Cardiovascular Risk Markers: Beyond the Lipid Profile
By Bruce E. Maniet, DO
ABSTRACT: Cardiovascular disease remains the main cause of illness and death in the United States in 2008 despite major advances in diagnosis and treatment. Thus, the cardiovascular risk assessment is paramount to physician decision-making and highest quality patient care. The traditional lipid profile, though useful in the assessment and treatment of cardiovascular disease, does not reveal a complete and accurate patient risk assessment. Despite appropriate preventative treatment based on traditional lipid profiles, morbidity and mortality resulting from cardiovascular disease remain unacceptably high. Huge advances have been made in our understanding of the pathologic process involved. Various advanced markers of cardiovascular risk have been developed. Understanding the meaning and usefulness of these new markers enables the osteopathic family physician to better identify, treat and prevent adverse cardiovascular outcomes.
Introduction
Advances in diagnosis and treatment of cardiovascular disease have brought about many exciting changes in the way we approach this all too common and devastating disease. Looking holistically at the entire disease state and how it interrelates within the body is an underlying concept that is taught in basic Osteopathic Philosophy. Developing a comprehensive approach to identification, management, and treatment of cardiovascular disease risk is essential for physicians. Treatment plans should be individualized for each patient.
Physicians must remain current and open to new thoughts on disease risks and treatments. Many new laboratory markers for the early identification of cardiovascular risk have been recognized, researched and validated. Early identification of patients at risk may allow for more timely interventions that can lead to improved outcomes. Family physicians are in the prime position to be leaders in disease prevention and modification because they see patients well before many disease processes manifest themselves. Prevention therefore is becoming more and more the responsibility and the obligation of the osteopathic family physician.
Cardiovascular risk assessment has traditionally been used by physicians to help direct treatment and patient behavior modification. Traditional risk factors that are considered to be modifiable include hypertension, diabetes mellitus, decreased physical activity, obesity, hyperlipidemia, and tobacco exposure. Male gender and family history of cardiovascular disease are also traditional risk factors, but are not modifiable. Despite the identification of these risk factors, cardiovascular disease continues to occur at alarming rates. This leads to the obvious question, “What other factors are involved in the pathophysiology of the disease process that will help identify risk and change the way physicians treat cardiovascular disease and improve outcomes?” Research is being directed towards the role of inflammation of the endothelial lining of the arterial wall and the body’s response to this process. New laboratory markers have been identified that indicate those persons who may be genetically at risk, the degree of inflammation that exists, and varying response rates to different treatments.
Case Presentation
Mr. W. was a 60-year-old white male who presented to his family physician’s office for continued care. He had a history of hypertension, hyperlipidemia, and obesity. There was no history of cardiovascular disease. His family medical history was obscured because he was a poor historian, but both his parents died in their 50’s.
He had been able to stop smoking after a 20-pack year history, but had not been able to lose weight. Further questioning revealed multiple trials of dieting and exercise with poor response. He had been treated for the last two years with atorvostatin 10 mg. and atenolol 50 mg.
At his initial visit, his blood pressure was well controlled at 124/78 and he had no complaints. Fasting lipids were taken which revealed normal values: Total Cholesterol = 160mg/dl, LDL-C = 89mg/dl, HDL-C = 45mg/dl and Triglycerides = 128mg/dl. Despite his controlled blood pressure and adequately treated lipids, he was considered at risk for cardiovascular disease because of his other risk factors including male gender, probable family history, obesity, sedentary lifestyle, and history of tobacco use. Additional cardiovascular risk markers were obtained to evaluate his risk for cardiovascular disease:
Three weeks later, and prior to his follow-up visit to the physician’s office, he developed chest pains and went to the emergency room. He was diagnosed with myocardial infarction and was taken to the catheterization lab where he underwent stent placement.
This case illustrates a rather common scenario in America today. Despite appropriate treatment, the frequency and the devastation of cardiovascular disease remain high. This leads us to consider the importance of evaluating additional cardiovascular markers beyond the typical lipid panel to identify those at increased risk of developing cardiovascular events, and then consider what treatments can be instituted to correct abnormalities. As can be seen in the case presented, numerous markers were elevated that indicated an inflammatory state and a markedly increased risk of cardiovascular events. This patient’s impending myocardial infarction was predictable by advanced serological testing, but not by the usual lipid testing employed by most family physicians today.
Role of Endothelial Dysfunction
The endothelium is an active organ responding to physical and chemical stimulus to maintain vasomotor balance and vascular homeostasis. It is able to produce agonist and antagonist substances to modulate both relaxation and contraction of the endothelial cells. Endothelial homeostasis includes controlling the production of prothrombotic and antithrombotic components, fibrynolitics and antifibrynolitics, cell proliferation and migration, leukocyte adhesion and activation, immunologic processes and inflammatory processes. Factors that cause oxidative stress to the endothelium alter the endothelial cell’s capacity to perform their homeostatic roles leading to inflammatory processes and vascular disease. This altered function is referred to as endothelial dysfunction. Factors that alter the endothelium are referred to as cardiovascular risk factors and are principal in the pathologic process of atherosclerotic disease. Endothelial dysfunction is considered an inflammatory, immunologic, polygenic and multifactorial disease process.1
A balance between Nitric Oxide and Angiotensin-II regulates vasodilatation and constriction of the endothelium. Nitric Oxide is responsible for the vasodilatation of the endothelium, inhibits proatherogenic and pro-inflammatory cytokines, favors fibrinolysis, and also causes a reduction of platelet aggregation, tissue oxidation, tissue inflammation, and activation of thrombogenic factors. Angiotensin-II is responsible for endothelial constriction, and causes prothrombogenic, oxidative and antifibrinolitic effects. When this balance is altered by any of the cardiovascular risk factors, a state of oxidative stress occurs which stimulates the production of proatherogenic cytokines leading to an inflammatory response.
Oxidant products are generated from normal aerobic metabolism and are balanced by antioxidants. LDL molecules do not promote an inflammatory response until they become oxidized. Small dense LDL molecules are more easily oxidized during the state of oxidative stress. Once oxidized, LDL molecules become highly immunogenic creating a cascade of events leading to thrombogenesis and plaque formation. Oxidized LDL molecules found in the subendothelial layers turn monocytes into macrophages that eventually turn into foam cells. Foam cells are the main component in the fatty streaks of the endothelium and are the initial step in plaque formation.
Endothelial cell inflammation produces molecules that contribute to thrombogenesis and platelet activation. An immunologic response occurs when a plaque is infiltrated by T-lymphocytes.4 Two distinct plaques have been identified. The first is a stable fibrous plaque with a small lipid core surrounded by a thick cover without signs of inflammation. This type of lesion usually causes a slow obstruction of the vessel. The second type of plaque, called a soft plaque, is an unstable plaque and has a large lipid core with a thin cover. This soft plaque contains large amounts of macrophages and T-lymphocytes that produce an inflammatory response. These soft plagues can rupture and cause thrombus formation leading to acute vascular obstruction. Soft plaque rupture with thrombus formation is considered the cause for many sudden unexpected cardiovascular events.
Role of Lipoprotein Metabolism
Disorders of lipoprotein metabolism have long been thought to be risk factors in atherosclerosis. Physicians have traditionally followed this by monitoring the traditional lipid profile of cholesterol, triglycerides, HDL, and LDL. Cholesterol is found in human cells and is necessary for the production of bile acids, estrogen, testosterone, aldosterone and progesterone, and is important for cell membrane maintenance. Two main sources provide the body with cholesterol: 1) intake of cholesterol containing foods and 2) cholesterol that the body produces (mainly in the liver).
HDL and LDL are two substances, referred to as lipoproteins, that transport cholesterol throughout the body. LDL results from the lipolysis of VLDL and IDL and is the major cholesterol transporter in the plasma. LDL is the lipoprotein that transports cholesterol from the liver to the peripheral tissues. HDL is responsible for transporting cholesterol from peripheral tissues back to the liver. It is generally accepted that decreasing LDL and increasing HDL lessens athrogenic risk resulting in reduced cardiovascular disease.
According to NCEP/ATP III (National Cholesterol Education Program’s Adult Treatment Panel III) guidelines, LDL reduction should be the focus for cardiovascular risk reduction even in high-risk patients with normal cholesterol levels. Despite its general acceptance and widespread use by physicians, is the traditional lipid panel adequate for physicians to assess the risk for cardiovascular events and develop best treatment regimens? Even with treatment using statin medications directed at lowering LDL, there continues to be a large number of patients who experience cardiovascular events.5
Further risk reduction needs to be considered with emphasis on additional combination cholesterol-lowering therapies, anti-platelet drugs, antihypertensive agents, smoking cessation and healthy lifestyle changes.6 Advanced lipid testing that looks at factors other than the traditional lipoproteins and their specific roles in the athrogenic process, need to be employed as an addition to the family physician’s armamentarium. The osteopathic family physician should become familiar with these new markers as more is learned about their role in assessing cardiovascular risk and directing cardiovascular treatment.
Lipoprotein Subclasses
In the 1950’s new techniques were reported that were able to show the heterogeneity of the lipoprotein particles. Lipoprotein particles float differently based on their size and density allowing them to be classified by their flotation rate (Svedberg flotation unit). These differences in the floatation rate led to the more specific classifications of lipoproteins to very low density (VLDL), intermediate density (IDL), low density (LDL), and high density (HDL) particles. These lipoprotein classes are further broken down into subclasses. Seven LDL subclasses and five HDL subclasses have been recognized based on their density:
LDL I, IIa, IIb, IIIa, IIIb, IVa, IVb
HDL 2a, 2b, 3a, 3b, 3c.
These lipoprotein subclasses are based on particle size and commonly referred to as small trait and large trait. As individual patients have varying amounts of these lipoprotein subclasses, identifying the clinical significance of each lipoprotein particle is useful in determining athrogenic risk.
LDL Particle Size
LDL particle size is thought to be an associated risk factor for cardiovascular events.8 LDL IIIa + IIIb and LDL IVb are subclasses that have an abundance of small particles. Measurement of these subclasses indicates the quantities of small particles present and the degree of risk for an individual. LDL I, IIa, and IIb are the larger sized LDL particles. Individuals with predominantly small LDL particles seem to have greater risk for cardiovascular disease than those who have larger-sized LDL particles.9,10 Having predominantly small LDL particles is referred to as Pattern B.
It has been thought that small, dense LDL particles are more susceptible to oxidative modification resulting in endothelial dysfunction. Pattern B individuals have a higher total number of small LDL particles and generally have higher triglyceride levels and lower HDL levels. It is uncertain if the relationship to small LDL size is independently related to increased cardiovascular risk or if it is due to its relationship with other associated factors.
In addition to Pattern B being a predictor for cardiovascular disease risk, it can also be a predictor for treatment response. Pattern B individuals have been shown to respond better to low fat diets and medical treatment than individuals with a larger LDL trait (Pattern A). The small LDL disorder is treated with low fat diet and use of niacin and resins as studies have shown a greater reduction of LDL particles with these modalities.11,12,13
In summary, Pattern B individuals have a greater risk for cardiovascular disease, but a better response to treatment and Pattern A individuals have a lower risk for cardiovascular disease, but respond less favorably to treatment.
Apo B
LDL particle number is another cardiovascular risk marker. Apolipoprotein B (Apo B) is the main structural component of the LDL particle and is an accurate measurement of LDL particle number. The two types of Apo B are Apo B-100 which represents the endogenously produced lipids from the liver (VLDL, IDL, LDL) and Apo B-48 which represents the lipids produced in the intestines (chylomicrons) obtained from dietary sources. Apo B measurement is more useful and a better indicator of cardiovascular risk than the measurement of LDL cholesterol.15
LDL particles vary in the amount of cholesterol they contain with the more atherogenic smaller LDL particles containing less cholesterol. This can lead to a false sense of success since an LDL measurement could be low but have an abundance of small dense LDL particles present.16 Apo B is a measurement of each VLDL and LDL particle and is therefore not affected by the quantity of cholesterol contained by those particles. Thus, Apo B measurement will identify those who are at higher risk for cardiovascular disease because of an increased number of small dense LDL particles.8 High Apo B is best treated with statins or bile acid binding resins.
Lp(a)
Lipoprotein(a) [Lp(a)] is a subclass of LDL particles that have been identified as a cardiovascular risk factor for development of atherosclerosis.17 Lp(a) consists of an apolipoprotein(a) [Apo a] molecule that is attached to the Apo B particle on the LDL particle. Lp(a) particles are genetically determined and have varying sizes (isoforms) determined by a variable number of what is called “Kringle IV repeats” in the LP(a) gene. The plasma concentration of Lp(a) is inversely proportional to the size of the Apo(a) isoform.18
Lp(a) is similar to plasminogen and tissue plasminogen activator so it competes with plasminogen for binding sites on the cell wall leading to a decreased level of plasmin. Plasminogen is the inactive precursor of plasmin whose responsibility is for the degradation of fibrin, which is essential to the blood clotting mechanism. Decreased levels of plasmin result in a decrease in fibrinolysis. Elevated Lp(a) is an independent risk factor and increases the risk for cardiovascular events.17 Statin medications are not considered to have much effect on Lp(a), but aspirin, niacin, fibrates, and hormone replacement therapy are able to lower Lp(a) levels.19
HDL2b
High-density lipoprotein (HDL) cholesterol continues to be a strong predictor of cardiovascular risk. HDL is distributed into subclasses HDL2b, HDL2a, HDL3a, HDL3b, and HDL3c. HDL is involved in reverse cholesterol transport which is the process of transporting cholesterol particles from the peripheral tissues back to the liver where it can be removed and secreted as biliary cholesterol and bile acid salts.
HDL2b is thought to be most associated with reverse cholesterol transport. High levels of HDL2b reabsorb cholesterol efficiently in the peripheral tissues so that it can be eliminated. HDL2b also is considered anti-inflammatory and anti-thrombotic due to its protective effect on the artery as it contains paraoxanase, an inhibitor of the oxidation of LDL leading to endothelial dysfunction.20 Thus, a lower level of HDL2b is considered a risk for atherosclerotic progression. Pharmacologic management has traditionally been directed mainly at lowering LDL. However, emphasis is now also being placed on increasing HDL for its beneficial effects in treating atherosclerotic progression. Niacin therapy has been shown to increase HDL by 15-30 percent.4,5
hs-CRP & Fibrinogen
C – Reactive protein and Fibrinogen levels are two inflammatory markers that have not been widely recognized as reliable measures of cardiovascular risk by themselves. Most steps in the atherosclerotic process are believed to involve an inflammatory response. As the role of inflammation is better understood in the atherosclerotic process, additional markers of inflammation are being evaluated for their usefulness. Elevations in CRP and Fibrinogen have been seen in plasma and associated with increased cardiovascular risk.3
Endothelial dysfunction leads to plaque rupture, which leads to the inflammatory response and thrombus formation. Fibrinogen is a glycoprotein synthesized in the liver and is converted into fibrin. Fibrin leads to thrombus formation in response to an inflammatory response. C-Reactive Protein and Fibrinogen both are considered “acute phase reactants,” meaning they rise in response to an inflammatory response.
Elevated hs-CRP levels have been associated with an increase in cardiovascular events.21,22,23 Hs-CRP is a nonspecific measure in response to inflammation and can result from any number of sources of inflammation. Thus, its use in clinical practice has been uncertain due to a lack of a protocol on how to respond to an elevated level. In 2003, the American Heart Association along with the CDC presented a statement regarding the use of inflammatory markers in assessing cardiovascular risk.
Hs-CRP is a reasonable test to pursue along with measurement of other risk factors in people who are at intermediate risk of cardiovascular disease. Measurements should be taken in stable individuals at least two weeks apart and averaged. The risk assessment includes: Low Risk – <1.0 mg/l, Intermediate - >1.0 and < 3.0 mg/l, High - >3.0 mg/l.24
Elevated Fibrinogen levels have also been associated with increased cardiovascular events.25 The elevation of fibrinogen and hs-CRP may indicate the presence of active endothelial dysfunction with concomitant higher risk and thus point to those individuals who may need a more aggressive treatment program.26 Factors that have been shown to reduce fibrinogen levels include smoking cessation, weight loss, exercise, alcohol, fibrates and niacin.
Lp-PLA2
Lipoprotein-associated Phospholipase A2 (Lp-PLA2) is a lesser-known inflammatory marker that plays a role in the vascular inflammatory process leading to atherosclerotic plaque formation and rupture. Lp-PLA2 is an enzyme that attaches to the LDL particles. After the LDL particle becomes hydrolyzed in the endothelium, it is susceptible to hydrolysis by Lp-PLA2 generating Lysophosphatidylcholine and Oxidized Fatty Acids.
These products lead to monocyte recruitment, which then convert to macrophages that ingest the oxidized LDL and become foam cells. The foam cells can aggregate to form unstable atherosclerotic plaques that lead to cardiovascular events. Elevated Lp-PLA2 levels have been shown to be a predictor of cardiovascular events.27,28 Elevated Lp-PLA2 levels should be considered a warning sign that the inflammatory process associated with endothelial dysfunction is active29 and should trigger aggressive treatment. Treatment with statins, niacin, or fibrates has been shown to reduce the levels of Lp-PLA2 levels.
Homocysteine
Homocysteine is an amino acid in the blood from the metabolic byproduct of methionine metabolism that may have an association with atherosclerosis. Research is being directed toward the possibility that homocysteine may promote atherosclerosis by damaging the inner lining of the arteries, initiating the clotting cascade. Homocysteine levels are influenced by genetic factors and the diet.
Folic acid, B6, and B12 have the greatest effects on lowering homocysteine levels. Even though there has been no evidence to prove lowering homocysteine levels reduces cardiovascular risk, it may be beneficial to ensure that high-risk individuals get enough folic acid, vitamin B6 and B12 in their diets. Since 1998, folic acid has been added to wheat flour adding approximately 100 micrograms per day to the average diet. The effect of this intervention on homocysteine levels is yet to be determined.
Apo E
Apolipoprotein E Genotype (Apo E) is a genetic marker that predicts altered lipoprotein metabolism. Apo E is a protein that combines with the lipoproteins in the blood stream, carrying them between the liver and peripheral tissues. Apo E binds to the lipoprotein and affects lipoprotein levels by influencing the clearance rate, lipolytic conversion and triglyceride-rich VLDL production.35 Apo E is the major component of VLDL. The APOE gene, located on chromosome 19, determines Apo E and there are three major alleles called e2, e3 and e4. These different versions on the APOE gene are expressed in Apo E as different isoforms. There are three different isoforms of Apo E, which are called Apo E2, Apo E3, and Apo E4.
The different isoforms are responsible for determining the six genotypes that are seen. There are three homozygous (E2/E2, E3/E3, E4/E4) and three heterozygous (E3/E4, E2/E4, E2/E3) genotypes. These different genetic expressions are responsible for their various effects on lipoprotein metabolism. Apo E2 is responsible for a slow change of IDL to LDL causing a decrease in cholesterol, but increased triglycerides. Apo E3 is considered normal metabolism. Apo E4 has limited HDL binding causing an increase in LDL and Triglycerides. Apo E 3/3 is considered the normal genotype and accounts for 62 percent of the population.
Apo E4/4 and E4/3 account for 25 percent of the population and are associated with most of the cardiovascular risk. Apo E2/2 only accounts for less than 1 percent of the population and is associated with Type III Hyperlipidemia.
Although rare, type III Hyperlipidemia is related with a strong predisposition for cardiovascular disease. Apo E genotypes influence variations in lipid metabolism under environmental conditions.30 Apo E4 genotypes have higher amounts of small dense LDL particles36 and an increased cardiovascular event risk of 40 percent.31 Genetic variation can explain some of the individual variations in response to therapies. Thus, identifying genotypes is a useful marker for identifying clinical management options between the different genotype groups.
Individuals with the Apo E4 genotype tend to have poor and variable responses to statin medications32 and therefore these agents have a limited role in LDL reduction. Apo E4 individuals do, however, respond to low fat diets intensely and show excellent reductions in LDL, Triglycerides, and small dense LDL with proper diet.33 Alcohol consumption in the Apo E genome causes an increase in LDL38 and a decrease in HDL and is therefore not recommended.37 In contrast, Apo E2 genotypes respond better to statins in lowering LDL consistently and respond less intensely to very low fat diets because there is limited reduction of LDL and an increase in small dense LDL. However, they do respond beneficially to moderate alcohol consumption which causes a decrease in LDL38 and increase in HDL. General guidelines are helpful, but consideration should be taken into account for individual responses based on genetic heterogeneity.34
KIF6
One of the newer genetic cardiovascular risk markers is the KIF6 marker. Carriers of the 719Arg allele of KIF6 have been associated with an increased risk of cardiovascular disease (34 percent higher risk of MI and 24 percent higher risk of Coronary Heart Disease).43 This genetic variant is considered an independent risk factor marker. Carriers of the KIF6 marker have been shown to have a much more robust response to statin therapy reducing cardiovascular events than do non-carriers. This greater response appears to be due to a different mechanism from lipid lowering.44 The mechanisms by which this KIF6 variant causes an increased risk or the understanding of why statins have a much greater positive effect in carriers than non-carriers is not presently known.
NT-pro BNP
The N-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) is a neurohormone secreted from ventricular cardiomyocytes in response to a cardiac stress. Elevated levels of NT-proBNP indicate the presence of an underlying cardiac disorder. The disease states that have been associated with elevations of NT-proBNP include heart failure, acute coronary syndrome, left ventricular hypertrophy, stable coronary artery disease, hypertension, and atherosclerosis.39
Natriuretic peptides have an effect on vascular tone by decreasing angiotensin II and norepinepnrine. They also have an effect on vascular function and remodeling by its effects on nitric oxide, inhibiting lipid uptake in the vascular wall, and increasing parasympathetic tone. NT-proBNP elevation has been associated with an increased coronary event risk.40 Individuals with elevated levels should be evaluated for underlying cardiovascular disease.
Insulin
Insulin is a protein that is involved with carbohydrate metabolism. Hyperinsulinemia may increase the risk of cardiovascular events independent of other risk factors41 thus it is considered a risk marker. Plasma concentrations of plasminogen-activator inhibitor type 1 are increased in individuals with elevated insulin levels impairing fibrinolysis and promoting thrombosis.42
Elevated insulin levels have been associated with even higher cardiovascular risk especially when combined with other risk factors of altered lipoprotein metabolism, and insulin resistance. Elevated insulin levels are seen in individuals with insulin resistance and insulin resistance is associated with the Metabolic Syndrome.
Conclusion
Despite many advances in the treatment of cardiovascular disease, it remains the number one cause of death in the United States. Cardiovascular disease is considered an inflammatory condition resulting from interaction between genetic and environmental factors. Physicians have been using traditional risk factors to evaluate patients at increased risk and monitoring treatment response for decades, however it is apparent this can be inadequate and ineffective in many patients as evidenced by the large number of people who continue to experience cardiovascular events.
As the role of genetics and how genetic mechanisms impact the environmental factors that are typically associated with cardiovascular disease are explored, new advances in diagnosis and treatment are emerging. With the development of cardiovascular risk markers, physicians have an improved ability to predict who will have cardiovascular events and how they will respond to different treatments.
The acceptance of anything new is usually determined by how useful the information is and understanding what to do with the information. Cardiovascular risk markers will allow physicians to evaluate patients beyond the traditional lipid panel and target therapies beyond simple statin use by realizing the heterogeneity of therapeutic responses in individuals.
In addition, the improved specificity of these advanced markers over the traditional value of LDL can indicate the effectiveness of various treatments. Combination therapy is now being considered earlier and more often even in people who were once considered adequately controlled. As the case presentation demonstrates, a person with a normal traditional lipid panel but elevated LDL IIIa, IIIb, IVa particles and increased Apo B levels would not be maximally treated with a single agent. The LDL small trait would be best treated with niacin or a fibrate while the elevated Apo B would be treated most effectively with a statin or bile acid binding resin.
Usefulness is measured in a variety of ways. It remains unclear how useful it is presently to follow these advanced cardiovascular risk markers in the management of cardiovascular disease. Will measuring the severity of risk by these and other markers be a powerful motivator for a person to reduce their environmental risk by taking an active role in prevention? Will markers be used to aid the physician in monitoring more specifically a treatment plan or by directing which individualized treatment should work the best? No matter how osteopathic family physicians use advanced cardiovascular risk markers, ultimately their usefulness will hinge upon a proven reduction in cardiovascular events for patients.
| CV Marker | Result | Goal |
| LDLllla + b | 25.4 percent | (<15) |
| LDL IVb | 3.3 percent | (<5) |
| HDL2b | 18 percent | (>20) |
| Apo B | 84mg/dL | (<60) |
| Lp(a) | 124mg/dL | (<30) |
| Homocysteine | 24.7umol/L | (<10) |
| Apo E Genotype | 3/3 | |
| Lp-PLA2 | 142ng/ml | (<200) |
| hs-CRP | 5.4mg/l | (<1.0) |
| Fibrinogen | 653mg/dL | (<350) |
| Insulin | 8uU/ml | (<10) |
| NT-proBNP | 1106pg/mL | (<125) |
Dr. Maniet is a 1985 graduate of the Philadelphia College of Osteopathic Medicine. He first received his certification in family in 1992, and is currently in private practice at the Bells Medical Clinic in Bells, Texas.
References