Case Study I: The Patient with Family History of Premature Coronary Heart Disease

Patient LH, a 39-year-old white male came to me for evaluation as he was concerned about his risk for coronary heart disease (CHD). His father had coronary artery disease at age 46. He had 99% blockage of his right coronary artery and subsequent stent placement. While not first degree relatives, he also has several aunts, uncles, and cousins with early coronary heart disease (defined as women prior to age 55 and women prior to age 65).

On his first visit he stated that he felt very well overall and denied chest pain, pressure, or dyspnea. He is very active. He runs 3 miles a day on weekdays and 5-7 miles a day on weekends. He does not smoke, he has an occasional alcoholic beverage and had states he never used illicit drugs. He admitted to a poor diet and often ate “take-out.” He worked as an architect and is married with no children. He took no medications. His blood pressure was 125/78. He was 175 cm tall and he weighed 70 kg. A 12-lead EKG showed normal sinus rhythm at 66 beats per minute and no other abnormalities.

The month prior to his first visit the following levels were reported:
Total cholesterol   215 mg/dL
LDL-C                 122 mg/dL
HDL-C                  45 mg/dL
Triglycerides        242 mg/dL

Based on NCEP ATP III, what are the lipid goals for this patient? He only has one traditional risk factor, so this and Framingham Risk Score may not be helpful for this patient. Based on ATP III his LDLcholesterol (LDL-C) goal is < 160 mg/dL. His triglycerides are elevated but may very well respond to dietary modification. Should I have stopped my evaluation here? What about the "family history?"

Our patients often relate a family history of early CHD which should raise a “red flag.” At present, it is difficult for clinicians to assess and incorporate this information into a management plan.

The independent association of early CHD in a first degree relative and associated risk has been demonstrated in many prospective cohort and case-control studies. In the Atherosclerosis Risk in Communities (ARIC) Study¹ it was found that a family history of premature CHD was independent of other risk factors. While many risk factors such as hypertension and dyslipidemia are present in those with early CHD, these risk factors account for only a portion of the aggregate CHD seen in families.^2,3

The Framingham Risk Score does not include family history. In a prospective study, Lloyd-Jones and colleagues used the Framingham cohort study data base to investigate risk due to family history. Using validated events, they found that parental cardiovascular disease independently predicted the future of offspring events in middle-aged adults. However, the investigators go on to say that the addition of validated parental data into multivariable functions predicting 10-year absolute risks may only increase the predictive accuracy to a small extent. "The overall C statistic for our multivariable model increased from 0.82 to 0.83."⁴

In 2001, the NCEP ATP III Guidelines stated: "The presence and age of onset of CHD in all first-degree relatives should be assessed. The family history should be considered positive for premature CHD if clinical CHD or sudden death can be documented in first degree male relatives younger than 55 years of age and in first degree female relatives younger than 65 years of age. Because a positive family history of premature CHD provides information about the risk for CHD and the probability of having modifiable risk factors, it should serve important information helpful in making treatment decisions relative to setting and reaching LDL-cholesterol goals in primary prevention."

The Reynolds Risk Score was introduced in 2007 to focus on risk for women. Thirty-five factors were assessed in healthy women who were 45 years of age or older. "Parental history of MI < age 60" is included in the score.⁵

More recently, the European Guidelines on Cardiovascular Disease Prevention state "The importance of familial prevalence of early-onset CVD is not yet sufficiently understood in clinical practice." "Family history is a variable combination of genetics and shared environment." "Because of the polygenic and polyfactorial determinants of the most common CVDs, the impact of any single polymorphism remains rather modest." The guidelines do go on to recommend "Familial prevalence of atherosclerotic disease or of major risk factors…should be systematically sought in the first-degree relatives of any patient affected before 55 years in men and 65 years in women."⁶

The reason for lack of complete understanding is that “family history” is a general term and does not reflect a particular environmental or genetic abnormality. In an editorial, Christopher J. O’Donnell of the Framingham Heart Study stated "…what has remained unclear are the pathophysiological/genetic mechanisms of the familial risk, the extent to which familial risk is independent of other risk factors, and the extent to which risk conferred by a positive family history of CHD is modifiable.^"7

While we cannot definitively assess whether a positive family history has conferred risk to our patients, many providers use a positive family history to weigh the balance towards aggressive treatment of other risk factors including lipids. Another approach is to perform advanced lipid testing to help assess overall risk and to help determine need for pharmacologic treatment.

Advanced Lipid and Biomarker Testing

Lipoprotein (a) [LP(a)]
LP(a) has a very strong genetic component—it is under the control of the LP(a) gene. LP(a) is unaffected by diet and most drugs; and has been associated with premature CHD. Lp(a) has positive predictive value that is additive to other lipid and traditional risk factors. A consensus panel of the European Atherosclerosis Society issued a statement stating that LP(a) should be measured once in all patients at intermediate or high risk of CVD/CHD who present with associated characteristics including family history of premature CVD. The panel goes on to state "For reduction of plasma Lp(a) as a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for LP(a) < 80th percentile (less than about 50 mg/dL). Treatment should primarily be niacin 1-3 g/day…"⁸

The panel’s recommendation for testing and treating has been criticized by many including Samuel Goldhaber who wrote that "problems with standardization and reporting of Lp(a) assays have persisted without resolution." More important, there has been no randomized prospective clinical trial of treatment of Lp(a).⁹

In 2011, an expert panel of the National Lipid Association issued a statement on the clinical utility of advanced lipid testing. Measurement of Lp(a) is reasonable when there is "a very strong family history of vascular events…" The statement outlines that the impact of treatment has yet to be determined by clinical trials, making use of niacin unclear, but other evidence suggests that an elevated Lp(a) should prompt aggressive reduction of LDL-C.¹⁰

Residual Risk: Non-HDL Cholesterol, Apolipoprotein B, and LDL Particle Number
The concept of non-HDL cholesterol was discussed in the NCEP ATP III guidelines. It was recommended that in patients with TG > 200 mg/dL, non-HDL cholesterol ("atherogenic cholesterol") should be a secondary target of therapy.

Non-HDL cholesterol has also been shown to improve on LDL-C in terms of risk prediction. Some recent investigations have identified LDL-particle number and ApoB as even better able to predict risk and targets for therapy as non-HDL^11,12,13 however others have not.^14,15

The NLA Expert Panel recommends that measuring LDL-P is "reasonable for many patients" with a family history of premature CHD "When LDL-P is discordantly elevated, consideration should be given to initiating LDL-lowering therapy." The panel also states that measurement of ApoB is "reasonable for many patients" with a family history of premature CHD based on the fact that "familial combined hyperlipidemia is the most common atherogenic dyslipoproteinemia associated with premature CHD.¹⁰

Lp-PLA2
This enzyme has shown to independently predict risk for CVD and to also be an active participant in development of atherosclerosis. At present there is no FDA-approved drug to treat Lp-PLA2 but existing lipid-lowering medications have been shown to lower levels. The NLA Expert statement recommends measurement of Lp-PLA2 be "considered for selected patients" with a positive family history.¹⁰ Lp-PLA2 is considered reasonable for patients in intermediate risk.

CRP
C-reactive protein is a non-specific inflammatory marker that has been extensively studied in terms of risk for CHD. The NLA panel recommends "In patients with a premature family history of CHD…CRP measurement is a reasonable option to help determine if therapy should be started…"¹⁰

Testing for presence of subclinical atherosclerosis
In addition to advanced lipid and biomarker testing, Coronary artery calcium and carotid intima-media thickness have been used to help risk-stratify patients with intermediate risk. While no guidelines specifically address their use in an otherwise low-risk patient with family history, these tests can also be considered to help determine risk and management in such patients.¹⁶

Follow-Up
Given his high triglycerides and poor diet, I counseled the patient and gave him educational material on a heart-healthy diet. I also ordered another fasting lipid profile and advanced lipid testing. The patient was compliant with the lifestyle modifications and three months later had another blood test.

Total cholesterol        187
LDL-particle number 1723
LDL-C                       125
HDL-C                        43
Triglycerides               95
Lp (a)                           4
Glucose                     98
TSH                          4.1 uIU/mL
Lp-PLA2                   155
CRP                            1 mg/L
Apolipoprotein B        120 mg/dL

The advanced testing results were all unremarkable with the exception of LDLparticle number and Apolipoprotein B. His TG had improved most likely due to the changes in his diet. His Lp(a), Lp-PLA2, and CRP were low.

Testing showed that there was discordance between the LDL-C and LDL-P and ApoB. While LDL-C and LDL-P are generally correlated, they may also be discordant— meaning one value is high and the other low, or vice versa. In this case, the LDL-C was low and at goal but the LDL-P number was quite high.

As discussed above, LDL-P has been shown to potentially improve risk predication for CHD in groups of individual patients better than LDL-C. Mechanistically, the particles, containing the cholesterol enter the arterial wall by a gradient-driven process. Once inside, the particles bind to the arterial wall and the process of plaque formation is initiated.¹⁷

I reviewed the lab testing with the patient. We discussed imaging studies (stress test, CAC, CIMT), further lifestyle modification, or pharmacologic treatment.

We decided on CAC; his score was zero. With the absence of other risk factors and zero calcium score, we decided to hold off on pharmacologic treatment. He agreed to go for medical nutrition counseling to enforce the improvements in his diet. We will recheck a basic lipid profile and LDL-P in six months.

Editors’ Note: Question—How many of you would have tried to normalize his lipid particles with medication given his family history and prior stent placement for the 90% occlusion?

Disclosure statement: Dr. Myerson has received consulting fees from LipoScience Inc. and Kowa Pharmaceuticals America. Dr. Myerson has received grants from Medtronic and LipoScience Inc.