Practical Pearls: Cardiac Auscultation for the Lipidologist: A Systolic Murmur You Do Not Want to Miss!

It is typically silent, but sometimes you can hear it, a soft systolic ejection murmur heard over the aortic area during cardiac auscultation on physical examination. As cardiovascular risk reduction specialists, we do not to want to miss this cardiac murmur. It is not innocent or benign; this is the murmur of aortic valve sclerosis (ASc). In addition, there is a normal split of the second heart sound, a normal carotid upstroke, and a peak transaortic systolic gradient noted on Doppler transthoracic echocardiography (TTE) typically less than 16 mmHg. The characteristic M-mode tracing on echocardiography is seen in Figure 1. ASc is characterized by calcification and thickening involving the aortic valve cusps with no hemodynamically significant transaortic systolic gradient noted on TTE. ASc shares many of the same clinical risk factors for coronary heart disease (CHD) including age, hypertension, and cigarette smoking.¹

ASc is prevalent among the elderly. Of 5,176 subjects >65 years of age enrolled in the prospective Cardiovascular Heart Study undergoing adequate echocardiographic study, 26% were found to have ASc.¹ Aortic valve stenosis was identified in 2% of the subjects. ASc is even more common among patients with known coronary heart disease. The prevalence is approximately 40%.^2,3 In a study of 425 patients presenting to the emergency room with chest pain, the prevalence of Asc was even higher at 49%.⁴ In patients undergoing coronary angiography for chest pain, the prevalence was related to the degree of obstructive coronary artery disease present. In patients with no obstructive CHD, single vessel CHD, double or triple vessel CHD prevalence respectively was 14%, 28%, and 58%.² Interestingly, ASc was found to be a more powerful predictor of obstructive CHD in patients < 60 years of age than in those >60 years.²

In a study of 338 consecutive patients undergoing myocardial perfusion single photon emission computed tomography (SPECT) and TTE, ASc was significantly associated with an abnormal SPECT.⁵

Among mitral and aortic valve sclerosis calcification sites, the odds for an abnormal SPECT in younger patients (<55 years) for 3 sites was nearly 4 times higher than for patients without calcium. In older patients (>55 years of age), the odds were only 1.94 times as high. After univariate analysis, CRP has been found to be associated with ASc (p<0.05) in 425 patients presenting to the emergency room with chest pain.⁴ After one year, in patients with established ASc, there was a marked decrease in event-free survival for those at the highest tertile of CRP (>1.18 mg/dL) compared to the patients at the lowest tertile (<0.32 mg/dL). The odds for an abnormal SPECT in patients with multiple calcific deposits, diabetes mellitus or multiple cardiac risk factors was striking for women when they had these factors. The OR was 20.00 in younger women (<55 years of age) vs. 10.00 for older women (>55 years of age) compared to women with no multiple calcium deposits without diabetes mellitus or multiple cardiac risk factors. ASc has important clinical ramifications. Not only can ASc progress to aortic valve stenosis; it is independently associated with adverse cardiovascular events.

In a study of 2,131 patients with ASc over a mean follow-up of 7.4 years, 10.5% developed mild, 2.9% developed moderate and 2.5% developed severe aortic valve stenosis.⁶ In the Cardiovascular Health Study, 9% of 1,091 subjects followed for a mean 5-year period developed aortic valve stenosis.7 ASc was independently associated with new coronary events (risk ratio 1.8) in a prospective study of 1980 subjects.⁸ In the large prospective Cardiovascular Health Study of over 5000 men and women >65 years of age, followed for 5 years, ASc was independently associated with increased risk of cardiovascular death and myocardial infarction (MI).⁹ ASc has been shown to be an independent predictor of MI in patients with known CHD also. In a prospective study of 814 patients with CHD, 40% having prevalent ASc had a 2.4 fold increased risk of MI during 4-years of follow-up.³

ASc is associated with lipid accumulation inflammation in addition to calcium deposition in the valve. Low density lipoprotein (LDL) and lipoprotein (a) [Lp(a)] were found in lesions of aortic stenosis.¹⁰ Elevated circulating Lp (a), and low high density lipoprotein (HDL) cholesterol have been shown to be independently associated with ASc.^11,12 LDL-C is associated with aortic valve stenosis^13-16 in patients with Familial Hypercholesterolemia, however the association in the general population has been inconsistent. In the Cardiovascular Health Study¹⁷, increased LDL-C was associated with ASc but not in the SPARC (Stroke Prevention: Assessment of Risk in Community)¹⁸ or in the Helsinki Aging Study.¹⁹

ASc is associated with systemic endothelial dysfunction as demonstrated by significantly lower flow mediated dilatation (FMD).²⁰ Recently, it has been shown that ASc is associated with platelet resistance to NO.²¹ Over a 4-year follow-up period, progression of ASc was also independently associated with tissue resistance to NO.²²

ASc lesions have histologic similarities with coronary atherosclerotic plaque including inflammatory cells: specifically macrophages and T-lymphocytes, in addition to lipid accumulation and disruption of the basement membrane.^23,24 After univariate analysis, CRP has been found to be associated with ASc (p<0.05) in 425 patients presenting to the emergency room with chest pain.4 After one year, in patients with established ASc, there was a marked decrease in event-free survival for those at the highest tertile of CRP (>1.18 mg/dL) compared to the patients at the lowest tertile (<0.32 mg/ dL). In patients without CHD or ASc and a CRP in the upper two tertiles, the cardiac death and MI incidence at 1 year was 0 versus 41% in patients with CHD and ASc. In this study, ASc was not an independent predictor. The presence of CHD and elevated CRP was associated with the adverse cardiovascular events however. Specifically, the increasing tertile of CRP was an independent predictor of cardiac death and nonfatal MI (HR 2.2). However, in a lower risk, prospective population study, CRP was not found to be associated with the development of ASc.⁷

In addition to inflammation and lipid accumulation, aortic ASc is associated with calcification. Calcification involving the aortic valve is an active osteogenic process which has been characterized as an osteoblast-like phenotype.²⁵ Compared to normal human aortic valves, explanted calcified aortic valves at the time of transplantation were shown to have increased levels of the proteins: Osteocalcin, Osteopontin, bone sialoprotein and the transcription factor Cbfa-1 all characteristics of osteoblast activity.²⁶ Furthermore, in patients with aortic valve stenosis undergoing surgery or routine echocardiography, increased plasma levels of Osteopontin were associated with the presence of aortic valve calcification and stenosis.²⁷ In addition to Osteocalcin and Osteopontin, low-density lipoprotein receptor-related protein 5 (Lrp5) was found to be increased in explanted calcified aortic valves by protein and gene expression at the time of surgical valve replacement.²⁷ Lrp5 is an important receptor in the activation of skeletal bone formation. In a study of hypercholesterolemic rabbits with aortic valve calcification, atorvastatin decreased Lrp5 and the aortic valve calcification.²⁸ Just recently, for the first time, a circulating osteogenic precursor cell in human blood has been identified to be associated with calcification of the aortic valve.²⁹

Patients with ASc are at higher risk for myocardial infarction and CHD and should be assessed for underlying CHD. Multiple retrospective studies^30-34 have shown statins to be beneficial in reducing progression of aortic valve stenosis; unfortunately, prospective, randomized^35-37 and non-randomized³⁸ clinical trials have not confirmed these observations. Furthermore, there has never been reported a randomized placebo controlled trial in patients with ASc with a TTE Doppler gradient of less than 16 mmHg. The average peak transaortic systolic gradient was at least 36 mmHg in all of these prospective trials. It still remains unknown whether statin therapy will reduce the progression of ASc to aortic stenosis in patients with milder forms of ASc. Of interest is a recent study in hypercholesterolemic mice with early aortic valve disease demonstrating that reducing plasma lipid levels by genetic inactivation normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve disease.³⁹

We believe that in patients with a cardiac murmur, when there is reasonable suspicion of valvular or structural heart disease, it is appropriate to obtain an echocardiogram.³⁹ It is also helpful to add on the TTE request: "Please evaluate for Aortic Valve Sclerosis/Stenosis." It is also appropriate to obtain an echocardiogram for routine surveillance (>3 years) of mild valvular stenosis or (>1 year) for moderate or severe valvular stenosis without a change in clinical status or cardiac exam.⁴⁰ If a patient is identified with ASc then intensive risk factor modification should be instituted including a regular exercise program. In a LDL receptor deficient mouse model, regular exercise training prevented ASc through several aspects including reduction and inflammation, oxidative stress and also an inhibition of the osteogenic pathway.⁴¹ This may be relevant to humans.

Patients with CHD, or CHD risk equivalents including diabetes mellitus, will all need to be on statins regardless of their LDL-C levels or the presence of ASc. We are looking forward to the future as studies address molecular targets for valvular calcification. ASc is an important murmur that we do not want to miss!

Disclosure statement: Dr. López has received honoraria from Abbott Laboratories, Aegerion, Amarin Corp., AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo Inc., Forest Pharmaceuticals, Gilead Pharmaceuticals, GlaxoSmithKline, Kowa Pharmaceuticals America, and ZonaHealth. Dr. Nelson has received honoraria from Abbott Laboratories, Amarin Corp., AstraZeneca, Atherotech, Bristol-Myers Squibb, Daiichi Sankyo Inc., GlaxoSmithKline, Gilead Pharmaceuticals, Kowa Pharmaceuticals America, Merck & Co., Pfizer Inc., and Novartis Pharmaceuticals.

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