Myocardial fibrosis and ventricular remodeling in severe chronic aortic regurgitation

Abstracts

FUNDAMENTO: A insuficiência aórtica crônica importante sintomática (IAo) leva a grande remodelamento ventricular esquerdo, à custa de hipertrofia de mióciotos e remodelamento da matriz extracelular. A relevância da concentração de fibrose intersticial nos pacientes acometidos é desconhecida. Analisamos o grau de fibrose no ventrículo esquerdo (VE) em pacientes sintomáticos com IAo submetidos a tratamento cirúrgico e sua relação com características funcionais e anatômicas. OBJETIVO: Avaliar a fibrose miocárdica na insuficiência aórtica crônica importante. MÉTODOS: Selecionaram-se 28 pacientes com IAo (16 com função VE normal e 12 com disfunção do VE), os quais foram analisados no pré e pós-operatório por ecodopplercardiografia. A capacidade funcional foi medida pelo teste de esforço cardiopulmonar. Para comparação dos resultados histopatológicos, um grupo-controle de 9 pacientes foi constituído. RESULTADOS: A média etária foi de 39 ± 12 anos, 75% do sexo masculino com 84% de etiologia reumática. Vinte e cinco pacientes permaneceram em classes funcionais I e II ao fim do estudo e apresentaram redução significativa dos diâmetros do VE entre os momentos pré e pós-operatórios. Houve três óbitos não relacionados à disfunção VE. Os parâmetros do teste cardiopulmonar não se modificaram entre o pré e o pós-operatório. O volume de fibrose intersticial em pacientes com IAo foi significativamente quando maior comparado ao grupo controle (3,47 ± 1,9% vs 0,82 ± 0,96%, respectivamente, p = 0,001). Não houve correlação entre o grau de fibrose do VE, parâmetros ecocardiográficos e funcionais. CONCLUSÃO: Em pacientes com IAo, a presença de fibrose miocárdica não se associou às alterações clínicas, ecocardiográficas ou funcionais.

Fibrose endomiocárdica; insuficiência da valva aórtica; função ventricular esquerda

FUNDAMENTO: La insuficiencia aórtica crónica severa sintomática (IAo crónica severa) ocasiona una gran remodelación ventricular izquierda, por cuenta de hipertrofia de miociotos y remodelación de la matriz extracelular. Se desconoce la relevancia de la concentración de fibrosis intersticial en los pacientes acometidos. Analizamos el grado de fibrosis en el ventrículo izquierdo (VI) en pacientes sintomáticos con IAo crónica severa sometidos a tratamiento quirúrgico y su relación con características funcionales y anatómicas. OBJETIVO: Evaluar la fibrosis miocárdica en la insuficiencia aórtica crónica severa. MÉTODOS: Se seleccionaron a 28 pacientes con IAo crónica severa (16 con función VI normal y 12 con disfunción del VI), los que se analizaron en el pre y el postoperatorio por ecocardiografía Doppler. Se midió la capacidad funcional por la prueba de esfuerzo cardiopulmonar. Para comparación de los resultados histopatológicos, se constituyó a un Grupo Control de 9 pacientes. RESULTADOS: El promedio de edad fue de 39±12 años, el 75% del sexo masculino con el 84% de etiología reumática. El total de 25 pacientes permanecieron en clases funcionales I e II al fin del estudio y presentaron reducción significativa de los diámetros del VI entre los momentos pre y postoperatorios. Hubo tres óbitos no relacionados a la disfunción VI. Los parámetros de la prueba cardiopulmonar no se modificaron entre el pre y el postoperatorio. El volumen de fibrosis intersticial en pacientes con IAo crónica severa fue significativo cuando mayor, comparado al Grupo control (3,47 ± 1,9% vs. 0,82 ±0,96%, respectivamente, p = 0,001). No hubo correlación entre el grado de fibrosis del VI, parámetros ecocardiográficos y funcionales. CONCLUSIÓN: En pacientes con IAo crónica severa, la presencia de fibrosis miocárdica no se asoció a las alteraciones clínicas, ecocardiográficas o funcionales.

Fibrosis endomiocárdica; insuficiencia de la válvula aórtica; función ventricular izquierda

ORIGINAL ARTICLE

Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil

Mailing address

SUMMARY

BACKGROUND: Significant symptomatic chronic aortic regurgitation (AR) leads to considerable left ventricular remodeling at the expense of myocyte hypertrophy and extracellular matrix remodeling. The relevance of interstitial fibrosis concentration in these patients is unknown. We analyzed the degree of fibrosis in the left ventricle (LV) in symptomatic patients with AR submitted to surgical treatment, and its relationship with functional and anatomical characteristics.

OBJECTIVE: To evaluate myocardical fibrosis in chronic severe aortic regurgitation.

METHODS: Twenty-eight patients with chronic symptomatic AR (16 with normal LV function and 12 with LV dysfunction) were selected and assessed pre- and postoperatively by echocardiography. Functional capacity was measured using maximal oxygen consumption (VO₂max) through the cardiopulmonary test. Myocardial fibrosis volume fraction (MFV) was quantified through endomyocardial biopsy performed in all patients during surgery. We compared the histopathologic results with a nine-patient control group.

RESULTS: The mean age was 39 ± 12 years, 75% of the patients were male, and the rheumatic etiology accounted for 84% of the cases. Twenty-five patients remained in FC l and ll at the end of the study, and there was a significant reduction of the LV diameters between the preoperative and late postoperative timepoints. Three deaths occurred but they were not related to postoperative ventricular dysfunction. The parameters of the cardiopulmonary test were similar between pre- and postoperative timepoints. MFV in patients with AR was significantly higher than in the control group (3.47 ± 1.9% vs 0.82 ± 0.96%, respectively, p=0.001). There was no statistical correlation among LV fibrosis and LV diameters, LVEF and MVO₂.

CONCLUSION: In patients with significant symptomatic AR, the presence of limited myocardial fibrosis was not associated with clinical, echocardiographic or functional complications.

Key words: Endomyocardial fibrosis; aortic valve insufficiency; ventricular function left.

Introduction

The natural history of chronic aortic regurgitation (AR) is characterized by a long asymptomatic period during which significant eccentric LV hypertrophy develops, as well as remodeling in response to volume-pressure overload¹.

Symptoms generally occur as a collapse of the LV adaptation mechanisms, and occasionally may result in permanent injury to the structure and function of the cardiomyocytes and changes in the extracellular matrix². The extent of the injury may be such that LV function may be incapable of returning to normal, even after aortic valve replacement^3,4.

Over the two last decades^5,6, clinical trials were based primarily on LV dimensions and systolic function as indications of the ideal timing for aortic valve replacement. This procedure interrupts the natural history of AR, but it exposes the patient to the risks of surgery and valve prosthesis implantation. Up until now, there is still controversy as to the optimum time to interrupt the disease's natural history.

Many of the indexes available are based on measurements of the left ventricular function, which depend much more on the pre- and post-overload than on LV contractility itself. However, the extracellular matrix is a significant component of the LV mechanism of adapting to the volume-pressure overload. The impact of how to interpret the accumulation of fibrosis on clinical, structural and functional parameters is unknown⁷. This information may help to improve and stratify prognostic indexes. Our aim was to assess the level of LV fibrosis in patients with AR and its correlation with functional and anatomical parameters.

Methods

Study population

AR patients with indications for surgery were prospectively selected according to modified Spagnuolo et al⁸ criteria.

Patients aged < 18 or > 60 years, who had atrial fibrillation, with any other cardiac problems except AR, were excluded. All patients signed informed consent term forms, and the research project was approved by the scientific and research ethics committees.

Patients were evaluated by clinical and laboratorial criteria, and cardiopulmonary stress testing.

Clinical assessment

It consisted of three timepoints for each patient: 1) preoperative assessment (baseline), 2) early postoperative (1 month after surgery), and 3) late postoperative (8 to 12 months after surgery).

At each timepoint, echocardiographic and laboratory evaluations were performed. Most patients were medicated with digitalis, diuretics and angiotensin converter enzyme inhibitors during the preoperative phase. All patients underwent thorough evaluations as to etiopathogeny and symptoms such as angina, syncope, dizziness and NYHA functional class.

Echocardiography

Interpretation was based on the recommendations of the American Society of Echocardiography⁹. The following items were assessed by Simpson's method: LV diastolic diameter (LVDd), LV systolic diameter (LVSd), and LV ejection fraction (LVEF). Patients were divided into two groups: LVEF > 0.55 (normal) and LVEF < 0.55 (left ventricular dysfunction).

Cardiopulmonary stress testing

This was performed in a Cardio O₂ (Medical Graphics Corporation) cycle ergometer with a Hans-Rudolf # 2600 valve and 100ml dead space. The ramp protocol was set with a load adjusted according to each patient's physical exercise capacity so as to obtain approximately 10 minutes of workout. This enabled measurement of the maximal oxygen consumption (VO₂max)¹⁰.

Collagen morphometry and histological analysis

Endomyocardial biopsy of the lateral LV wall was performed in all patients during surgery. This area was selected for biopsy because it has no conduction bundle.

The incision was carefully performed, always by the same surgeon, with a # 11 scalpel blade, in order to obtain 3mm depth and 6mm length.

Tissue fragments were fixed in 10% formaldehyde and later embedded in paraffin. Serial 5mm sections were mounted onto labeled slides and stained with Masson's trichrome for detection and quantification of collagen, and with hematoxylin-eosin for histological analysis. The fractions of myocardial fibrosis volumes (MFV) were quantified by video-morphometry using an image analysis system (Quantimet 520 Image Analysis System-Cambridge Instruments, Cambridge, UK). The quantification of the MFV fraction was calculated as the ratio of the area positively stained for fibrosis to the total myocardial area. The endocardium was not considered. Measurements were made on the serial sections, in all fields observed with 10X optical microscopy. In order to compare the histopathological results, a nine-patient (mean age 27 ±16 years) control group was assembled; three of them died of non-cardiac causes and their hearts had normal aspects. Myocardial biopsy samples were taken from the LV lateral wall. Calculation of the myocardial fibrosis volume (MFV) was made using methodology with Masson's trichrome and video-morphology previously mentioned.

Statistical analysis

Statistical analysis was performed using the SAS software. The statistical significance was set as 0.05. Continuous variables were expressed as mean ± standard deviation (SD), whereas the categorical variables were expressed as absolute and relative frequencies. Paired and non-paired T tests were used. Qualitative data were analyzed using the ratio equivalence hypothesis, the chi-square test or, when the number was limited, Fisher's exact test. Multivariate analysis of the profile was used to analyze the echocardiographic changes occurred during the follow-up.

Results

We analyzed 28 patients who had undergone aortic valve replacement, with a mean age of 39±12 years, 75% of them male, and 84% with rheumatic etiology. At the end of the study, twenty-five patients were in functional classes I and II. Three patients died, one of them on the 5th postoperative day due to aortic rupture, and the other two during the 4^th and 9^th postoperative months due to infectious endocarditis.

There was a significant reduction in left ventricular diameters between the preoperative and the late postoperative timepoints (Table 1). LVEF and cardiopulmonary stress test data were similar between the two timepoints (pre- and late postoperative).

All AR patients had a high content of fibrosis relative to the control group. MFV in patients with AR was 3.47±1.9%, compared to 0.82±0.96% in the control group (p=0.001).

Figures 1, 2 and 3 show no correlation between the grade of fibrosis and the left ventricular diameters, left ventricular function, and VO₂max.

Sixteen patients had LVEF >0.55, and 12 patients had LVEF <0.55. The mean age of patients with a normal LVEF (35±11 years) was lower than that of the group with LV dysfunction (45±11 years, p=0.02). There was no significant difference of MFV between the groups with and without LV dysfunction (3.52±1.82% vs 3.33±2.10%, respectively, p=0.799).

Discussion

AR patients may have a difficult follow-up, as the frequent morphological changes do not correlate with clinical symptoms^4,11. Over the past two decades, a few parameters emerged such as LVDd >70mm, LVSd >55mm, and shortening fraction < 0.25, which indicated poorer postoperative results. However, studies on the correlations between the reduction in ejection fraction, increase in left ventricular diameters, and myocardial fibrosis in AR are scarce.

Fibrosis is a restrictive element in LV remodeling. The patient may benefit from surgery through the reduction of volume-pressure overload and the resulting improvement in contractility. Nevertheless, the degree of established fibrosis may determine an incomplete regression of left ventricular remodeling, especially from a viscoelastic point of view. During the adaptive hypertrophy phase, there is an increase of more elastic forms of collagen that maintain the LV relatively compliant, despite the increased muscle mass¹². Myocardial fibrosis is an important prognosis marker in heart failure. In our study, however, we were not able to detect a correlation between myocardial fibrosis and left ventricular function, probably due to the significant degree of left ventricular hypertrophy even in the presence of ventricular dysfunction.

The magnitude of the myocardial fibrosis volume (MFV) in our patients was 3.47%, smaller than the 4.97% value identified in the cases of idiopathic dilated cardiomyopathy¹³. In hypertensive cardiomyopathy, the value reported was even higher (approximately 8.50%)¹³, similar to that found in alcoholic cardiomyopathy (10.77%)¹⁴. In our study, the normal MFV value in the control group was 0.82%. Paradoxically, the worst prognosis in the groups abovementioned was reported in the cases of idiopathic dilated myocardiopathy, precisely the group with the smallest quantity of myocardial fibrosis. Our results, along with the data above, indicate that fibrosis does not seem to be a determinant factor for the prognosis of myocardial diseases.

With our study, we can speculate that the interstice does not necessarily reflect the degree of left ventricular dysfunction, a fact asserted by some authors^12,15 in other series of AR patients. An important datum in our group of patients is the predominance of young rheumatic individuals (84%, with a mean age of 39 years), which distinguishes this study from other studies in literature, where the age bracket is higher (approximately 55 years of age) and with predominant non-rheumatic etiology^1,11. Another possible explanation for such a discrepancy is that the level of ventricular impairment does not consist of collagen alone, but also of other non-collagen elements of the extracellular matrix, such as fibronectin¹⁶.

The similar magnitude of fibrosis in both groups studied (3.52±1.82% in the group with no LV dysfunction vs 3.33±2.10% in the group with LV dysfunction, p=0.799) suggests that fibrosis is not an essential determinant in the natural history of AR. The absence of a correlation between the fibrosis and VO₂M also corroborates this theory.

Conclusion

Our conclusion is that in patients with significant chronic symptomatic aortic regurgitation submitted to surgery, myocardial fibrosis did not correlate with clinical and functional parameters, or left ventricular remodeling.

Therefore, in view of the complexity of the physiopathology, we continue to follow ventricular remodeling through clinical, laboratorial, and histopathological studies, since we have not found in medical literature a reliable laboratory parameter that may foresee prognosis.

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 Nelson Elias, from Faculdade de Medicina da Universidade de São Paulo.

Abbreviations

AR - Chronic aortic regurgitation.

MFV - Myocardial fibrosis volume.

FC - Functional class.

LV - Left ventricle.

LVDd - Left ventricular diastolic diameter.

LVSd - Left ventricular systolic diameter.

LVEF - Left ventricular ejection fraction.

VO₂max - Maximal oxygen consumption.

NYHA - New York Heart Association.

AVR - Aortic valve replacement.

References

• 1. Bonow RO, Lakatos RO, Maron BJ, Epstein SE. Serial long-term assessment of natural history of asymptomatic patients with chronic aortic regurgitation and normal left ventricular systolic function. Circulation. 1991; 84: 1625-35.
• 2. Baandrup U, Olsen EGJ. Critical analysis of endomyocardial Biopsias from patients suspected of having cardiomyopathy. Br Heart J. 1981; 45: 475-7.
• 3. Zile MR. Chronic aortic and mitral regurgitation: choosing the optimal time for surgical correction. Cardiol Clin. 1991; 9: 239-53.
• 4. Tarasoutchi F, Grinberg M, Spina GS, Sampaio RO, Cardoso LF, Rossi EG, et al. Ten-year clinical laboratory follow-up after application of a symptom-based therapeutic strategy to patients with severe chronic aortic regurgitation of predominant rheumatic etiology. J Am Coll Cardiol. 2003; 41: 1316-24.
• 5. Rahimtoola SH. Valve replacement should not be performed in all asymptomatic patients with severe aortic incompetence. J Thorac Cardiovasc Surg. 1980; 79 (2): 163-72.
• 6. Fioretti P, Roelandt J, Bos RJ, Meltzer RS, van Hooglnhuijze D, Serruys PW, et al. Echocardiography in chronic aortic insufficiency. Is valve replacement too late when left ventricular end-systolic dimension reaches 55 mm? Circulation. 1983; 67: 216-21.
• 7. Liu SK, Magid NR, Fox PR, Goldfine SM, Borer JS. Fibrosis, myocyte degeneration and heart failure in chronic experimental aortic regurgitation. Cardiology. 1998; 90: 101-9.
• 8. Spagnuolo M, Kloth H, Taranta A, Doyle A, Pasternak B. Natural history of rheumatic aortic regurgitation: criteria predictive of death, congestive heart failure, and angina in young patients. Circulation. 1971; 44: 368-80.
• 9. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R. Recommendations for quantification of the ventricle by two dimensional echocardiography: American Society of Echocardiography Committee on Standards Subcommittee. J Am Soc Echocardiogr. 1989; 2: 358-67.
• 10. Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis. 1984; 129: S49-S55.
• 11. Borer JS, Hochreiter C, Herrold E, Supino P, Aschermann M, Wencker D, et al. Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance. Circulation. 1998; 97: 525-34.
• 12. Krayenbuehl HP, Hess OM, Schneider J, Turina M. Left ventricular function and myocardial structure in aortic valve disease before and after surgery. Herz. 1984; 9: 270-8.
• 13. Weber KT, Janicki JS, Pick R, Abrahms C, Shroff SG, Bashey RI, et al. Collagen in the hypertrophied, pressure overloaded myocardium. Circulation. 1987; 75 (1): 140-7.
• 14. Soufen HN. Análise histológica e molecular da fibrose miocárdica em pacientes portadores de miocardiaopatia dilatada de diferentes etiologias. J Insuf Card. 2002; 3 (2): 39-40.
• 15. Taniguchi K, Kawamaoto T, Kuki S, Masai JMitsuno M, Nakano S, et al. Left ventricular myocardial remodeling and contractile state in chronic aortic regurgitation. Clin Cardiol. 2000; 23: 608-14.
• 16. Shekhonin BV, Domogatsky SP, Idelson GL, Kateliansky VE. Participance of fibronectin and various collagen types in the formation of fibrous extracellular matrix in cardio sclerosis. J Mol Cell Cardiol. 1988; 20: 501-8.

Myocardial fibrosis and ventricular remodeling in severe chronic aortic regurgitation

Nelson Elias; Flávio Tarasoutchi; Guilherme Sobreira Spina; Roney O. Sampaio; Pablo M.A. Pomerantzeff; Francisco Rafael Laurindo; Max Grinberg

Publication Dates

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

History

• Received
  07 Jan 2008
• Reviewed
  21 Feb 2008
• Accepted
  01 Apr 2008