[ Scientific Activities - Actividades Científicas ]Clinical, Cellular and Molecular Descriptors of CHF Due to Regurgitant Valvular Diseases
Jeffrey S. Borer, M.D.Chief, Division of Cardiovascular Pathophysiology
Regurgitant valvular diseases are among the more important causes of both congestive heart failure and sudden death. Among asymptomatic patients with severe aortic regurgitation, the rate of progression to CHF, ventricular dysfunction or sudden death is 6% per year. Among asymptomatic patients with severe mitral regurgitation, the rate of progression to CHF is even more rapid, approximately 10% per year, and the likelihood of sudden death is greater than in aortic regurgitation.
Currently, the most effective treatment for CHF in this setting is valve replacement or repair. Surgery also is the most effective means of preventing CHF and sudden death in these diseases if appropriate objective predictors of deterioration are applied, like the non-invasive measure of contractility constructed from radionuclide cineangiographic LV performance at rest and exercise modified by echocardiographic LV afterload. However, for the future, potential exists to prevent myocardial decompensation by effecting fundamental alterations in myocardial cell biology and molecular controls. The basis for such new approaches to prevention and treatment now are being developed with investigation into cellular and molecular bases of CHF in regurgitant valvular diseases.
First, lets talk about timing of surgery. In aortic regurgitation, using the non-invasive index of contractility, it is possible to determine prognosis more precisely than with performance descriptors alone. To demonstrate this, a population of 104 patients with severe AR was divided arbitrarily into terciles. The third with the best contractility had only a 1.8% annual progression rate to CHF. The third with the poorest contractility, despite normal LVEF at rest, had a ten-fold greater rate of progression. This group also had almost a 10% per year progression to LV dysfunction at rest and a 1% per year risk of sudden death, even if asymptomatic.
In addition, from immediately before aortic valve replacement, it takes three years before cardiac performance is maximally recovered, both at rest and during exercise. This finding suggests that extensive remodeling is possible and, indeed, occurs, and indicates the potential for important therapeutic alteration of cellular function if we can understand the processes.
Among patients with mitral regurgitation, LV performance also can predict outcome, but the right ventricle provides better basis of prediction. Our asymptomatic population with severe MR was divided into those whose RVEF increased with exercise, and those whose RVEF didnt increase with exercise. Over a 10 to 12 year follow-up, rate of progression to heart failure was more than three-fold greater in those with poorer RV functional reserve. This predictor was more powerful than any LV performance or size descriptor in prognostication. In another study, we found that, once RVEF fell to subnormal levels, even in the absence of symptoms, sudden death is an important risk. Indeed, most recently, our data have indicated that this outcome can be further pinpointed by the presence of abnormal R-R dispersion.
Again, however, a key observation for the future is that, once valve surgery is performed, it takes 3 years until LV or RV performance are maximally improved. Characteristically, there is a fall in LVEF early after valve replacement or repair, and a slow recovery during the next several years. The point is, remodeling and alteration of cell biology is possible in these diseases. Our job is to figure out how to make it happen by treatments focused at the cellular and molecular levels.
The pathophysiology underlying the coupling of cellular and clinical events is as follows. Valvular regurgitation leads to ventricular dilatation which unleashes a cascade of cellular processes, including alteration in cell signaling and gene expression, which lead to pathologic hypertrophy and myocardial dysfunction. By teasing out the specific cellular and molecular abnormalities, we should be able to find ways of preventing the progression of these processes to decompensation.
To do this, weve begun with studies in experimental animals. Since contractility descriptors seem most effective in prognosis, our first series of studies has explored the cellular metabolism of the contractile proteins. LV mass increases rapidly during the month after induction of AR. However, this phenomenon is driven by a process which varies dramatically over time: during the first week of AR, when growth is most rapid, myocardial protein synthesis rate is considerably greater than control. Contractile protein synthesis rate also is abnormal. Protein degradation rates tend to be slightly below normal at one week, but growth is predominantly driven by abnormal synthesis of contractile proteins. One month later, growth continues, but now, synthesis rates are subnormal, and continuing hypertrophy is driven by significantly subnormal protein degradation rates.
We followed these animals out for 3 years. Some developed CHF, while others remained compensated. However, those with CHF manifested markedly subnormal synthesis and degradation rates, while compensated animals manifest near-normal contractile protein metabolic kinetics.
Recently, we have completed our initial series of kinetic studies in experimental mitral regurgitation. In MR, synthesis rates at one month not only are markedly subnormal, as compared with control, but also are even lower than we found in AR. In other words, at least one aspect of the disordered cell biology of regurgitant valvular diseases is abnormality of the metabolic kinetics of myocyte-derived contractile proteins.
In addition, our preliminary data suggest that these changes may be measurable non-invasively with PET scanning, a project currently proceeding in our unit.
However, myocyte-derived protein metabolism is not the only myocardial process which is disordered in regurgitant diseases. Histological study reveals that, even in compensated animals with AR, not only are the myocytes hypertrophied but there is a mildly abnormal amount of fibrous tissue.
In animals with similarly severe AR, but with heart failure, marked fibrosis is present, together with myocytolysis. However, there is no inflammatory infiltrate, suggesting that the fibrosis is not a secondary process, but a primary response to ventricular dilatation. Indeed, it is possible that the fibrosis caused the myocytolysis by mechanical alteration in blood flow or other stresses (More recent, preliminary observations suggest that, in AR, myocytolysis may result in part from apopotosis).
The myocytolysis and fibrosis also may be amenable to non-invasive discovery, as we have shown by external imaging with radiolabeled antimyosin antibody. Indeed, the magnitude of antimyosin uptake in experimental AR is directly related to the extent of myocardial fibrosis.
Our findings suggest that pathological fibrosis is an important part of pathological hypertrophy seen in CHF of regurgitant valve diseases. These findings also suggest that new therapies may be facilitated by further understanding of the biology of the cardiac fibroblast in these diseases. With this in mind, we have isolated and cultured cardiac fibroblasts from animals with AR. Study of these cells indicates abnormality of growth curves. More importantly, responses to certain drugs vary with the presence of AR. Thus, for example, Ive depicted the dose response curves of fibroblast survival when the cells are treated with the drug vesnarinone. These observations recently have resulted in a U.S. patent for the use of the drug for fibrosis suppression. On the ordinate, weve plotted the ratio of cell number among treated cells in culture compared with untreated controls. When the drug, vesnarinone, is given in very low doses to normal cells, 50% suppression in cell survival is achieved. In AR cells, the effect is even more marked, peaking at a dose one-tenth of that which causes maximal suppression normally.
To determine the molecular basis of abnormal fibrosis in AR with CHF, and to define a path to its suppression at the most fundamental level, we extracted RNA from these populations of fibroblasts, developed cDNA by RT-PCR, amplified the product by PCR, and displayed the different cDNAs by gel electrophoresis to enable identification of abnormal gene expression in AR. Our preliminary evaluation identified 26 differences of this kind between normal and AR genetic material, but more complete evaluation indicates approximately 9 identifiable genes that are differentially expressed, specifically including several for single extracellular matrix elements. Further work in our lab currently is identifying these fragments completely, and assessing their importance in the pathogenesis of heart failure. Knowledge of these should form the basis for adjunctive, mechanism-specific prophylactic therapy.
In summary, regurgitant valvular diseases commonly cause CHF and sudden death. While we continue efforts to optimize timing of valve surgery with hemodynamic and cellular predictors, continuing efforts are needed to clarify the fundamental cellular and molecular processes which underly cardiac decompensation in these diseases in order to retard or preclude the need for surgery.
1. Borer JS, Hochreiter C, Herrold EM, Supino P, Aschermann M, Wencker D, Devereux RB,
Roman MJ, Szulc M, Kligfield P, Isom OW. Prediction of indications for valve replacement
among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and
normal left ventricular performance. Circulation. 1998;97:525-534.
2. Borer JS, Herrold EM, Hochreiter C, Roman MJ, Supino P, Devereux RB, Kligfield P, Nawaz H. Natural history of left ventricular performance at rest and during exercise after aortic valve replacement for aortic regurgitation. Circulation. 1991;84(suppl III):III-133-III-139.
3. Herrold EM, Carter JN, Borer JS. Volume overload related shape change limits mass increase with wall thickening but only minimally reduces wall stress. Computers in Cardiology 1992. IEEE Computer Society publication 0276-6547/92:287-290.
4. Hochreiter C, Niles N, Devereux RB, Kligfield P, Borer JS. Mitral regugitation: relationship of non-invasive descriptors of right and left ventricular performance to clinical and hemodynamic findings and to prognosis in medically and surgically treated patients. Circulation. 1986;73:900-912.
5. Magid NM, Borer JS, Young MS, Wallerson DC, DeMonteiro C. Suppression of protein degradation in the progressive cardiac hypertrophy of chronic aortic regurgitation. Circulation. 1993;87:1249-1257.
6. Magid NM, Wallerson DC, Borer JS. Myofibrillar protein turnover in cardiac Hypertrophy due to aortic regurgitation. Cardiology. 1993;82:20-29.
7. Rosen SE, Borer JS, Hochreiter C, Supino P, Roman MJ, Devereux RB, Kligfield P, Bucek J et al. Natural history of the asymptomatic/minimally symptomatic patient with severe mitral regurgitation secondary to mitral valve prolapse and normal right and left ventricular performance. American Journal of Cardiology. 1994;74:374-380.
8. Ross JS, Goldfine SM, Herrold EM, Borer JS. Differential response to vesnarinone by cardiac fibroblasts isolated from normal and aortic regurgitant hearts. American Journal of Therapeutics. 1998;5:369-375.
9. Borer JS, Pena M, Falcone D, Truter SL, Kolesar JA, Dumlao TF. Chronic aortic Regurgitation: pre-heart failure fibrosis characterized by fibronectin excess. Circulation. 1999, in press.
10. Supino P, Hochreiter C, Borer JS, Herrold EM, Devereux RB, Roman MJ, Kligfield P, Kendall C. Chronic aortic regurgitation: natural history of rest and exercise ejection fraction and relation to outcome. Circulation. 1999, in press.
11. Carter JN, Jacobson MH, Pena M, Herrold EM, Magid N, Borer JS. LV hypertrophy in chronic, severe AR is not driven by increased protein synthesis. Circulation. 1999, in press.
12. Truter SL, Dumalo TF, Kolesar JA, Borer JS. Amlodipine downregulates Expression of L-type Ca2+ channel DHP-a 2 receptor in normal and aortic regurgitant cardiac fibroblasts. Circulation. 1999, in press.