Cardiovascular Disease — A Comprehensive Approach to Manage the Risks of Cardiac Events

Molina, Cesar, MD
Medical Director
South Asian Heart Center
El Camino Hospital
Mountain View, CA Also by this Author 

Lowering low-density lipoprotein cholesterol (LDL-C) is the primary target for cardiovascular disease (CVD) risk reduction and can significantly reduce the incidence of cardiovascular (CV) events.1 The latest guidelines, released November 2013, reiterate the need to continue to use evidence-based medicine in the pursuit of the treatment of cholesterol for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in women and men.2 However, even with effective LDL-lowering, many patients with underlying cardiometabolic risk continue to experience cardiac events.3-5 In fact, even at very low levels of LDL-C in response to therapy, a significant rate of cardiac events persists.6

Dr. Cesar Molina, Heart and Vascular Associates, Mountain View, California discusses the significance of residual risk and outlines how a more comprehensive approach to patient management, beyond a single focus on reducing LDL-C, can reduce clinical events in at-risk populations.

The Nature of Residual Risk

“When coronary artery disease is treated with the available modalities, we can only reduce the incidence of recurrent events by 30%,” notes Dr. Molina. “Yet the data show that we can achieve reversal of atherosclerosis, if we properly treat their metabolic disorder. To do that we need to better identify and diagnose the patient, as well as minimize the residual risk through a comprehensive evaluation, that goes beyond standard cholesterol testing.”

“The first step in making an accurate diagnosis is to identify the underlying factors of the patient’s vascular disease”, says Dr. Molina. He is careful to point out that a narrow focus on lowering cholesterol through statin therapy may only partially address the issue. “The analogy here is that we cannot conclude that a strep throat is caused by the absence of penicillin,’ he says. “Similarly, just because we can lower cholesterol and decrease the incidence of CV events partially it doesn’t mean that’s the whole story.”

“We need to identify the underlying factors driving the disease,” he continues. “It could be hyperinsulinemia, or non-specific inflammation, or in some cases the presence of small particles of LDL. Unless you understand the factors at work and treat the pathophysiology with multiple modalities, the process remains unchecked and is destined to continue.”

Identifying Risk Factors

Since there are many possible causes of atherosclerotic disease, Dr. Molina stresses the importance of considering the full range of potential factors. These can broadly be divided between lifestyle related factors, such as tobacco use, obesity and sedentary lifestyle, and dysmetabolic factors such as dysmetabolic syndrome, dyslipidemia, hyperglycemia, or hypertension, which may also be related to hyperinsulinemia and obesity.

“Other factors may be involved,” he says, “such as elevations in lipoprotein(a) (LP(a)) and its lethal interaction with dyslipidemia, hypertriglyceridemia, low HDL cholesterol and low activation of the lipoprotein lipase. It can be due to the presence of small particles of LDL, driven by genetic factors and lifestyle, or it could be on account of vitamin deficiency.”

Advanced Testing – More Comprehensive, More Precise

Advances in diagnostic methodologies, enabling testing for a wide range of risk factors, can help a physician make a more accurate assessment of causative factors following a cardiac event than is possible with traditional cholesterol testing. “Standard approaches do not actually measure LDL cholesterol,” explains Dr. Molina. “They’re a calculated measure of cholesterol distribution. With advanced technology, such as Ion Mobility testing, we now have the capacity to measureactual cholesterol containing particles. Rather than having an estimation of cholesterol distribution you can identify the actual number ofatherogenic lipoprotein particles. It’s the smaller, dense, cholesterol-depleted particles that are the ones to worry about in terms of heart disease risk, but standard LDL-C is not a good measure of those particles.” Ion Mobility lipoprotein fractionation identifies the full spectrum of lipoprotein particles, along with direct quantification of particles in each lipoprotein subclass fraction. This more precise measurement allows physicians to identify the levels of specific sub-particles. 

The sub-particles of LDL have a set of distinct properties including size and density. Work done by Dr. Robert Krauss and his colleagues7 performed a number of years ago established that LDL sub-classes differ in their relationship to risk. The small LDL particles, in particular, are much more strongly related to risk than the larger LDL particles

The small dense particles, because they have a great triglyceride content and less cholesterol, are termed Pattern B.  The Pattern B group of individuals carry a 3-fold increased CVD risk than the patients termed Pattern A7, so having the in- depth direct measurement option of Ion Mobility is preferable to allow for optimization and customization of treatment.

“Using Ion Mobility to measure particles which contain apolipoproteinB (ApoB), for example, provides additional understanding of the exact composition of a patient’s LDL,” notes Dr. Molina. “It allows you to see the distribution of particle size and number and thereby assess risk on that basis.” Higher levels of plasma ApoB may signify increased coronary disease risk, even when LDL-C is not in the high-risk range.  Prospective epidemiologic studies support the benefit of tracking ApoB in identifying CVD progression and risk for CVD events.8-10

Another sub-particle of interest is lipoprotein(a)(Lp(a)), a LDL particle with an inherited apoprotein (a) variant attached, which has been linked to the promotion of both early and advanced-stage atherosclerosis. Elevated Lp(a) is associated with increased coagulation and a three to five-fold increased incidence of cardiovascular disease (CVD). An elevated level of Lp(a) is an independent risk factor for CVD. In combination with other abnormal disease markers, the associated risk increases further.

The American Heart Association (AHA) endorses testing for inflammatory risk factors which include Lipoprotein-associated phospholipase A2 (Lp-PLA2) and C-Reactive Protein-high sensitivity (hs-CRP). Ongoing inflammation can be measured by testing for these inflammatory markers.  

Lp-PLA2is an enzyme that causes hydrolysis of oxidized LDL in the intima of the artery, which generates pro-inflammatory mediators and a variety of inflammatory stimuli associated with atherosclerosis. Elevated circulating Lp-PLA2 is a specific marker for vascular inflammation and has been shown to be a powerful predictor of ischemic stroke and heart attack risk.

Hs-CRPis a plasma protein produced by the liver in response to systemic inflammation as an "acute phase reactant." When coupled with elevated levels of either fibrinogen or Lp-PLA2, risk for cardiovascular disease progression or events increases.

Identifying Patients for Comprehensive Assessment

Physicians should determine when comprehensive testing is appropriate, based on their assessment of a patient’s risk. “Clearly, there are many things to consider,” says Dr. Molina. “Lifestyle, family history and environment should all be taken into account. Certainly, anyone who has had a prior event needs to have a comprehensive evaluation. Also, anyone who belongs to a high-risk group such as south Asians, who have a four-fold risk of cardiovascular disease, diabetics and individuals with multiple risk factors such as tobacco use and hypertension should be evaluated.”

The use of more precise diagnostic tests enables an analysis of specific biomarkers to identify a risk, which could otherwise be missed. Dr. Molina summarizes this comprehensive approach as providing a physician with the most complete picture possible to help assess a patient’s risk.  “We’re trying to obtain a better understanding of that person’s complete metabolism. We look at glucose metabolism. We look at lipid metabolism and we’re trying to better understand the distribution of the cholesterol and the different cholesterol particles that behave differently. We look at endpoints such as inflammation and we look at white blood cell count.”  

“This represents a paradigm shift away from focusing on a single number for LDL to focusing on the complete patient, by taking into account a range of biomarkers that give additional insight,” he concludes. “It’s a bit more complicated but it’s more inclusive, particularly when you also consider lifestyle modifications, such as stress management, sleep hygiene, physical activity and diet. It’s the people who can change their behavior, rather than just taking a pill, who do the best.”


  1. Smith S, Jr., Allen J, Blair S et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006 May 16;113(19):2363-72.
  2. Stone, NJ, Robinson, J, Lichtenstein, A, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation.2013;01.cir.0000437738.63853.7a published online before print November 12 2013, doi:10.1161/01.cir.0000437738.63853.7a
  3. Brunzell J, Davidson M, Furberg C et al. Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008 April 15;51(15):1512-24.
  4. Kastelein JJ, van der Steeg WA, Holme I et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation 2008 June 10;117(23):3002-9.
  5. Sniderman AD. Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy:  implications for clinical practice. Journal of Clinical Lipidology 2, 36-42. 2008. Ref Type: Abstract
  6. Wilson PWF, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of Coronary Heart Disease Using Risk Factor Categories. Circulation 1998 May 19;97(18):1837-47*
  7. Kiran Musunuru K, Orho-Melander M, Caulfield M et al. On Mobility Analysis Of Lipoprotein Subfractions Identifies Three Independent Axes Of Cardiovascular Risk Arterioscler Thromb Vasc Biol. 2009 November ; 29(11): 1975–1980. doi:10.1161/ATVBAHA. 109.190405.
  8. St-Pierre AC, Cantin B, Dagenais GR et al. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 2005 March;25(3):553-9.
  9. Lamarche B, Moorjani S, Lupien PJ et al. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec cardiovascular study. Circulation 1996 August 1;94(3):273-8.
  10. Moss AJ, Goldstein RE, Marder VJ et al. Thrombogenic Factors and Recurrent Coronary Events. Circulation 1999 May 18;99(19):2517-22.

Released on Monday, December 30, 2013