Correlation of myocardial interstitial collagen in the right ventricular septum with ventricular function of patients with ischemic cardiomyopathy

Abstracts

FUNDAMENTO: O conteúdo de colágeno intersticial (CI) no miocárdio exerce influência no relaxamento e na contração ventricular. A sua relação com a função ventricular em pacientes (pcts) com cardiomiopatia isquêmica (CMPI) não está plenamente estudada em humanos. OBJETIVO: Avaliar a relação da quantidade de CI nas áreas não-infartadas no septo do ventrículo direito com a função ventricular na CMPI. MÉTODOS: 31pcts com doença arterial coronariana foram classificados em quatro grupos: Grupo C (Controle): 7pcts com as frações de ejeção dos ventrículos esquerdo (FEVE) e direito (FEVD) normais; Grupo 1: 5 pcts com FEVD < 40%;Grupo 2: 9 pcts com FEVE < 40%; Grupo 3: 10 pcts com disfunção de ambos os ventrículos. A FEVD e a FEVE foram calculadas por meio da angiocardiografia radionuclídica. As amostras para análise do %CI foram obtidas por meio de biópsia endomiocárdica do ventrículo direito e coradas pela técnica do picrosirius red. RESULTADOS: A média do %CI foi significativamente maior no grupo 3 quando comparada com o grupo-c e com os grupos 1 e 2 (30,2 ± 7,9% vs. 6,8 ± 3,3% vs. 15,8 ± 4,1% vs. 17,5 ± 7,7%, respectivamente; p = 0,0001). O %CI foi também significativamente maior nos pacientes do grupo 2 quando comparado com o controle(17,5 ± 7,7% vs. 6,8 ± 3,3%, p = 0.0001). O %CI apresentou correlação inversa com a FEVD (r = -0,50, p = 0.003) e FEVE (r = -0,70, p = 0,0001). CONCLUSÃO: Na CMPI, o %CI encontra-se elevado nas áreas não-infartadas no septo do ventrículo direito e apresenta correlação inversa com o a função ventricular direita e esquerda.

Isquemia miocárdica; baixo débito cardíaco; função ventricular direita; função ventricular esquerda; colágeno

FUNDAMENTO: El contenido de colágeno intersticial (CI) en el miocardio ejerce influencia en la relajación y en la contracción ventricular. Su relación con la función ventricular en pacientes (pcts) con cardiomiopatía isquémica (CMPI) no está plenamente estudiada en humanos. OBJETIVO: Evaluar la relación de la cantidad de CI en las áreas no infartadas en el septo del ventrículo derecho con la función ventricular en la CMPI. MÉTODOS: Se clasificaron a 31 pcts con enfermedad arterial coronaria en cuatro grupos: Grupo C (Control): 7 pcts con fracción de eyección de los ventrículos izquierdo (FEVI) y derecho (FEVD) normales; Grupo 1:5 pcts con FEVD < 40%; Grupo 2:9 pcts con FEVI < 40%; Grupo 3:10 pcts con disfunción de ambos los ventrículos. La FEVD y la FEVI se calcularon por medio de la angiocardiografía con radionúclidos. Las muestras para análisis del porcentaje de colágeno intersticial (%CI) se obtuvieron mediante biopsia endomiocárdica del ventrículo derecho y se colorearon con la técnica del picrosirius red. RESULTADOS: El promedio del %CI fue significativamente mayor en el grupo 3 cuando comparado al grupo-c y a los grupos 1 y 2 (30,2 ± 7,9% vs. 6,8 ± 3,3% vs. 15,8 ± 4,1% vs. 17,5 ± 7,7%, respectivamente; p = 0,0001). El %CI fue asimismo significativamente mayor en los pacientes del grupo 2 cuando comparado al control (17,5 ± 7,7% vs. 6,8 ± 3,3%, p = 0.0001). El %CI presentó correlación inversa con la FEVD (r = -0,50, p = 0.003) y la FEVI (r = -0,70, p = 0,0001). CONCLUSIÓN: En la CMPI, el %CI se encuentra elevado en las áreas no infartadas en el septo del ventrículo derecho y presenta correlación inversa con la función ventricular derecha e izquierda.

Isquemia miocárdica; bajo débito cardíaco; función ventricular derecha; función ventricular izquierda; colágeno

ORIGINAL ARTICLE

^IUniversidade de São Paulo, Instituto do Coração (InCor), São Paulo, SP Hospital Pró-Cardíaco

^IICentro de Insuficiência Cardíaca -

^IIILaboratório de Medicina Nuclear

^IVLaboratório de Cateterismo Cardíaco, Rio de Janeiro, RJ; Santa Casa de Misericórdia -

^VDepartamento de Cardiologia, Rio de Janeiro, RJ, Universidade Federal do Rio de Janeiro -

^VIDepartamento de Histologia, Rio de Janeiro, RJ - Brazil

Mailing address

SUMMARY

BACKGROUND: Myocardial collagen content influences ventricular relaxation, contraction, and morphology. Its relationship with ventricular function in patients (Pts) with ischemic cardiomyopathy (ICMP) has not yet been fully studied in humans.

OBJECTIVE: To assess the relationship between interstitial collagen content in non-infarcted areas of the right ventricular septum and ventricular function in ICMP.

METHODS: 31 pts with coronary artery disease were divided into four groups as follows:The control group consisted of 7 pts with normal left (LVEF) and right (RVEF) ventricular ejection fraction (group C); Group 1: 5 patients with RVEF < 40%; Group 2: 9 pts with LVEF < 40%; and Group 3, 10 pts with biventricular dysfunction. RVEF and LVEF were measured by radionuclide angiography. For quantitative analysis of interstitial collagen volume fraction (CVF), endomyocardial biopsy specimens were taken from the right ventricle and stained with picrosirius red.

RESULTS: Mean CVF was significantly higher in group 3, compared with the control group and with groups 1 and 2 (30.2 ± 7.9% vs. 6.8 ± 3.3% vs. 15.8 ± 4.1% vs. 17.5±7.7%, respectively; p =0.0001). It was also significantly higher in patients belonging to group 2, compared with those in the control group (17.5 ± 7.7% vs. 6.8 ± 3.3%, p =0.0001). CVF was inversely correlated with RVEF (r = - 0.50, p = 0.003) and LVEF (r = -0.70, p = 0.0001).

CONCLUSION: In ICMP, CVF is elevated in non-infarcted areas of the right ventricular septum and inversely correlated with right and left ventricular function.

Key words: Myocardial ischemia; cardiac output, low; ventricular function, right; ventricular function, left; collagen.

Introduction

Heart failure (HF) is a highly prevalent syndrome that affects approximately 1% to 1.5% of the adult population. It is estimated that 4.7 million people in the United States have heart failure, with 400,000 new cases being diagnosed every year^1-3. The majority of cases result from heart muscle diseases, known as cardiomyopathies, of which ischemic cardiomyopathy (ICM) is the most common, accounting for 40% to 80% of all cardiomyopathies^1,4. Ischemic cardiomyopathy carries a worse prognosis than idiopathic dilated cardiomyopathy^4-7, probably due to the presence of areas of myocardial ischemia and fibrosis from prior infarction, which may predispose to arrhythmias and extensive ventricular remodeling.

The activation of ventricular remodeling is related to the extent of myocardial necrosis, fibrosis, and ischemia in the infarcted area. However, it has been demonstrated that morphological changes in the remote non-infarcted myocardium play a major role in the development of ventricular remodeling^8,9. These include diffuse perivascular fibrosis, interstitial fibrosis, and diffuse atrophy of cardiac myocytes¹⁰. Changes in myocardial matrix at sites distant from myocardial scarring account for approximately two-thirds of all cardiac fibrous tissue and are regarded as the primary component of ventricular remodeling in ischemic cardiomyopathy^11,12.

The morphological and morphometric changes that occur in the myocardium following myocardial infarction, with the development of left ventricular (LV) systolic and diastolic dysfunctions, are well described in the literature^8,13-16. However, the relationship between these changes in the extracellular matrix of the non-infarcted myocardium and right (RV) and left (LV) ventricular systolic function in ICM is not well-established.

The aim of this study is to assess the relationship between interstitial collagen content, measured by right ventricular septal biopsy, and right and left ventricular systolic function in ICM patients with varying degrees of ventricular dysfunction.

Methods

From January to December 2003, thirty-one patients with angiographically documented coronary artery disease were consecutively included in the study for diagnostic evaluation of precordial pain or left ventricular dysfunction. They were divided into four groups according to left (LVEF) and right (RVEF) ventricular ejection fractions measured by radionuclide angiography as follows: Control group (Group C), seven patients with preserved LV and RV systolic function; Group 1, five patients with isolated RV systolic dysfunction (RVEF < 40%); Group 2, nine patients with isolated LV systolic dysfunction (LVEF < 40%); and Group 3, ten patients with right and left ventricular systolic dysfunction. Patients with pulmonary hypertension, chronic obstructive pulmonary disease (COPD), infiltrative or restrictive myocardial diseases, and collagen diseases were excluded from the study, as were those with suspected myocarditis, myocardial infarction with septal involvement or right ventricular dysfunction secondary to right ventricular cardiomyopathy. The study protocol was approved by the Institutional Ethics Committee, and an informed consent was obtained from all patients.

All patients underwent biochemical tests, including renal function tests, electrocardiography (ECG), and transthoracic echocardiography (ECHO). Exclusion criteria were septal myocardial infarction on ECG and ECHO, significant valvular heart disease, systemic hypertension (blood pressure > 140x90 mmHg), serum creatinine above 1.4 mg/dL, atrial fibrillation, clinical instability of less than two weeks, and chronic obstructive pulmonary disease.

Cardiac catheterization

All patients underwent coronary angiography via the femoral approach using Sones' technique. Coronary artery disease was defined as stenosis greater than 50% in at least one major epicardial coronary artery. Ventriculography was also performed in all subjects.

Analysis of ventricular function

Both right and left ventricular functions were assessed by equilibrium and first-pass radionuclide angiography. Left and right ventricular ejection fractions were calculated using the standard method recommended by the American Society of Nuclear Cardiology¹⁷, with the lower limit of normal set at 40% for both ventricles. Right ventricular ejection fraction (RVEF) was measured by first-pass radionuclide angiography using a DIACAM Siemens gamma camera connected to an ICON computer. The study protocol was validated by the Cardiovascular Nuclear Imaging Laboratory of the Yale University School of Medicine¹⁸. Tc-99m was injected at rest in all patients to assess ventricular function. Images were acquired in the supine position, with the detector in the right anterior oblique (RAO) projection (20° to 30°). First-pass images were analyzed independently by two nuclear medicine physicians, using two regions of interest. Mean values for right and left ventricular functions were used for statistical analysis. Beats with end-diastolic counts below 50% of the maximum end-diastolic count were excluded, as were premature ventricular beats and post-premature ventricular contraction (PVC) beats. For statistical analysis purposes, normal right ventricular ejection fraction was considered to be equal to or greater than 40%.

LVEF was measured by planar equilibrium radionuclide angiography with the modified technique for in-vivo labeling, using 2 to 3 mg of stannous pyrophosphate 15 minutes before injecting 20 mCi of Tc-99m-pertechnetate¹⁹. Images were acquired in the supine position with the detector in the left anterior oblique (LAO) projection at 45 degrees. Left ventricular systolic dysfunction was defined as LVEF d" 40%.

Endomyocardial biopsy

Right ventricular endomyocardial biopsies were performed percutaneously according to Mason's technique²⁰ using a Cordis bioptome, and four tissue samples were obtained from the interventricular septum of each patient.

Histological study and quantification of interstitial collagen

Biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin. Serial, 5-¼m-thick sections were mounted on glass slides and stained with hematoxylin-eosin, Masson's trichrome, and Sirius Red (0.1% Sirius red F3BA dissolved in saturated picric acid, pH 2.0). Ten fields per section were analyzed at a magnification of x320. Collagen content was measured by quantitative morphometric analysis of sirus-red-stained sections, with an automatic image analyzer (Image-Pro Plus 4.5.1 software, Media Cybernetics, Silver Spring, MD, USA). Images were captured using a Coolpix 900 digital camera attached to an Eclipse E400 light microscope (both manufactured by Nikon, Japan). Each histological section was viewed at a magnification of x40. Collagen fibers were stained blue under direct light, and images were digitized. Interstitial collagen volume fraction (CVF) in each field was calculated as the sum of all connective tissue area divided by the sum of all connective tissue and cardiac myocyte areas, as demonstrated previously in a number of studies^21-24.

Statistical analysis

Quantitative data among the four groups were compared by Kruskal-Wallis analysis of variance. The Kruskal-Wallis test for multiple comparisons was applied as a complementary method to ANOVA, since some variables were not normally distributed (Gaussian distribution). Given the small number of cases, Fisher's exact test was used to compare proportions between groups (qualitative data). The Mann-Whitney test was used to compare means, and the Spearman correlation coefficient, to assess the correlation between collagen fraction and numerical variables. A receiver operating characteristic (ROC) curve was constructed to determine the best cut-off point for CVF to predict right and left ventricular dysfunction. The significance level was set at 5%. Statistical analyses were performed using SAS^® statistical software.

Results

Patients' characteristics

Clinical characteristics of the patients are summarized in Table I. No significant difference was found in clinical and demographic variables among the four groups, except for lower incidence of smoking in group 3. Most patients were on angiotensin-converting enzyme inhibitors and beta-blockers, with no significant differences among groups regarding drug regimen.

Coronary artery disease

The majority of patients (84%) had two- or three-vessel disease, the left anterior descending artery (LAD) being the most frequently affected. There was no difference among the four groups with regard to the presence of lesions involving the proximal left anterior descending and right coronary (RC) arteries (p = 0.91) Table 2.

Analysis of ventricular function

Mean LVEF was 51.5 ± 8.5 in the control group and 50.6 ± 8.8, 27.9 ± 5,1, and 21.7 ± 4.7% in groups 1, 2, and 3, respectively. Mean RVEF in the four groups were, respectively, 42.4 ± 4.7, 28.2 ± 2.7, 50.3 ± 5.1, and 22.0 ± 6.5%. No significant difference was found in LVEF between groups with biventricular dysfunction and isolated left ventricular dysfunction (21.7 ± 4.7% vs. 27.9 ± 5.1, p = 0.10). This was also true for RVEF between groups with biventricular dysfunction and isolated left ventricular dysfunction (28.2 ± 2.7 vs. 22.0 ± 6.5%, p = 0.10).

Analysis of collagen volume fraction

Mean collagen volume fraction (CVF) is shown in figure 1. Collagen content was higher in the group with biventricular dysfunction, compared with the control group and groups with isolated right or left ventricular dysfunction (30.2 ± 7.9 vs. 6.8 ± 3.3, 15.8 ± 4.1, and 17.5 ± 7.7%, respectively; p = 0.0001). Patients with isolated left ventricular dysfunction had higher CVF than the control group (17.5 ± 7.7 vs. 6.8 ± 3.3%, p = 0.0001). The group with isolated right ventricular dysfunction showed a tendency to higher CVF, compared with the control group (15.8 ± 4.1 vs. 6.8 ± 3.3, p = 0.08) (Figure 2).

Correlation between collagen volume fraction and ventricular function

There was a significant inverse linear relationship between collagen fraction and RVEF (r = -0.50; p = 0.003, n = 31) and LVEF (r = -0.70; p = 0.0001, n = 27), demonstrating that the higher the collagen fraction the lower the RVEF and LVEF, as shown in Figures 3 and 4.

ROC curve analysis

The best cut-off point for CVF for the association with LVEF <40% was 18.3%, with sensitivity of 70.5%, specificity of 90%, and area under the ROC curve of 0.87 (95% CI: 0.7- 0.9; p = 0.0001) (Figure 5 a). For the association with RVEF d" 40%, the cut-off point was 12.9%, with sensitivity of 82%, specificity of 64.2%, and area under the ROC curve of 0.77 (CI 95%: 0.59-0.9; p = 0.0001) (Figure 5 b).

Discussion

This is the first human study published in the literature to demonstrate a direct relationship between interstitial collagen content in the right ventricle and right and left ventricular dysfunction in patients with ischemic cardiomyopathy. A linear correlation was observed between CVF in the non-infarcted myocardium and the degree of right and left ventricular dysfunction. Interstitial collagen fraction was 4.4 times higher in patients with biventricular dysfunction, 2.5 times higher in patients with isolated left ventricular dysfunction, and 2.3 times higher in patients with isolated right ventricular dysfunction, as compared with those with preserved ventricular function, showing an inverse correlation between collagen content and LVEF and RVEF. The association between ventricular dysfunction and the degree of interstitial collagen proliferation was reinforced by the demonstration of an inverse linear correlation between collagen content and RVEF and LVEF (Figures 3 and 4). The analysis of the relationship between several volume fractions of interstitial collagen and ventricular function allowed us to establish a cut-off point of 12.9% and 18%, respectively, for the prognosis of right ventricular dysfunction and left ventricular dysfunction, with high sensitivity (82.0% and 70.5%, respectively) and specificity (64.2% and 90.0%, respectively), and areas under the ROC curve of 0.87 and 0.77, respectively, indicating that these cut-off points are strongly correlated with CVF for discriminating the presence of ventricular dysfunction (Figures 5 a and b).

Studies in human and animal models have demonstrated that changes in myocardial collagen network in ischemic and non-ischemic cardiomyopathy play a major role in the development of ventricular dysfunction. Particularly, the possibility was raised that collagen deposition within the cardiac interstitium may be a primary factor contributing to, rather than only a marker of, the development of myocardial dysfunction^{8,9,12-16,25,26}. This has been emphasized in studies demonstrating that post-myocardial infarction remodeling is associated with increased interstitial fibrosis in the non-infarcted myocardium, which is correlated with progressive myocardial stiffness and thus to systolic and diastolic dysfunction^12,13,26-28. Also supporting our findings of greater proliferation of interstitial collagen in biventricular dysfunction is the evidence of increased production of angiotensin in the myocardium of patients with right ventricular dysfunction secondary to pulmonary hypertension²⁹.

The difficulty in confirming the association between the degree of right or left ventricular dysfunction and interstitial collagen content lies in the lack of human in vivo studies analyzing collagen and the degree of ventricular dysfunction, particularly right ventricular dysfunction. This may be partly due to a failure of current methods to accurately assess right ventricular systolic and diastolic function.

Pauschinger et al²⁵ have found that interstitial collagen was increased in patients with dilated cardiomyopathy and LVEF < 50%, compared with those with LVEF > 50% (4.3 ± 0.1% vs. 2.7 ± 0.9 %, p < 0.0035), in addition to increased collagen type I/III ratio.

Interstitial collagen content is also increased in non-ischemic dilated cardiomyopathy³⁰, but to a lesser extent than in ischemic cardiomyopathy^12,13. This increased collagen content in ischemic cardiomyopathy results not only from ventricular remodeling induced by myocardial infarction, but also from the trophic stimulation of myocardial ischemia^31,32. An excessive amount of interstitial collagen leads to myocardial fibrosis and, consequently, myocardial stiffness and diastolic dysfunction, in addition to subsequent impairment of systolic function^8,33-36. Weber and Brilla¹⁴ suggest that deposition of interstitial collagen is the primary determinant of impaired ventricular relaxation. Collagen accumulation is also related to the clinical severity of heart failure, the degree of hemodynamic impairment, hyponatremia, and need for heart transplantation³⁷. In contrast, hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have shown a reduction in myocardial fibrosis and ventricular hypertrophy, regardless of the decrease in blood pressure, with improvement in systolic and diastolic ventricular function, cardiac arrhythmias, and clinical symptoms, as well as reduced ventricular mass^38-40 .

This strongly suggests that increased interstitial collagen in ischemic cardiomyopathy is a major determinant of ventricular dysfunction, and not only a marker of the degree of ventricular remodeling. In patients with ischemic cardiomyopathy, collagen content was found to be increased not only in the infarcted, but specially in the non-infarcted myocardium^8,12,16, a finding that was challenged by Marijianowski et al⁴¹ but corroborated by others^37,42.

Our findings have important implications for clinical practice, since they demonstrate that, in less severe forms of ventricular dysfunction, there is a significant increase in collagen content and that its progression is directly related to worsening ventricular dysfunction and the degree of ventricular remodeling. They also suggest that in less advanced phases of ventricular dysfunction, the inhibition of collagen production with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists may contribute to reduce both the progression of ventricular remodeling and mortality, as was demonstrated in advanced ventricular dysfunction^43-47.

Study limitations

Some limitations of our study should be noted. Most patients were using ACE inhibitors, which may have affected collagen content, since these agents can reduce myocardial fibrosis. However, no difference was found between groups regarding the use of these medications and their dosage. Another limitation was that only endomyocardial biopsies from the right ventricular septum were used, restricting our study to a single ventricular region, without an analysis of the regional distribution of collagen content. Yet, only in explanted hearts with end-stage heart failure would such analysis be possible, and this was beyond the scope of this study. Another limiting factor was the lack of a control group, that is, patients without coronary disease who underwent endomyocardial biopsy, which was not feasible due to ethical reasons. However, mean collagen content in the group with preserved ventricular function was similar to that found in studies of patients without coronary artery disease that used endomyocardial biopsies taken from the RV septum⁴⁸ and LV free wall⁴⁹. An analysis of collagen type I/III ratio would have provided information on the potential reversibility of myocardial fibrosis and enhancement of ventricular function, as suggested by Pauschinger et al²⁵. Finally, the presence of myocardial ischemia, which might have influenced the degree of collagen content, was not evaluated in our study, although the extent of coronary artery disease, as documented by coronary angiography, was found to be similar among groups.

Conclusion

Concluding, in patients with ischemic cardiomyopathy, there is an increase in collagen content in the non-infarcted region of the right ventricular septum, which is inversely correlated to the degree of right and left ventricular systolic dysfunction.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of Doctoral submitted by Marcelo Westerlund Montera, from Universidade de São Paulo.

References

• 1. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998; 97: 282-9.
• 2. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology / American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in Collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America. Circulation. 2001; 104: 2996-3007.
• 3. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002; 347: 1397-402.
• 4. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000; 342: 1077-84.
• 5. Likoff MJ, Chandler SL, Kay HR. Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol. 1987; 59: 634-8.
• 6. Franciosa JA, Wilen M, Ziesche S, Cohn JN. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol. 1983; 51: 831-6.
• 7. Bart BA, Shaw LK, McCants CB Jr, Fortin DF, Lee KL, Califf RM, et al. Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. J Am Coll Cardiol. 1997; 30: 1002-8.
• 8. Volders PGA, Willems IE, Cleutjens JP, Arends JW, Havenith MG, Daemen MJ. Interstitial collagen is increased in the noninfarcted myocardium after myocardial infarction. J Mol Cell Cardiol. 1993; 25: 1317-23.
• 9. Wei S, Chow LT, Schum IO, Chin L, Sanderson JE. . Left and right ventricular collagen type I/III ratio and remodeling post-myocardial infarction. J Card Fail. 1999; 5: 117-26.
• 10. Cooper GIV. Basic determinants of myocardial hypertrophy: a review of molecular mechanisms. Annu Rev Med. 1997; 48: 13-23.
• 11. Iwai N, Shimoike H, Kinoshita M. Genes up-regulated in hypertrophied ventricle. Biochem Biophys Res Commun. 1995; 209: 527-34.
• 12. Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cígola E, et al. Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation. 1994; 89: 151-63.
• 13. Schaper J, Froede R, Hein ST, Buck A, Hashizume H, Speiser B, et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation. 1991; 83: 504-14.
• 14. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Circulation. 1991; 83: 1849-65.
• 15. Litwin SE, Litwin CM, Raya TE, Warner AL, Goldman S. Contractility and stiffness of noninfarcted myocardium after coronary ligation in rats: effects of chronic angiotensin converting enzyme inhibition. Circulation. 1991; 83: 1028-37.
• 16. Hare JM, Walford GD, Hruban RH, Hutchins GM, Deckers JW, Baughman KL. Ischemic cardiomyopathy: endomyocardial biopsy and ventriculographic evaluation of patients with congestive heart failure, dilated cardiomyopathy and coronary artery disease. J Am Coll Cardiol. 1992; 20: 1318-25.
• 17. Port SC. Imaging guidelines for nuclear cardiology procedures. Part II. American Society of Nuclear Cardiology. J Nucl Cardiol. 1999; 6: G47-84.
• 18. Berger HJ, Gottschalk A, Zaret BL. First-pass radionuclide angiocardiography for evaluation of right and left ventricular performance: computer applications and technical considerations. In: Sorenson JA (ed). Nuclear cardiology: selected computer aspects. New York: Society of Nuclear Medicine; 1978. p. 29-44.
• 19.Callahan RJ, Froelich JW, Mckusick KA, Leppo J, Strauss HW. A modified method for the in vivo labeling of red blood cells with Tc-99m: concise communication. J Nucl Med. 1982; 23: 315-8.
• 20. Mason JW. Techniques for right and left ventricular endomyocardial biopsy. Am J Cardiol. 1978; 41: 887-92.
• 21. Brilla CG, Janicki JS, Weber KT. Impaired diastolic function and coronary reserve in genetic hypertension: role of interstitial fibrosis and medial thickening of intramyocardial coronary arteries. Circ Res. 1991; 69: 107-15.
• 22. Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res. 1990; 67: 1355-64.
• 23. Doering CW, Jalil JE, Janicki JS, Pick R, Aghili S, Abrahams C, et al. Collagen network remodeling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res. 1988; 22: 686-95.
• 24. Brilla CG, Janicki JS, Weber KT. Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy. Circulation. 1991; 83: 1771-9.
• 25. Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, et al. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation. 1999; 99: 2750-6.
• 26.Mukherjee D, Sen S. Alteration of collagen phenotypes in ischemic cardiomyopathy. J Clin Invest. 1991; 88: 1141-6.
• 27. Weber KT, Anversa P, Armstrong PW, Brilla CG, Burnett JC Jr, Cruickshank JM, et al. Remodeling and reparation of the cardiovascular system. J Am Coll Cardiol. 1992; 20: 3-16.
• 28.Zisman LS,Asano K,Dutcher DL, Ferdensi A, Robertson AD, Jenkin M, et al. Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation. 1998; 98: 1735-41.
• 29.Bishop JE, Greenbaum R, Gibson DG, Yacoub M, Laurent GJ. Enhanced deposition of predominantly type I collagen in myocardial disease. J Mol Cell Cardiol. 1990; 22: 1157-65.
• 30.Brooks A, Schinde V, Bateman AC, Gallagher PJ. Interstitial fibrosis in the dilated non-ischaemic myocardium. Heart. 2003; 89: 1255-6.
• 31.Karsch KR, Kreuzer H, Neuhaus KL. Myocardial function of the right ventricle in coronary disease. Z Kardiol. 1976; 65 (11): 972-82.
• 32.La Vecchia L, Luca Spadaro G, Paccanaro M, Favero L, Zanolla L, Vincenzi P, et al. Predictors of right ventricular dysfunction in patients with coronary artery disease and reduced left ventricular ejection fraction. Coron Artery Dis. 2002; 13 (6): 319-22.
• 33. Hess OM, Schneider J, Koch R, Bamert C, Crimm J, Krayenbuehl HP. Diastolic function and myocardial structure in patients with myocardial hypertrophy: special reference to normalized viscoelastic data. Circulation. 1981; 63: 360-71.
• 34. Pelouch V, Dixon IMC, Golfman L, Beamish RE, Dhalla NS. Role of extracellular matrix proteins in heart function. Mol Cell Biochem. 1993; 129: 101-20.
• 35. Smits JFM, Van Krimpen C, Schoemaker RG, Cleutjens JP, Daemen MJ. Angiotensin II receptor blockade after myocardial infarction in rats: effects on hemodynamics, myocardial DNA synthesis, and interstitial collagen content. J Cardiovasc Pharmacol. 1992; 20: 772-8.
• 36. Pfeffer JM, Pfeffer MA, Fishbein MC, Frohlich ED. Cardiac function and morphology with aging in the spontaneously hypertensive rat. Am J Physiol. 1979; 6: H461-8.
• 37. Klappacher G, Franzen P, Haab D, Mehrabi M, Binder M, Plesch K, et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol. 1995; 175 (14): 913-8.
• 38. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation. 2000; 102: 1388-93.
• 39. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metanalysis of 109 treatment studies. Am J Hypertens. 1992; 5: 95-110.
• 40. Diez R, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left-ventricular chamber stiffness in hypertensive patients. Circulation. 2002; 105: 2512-7.
• 41. Marijianowski MMH, Teeling P, Becker A. Remodeling after myocardial infarction in humans is not associated with intersticial fibrosis of noninfarcted myocardium. J Am Coll Cardiol. 1997; 30: 76-82.
• 42. Volders PGA, Daemen MJAP. Interstitial fibrosis and angiotensin-converting enzyme inhibition in patients with end-stage myocardial infarction. (letter). J Am Coll Cardiol. 1998; 32: 552.
• 43. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992; 327: 669-77.
• ⁴⁴
  Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left-ventricular ejection fractions: the SOLVD Investigators. N Engl J Med. 1992; 327: 685-91.
• 45. Pitt B, Zanna F, Remm WJ, Cody R, Castaigne A, Perez A, et al. for The Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709-17.
• 46. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterona blocker in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309-21.
• 47. Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K, et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents postinfarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation. 2003; 107: 2559-65.
• 48. Pickering JG, Boughner DR. Fibrosis in the transplanted heart and its relation to donor ischemic time. Circulation. 1990; 80: 949-58.
• 49. Chello M, Mastroroberto P, Romano R, Perticone F, Marchese AR. Collagen network remodeling and left ventricular function in constrictive pericarditis. Heart. 1996; 75: 184-9.

Correlation of myocardial interstitial collagen in the right ventricular septum with ventricular function of patients with ischemic cardiomyopathy

Marcelo Westerlund Montera^I,II,III; Cantídio Drumond^V; Cristina Takiya^VI; Cláudio Tinoco Mesquita^III; Hans Fernando R. Dohmann^IV, Charles Mady^I

Publication Dates

• Publication in this collection
  04 Feb 2009
• Date of issue
  Jan 2009

History

• Reviewed
  18 Feb 2008
• Received
  29 Nov 2007
• Accepted
  05 Mar 2008