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1 The Association of Heart Valve Diseases with Coronary Artery Dominance Gwilym M. Morris 1, Anthony L. Innasimuthu 2, Jonathan P. Fox 3, Raphael A. Perry 4 1 Division of Cardiovascular and Endocrine Sciences, University of Manchester, 2 University Hospital Aintree, Liverpool, 3 Southport and Ormskirk NHS Trust, 4 The Cardiothoracic Centre, Liverpool, United Kingdom Background and aim of the study: Aortic stenosis (AS) is thought to be caused by calcific degeneration of the aortic valve. Clinical observations suggest an association between a left dominant coronary circulation and AS, a situation previously investigated at necropsy and with small observational studies. Mitral regurgitation (MR) and aortic regurgitation (AR) are both disorders with multiple etiologies, but neither has any known association with coronary artery dominance. Methods: The coronary angiogram database of a tertiary referral centre was reviewed for consecutive left heart catheter data acquired over a six-year period. The severity of AS was classified by measured pressure gradient (in mmhg) as none (0), mild (<30), moderate (30-49), or severe (>49). Both, MR and AR were assessed visually by the operator. Results: A total of 1,891 patients was included. In the AS group there was a significant association with a left dominant coronary circulation (p <0.0001), and the proportion of patients with left dominance increased with the severity of AS (p <0.005). There was no significant association of AR with coronary artery dominance (p = 0.84). MR was associated with a reduced prevalence of left dominance (p <0.005). Conclusion: AS was associated with a left dominant coronary circulation, and the incidence of left dominance was increased with the severity of AS, but the opposite situation was true for MR. The reasons for these observations remain unclear. The Journal of Heart Valve Disease 2010;19: Heart valve disease is a common cause of morbidity and mortality. During a routine left heart catheterization, hemodynamic data regarding aortic stenosis (AS), aortic regurgitation (AR) and mitral regurgitation (MR) can be obtained. Among these conditions, AS is the most common, with a prevalence of 2% by the age of 65 years (1). Known risk factors for AS are similar to those for atherosclerosis, and include hypertension, hypercholesterolemia, and smoking (1). Evidence shows that over 80% of AS is caused by calcific degeneration (2), a process which shares histological and molecular mechanisms with atherosclerosis, including lipid deposition, inflammation, macrophage infiltration, and consequent calcification (3-5). Despite these similarities, there is evidence that AS is a distinct disease, since most patients with atherosclerosis do not develop AS, and aggressive lipid-lowering Address for correspondence: Dr. Gwilym M. Morris, Department of Cardiac Electrophysiology, 3rd Floor, Core Technology Facility, Grafton St., Manchester M13 9NT, UK gwilym.morris@postgrad.man.ac.uk therapy does not affect AS disease progression (6,7). Hence, despite its high prevalence the underlying process of AS is not fully understood. It has been suggested that the development of AS is due to endothelial shear stress (3,8) and, indeed, it is conceivable that the fractional distribution of blood flow to the left and right coronary ostia might cause variations in shear stress on the aortic surface of the aortic valve. The results of necropsy studies have suggested an association between a left dominant coronary artery circulation and congenital bicuspid aortic valve (9,10), while other smaller studies have proposed a correlation between AS and a left dominant circulation (11,12). Aortic regurgitation may coexist with degenerative AS, but has many other causes that include connective tissue disorders (e.g., Marfan s syndrome and pseudoxanthoma elasticum), infective endocarditis, and dilatation of the aortic root. In western countries, the major causes of significant MR are degenerative (e.g., myxomatous disease, flail leaflets, annular calcification), representing 60-70% of cases, ischemic MR (representing 20%), endocarditis (2-5%), and rheumatic (2-5%). Ischemic disease most likely represents a larger Copyright by ICR Publishers 2010

2 390 Valve disease and coronary dominance Table I: Dataset requirements for inclusion in the sample for each valve lesion. Valve lesion AS AR MR proportion of mild MR cases (13). To date, however, no association between these regurgitant valve disorders and coronary artery dominance has been reported. Left heart catheterization allows the assessment of AS (via the withdrawal gradient), MR (by visual assessment at left ventriculography), and AR (by visual assessment at aortography). The dominance of the coronary artery system can easily be determined from coronary angiography by studying the supply of the posterior descending artery. In the present study, a large left heart catheter database was studied to investigate the association between AS, AR and MR and coronary artery dominance. Herein, the data are presented which show that coronary artery dominance is a previously unrecognized risk factor for both AS and MR. Materials and methods Data pressure gradient (mmhg) severity (none, mild, moderate or severe) severity (none, mild, moderate or severe) LVEF: Left ventricular ejection fraction A retrospective review was conducted of the left heart catheter data from a tertiary referral center (the Cardiothoracic Centre, Liverpool, UK) for the period between 1st January 2000 and 31st December Inclusion in the sample set for each valve lesion required a complete record of the parameters for that valve, as described in Table I. The severity of AS was classified by the measured aortic valve pressure gradient as: none (0 mmhg); mild (1-29 mmhg); moderate (30-49 mmhg); or severe (>49 mmhg). The severity of AR and MR was assessed visually by the operator. For each valve lesion, contingency tables were constructed to study the association with a dominant left coronary artery circulation. Statistical analyses were performed using the chisquare test for independence, and for linear trend using software from StatsDirect (Altrincham, UK). Results J Heart Valve Dis Among a total of 2,027 patients who underwent angiography, 1,938 were included in the initial sample. Eighty-nine were excluded from the study due to insufficient data (dominance was not mentioned in 37 patients, and the ejection fraction was <30% in the remaining 52). Aortic stenosis A total of 1,891 patients was identified with a complete AS data set (Table II). The presence of AS was associated with a dominant left coronary circulation (Fig. 1; p <0.0001). A linear trend analysis showed that an increasing severity of AS was associated with an increased prevalence of left dominance (p = ). Aortic regurgitation A total of 1,265 patients was identified with complete Table II: Numbers of coronary angiograms identified with complete data for each sample group. Condition Left dominant Right dominant Co-dominant Total coronary artery coronary artery coronary arteries Aortic stenosis None Mild Moderate Severe Aortic regurgitation None Mild Moderate Severe Mitral regurgitation None Mild Moderate Severe

3 J Heart Valve Dis Valve disease and coronary dominance 391 Figure 1: Aortic stenosis (AS) is associated with a dominant left coronary circulation (p <0.0001). This association shows a linear trend with increasing severity of stenosis (p = ). Figure 2: There was no significant association between the prevalence of aortic regurgitation (AR) and the coronary arterial dominance. AR data (Table II). The presence of AR had no significant association with a left dominant circulation (Fig. 2; p = 0.17). Mitral regurgitation A total of 744 patients was identified with sufficient MR data (Table II). Patients with MR were less likely to have a left dominant coronary circulation (Fig. 3; p = ), an association which showed a linear trend (p = ). Discussion The data acquired showed that a dominance of the coronary artery system has an association with the presence of AS and MR. Furthermore, this association shows a linear trend with increasing severity of the valve lesion. When taken in the context of current knowledge, such an observation provides some insight into the underlying pathology of these diseases. During the early 20th century, the most common cause of heart valve disease was rheumatic fever. However, the incidence of this condition has steadily declined over the past three decades, such that today the most common cause of AS is calcific degeneration (14). Both, mitral valve degeneration and cardiac ischemia are today the most common causes of MR (15,16). Non-rheumatic causes are incompletely understood, especially in the case of AS. Calcific AS, which may occur in both the tricuspid and bicuspid valves, is a degenerative disease that is characterized by thickening and macroscopic nodular calcification of the aortic aspect of the valve cusps, leading to a reduced excursion of the valve leaflets and an obstruction of ventricular outflow. Histological examination shows the presence of fibrosis, lipid accumulation, and macrophage infiltration (4,5), an appearance which bears similarities to arterial atherosclerotic plaques. Moreover, both conditions share many risk factors, including hypercholesterolemia, hypertension, smoking, and diabetes. There is, however, a significant discordance between the development of the two diseases, in that not all patients with AS have coronary artery disease, and vice versa. How then, might this situation, and also the association of left dominance with AS, be accounted for? The simplest explanation is one of altered hemodynamics at the valve level. The increased rate of calcification of unicuspid and bicuspid aortic valves has been attributed in part to such a phenomenon (3). A small nondominant right coronary artery could mean a greater volume of blood flowing into the left mainstem coronary artery; furthermore, the pressure waves of blood flow in the right and left coronary arteries would differ. In the left coronary artery the flow is pulsatile, and this may cause an increase in endothelial shear stress (17). Consequently, a change in flow rate and pressure wave (especially at the left coronary valve cusp) may subject the endothelium of the aortic valve to an increased shear stress, which is known to cause arterial calcification and plaque formation (18). A similar process could be occurring at the level of the aortic valve in the presence of a dominant left coronary artery. Shear stress has been shown to regulate matrix metalloproteinase and cathepsin activity in porcine aortic valves, leading to an increase in the extracellular matrix compared to the cell content, and consequent valve remodeling (19). It is possible that an inherited predisposition for the development of AS may be genetically linked to a left

4 392 Valve disease and coronary dominance J Heart Valve Dis Study limitations The primary limitation was that the results might have been biased, as the data were acquired from patients who were sufficiently symptomatic as to warrant an invasive investigation. However, to perform cardiac catheterization on asymptomatic or minimally symptomatic patients solely to determine a coronary artery dominance would clearly be unethical (27). The present results have provided some indications as to the mechanisms of AS and MR. In clinical practice, when arterial dominance is recognized, it might be used as a factor to help predict the likelihood of disease progression. Figure 3: Mitral regurgitation (MR) is associated with a reduced prevalence of a dominant left coronary artery circulation. There is an inverse correlation between the severity of MR and left dominance. dominant circulation. Indeed, there is evidence of a genetic contribution to AS, with familial clustering of AS having been identified in western France (20). A vitamin D receptor polymorphism has also been associated with AS, as have a number of apolipoprotein E alleles, suggesting a polygenic contribution to the disease (21,22). The genetic determinism of the coronary artery dominance is not known, however. As identical twins may have different arterial dominances (23), it is tempting to conclude that dominance is a result of nurture in utero, and that nature bears little influence. Yet, it is more likely that both play a role, such that a genetic disposition towards left dominance is modulated on a local level during cardiac development. This view is supported by the known association of bicuspid aortic valves and a left dominant circulation (9,24). The anatomy of the bicuspid valve is unable to influence the development of the coronary arteries, as the arteries develop from distal to proximal and join to the aorta at a later stage. Thus, this association must be due to factors other than the valve itself (25). In contrast, the major causes of MR are degenerative (60-70%), ischemic MR (20%), endocarditic (2-5%) and rheumatic (2-5%) (13). The results of the present study showed that a left dominant coronary circulation would protect against MR, and would mean the presence of a large circumflex artery. As the circumflex artery is closely related to the posterior aspect of the mitral valve annulus, where the valve is least well supported by connective tissue, a large circumflex artery might strengthen the annulus in this area. This might explain why circumflex territory infarction caused the most MR in a sheep model of myocardial infarction (26). References 1. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29: Iung B, Baron G, Tornos P, Gohlke-Barwolf C, Butchart EG, Vahanian A. Valvular heart disease in the community: A European experience. Curr Probl Cardiol 2007;32: Ramaraj R, Sorrell VL. Degenerative aortic stenosis. Br Med J 2008;336: O Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of degenerative valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16: Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O Brien KD. Characterization of the early lesion of degenerative valvular aortic stenosis. Histological and immunohistochemical studies. Circulation 1994;90: Otto CM, O Brien KD. Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart 2001;85: Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359: Otto CM. Calcific aortic stenosis - time to look more closely at the valve. N Engl J Med 2008;359: Hutchins GM, Nazarian IH, Bulkley BH. Association of left dominant coronary arterial system with congenital bicuspid aortic valve. Am J Cardiol 1978;42: Scholz DG, Lynch JA, Willerscheidt AB, Sharma RK, Edwards JE. Coronary arterial dominance associated with congenital bicuspid aortic valve. Arch Pathol Lab Med 1980;104: Chandrasekar B, Sudarsana G, Abraham KA. Aortic valve disease and left dominant coronary system: A significant association. J Assoc Physicians India

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