Cardiovascular disease (CVD) is usually characterized by disease of the heart muscle, valvular disease, or coronary artery disease (CAD), a condition of blood vessel damage due to a combination of silent inflammation, endothelial dysfunction, and plaque buildup. As the immune system repairs damage in blood vessel walls, a silent but deadly process unfolds in time as arteries begin to calcify.
As inflammation increases, so does the likelihood that plaques in arterial walls will become unstable and rupture. When unstable plaques break open, blood clots can enter the bloodstream, become lodged in blood vessels, and block blood flow. Devastating events that stem from such a blockage include death of heart muscle cells, stroke, or potentially dangerous arrhythmias. All of these conditions are produced by the resulting loss of oxygen to the local tissues.
Although the cholesterol theory of coronary heart disease remains controversial and poorly understood, the most recent publication in the British Medical Journal strongly negates its hypothesis. Thus, inflammation as the source of cardiovascular disease looks more promising and continues to gain momentum among progressive health care professionals.
When considering inflammation as a contributor to cardiovascular disease, evaluating for diastolic dysfunction (DD)—an early form of heart failure— as well as 5 common blood markers are helpful for assessment: fibrinogen, highsensitivity C-reactive protein (hs-CRP), lipoprotein(a) (Lp[a]), lipoproteinassociated phospholipase A2 (LpPLA2), and myeloperoxidase (MPO). This is not a complete list of all inflammatory markers, but offers a very useful set of data points.
Diastolic dysfunction is a condition that is poorly understood and currently underdiagnosed in the medical community. In comparison to diastolic heart failure, which is a clinical syndrome, DD represents frequently abnormal mechanical function without the outward signs of heart failure. For example, in early DD, the first presenting symptoms may be fatigue, a chronic cough, or exercise intolerance, yet neither imaging nor labs will suggest a diagnosis of heart failure. It is thought that DD may be caused by hypertension, narrowing of the aorta, disease of the heart muscle, aging, and CAD.
It is also suspected that defects in adenosine triphosphate (ATP) production from impaired mitochondrial function may contribute to DD. Mitochondria are mini-organs within each cell that produce the body’s most important energy molecule, ATP. The chambers of the heart require more energy to relax and fill, than to contract. Because of oxidative stress and chronic inflammation, damaged mitochondria are unable to produce sufficient ATP to help the heart relax and fill with blood. All patients with heart failure have DD to some degree.
Because the requirements of muscle cells for ATP are absolute, incorporating a metabolic approach with nutritional biochemical interventions that preserve mitochondrial health and support efficient ATP production must be considered. For example, in a randomized controlled trial, 300 mg of coenzyme Q10 (CoQ10) promoted reversal of mitochondrial dysfunction in CVD patients. Such a metabolic cardiology approach does not create adverse effects and may be supportive for patients with DD.
Metabolic cardiology may be another treatment option to support DD, along with use of targeted nutraceutical therapies including CoQ10, D-ribose, L-carnitine, and magnesium to help fortify insufficient ATP levels in heart tissue. Although inflammatory cardiomyopathy may be a cause of DD, inflammatory CAD is a more common manifestation of inflammation in the heart. Clinically, we find the five biomarkers listed previously useful for helping clinicians assess cardiovascular risk in healthy and diseased populations. In addition, in comparison to standard lipid panels, these biomarkers can also provide additional information to guide clinicians with targeted treatments to reduce the inflammatory burden in the body as well as the heart.
Fibrinogen is a crucial protein for regulating coagulation and bloodvessel integrity. It plays many important roles in the body including platelet aggregation, providing a surface for fibrin formation, and facilitating wound healing. If levels begin to rise, the blood has the potential to become thick and sticky, which can lead to the formation of a blood clot in the heart.
Fibrinogen levels may rise quickly in any condition that causes inflammation or tissue damage, such as infections, injury, and vascular-related diseases. Therefore, fibrinogen can be used as a high-risk marker for vascularrelated conditions, such as hypertension and hardening of the arteries, and is involved in the pathophysiology and prognosis of CAD. Fibrinogen is also a risk factor for peripheral artery disease along with smoking, diabetes, hyperlipidemia, and hypertension. As with hs-CRP, fibrinogen may be elevated with other inflammatory conditions including rheumatoid arthritis, cancer, stroke, acute trauma, pregnancy, and acute infections, as well as in cigarette smokers.
Ideally, levels should be between 180 and 350 mg/dL. One of the best lifestyle interventions for lowering fibrinogen is to stop smoking. Weight loss and exercise seem to have only a modest effect. Omega-3s and nattokinase may lower fibrinogen as well.
C-reactive protein (CRP) is produced by liver cells in response to tissue damage, such as when inflammatory cytokines, such as IL-6, interferon gamma, or TNF-α, are elevated in the blood. CRP is an independent predictor of heart disease. A more precise marker is provided by hs-CRP, or high sensitivity CRP. For example, CRP can be measured down to concentrations of 3 to 5 mg/L, whereas hs-CRP can be measured down to concentrations near 0.3 mg/L. Several large-scale epidemiological studies have shown that an elevated hs-CRP is a strong independent risk factor for stroke, myocardial infarction, peripheral artery disease, and vascular death among people without known cardiovascular disease. In those with preexisting heart disease such as history of myocardial infarction, acute coronary ischemia, or stable angina, elevated hs-CRP is also associated with an increased rate of vascular events. According to the US Centers for Disease Control and Prevention and the American Heart Association, in terms of assessing risk, the following ranges for hs-CRP can be used as a guideline: Low risk: less than 1.0 mg/L; Average risk: 1.0 to 3.0 mg/L.; High risk: ≥3.0 mg/L. It should be noted that hs-CRP is a nonspecific marker of inflammation and cannot be used to identify a specific disease, including CAD. For example, hs-CRP can be elevated in acute and chronic inflammatory conditions including lupus, rheumatic disorders, infections, trauma, and some cancers. Therefore, we suggest ruling out these conditions to better understand the causes of hs-CRP elevation and its relationship to the cardiovascular system. There are ways to lower hs-CRP and these may include exercise, weight loss—if indicated, CoQ10, and curcumin.
Lipoprotein(a) is basically a small cholesterol particle. Although its physiological function remains unknown, it is thought that Lp(a) may play a role in the mediation of wound healing. Lp(a) is strongly influenced by genetics, with a small influence from diet, exercise, and lifestyle. According to the Lipoprotein A Foundation, Lp(a) is currently the strongest monogenic risk factor for coronary heart disease and aortic stenosis. It is elevated in 1 in 5 people, and an elevated level increases risk of developing early heart and blood vessel disease by 2 to 4 times compared to those with normal levels.
Elevated levels of Lp(a) can thicken blood with time. Oxidized lipoproteins, in particular LDL, can lead to the generation of macrophage-derived foam cells, the first major initiating factor in the development of plaque formation. In fact, macrophages have been implicated in the induction of plaque rupture through the breakdown of fibrous caps. Elevated levels of Lp(a) are associated with congenital heart defect, venous thromboembolism, and stroke.
Ideally, Lp(a) levels should be below 25 mg/dL, as cardiovascular risk begins with an Lp(a)>25 mg/dL. Omega-3 fatty acids from fish oil or squid oil will help to neutralize the toxic effects of thrombosis and inflammation resulting from high levels of Lp(a). Estrogen replacement therapy in women, testosterone therapy in men, fast-acting niacin, and aspirin may help lower Lp(a).
Lipoprotein-associated phospholipase A2
Lipoprotein-associated phospholipase A2, also known as platelet-activating factor acetylhydrolase, is an enzyme produced by macrophages and platelets. LpPLA2 has emerged as a potential therapeutic target in CAD, and when LpPLA2 levels rise, the risk for CAD increases independently of traditional risk factors.
The LpPLA2 test is also known as the PLAC test. It is increasing in popularity as a CAD risk factor. Ideally, levels should be below 75 (nmol/min/ mL). Omega-3 polyunsaturated fatty acids can reduce LpPLA2 in patients with stable angina, and extended release niacin can lower LpPLA2.
MPO is an enzyme released by white blood cells in response to damaged or inflamed arterial walls. MPO is associated with vascular inflammation because it catalyzes the formation of reactive oxygen species, which can, in turn, damage tissue and lead to hardening of the arteries. MPO is a specific marker of vascular inflammation including vulnerable plaque, erosions, and fissures.
Elevated levels of MPO have been shown to be independently associated with increased risk of incident CAD. In addition, elevated MPO levels predict future risk for CAD in apparently healthy individuals. According to the Cleveland Heart Lab, individuals with elevated MPO are twice as likely to experience cardiovascular mortality and MPO can enhance cardiovascular risk prediction in combination with biomarker testing such as hs-CRP.
MPO low risk is <470 pmol/L, and moderate risk is 470 to 539 pmol/L.
Melatonin supplementation may have the potential to inhibit MPO. CoQ10 utilized for cutaneous healing of skinincised mice also showed significant inhibition of MPO.
As recent research continues to disprove the cholesterol theory of heart disease, we need to shift our focus from the cholesterol theory to one that addresses inflammation. This will take time and education of health practitioners. There are many cardiovascular biomarkers of inflammation available to health practitioners. At this time, five main markers help assess risk in relation to cardiovascular disease: fibrinogen, hs-CRP, Lp(a), LpPLA2, and MPO. We believe these biological serum markers can help assess the level of inflammation throughout the cardiovascular system so that dietary, lifestyle, and nutraceutical changes can be made to reduce chronic inflammation. The nutraceutical interventions discussed are not a complete list; however, we have had success with those mentioned. As more fruitful research becomes available, this list will undoubtedly expand. Metabolic cardiology is a novel intervention to support failing and feeble ATP levels in heart muscle cells. Influencing the availability of ATP is a simple, cost-effective metabolic solution for insidious diastolic dysfunction.
Stephen Sinatra, MD, FACC, and Drew Sinatra, MD, are father and son cardiologists and naturopathic doctors. They share a passion for integrating the best of functional, biological, and conventional medicines.