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:

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).

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

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.

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 CD28^null 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 23.2 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

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 23.4 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

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: