Coronary Heart Disease Risk Factors, Coronary Heart Disease, Congestive Heart Failure, and Metabolic Cardiology

Coronary Heart Disease Risk Factors, Coronary Heart Disease, Congestive Heart Failure, and Metabolic Cardiology

Stephen T. Sinatra, MD, FACC, FACN, CNS



CVD remains the number one cause of morbidity and mortality in the United States.1,2 The annual cost, direct and indirect, of treating CVD is approximately $320 billion USD.2 Every one in three deaths in the United States is due to CVD with over 2200 citizens dying from MI or stroke daily.2,3,4,5

Clinical studies suggest that a limit has been reached in the ability to reduce CHD and CVD.1 About 80% of CHD can be prevented by optimal nutrition, optimal exercise, optimal weight and body fat, mild alcohol intake, and avoiding smoking.1 More than 400 CHD risk factors have been defined.2 The three finite responses of the cardiovascular system to the infinite insults include vascular inflammation, vascular oxidative stress, and vascular immune dysfunction. Laboratory measurement of the finite responses allows the physician “to backtrack” and determine the “why” or the genesis of CHD and CVD, remove the insult(s), and initiate optimal prevention and treatment methodologies to meet defined clinical, noninvasive testing, and laboratory goals.

Prevention and treatment strategies must be directed at these three finite vascular responses while reducing the allostatic load of the 400 or more CHD risk factors and biomarkers.2

The traditional diagnostic testing, evaluation, prevention, and treatment strategies for the top five cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity, and smoking) have resulted in a CHD gap.4 Approximately 50% of patients admitted to a hospital with acute coronary syndrome (ACS) or MI have “normal” levels of the top five CHD risk factors.2,5 The “cholesterol-centric” approach to prevent CHD is clearly important, but the other risk factors must be redefined and treated early and aggressively. Simultaneously, the clinician should measure and treat the three finite cardiovascular responses. Advances in the direct assessment of the top five risk factors and the refinement of their definitions are often not utilized by physicians so that optimal prevention and treatment strategies for CHD are not clinically applied.2 Physicians should also evaluate new CHD risk
scoring systems, novel and redefined CHD risk biomarkers and risk factors, micronutrient testing, cardiovascular genetics, nutrigenomics, genetic expression testing, and noninvasive cardiovascular testing, which will allow cardiovascular medicine to become more personalized and precise.

Revolutionizing the Treatment of Coronary Heart Disease

Addressing cell membrane physiology and identification of dysfunction represents the first step in the prevention and treatment of CHD. Cell membranes are the primary barrier between the external milieu (attacked by various hemodynamic or biochemical insults) and the internal cell organelles. The interaction of the various insults with the endothelial vascular receptors such as pattern recognition receptors (PRR), nod-like receptors (NLR), toll-like receptors (TLR), and caveolae determine the signaling transduction into the cell.2 The external insults stimulate these inflammatory vascular receptors directly or through epitopes.2

Any cell membrane insult, such as hypertension, alterations in hemodynamics, modified low-density lipoprotein cholesterol (LDL-C), glucose, advanced glycosylation end products, microbes, internal tissue breakdown, toxins, heavy metals, homocysteine, or the other CHD risk factors, results in a reaction diffusion wave (tsunami effect) throughout the cell membrane that may disrupt cell receptors and the signaling mechanisms with subsequent membrane damage and dysfunction.6,7 Depending on the biological fatty acid makeup of the cell membrane with trans fats (TFAs), saturated fats (SFAs), monounsaturated fats (MUFAs), or omega-3 fats (PUFAs), the responses will vary. Fluidity within the cell membrane (MUFA, PUFA) dampens injury at the site of the insult as well as throughout the rest of the cell membrane. However, stiff cell membranes (SFA, TFA) will exacerbate local and distant cell membrane dysfunction and damage. In addition, a heightened response (metabolic memory) from the inflammatory/oxidative stress/immune cascade can create additional cell dysfunction and damage.6,7 The acute response to cell injury is defensive, short lived, regulated, and appropriate, but with chronic insults of any type, the vascular inflammatory, oxidative stress, and immune responses become dysregulated and dysfunctional to the point that there is damage to the cardiovascular system. In this regard, the blood vessel becomes an “innocent bystander” to its own defense mechanisms that lead to functional and structural cardiovascular injury then to preclinical CHD and clinical CHD.2 The maladaptation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and the inflammatory/oxidative stress/immune pathways contribute to the cardiovascular dysfunction and disease.2

The CHD risk factors have well-defined clinical goals that indicate the “normal” level at which the risk for CHD is minimal. There exists a continuum of risk of CHD with all risk factors such that a “true” normal level can be somewhat misleading.2,8,9,10,11,12,13 Normal blood pressure (BP) is now defined as 120/80 mm Hg.8,12 The new ACC/AHA Hypertension Guidelines are as follows12:

Systolic, Diastolic Blood Pressure (mm Hg)

2017 ACC/AHA

120-129 and <80

Elevated BP

130-139 or 80-89

Stage 1 hypertension

140-159 or 90-99

Stage 2 hypertension

>160 or >100

Stage 3 hypertension

Dyslipidemia is defined as an LDL-C greater than 100 mg/dL depending on the clinical setting, and glucose intolerance is defined as a fasting glucose over 99 mg/dL.2 However, the continuum of risk starts at even lower levels for BP, LDL-C, and glucose, as well as for most of the other CHD risk factors.2 The risk for CHD actually starts with a fasting glucose of 75 mg/dL. For each 1 mg/dL increase in fasting blood sugar (FBS), the risk for CHD and MI increase by 1%.2,9,10,11,12 The risk for CHD starts at a BP level of 110/70 mm Hg. For every 20/10 mm Hg increase in BP the risk for CHD is doubled.2,12,13 As the LDL-C increases over 60 mg/dL there is a gradual reduction in endothelial nitric oxide (NO) as well as risk for CHD.2,13

The concept of “translational vascular medicine” correlates CHD risk factors with the actual presence of CVD. The question is whether or not measured CHD risk factors accurately translate into cardiovascular pathology that can be evaluated by noninvasive or invasive vascular testing. Conversely, does the absence of measured CHD risk factors accurately define the absence of cardiovascular pathology or cardiovascular health? Evaluation of this correlation requires more sophisticated technology and advanced CHD risk factor analysis combined with comprehensive CHD risk factor scoring systems such as those of COSEHC13,14 and Rasmussen15 (Tables 23.1 and 23.2).


The endothelium is a very thin lining of vascular cells forming an interface between the arterial lumen and the vascular smooth muscle (VSM).2,4,16 Endothelial dysfunction occurs when nitric oxide bioavailability is reduced, which leads to vascular inflammation, oxidative stress, immune dysfunction, abnormal vascular growth, vasoconstriction, increased permeability, thrombosis, and CHD.2,4,16,17

LDL-C has a primary role in the development of atherosclerotic plaque formation starting at birth (Figure 23.1).18 LDL-C migrates from the blood into the subendothelial layer and attaches to proteoglycans and becomes modified, antigenic, and toxic primarily via oxidation of LDL (oxLDL) and glycation of LDL (glyLDL).18 The modified LDLs produce numerous cytokines and chemokines that attract monocytes into the subendothelial layer, which transform into macrophages. The modified LDL is taken up by scavenger receptors (SRA) on the macrophage cell membranes, which transform into foam cells, then fatty streaks, and eventually form a coronary artery
plaque (stable plaque or a soft rupture-prone plaque) that can result in an MI. Approximately 45 different steps exist in this process of dyslipidemia-induced vascular disease that can be interrupted with nutrition, nutritional supplements, and drugs.18 Endothelial dysfunction, arterial pathology, cardiac dysfunction, and CHD represent a delicate balance of vascular injury (angiotensin II and endothelin), vascular protection with nitric oxide, and vascular repair from endothelial progenitor cells, produced by the bone marrow.2,4,6


  • Absolute Risk: probability of an adverse event occurring in an individual within a defined period of time

  • Relative Risk: probability of an adverse event happening in an individual compared with average or normal individuals sharing similar demographics other than the risk factor

High Cardiovascular Risk

  • Relative Risk ≥ 60th percentile

  • Absolute Risk: Risk score ≥ 40 ≥ 2.3% risk of CV death/5 y

Approximate 60th Percentile Relative Risk Scores


Age Range (years)


























  • Men at age 50 y = relative risk of ≥ 60th percentile

  • Women at age 60 y = relative risk of ≥ 60th percentile

Women (12 CHD risk factors)

  • Age (years)

  • Cigarette smoking

  • Systolic blood pressure (mm Hg)

  • Total cholesterol concentration (mg/dL)

  • Height (inches)

  • Creatinine concentration (mg/dL)

  • Homocysteine (µmol/L)

  • Prior MI

  • Prior stroke

  • LVH

  • Diabetes

  • Nondiabetic, FBS (mg/dL)

Men (17 CHD risk factors)

  • Being male

  • Age (years)

  • Cigarette smoking

  • Systolic blood pressure (mm Hg)

  • Total cholesterol concentration (mg/dL)

  • LDL cholesterol (mg/dL)

  • HDL cholesterol (mg/dL)

  • Triglyceride (mg/dL)

  • Height (inches)

  • Creatinine concentration (mg/dL)

  • Homocysteine (µmol/L)

  • Prior MI

  • Family history of MI pre-60

  • Prior stroke

  • LVH

  • Diabetes

  • Nondiabetic, FBS (mg/dL)

Calculated Risk Score

% dying from cardiovascular disease in 5 y



























CHD, coronary heart disease; CV, cardiovascular; FBS, fasting blood sugar; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy; MI, myocardial infarction.


The primary causes of CHD are the three finite responses that are generated from the large number of allostatic environmental insults coupled with cardiovascular genetics, nutrigenomics, metabolomics, proteomics, and gene expression patterns. The three finite vascular responses are vascular oxidative stress, vascular inflammation, and vascular immune dysfunction.

Apart from targeting the derangements in lipid metabolism, blood pressure, glucose, and obesity, therapeutic modulation to regulate chronic inflammation, oxidative stress, and the immune system response may prove to be a promising strategy in the management of atherosclerosis and CHD.

Oxidative Stress

Oxidative stress is an imbalance of radical oxygen species (ROS) and radical nitrogen species (RNS) with a decrease in antioxidant defenses that contribute to CHD.2,3,4,19 In CHD, ROS and RNS are increased in the vasculature and
kidneys.2,3,4,19 The predominate ROS produced is superoxide anion, which is generated by numerous cellular sources, especially increases in angiotensin-II levels with an increased stimulation of the angiotensin I receptor (AT1 R).2,3,4,19 The interaction of superoxide anion with nitric oxide (NO) will partially or completely eliminate NO. In addition, there may be uncoupling of endothelium-derived NO synthase (eNOS) and production of downstream ROS, such as peroxynitrite, hydroxyl ion, and hydrogen peroxide, which induce more vascular damage.2,3,4,19 All of these events lead to a reduction in NO bioavailability, endothelial dysfunction, loss of vascular compliance, vascular and cardiac smooth muscle hypertrophy, hypertension, vascular oxidative stress, vascular inflammation, vascular immune dysfunction, CHD, and MI.2,19


  • Disease score 0-2: no CV events in 6 y

  • Disease score 3-5: 5% CV events in 6 y

  • Disease score over 6: 15% CV events in 6 y

  • Superior to Framingham risk score

  • Variables measured: CAPWA, blood pressure at rest and exercise, LV mass by ECHO, microalbuminuria, BNP, retinal score, carotid IMT, and ultrasound and EKG





Score for each test




Large artery elasticity

(age and genderdependent)

Small artery elasticity

(age and genderdependent)

Resting BP (mm Hg)

SBP <130 and DBP <85

SBP 130-139 or DBP 85-89

SBP ≥140 or DBP ≥90

Treadmill exercise BP (mm Hg)

SBP increase <30 and SBP ≤169

SBP increase 30-39 or SBP 170-179

SBP increase ≥40 or SBP ≥180

Optic fundus photography retinal vasculature

A/V ratio >3:5

A/V ratio ≤3:5 or mild A/V crossing changes

A/V ratio ≤1.2 or A/V nicking

Carotid IMT

(age and genderdependent)

Microalbuminuria (mg/mmol)





No abnormalities

Nonspecific abnormality

Diagnostic abnormality

LV ultrasound LVMI (g/m2)




NT-proBNP (pg/dL)




BNP, brain natriuretic peptide; CAPWA, computerized arterial pulse wave analysis; CV, cardiovascular; DBP, diastolic blood pressure; ECHO, echocardiogram; EKG, electrocardiogram; IMT, intimal medial thickness; LV, left ventricular; SBP, systolic blood pressure.


Increased inflammation in the vasculature and kidney can be assessed by measuring inflammatory markers such as high-sensitivity C-reactive protein (hsCRP), leukocytosis with increased neutrophils and decreased lymphocytes, increased levels of cytokines and chemokines such as interleukins (IL-6 and IL-1B), interferon gamma, and tumor necrosis factor (TNF) alpha.2,3,4,20,21,22,23 In addition, there is an increased activity of the RAAS, especially angiotensin II and aldosterone, in the arteries and kidneys with stimulation of the PRR, NLR, and TLR.2,3,4,20,21,22,23 Elevation of hsCRP is both a risk factor and risk marker for CHD.20 Nitric oxide and eNOS are inhibited by hsCRP, which increases the risk of hypertension, CHD, and MI.20 The hsCRP is produced in the liver from the precursor cytokines of IL-6, IL-1b, and TNF alpha from various systemic sources such as adipose tissue, macrophages, the heart, and the vasculature.

Vascular Immune Dysfunction

The immune system is involved in the pathogenesis of hypertension, atherosclerosis, and CHD in the general population.2,3,4,22,23,24,25,26,27,28,29,30,31 The immune system contributes to the pathogenesis of hypertension, CVD, and CHD via action in the kidney, the vasculature, and the brain, such that immunomodulation may represent a novel approach to reduce these CV complications.2,3,4,22,23,24,25,26,27,28,29,30,31 Emerging evidence points to a role of adaptive cellular immunity in the development of CHD, CVD, and hypertension, especially expansion of proinflammatory and antiapoptotic and cytotoxic CD4+ and CD28null T cells, which are closely associated with incident CVD in
various study populations.2,3,4,22,23,24,25,26,27,28,29,30,31 Autoimmune dysfunction of both the arteries and kidneys occurs with leukocytosis and involvement of CD4+ (T-helper cells) and CD 8+ (cytotoxic T-cells) to induce hypertension and CHD.2,3,4,22,23,24,25,26,27,28,29,30,31 Innate and adaptive immune responses induce both hypertension and CHD by numerous mechanisms that include angiotensin II, cytokines, chemokines, interferon gamma, TGF-beta, interleukins, monocytes, macrophages, T cells, dendritic cells, ROS, PPR, TLR, and NLR activation and increase in sympathetic tone.2,3,4,22,23,24,25,26,27,28,29,30,31 Monocytes cross the endothelial lining, invade the subintimal layer, and transform into macrophages and various T-cell subtypes that promote vascular damage and vascular immune dysfunction.22,23,24,25,26,27,28,29,30,31 Activation of the AT1R expressed on CD4+T lymphocytes release TNF alpha, interferon, and interleukins within the vascular wall; increases blood pressure; and allows for progression of vascular immune dysfunction.2,3,4,22,23,24,25,26,27,28,29,30,31 T-lymphocytes impair natriuresis by suppression of renal NOS 3 and COX-2, which increases intravascular volume and blood pressure.23

Figure 23.1 The pathogenesis of atherosclerotic plaque formation. The movement of low-density lipoprotein cholesterol (LDL-C) into the subintimal layer is followed by modification of the LDL-C, uptake by macrophages and then inflammation, oxidative stress and vascular immune dysfunction that leads to fatty streaks, foam cells and complex plaque formation, and finally thrombosis with acute myocardial infarction. HDL, high-density lipoprotein; Lp(a), lipoprotein a; RLP, remnant lipoprotein.

Figure 23.2 illustrates the interconnection of the external insults and the vascular receptors (PRR, NLR, TLR, caveolae) on the endothelium.30,31 These insults are divided into two major categories; biomechanical (blood pressure, pulse pressure, shear stress, and oscillatory pressure) within the arterial system and external biochemical factors that include dietary factors, various biohumoral and metabolic factors, microbes, sterile and nonsterile antigens, and environmental toxins.30,31


Reducing the allostatic load; interrupting the insult-vascular receptor interaction to the PPR, NLR, TLR, and caveolae; and disruption of the downstream mediators are paramount to a successful prevention and treatment regimen for CHD. Numerous scientifically validated nutritional or dietary components and nutraceutical supplements have great promise in this regard.31 These will be discussed in detail in the treatment section.

Preventing and treating CHD and establishing cardiovascular ecology and balance involve utilizing a more complex and logical approach such as dynamic systems biology, functional and metabolic medicine, CV genetics, nutrigenomics, and gene expression testing. As one might expect with a complex network of physiological interactions underlying vascular responsiveness and development of CHD, a single genetic cause has not been identified. Instead, as many as 30 separate loci are associated with MI and CHD. The majority of these involve inflammatory pathways, but only a minority of those 30 loci relate to the top five cardiovascular risk factors.3

Atherosclerosis and Endothelial Dysfunction

Atherosclerosis and endothelial dysfunction are postprandial diseases.32 The consumption of sodium chloride (NaCl), refined carbohydrates (CHO), sugars, starches, and some but not all SFA and TFA will promote glucotoxicity,
triglyceride toxicity, vascular metabolic endotoxemia, inflammation, oxidative stress, and vascular immune dysfunction that may persist long after the initial insult. This may also result in an exaggerated response (metabolic memory) with repeated or chronic dietary insults.6,32 Fortunately, studies have shown that eating a diet rich in low-glycemic foods; low in refined CHO, sugars, and starches; low in NaCl; high in potassium and magnesium; and enriched with MUFA, PUFA, polyphenols, and antioxidants can help to prevent the postprandial endothelial dysfunction and endotoxemia.18 Early evidence of CHD in the form of fatty streaks in the aorta and coronary arteries has been documented in children in the first and second decades of life and in postmortem examinations of teenagers and war victims (Figure 23.3).2 The CVD is subclinical for decades before any cardiovascular events.2,4,16 Endothelial dysfunction is the earliest functional abnormality, followed later by changes in arterial compliance of small resistance arteries and then larger conduit arteries with loss of elasticity leading to hypertension, VSM hypertrophy, diastolic dysfunction (DD), left ventricular hypertrophy (LVH), congestive heart failure (CHF) and CHD.17

Figure 23.2 Biochemical and biomechanical insults that interact with vascular receptors (pattern recognition receptors [PRR], nod-like receptors [NLR], toll-like receptors [TLR], caveolae) to induce the three finite responses of vascular inflammation, oxidative stress, and vascular immune dysfunction, which lead to endothelial dysfunction and vascular smooth muscle (VSM) and cardiac dysfunction.

Figure 23.4 shows the progression from subintimal coronary atherosclerosis to obstructive CHD. The coronary artery on the left is normal; the one in the center demonstrates mild subintimal disease with increased intimal medial thickening (IMT) but a normal and unchanged arterial lumen. This extraluminal disease and inflammation would be captured using computed tomography angiogram (CTA) or intravascular ultrasound but missed by conventional coronary arteriogram (Figure 23.5). The image on the right in Figure 23.4 illustrates extensive extraluminal and intraluminal obstructive CHD. Most MIs occur with mild stenosis of the coronary arteries.2,4,16

Some of the Top CHD Risk Factors and the CHD Gap Hypertension, Dyslipidemia, and Diabetes Mellitus

The “CHD gap” is related to incorrect definitions, assessment, and treatment of the top five CHD risk factors; the lack of assessment and treatment of the other 395 risk factors; not performing various noninvasive cardiovascular tests; genomic CV individuality; and possibly other unknown factors.2


A 24-hour ambulatory blood pressure monitor accurately measures blood pressure and CV risk and predicts CHD

and other CV target organ damage and is superior to office BP and home BP monitors.2,16 Measurements of nocturnal BP and dipping status (normal is a 10% reduction from the mean daytime BP during the night), BP surges, BP load (normal is below 140/90 mm Hg in 15% of the total BP measurements), and BP variability are superior to office BP readings as a predictor of CHD risk.2,16 Excessive dipping is associated with an increased risk of ischemic stroke, and reverse dipping is associated with an increased risk of intracerebral hemorrhage.2,16 Nocturnal blood pressure is clinically more important than daytime blood pressure and drives CV target organ damage (a 27/15-mm Hg difference is optimal).2,16 Morning blood pressure surges (both the level and rate of BP rise) increase the risk of ischemic stroke, MI, and LVH.2,16 Hypertension is marker for vascular endothelial dysfunction with reduced nitric oxide bioavailability, but the vascular damage and disease is increased in a bidirectional manner.17 This means that as NO decreases the vascular damage increases and as vascular damage increases there is more reduction in NO bioavailability. The items that should always be considered when evaluating blood pressure include16:

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Feb 27, 2020 | Posted by in CARDIOLOGY | Comments Off on Coronary Heart Disease Risk Factors, Coronary Heart Disease, Congestive Heart Failure, and Metabolic Cardiology
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