0.03. When adenosine was administered repeatedly in six mice after its effects on coronary blood flow were allowed to dissipate, CV for repeated measurements of CFR was 0.07.
Histopathology.
Myocardial samples were cut in 4-µm sections and stained with hematoxylin and eosin. Histopathological severity of myocarditis was graded in a midventricular section from 0 to 4 (0, no necrosis or inflammation; 1, 1–10 foci of necrosis or inflammation per section; 2, 11–20 foci; 3, 21–40 foci; and 4, >40 foci or confluent areas of necrosis) as previously described (1).
Statistical analyses.
Data are expressed as means (SD) unless otherwise stated. Student's t-test for paired data or one-way Anova and Bonferroni's method (more than two comparisons) were used to compare echocardiographic parameters before and after infection with either virus variant at different time points. Correlations were calculated by using Spearman's method. Values of P < 0.05 were considered statistically significant.
|
RESULTS
|
|---|
Infection of mice with the Woodruff variant of CVB3 caused severe myocarditis characterized by large areas of necrosis and inflammation. Typically, 20–30% of all cardiomyocytes were affected. In contrast, infection with the Nancy variant resulted in mild myocarditis with few small necrotic foci (<1% of cardiomyocytes). The lesions were randomly located in all midventricular sections and across the ventricular wall. The results of histopathological grading are shown in Table 1. All mice infected with the Nancy variant survived, but eight (40%) mice infected with the Woodruff variant died during the follow-up. Heart rates did not differ significantly between baseline and after infection with either CVB3 variant (Table 1).
View this table:
[in this window]
[in a new window]
|
Table 1. Histolopathological and echocardiographic characteristics of mice with mild and severe forms of myocarditis
|
|
Cardiac function and left ventricular size.
Representative images of M-mode echocardiography are shown in Fig. 1. As shown in Table 1 and Fig. 2, FS was decreased 1 and 2 wk after infection with either the Nancy (P < 0.05) or the Woodruff (P < 0.01) variant of CVB3 compared with baseline. FS did not differ between mice with mild and severe myocarditis before infection [0.51 (SD 0.03) and 0.54 (SD 0.02), respectively] or 1 wk after infection [0.44 (SD 0.02) and 0.43 (SD 0.03), respectively]. In contrast, 2 wk after infection, FS was significantly lower in severe than in mild myocarditis [0.31 (SD 0.03) vs. 0.47 (SD 0.02), P < 0.001]. Left ventricular diastolic diameter (LVDD) remained unchanged in mild myocarditis during the follow-up. When compared with the LVDD before infection, LVDD was increased 2 wk after infection in severe myocarditis [3.7 (SD 0.3) vs. 4.2 mm (SD 0.3), P < 0.05]. Thickness of interventricular septum or posterior wall of the left ventricle did not change after infection with either virus variant.
View larger version (112K):
[in this window]
[in a new window]
|
Fig. 1. Color Doppler visualizes middle left coronary artery flow (arrows) at rest (A) and during maximal adenosine-induced vasodilatation (B). Note the accelerated flow and aliasing despite increased velocity scale (upper left-hand corner) during adenosine infusion. Flow velocity profile obtained with pulsed-wave Doppler shows increased peak diastolic flow velocity (arrows) from 0.31 m/s at rest (A) to 0.62 m/s during adenosine infusion (B). Two weeks after infection, M-mode parasternal short-axis image of left ventricle in mouse with severe myocarditis showed reduced systolic contraction and dilatation of the left ventricle (D) when compared with mice with mild myocarditis (C). Lines demonstrate left ventricular diameters during diastole (LVDD) and systole (LVSD).
|
|
View larger version (14K):
[in this window]
[in a new window]
|
Fig. 2. Mice infected with either virus variant had comparable reductions in fractional shortening 1 wk after infection (A). However, in contrast to mice with mild myocarditis (open bars), those with severe myocarditis (shaded bars) showed progressive worsening of fractional shortening together with an increase in LVDD 2 wk after infection (A and B). Infection of mice with either coxsackievirus variant resulted in a decrease in coronary flow reserve (CFR) 1 wk after infection (C). However, CFR was significantly more reduced in mice with severe myocarditis. Two weeks after infection, CFR was reduced only in mice with severe myocarditis. *P < 0.05; **P < 0.01.
|
|
Assessment of CFR.
CFR was successfully assessed in all animals before infection and again 1 or 2 wk after infection. Adenosine increased flow velocity in the middle LCA when compared with resting flow, as shown in Fig. 1 and Table 1. Before infection, average CFR was 2.4 (SD 0.6). The use of mean diastolic flow velocities instead of peak diastolic flow velocities resulted in comparable CFR values [2.4 (SD 0.4)]. In the dose-response study, mean CFR in six mice did not significantly differ when adenosine infusion rate varied from 0.16 [2.3 (SD 0.6)] to 0.32 [2.5 (SD 0.4)], or to 0.64 mg·kg–1·min–1 [2.4 (SD 0.5)]. Heart rate remained similar at rest [416 beats/min (SD 75)] and during adenosine infusion rates of 0.16 [421 beats/min (SD 46)], 0.32 [433 bets/min (SD 49)], or 0.64 mg·kg–1·min–1 [419 beats/min (SD 50)]. There were no deaths during or immediately after adenosine infusion.
CFR and myocarditis.
When compared with those before infection, resting flow velocities in the LCA did not differ after infection with either virus variant, as shown in Table 1. In contrast, adenosine-induced flow velocity was significantly lowered 1 wk after infection with either virus variant (P < 0.01). Thus CFR was reduced in all mice 1 wk after infection with either virus variant when compared with baseline, as shown in Table 1 and Fig. 2. At this time, average CFR had decreased from 2.5 (SD 0.3) to 2.1 (SD 0.3) (P < 0.05) after infection with the Nancy variant and from 2.4 (SD 0.4) to 1.4 (SD 0.1) (P < 0.01) after infection with the Woodruff variant. CFR remained low 2 wk after infection with the Woodruff variant [1.6 (SD 0.2), P < 0.05], whereas it was comparable to baseline in mice infected with the Nancy variant [2.4 (SD 0.6)].
When compared with that in mild myocarditis, CFR was significantly more reduced in severe myocarditis both 1 wk and 2 wk after infection (P < 0.01), as shown in Table 1 and Fig. 2. Thus reduced CFR 1 wk after infection preceded the progressive worsening of systolic function and the increase of LVDD in severe myocarditis. Two weeks after infection, reduced CFR significantly correlated with reduced FS (r = 0.65, P < 0.05). Reduced CFR also correlated with increased histopathological severity of myocarditis 1 wk (r = –0.80, P = 0.01) and 2 wk (r = –0.73, P < 0.05) after infection.
|
DISCUSSION
|
|---|
We found that CFR is reduced in experimental CVB3 myocarditis. To our knowledge, this is the first report to demonstrate that noninvasive TTDE with adenosine can detect dysfunction of coronary microcirculation in mice. Low CFR in the acute phase was associated with dilatation and progressive deterioration of systolic function of the left ventricle, indicating that dysfunction of coronary microcirculation is a determinant of poor outcome in viral myocarditis.
Infection of mice with CVB3 is the most common experimental model of myocarditis that has provided important insights into the pathogenesis of human disease (1, 6, 15, 16). Both viral infection of the myocardium and the associated inflammatory response contribute to the pathogenesis of disease. Previous studies (4, 14, 20) using microperfusion techniques have shown structural changes in myocardial microcirculation, such as obstruction and narrowing of small arteries, during acute viral myocarditis in mice. Intracoronary measurements have provided evidence of endothelial dysfunction in response to acetylcholine in epicardial coronary arteries of some patients with histologically proven myocarditis (12). More recently, intracoronary guide wire study demonstrated endothelial dysfunction in patients with inflammatory cardiomyopathy and persistent myocardial viral infection (22). However, the significance of microvascular damage in the development of cardiac dysfunction due to myocarditis remains unknown.
To study the effects of CVB3 infection on function of coronary microcirculation, we used TTDE to measure CFR after maximal vasodilatation induced by adenosine. This noninvasive approach has been extensively validated in various clinical conditions in humans (23) and, recently, in mice with atherosclerotic coronary arteries (7, 24). In the absence of significant stenosis in epicardial coronary arteries, reduced CFR reflects a dysfunction of coronary microcirculation (9, 23). Although adenosine may not be the most sensitive drug to detect microvascular dysfunction because its potent vasodilator effect on small arterioles may overwhelm vasoconstriction due to other causes (23), its advantage over acetylcholine is its suitability for intravenous use. Thus it is the drug of choice for noninvasive studies. We could visualize blood flow in the middle LCA in all mice by TTDE, and the flow velocity profile obtained with pulsed-wave Doppler was clearly distinct from mitral inflow and left ventricular outflow tract. CFR values obtained during adenosine-induced vasodilatation were highly reproducible. A previous study by Wikström and coworkers (24) found that a dose of 0.16 mg·kg–1·min–1 was enough to cause maximal vasodilatation in mice. However, doses up to 0.32 mg·kg–1·min–1 did not exert any systemic hemodynamic adverse effects. We used an adenosine dose of 0.32 mg·kg–1·min–1, because in our dose-response study, it appeared to provide most consistent results in repeated measurements. This dose did not affect heart rate (
400 beats/min) during ketamine-diazepam anesthesia, which is close to that reported in mice in the physiological state (8). Adenosine was well tolerated as none of the mice died during or immediately after infusion, allowing repeated assessment of CFR. CFR in noninfected BALB/c mice was in line with a previous study (24) using TTDE in healthy C57BL/6 mice. We found a consistent reduction of CFR in the acute phase of myocarditis after infection with either CVB3 variant. This was due to reduced flow velocity during adenosine infusion, whereas resting flow velocity remained unchanged. Thus TTDE can be used to study CFR and microvascular dysfunction caused by viral myocarditis in a noninvasive fashion.
To study the significance of coronary microvascular dysfunction in the development of cardiac injury and dysfunction caused by myocarditis, we compared CFR with histopathology and left ventricular function in mild and severe disease forms. Echocardiography plays a critical role in the assessment of myocarditis and its complications in the clinical practice (19). It has also become a routine tool to study various models of cardiac disease in the mouse (8, 21), but the experimental murine model of viral myocarditis remains uncharacterized. We found comparable reduction of systolic function in mild and severe forms of myocarditis 1 wk after infection, but only the severe myocarditis was associated with a progressive worsening of systolic function and dilatation of the left ventricle 2 wk after infection. CFR was significantly more reduced in severe than in mild myocarditis both 1 and 2 wk after infection, correlating closely with histopathological severity of myocardial injury. One week after infection, strongly reduced CFR preceded the development of progressive heart failure, indicating that early microvascular dysfunction may be an important determinant of poor outcome in viral myocarditis. Whether reduced CFR can be detected by TTDE in patients with severe myocarditis and cardiac dysfunction remains to be seen.
The observed microvascular dysfunction may be related to the replication of CVB3 in endothelial cells during acute myocarditis (13). Consistent with this, mice infected with the Woodruff variant of CVB3 that had strongly reduced CFR also show more than 10 times higher titers of infectious virus in the myocardium than mice infected with the Nancy variant that had milder reductions of CFR (1, 16). However, CFR remained low in the severe disease form 2 wk after infection, despite the fact that virus was no longer detectable in the heart (1, 16). Thus there are likely other factors than the viral infection itself that contribute to microvascular dysfunction. These may be related to continuing myocardial inflammation (14) or damage to the microvasculature sustained in the acute phase (3, 12). Microvascular abnormalities have also been observed in cardiomyopathies of various etiologies, for example in Chagas' disease (9). Interestingly, CVB3 is able to cause a long-lasting infection in dermal endothelial cells in vitro (25) that may be associated with prolonged endothelial dysfunction. Some therapeutic approaches, such as verapamil and therapeutic inhibition of elastase enzymes that improved outcome of myocarditis, also reduced microvascular changes as seen with microperfusion techniques (12, 14). With the findings of systolic function and CFR taken together, TTDE may provide a valuable tool to study the effects of therapeutic approaches on microvascular dysfunction and outcome in viral myocarditis.
|
GRANTS
|
|---|
This study was supported by the Clinical Research Funds of the Turku University Central Hospital, the Ester Uotila Foundation, the Finnish-Norwegian Medical Foundation, the Turku University Foundation, the Research Foundation of Orion Corporation, and the Finnish Foundation for Research on Viral Diseases.
|
FOOTNOTES
|
|---|
Address for reprint requests and other correspondence: A. Saraste, Dept. of Clinical Physiology, Turku Univ. Central Hospital, Kiinamyllynkatu 6-8, 20520 Turku, Finland (e-mail: antti.saraste{at}utu.fi)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
* A. Saraste and V. Kytö contributed equally to this study. 
|
REFERENCES
|
|---|
- Arola A, Kalimo H, Ruuskanen O, and Hyypiä T. Experimental myocarditis induced by two different coxsackievirus B3 variants: aspects of pathogenesis and comparison of diagnostic methods. J Med Virol 47: 251–259, 1995.[ISI][Medline]
- Caiati C, Montaldo C, Zedda N, Montisci R, Ruscazio M, Lai G, Cadeddu M, Meloni L, and Iliceto S. Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J Am Coll Cardiol 34: 1193–1200, 1999.[Abstract/Free Full Text]
- Choy JC, Lui AH, Moien-Afshari F, Wei K, Yanagawa B, McManus BM, and Laher I. Coxsackievirus B3 infection compromises endothelial-dependent vasodilatation of coronary resistance arteries. J Cardiovasc Pharmacol 43: 39–47, 2004.[CrossRef][ISI][Medline]
- Dong R, Liu P, Wee L, Butany J, and Sole MJ. Verapamil ameliorates the clinical and pathological course of murine myocarditis. J Clin Invest 90: 2022–2030, 1992.[ISI][Medline]
- Factor SM, Minase T, Cho S, Dominitz R, and Sonnenblick EH. Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cause of focal myocardial necrosis. Circulation 66: 342–534, 1981.
- Feldman AM and McNamara D. Myocarditis. N Engl J Med 343: 1388–1398, 2000.[Free Full Text]
- Gan L, Wikström J, Bergström G, and Wandt B. Non-invasive imaging of coronary arteries in living mice using high-resolution echocardiography. Scand Cardiovasc J 38: 121–126, 2004.[CrossRef][ISI][Medline]
- Gardin JM, Siri FM, Kitsis RN, Edwards JG, and Leinwand LA. Echocardiographic assessment of left ventricular mass and systolic function in mice. Circ Res 76: 907–914, 1995.[Abstract/Free Full Text]
- Gavin JB, Maxwell L, and Edgar SG. Microvascular involvement in cardiac Pathology. J Mol Cell Cardiol 30: 2531–2540, 1998.[CrossRef][ISI][Medline]
- Hirata K, Shimada K, Watanabe H, Muro T, Yoshiyama M, Takeuchi K, Hozumi T, and Yoshikawa J. Modulation of coronary flow velocity reserve by gender, menstrual cycle and hormone replacement therapy. J Am Coll Cardiol 38: 1879–1884, 2001.[Abstract/Free Full Text]
- Hozumi T, Yoshida K, Akasaka T, Asami Y, Ogata Y, Takagi T, Kaji S, Kawamoto T, Uedo Y, and Morioka S. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography, comparison with invasive technique. J Am Coll Cardiol 32: 1251–1259, 1998.[Abstract/Free Full Text]
- Klein RM, Schwarzkopf B, and Strauer BE. Evidence of endothelial dysfunction of epicardial coronary arteries in patients with immunohistochemically proven myocarditis. Am Heart J 136: 389–397, 1998.[CrossRef][ISI][Medline]
- Klingel K, Rieger P, Mall G, Selinka HC, Huber M, and Kandolf R. Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridisation: identification of target cells and cytopathic effects. Lab Invest 78: 1227–1237, 1998.[ISI][Medline]
- Lee JK, Zaidi SH, Liu P, Dawood F, Cheach AYL, Wen WH, Saiki Y, and Rabinovitch M.. A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis. Nat Med 4: 1383–1391, 1998.[CrossRef][ISI][Medline]
- Martino TA, Liu P, and Sole MJ. Viral infection and the pathogenesis of dilated cardiomyopathy. Circ Res 74: 182–188, 1994.[Abstract/Free Full Text]
- Saraste A, Arola A, Vuorinen T, Kytö V, Kallajoki M, Pulkki K, Voipio-Pulkki LM, and Hyypia T. Cardiomyocyte apoptosis in experimental coxsackievirus B3 myocarditis. Cardiovasc Pathol 12: 255–262, 2003.[CrossRef][ISI][Medline]
- Saraste M, Koskenvuo J, Knuuti J, Toikka J, Laine H, Niemi P, Sakuma H, and Hartiala J. Coronary flow reserve: measurement with transthoracic Doppler echocardiography is reproducible and comparable with positron emission tomography. Clin Physiol 21: 114–122, 2001.[CrossRef][ISI][Medline]
- Saraste M, Vesalainen RK, Ylitalo A, Saraste A, Koskenvuo JW, Toikka JO, Vaittine MA, Hartiaka JJ, and Airaksinen KE. Transthoracic Doppler echocardiography as a noninvasive tool to assess coronary artery stenoses–a comparison with quantitative coronary angiography. J Am Soc Echocardiogr 18: 679–685, 2005.[CrossRef][ISI][Medline]
- Shirani J, Ilercil A, Chandra M, Jelicks LA, and Tanowitz HB. Cardiovascular imaging in clinical and experimental acute infectious myocarditis. Front Biosci 8: e323–e36, 2003.[ISI][Medline]
- Silver MA and Kowalczyk D. Coronary microvascular narrowing in acute murine coxsackievirus B3 myocarditis. Am Heart J 118: 173–174, 1989.[CrossRef][ISI][Medline]
- Tanaka N, Dalton N, Mao L, Rockman HA, Peterson KL, Gottshall KR, Hunter JJ, Chien KR, and Ross J Jr. Transthoracic echocardiography in models of cardiac disease in the mouse. Circulation 94: 1109–1117, 1996.[Abstract/Free Full Text]
- Vallbracht KB, Schwimmbeck PL, Kühl U, Rauch U, Seeberg B, and Schultheiss HP. Differential aspects of endothelial function of the coronary microcirculation considering myocardial virus persistence, endothelial activation, and myocardial leukocyte infiltrates. Circulation 111: 1784–1791, 2005.[Abstract/Free Full Text]
- Voci P, Pizzuto F, and Romeo F. Coronary flow: a new asset for the echo lab? Eur Heart J 25: 1867–1879, 2004.[Free Full Text]
- Wikström J, Grönros J, Bergström G, and Gan L. Functional and morphologic imaging of coronary atherosclerosis in living mice using high-resolution color Doppler echocardiography and ultrasound biomicroscopy. J Am Coll Cardiol 46: 720–727, 2005.[Abstract/Free Full Text]
- Zanone MM, Favaro E, Conaldi PG, Greening J, Bottelli A, Perin PC, Klein NJ, Peakman M, and Camussi G. Persistent infection of human microvascular endothelial cells by coxsackie B viruses increased expression of adhesion molecules. J Immunol 171: 438–446, 2003.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
F. Tona, A. L.P. Caforio, and S. Iliceto
Microvascular dysfunction in left apical ballooning syndrome: Primary cause or secondary phenomenon?
Eur J Echocardiogr,
December 1, 2007;
8(6):
411 - 412.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Thibault, L. Gomez, E. Donal, G. Pontier, M. Scherrer-Crosbie, M. Ovize, and G. Derumeaux
Acute myocardial infarction in mice: assessment of transmurality by strain rate imaging
Am J Physiol Heart Circ Physiol,
July 1, 2007;
293(1):
H496 - H502.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2006 by the American Physiological Society.
TOP
ABSTRACT
MATERIALS AND METHODS
