Context of Cardiac Diseases

and low-density lipoprotein receptor (LDLR) $^-$ mice can develop atherosclerosis both with and without high-fat feeding, hence their selection as a representative model of human situation. However, lesions that develop over a period of weeks do not mimic accurately those that evolve over decades in humans, in particular fibrous plaques as well as lesions with calcification, ulceration, hemorrhage, and/or thrombosis. Whatever the animal species, some mediators can lack or intervene at a different concentration. Therefore, the process in a given species can vary in comparison with that in another species. For example, cholesteryl ester transferase exists at a much greater level in humans than in mice. Conversely, HDL concentration is higher in mice than humans. In any case, all models are a simplification of the reality.




2.3 Risk Factors


Genetic and environmental risk factors contribute to the variability in disease susceptibility for cardiovascular diseases. The occurrence of cardiovascular diseases also depends on the subjected pathophysiological ground and habits.

The two most important risk factors are smoking addiction and abnormal ratio of blood lipids ( apolipoprotein-B/apolipoprotein-A1 ratio). In fact, major cardiovascular risk factors include diabetes, hypertension, obesity, and the familial context (family members with heart diseases), in addition to hypercholesterolemia and smoking. Minor cardiovascular risk factors are age, high-stress job, sedentary habits, lack of daily consumption of fruits and vegetables, and high resting cardiac frequency (∼1.25 Hz [75 beats/min]).

The Framingham risk scores for men and women (Tables 2.1–2.5) are aimed at estimating the 10-year cardiovascular risk of an individual, more precisely, development of coronary heart diseases within the next decade in particular from plasma concentrations of lipids (total cholesterol and HDL–cholesterol [mg/dl]), value of the systolic blood pressure, and smoking habit. In fact, the LDL score is a better index than HDL and triglyceride scores [111].


Table 2.1
Age score. (Framingham point score; Source: National Institutes of Health—National Heart, Lung, and Blood Institute)






















































Age
Point

Men
Women

20–34
−9
−7

35–39
−4
−3

40–44
0
0

45–49
3
3

50–54
6
6

55–59
8
8

60–64
10
10

65–69
11
12

70–74
12
14

75–79
13
16



Table 2.2
Smoking habit score. (Framingham point score; Source: National Institutes of Health—National Heart, Lung, and Blood Institute)






















































 
Points
 
20–39
40–49
50–59
60–69
70–79
20–39
40–49
50–59
60–69
70–79

NS
0
0
0
0
0
0
0
0
0
0

S
8
5
3
1
1
9
7
4
2
1


NS nonsmoker, S smoker



Table 2.3
Systolic blood pressure (BP) score (Framingham point score; Source: National Institutes of Health—National Heart, Lung, and Blood Institute)

















































Systolic BP (mmHg)
Men
Women

Untreated
Treated
Untreated
Treated

$<$  120
0
0
0
0

120–129
0
1
1
3

130–139
1
2
2
4

140–159
1
2
3
5

≥ 160
2
3
4
6



Table 2.4
Total cholesterol score. (Framingham point score; Source: National Institutes of Health—National Heart, Lung, and Blood Institute)





























































































 
Points

Men
Women

Age
20–39
40–49
50–59
60–69
70–79
20–39
40–49
50–59
60–69
70–79

< 160
0
0
0
0
0
0
0
0
0
0

160–199
4
3
2
1
0
4
3
2
1
1

200–239
7
5
3
1
0
8
6
4
2
1

240–279
9
6
4
2
1
11
8
5
3
2

≥280
11
8
5
3
1
13
10
7
4
2


2.3.1 Lifestyle


Lifestyle plays a major role in the prevention of complications of numerous chronic diseases. Although epidemiology does not give proof for the existence of a cause-and-effect relation, but provides statistical links between an investigated disease and explored parameters.


2.3.1.1 Inactivity


Inactivity can diminish life expectancy because it influences aging and predisposes to aging-related diseases. In particular, a relation was found between leukocyte telomere length and physical activity.

Moreover, combined to overnutrition, sedentary life causes obesity. Normal values of the body mass index, the ratio between the weight (kg) and the square height (m), range between 18.5 and 25. A value between 25 and 30 means moderate overweight; greater than 30, obesity. Obesity associated with adipose tissue dysfunction, characterized by infiltration of inflammatory cells and aberrant production of adipokines, yields an increased risk for metabolic and cardiovascular disorders, especially insulin resistance.

Sedentary lifestyle is associated with impaired endothelial functions exhibited by elevated plasma levels of endothelial microparticles [112]. Months of bed rest increase markers of endothelial dysfunction, such as circulating endotheliocytes and endothelial microparticles, which are released from the membrane of activated, injured, or apoptotic endothelial cells (Vol. 8—Chap. 5. Adverse Wall Remodeling), as well as impaired endothelial vasodilatory capacity (reduced cutaneous acetylcholine-induced vasodilation) [112].


2.3.1.2 Diet


Diet recommendations aimed at optimizing lipid and lipoprotein profiles, blood pressure values, glycemia, and body weight, currently rely on the consumption of plant-based foods, vegetables and fruits, and beverages that contain essential nutrients, such as vitamins (e.g., vitamin-B, -C, and -E ), potassium, and magnesium, and healthy phytochemicals, such as flavanols, a subset of flavonoids.2 In addition, vegetables and fruits have a low lipid and high fiber content, as well as an adequate sodium/potassium ratio.

Long-chain polyunsaturated ${\upomega}$ 3-fatty acids such as docosahexaenoic acid (DHA) that abound in oily fish (e.g., anchovy, herring, mackerel, and salmon) protect the immune, nervous, and cardiovascular systems. In vascular smooth myocytes, DHA (but not its ethyl ester derivative) directly, rapidly, potently, and reversibly activates large-conductance, voltage- and Ca $^{2+}$ -activated K $^+$ channels (BK or K $_{\mathrm{Ca}}$ 1.1)3 that acts as a vasodilator, thereby lowering blood pressure [113]. The BK channel is activated by intracellular Ca $^{2+}$ and depolarization. It keeps the membrane hyperpolarized (negative feedback on cellular excitability). This proteic complex operates as a high-affinity receptor for DHA without needing Ca $^{2+}$ ions. Lipid DHA is released from the plasma membrane by G-protein-activated, Ca $^{2+}$ -dependent phospholipase-A2. The concentration required to activate BK channel is about 20 times lower than that needed to stimulate GPR120 involved in anti-inflammatory action of DHA [113].

Ester-conjugated ${\upomega}$ 3-fatty acids refer to esterification with ethanol (i.e., ethyl esters) or with glycerol as triglycerides. Various ${\upomega}$ 3 and ${\upomega}$ 6-fatty acids as well as their ethyl and glycerol ester derivatives have distinct effects on BK channels and blood pressure when acutely applied. In particular, ethyl ester of DHA fails to reduce blood pressure. Oral or parenteral administration of these products thus has different clinical impact. In addition, the physiological response of healthy individuals and patients to various types of fatty acids may differ appreciably.


Table 2.5
HDL score. (Framingham point score; Source: National Institutes of Health—National Heart, Lung, and Blood Institute)






























HDL (mg/dl)
Points

Men
Women

≥60
− 1
− 1

50–59
0
0

40–49
1
1

$<$  40
2
2


Flavonoids

Flavonoids share a common basic chemical structure. Important flavonoid subsets encompass:



  • flavonols (e.g., kaempferol, myrestin, and quercetin [in onions]);


  • flavanols (e.g., catechin and epicatechin [in cocoa, red wine, green tea, and apples]);


  • flavones (e.g., apigenin and luteolin [in peppers]);


  • isoflavones;


  • flavanones (e.g., eriodictyol, hesperetin, and naringenin [in oranges]); and


  • anthocyanidines (e.g., cyanidin, delphinidin, malvedin, and pelargonidin [in blueberries]), which are defined by the chemical residues attached to the basic flavonoid structure.
Flavanols are monomers and procyanidins are oligomers of flavanols.

Major flavanol sources include green tea (up to 300 mg/infusion), red wine, cocoa (up to 920–1220 mg/100 g), fruits, such as grapes, pears, berries, and especially apples (up to 120 mg/200 g). However, the flavanol profile (e.g., ${}^{-}$ catechin and ${}^{+}$ catechin as well as ${}^{-}$ epicatechin and ${}^{+}$ epicatechin) can vary considerably according to the food type.

Most of the flavanols in foods exist as oligomers (procyanidins). Only monomers and dimers are absorbed and rapidly metabolized. In plasma, ${}^{-}$ epicatechin (5–250 nmol) represents a minor part of total plasma flavanols ( $<$ 3  ${\upmu}$ mol; short half-life) [115]. Epicatechin metabolites include methylated, glucuronidated, and sulfated adducts. Monomeric flavanols are further processed in the liver.

Endothelium-dependent (nitric oxide-mediated) vasodilation is related to the intake of flavanols in healthy subjects with cardiovascular risk factors (smoking, diabetes mellitus, hypertension, and hypercholesterolemia) [116]. In addition to the recovery of endothelial function, flavanol-rich diets improve insulin sensitivity, decrease blood pressure, and reduce platelet aggregation [115].

Regular, moderate consumption of some red wine reduces the risk of coronary heart disease. Red wines are sources of low levels of resveratrol and larger quantities of procyanidins. Procyanidins constitute a subclass of flavonoids. These vasoactive polyphenols lower blood pressure [117]. However, consumption of red wine alone cannot explain the French paradox (low rate of cardiovascular mortality in France despite high saturated fat consumption).

Chocolates and apples contain the largest procyanidin content (164.7 and 147.1 mg, respectively) with respect to red wine and cranberry juice (22.0 and 31.9 mg, respectively) [118]. However, the procyanidin content varied greatly between apple species with the highest amounts in Red Delicious (average 207.7 mg/serving) and Granny Smith apple (average 183.3 mg/serving) and the lowest amounts in Golden Delicious (average 92.5 mg/serving) and McIntosh apple (average 105.0 mg/serving). Flavonoid-rich cocoas contain monomeric flavanols (epicatechin and catechin) and oligomeric procyanidins formed from monomeric units. Both monomers and oligomers support cardiovascular health.

Cocoa and, hence, dark chocolate contain various active compounds, such as flavanols, theobromine, and caffeine, among others. The cocoa content varies greatly between chocolates; the flavanol profile and content differ strongly between cocoas. An inverse relation between flavanol-rich chocolate consumption and cardiovascular disease risk (myocardial infarction and stroke) was observed in a middle-aged (35–65 years) German population of both sexes, without complications of cardiovascular diseases at the time of enrollment [119]. In the group with the highest chocolate consumption (7.5 g/d), both systolic and diastolic blood pressure are 1 mmHg lower on average than that in the low-chocolate consumption group. The group with the highest chocolate intake is also the group with the lowest vegetable diet.


Sulfides

Excess salt intake over many years can lead to hypertension. On the other hand, garlic consumption is correlated with the reduction of risk factors of cardiovascular diseases. Garlic is rich in organosulfur compounds.4 Garlic-derived organic polysulfides are converted by red blood capsules and vascular cells into hydrogen sulfide [120]. The gasomediator hydrogen sulfide decreases blood pressure, protects against ischemic reperfusion damage, and induces O $_2$ -dependent vasodilation.


Cheese and Fungus Metabolites

Molded cheese, especially blue cheeses such as Roquefort, may favor cardiovascular health due to the presence of metabolites produced by Penicillium roqueforti of the Trichocomaceae set and other fungi, such as andrastin-A to andrastin-D and roquefortine, which can prevent cholesterol synthesis and bacterial growth [121].


Mediterranean Diet and Nitrofatty Acids

The Mediterranean diet is characterized by a high consumption of unsaturated fatty acids, especially from olive oil and fish rich in oleic and linoleic acids, with vegetables rich in nitrite and nitrate, resulting in endogenous formation of reactive nitrofatty acids.5 In particular, linoleic acid and nitrite are major constituents of the Mediterranean diet that elevates concentrations of thiol-reactive electrophilic nitrofatty acids. The acidic and low-oxygen environment in the stomach enables an efficient nitration of such unsaturated fatty acids by nitrite. Nitro-oleic acid (or 9- and 10-nitrooctadeca 9-enoic acid [NO $_2$ OA]) and other free and esterified fatty acid nitroalkenes are formed at elevated levels when unsaturated fatty acids are ingested together with a source of nitrite [123].

The endogenous lipid electrophile nitro-oleic acid and other fatty acid nitroalkenes signal via pleiotropic mechanisms, such as activation of peroxisome proliferator-activated receptor (PPAR) ${\upgamma}$ (nuclear receptor NR1c3), the stress sensor and NFE2L2 sequestrator Kelch-like erythroid cell-derived protein with CNC homology (EHC)-associated protein KEAP1,6 and nuclear factor erythroid-derived-like factor NFE2L2-regulated antioxidant response genes, and inhibition of proinflammatory gene expression regulated by NF ${\upkappa}$ B [123]. Nitrofatty acids also inhibit lipopolysaccharide-induced cytokine expression and induce HO1 expression via activation of NFE2L2-regulated gene expression. Therefore, electrophilic lipid derivatives can control gene transcription that overall engenders an anti-inflammatory response.

Nitroalkenes react with nucleophiles, such as cysteine and histidine in various target proteins. In particular, they target transient receptor potential (TRP) channels in the central and peripheral nervous system [124]. Nitroalkene fatty acid derivatives can activate TRP channels on capsaicin-sensitive afferent nerve terminals, leading to increased smooth myocyte contractility via release of neuropeptides (neurokinins) and activation of Ca $_{\mathrm{V}}$ 1.2b channel. Nitro-oleic acid activates TRPA1 and TRPV1 channels in sensory neurons involved in neurogenic inflammation and pain induced by noxious chemicals or thermal stimuli, thereby provoking calcium influx, membrane depolarization, and firing. In addition, high concentrations of nitro-oleic acid suppress firing in dorsal root ganglion neurons, hence contributing to anti-inflammatory effects.

Nitrofatty acids that can be detected in healthy human urine are produced at heightened levels during metabolic stress and inflammatory conditions (from nmol to ${\upmu}$ mol concentrations) [124].

Nitro-oleic acid is a member of the category of electrophilic nitroalkenyl fatty acids formed by reactions between unsaturated fatty acids, nitric oxide (NO)- and nitrite (NO $_2^-$ )-derived nitrogen dioxide (NO $_2$ ), these reactions being favored by the prooxidative condition of inflammation. In addition, when pH is low enough ( $<$  6) to protonate NO $_2^-$ to nitrous acid (HNO $_2$ ), this condition also yields the nitrating species NO $_2$ . Therefore, nitrogen dioxide is both a product of oxidative inflammatory reactions involving nitric oxide and nitrite and acidic conditions in the presence of nitric oxide or nitrite. Similarly, nitroalkenes are produced by addition of the radical nitrogen dioxide (NO $_2^{\bullet}$ ) to one or more of the olefinic carbons of unsaturated fatty acids [123].

Linkage of electron-withdrawing nitro group to alkenyl groups confers a potent and reversible electrophilic reactivity to fatty acids. Fatty acid nitroalkenes can modify proteins covalently, thereby associating metabolic and redox signaling with the posttranslational regulation of target proteins.

Lipidic electrophiles mediate antihypertensive signaling, as they connect to soluble epoxide hydrolase (sEH; at Cys521 proximal to its catalytic site), thereby precluding its activity, especially hydrolysis of its vasoactive substrates epoxyeicosatrienoic acids (EET) [123]. EETs are metabolites of arachidonic acid processed by cytochrome-P450 epoxygenase. They are hydrolyzed into corresponding dihydroxyepoxyeicosatrienoic acids (DHET) by sEH. Upon sEH inhibition, EETs accumulate and provoke vasodilation, hence lowering blood pressure. The EET/DHET ratio is elevated in plasma.

Vasodialation is unaffected by inhibition of soluble guanylate cyclase. Nitrofatty acids not only relax vascular wall, but also attenuate platelet activation and inflammation via a cGMP-independent mechanism [123].


Ketone Bodies

Ketone body and anaplerotic metabolisms have been introduced in Vol. 6, Chap. 3. Cardiovascular Physiology.


Ketone Bodies in Cardiovascular Diseases

Defective ketone body synthesis and catabolism are pathogenic factors. Conversely, some diseases disturb ketone body metabolism. Hepatic ketogenesis is suppressed at later stages of hyperinsulinemic obesity [125]. Ketone bodies participate in the regulation of mitochondrial metabolism, energetics, and ROS production.

Impaired cardiac energetics cause cardiomyopathy. Conversely, cardiomyopathies are associated with changes in energetic metabolism. In dilated and hypertrophic cardiomyopathies, the contribution of ketone bodies to cardiac energetics is augmented [125]. Decayed myocardial ketone body oxidation causes pathological outcomes.

In addition, hepatic ketogenesis is reinforced and circulating ketone body concentration rises during the development of heart failure. Ketone body metabolism may contribute to myocardial adaptation to ischemia–reperfusion injury, at least in rodents [125].


Ketogenic Diet

Ketogenic diet raises blood levels of cholesterol and free fatty acids [125]. Anaplerotic 5-carbon ketone bodies and their precursor odd-chain fatty acids are proposed for the treatment of long-chain fatty acid oxidation (LCFAO) disorders. Ingestion of odd-chain fatty acids promotes hepatic C5-ketogenesis; ${\upbeta}$ -oxidation of odd-chain fatty acids yields propionylCoA, an anaplerotic substrate that, in the liver, can also be packaged into C5 ketone bodies [125]. In extrahepatic cells, C5 ketone bodies are oxidized by CoA transferase SCOT, hence regenerating propionylCoA.


Dietary Phosphate

A deranged calcium–phosphate metabolism and elevated phosphate concentrations are correlated with reduced life expectancy and cardiovascular events because of endothelial dysfunction, vascular calcification, and myocardial hypertrophy [126]. Phosphate intake (by ingestion) and phosphatemia are indices of cardiovascular risk, not only in chronic kidney disease, but also in individuals with intact renal function [127].


Sources of Dietary Phosphate

Sources of dietary phosphate include: (1) phosphate additives, i.e., inorganic phosphate salts (i.e., sodium phosphate) that serve as preservatives, flavor enhancers, color stabilizers, sweeteners, antioxidants, and emulsifiers, and (2) natural phosphate (phosphoproteins, phospholipids, phosphate esters, and phytates from milk products, fish, meat, and vegetables, respectively), i.e., organic phosphates in unprocessed foods.

Intestinal absorption is regulated by calcitriol. Natural phosphates are not only slowly and incompletely hydrolyzed but also slowly and incompletely (30–60 %) absorbed in the digestive tract in the presence of adequate vitamin-D levels [126]. On the other hand, inorganic phosphate is absorbed in the gut in larger proportions (80–100 %).


Calcium–Phosphate Metabolism and its Regulation

Average western diets provide a daily phosphate intake of 1000–1700 mg according to food composition. The major determinant of plasma phosphate concentration is renal phosphate excretion; phosphaturia balances oral intake and intestinal absorption. Calcium and phosphate are regulated by parathyroid hormone (PTH), active vitamin-D, or calcitriol ([1, 25](OH) $_2$ D $_3$ ),7 and fibroblast growth factor FGF23.

The major fraction of total body calcium localizes in bones, only a small part of calcium circulates in plasma as free (ionized) calcium (50 %) and binds to proteins (mostly albumin) as well as citrate, sulfate, and phosphate.

A reduced plasma Ca $^{2+}$ concentration rapidly provokes secretion of PTH that inhibits renal calcium excretion and stimulates renal hydroxylation of 25OH-vitamin-D to calcitriol. The latter triggers intestinal calcium absorption (Table 2.6). In addition, calcitriol and PTH cause bone resorption by osteoclasts. Conversely, hypercalcemia inhibits PTH secretion via parathyroid calcium-sensing receptors.


Table 2.6
Calcium–phosphate metabolism. (Source: [127])




























































Organ
Effect
Regulators

Gut
Ca $^{2+}$ absorption
Calcitriol (⊕)

Phosphate absorption
Calcitriol (⊕)

FGF23 (⊖)

Kidney
Ca $^{2+}$ excretion
PTH (⊖)

Hypercalcemia (⊕)

Phosphate excretion
PTH (⊕)

FGF23 (⊕)

Hyperphosphatemia (⊕)

Calcitriol synthesis
PTH (⊕)

Hypercalcemia (⊖)

Hyperphosphatemia (⊖)

Bone
Ca $^{2+}$ release
PTH (⊕)

Calcitriol (⊕)

Phosphate release
PTH (⊕)

Calcitriol (⊕)

PTG
PTH secretion
Hypercalcemia (⊖)

Hyperphosphatemia (⊕)

Calcitriol (⊖)


⊕ stimulation, ⊖ inhibition, PTG parathyroid gland, PTH parathyroid hormone


FGF23

The master regulator of renal phosphate handling is fibroblast growth factor FGF23 liberated by osteocytes upon high calcitriol and phosphate levels, rather than PTH. Factor FGF23 is mainly synthesized and secreted by osteoblasts stimulated by calcitriol, PTH, and hyperphosphatemia.

Target cells of FGF23 comprise renal and parathyroid gland cells as well as cardiomyocytes [126]. In the kidney and parathyroid glands, FGF23 interacts with ${\upbeta}$ -glucoronidase Klotho coreceptor. Membrane-bound Klotho selectively localizes to the kidney, parathyroid gland, and choroid plexus. The FGF23–Klotho dimer binds to the fibroblast growth factor receptor, a receptor Tyr kinase, thereby causing its autophosphorylation and triggering signaling via 3 major pathways: PI3K–PKB, PLC ${\upgamma}$ –PKC, and Ras–MAPK. Factor FGF23 regulates phosphate balance via expression of genes involved in PTH, vitamin-D, and phosphate metabolism. In cardiomyocytes, FGF2 uses heparan sulfate proteoglycans as coreceptors, FGFR, and primarily the Ras–MAPK pathway, whereas FGF23 signals primarily via the PLC ${\upgamma}$ –PP3 pathway.

Factor FGF23 impedes calcitriol synthesis and promotes its degradation. It indeed represses renal 1 ${\upalpha}$ -hydroxylase, hence the renal synthesis of calcitriol [126]. Proximal tubule cells of the nephron produce fibroblast growth factor receptors FGFR1, FGFR3, and FGFR4, FGFR1 being the predominant receptor for the FGF23 hypophosphatemic action [128]. In the proximal tubule, FGF23 reduces production and activity of 2 sodium–phosphate cotransporters NaPi2a and NaPi2c ( SLC34a1 and SLC34a3), hence augmenting phosphaturia. In addition, FGF23 suppresses PTH synthesis in the parathyroid glands.


Endothelial Dysfunction

Even transient hyperphosphatemia, such as that during the postprandial period, can cause endothelial dysfunction and imbalance between nitric oxide and reactive oxygen species. Increased influx of phosphate via Na $^+$ –Pi cotransporters leads to inhibitory phosphorylation of NOS3 synthase.


Vascular Calcification

Intake of calcium salts (acetate or carbonate) can lead to calcium tissue deposition, in particular vascular calcification, even in the absence of hypercalcemia. In the case of overload, calcium–phosphate crystals may dispose in the vessel wall and myocardium.

High phosphatemia initiate osteogenic transdifferentiation, i.e., the evolution of vascular smooth myocytes toward a osteochondrogenic phenotype, vascular smooth myocytes differentiating into osteoblast-like cells [127]. Extracellular phosphate is actively taken up by Na $^+$ –Pi cotransporters into the cell. Calcium ion stimulates Na $^+$ –Pi cotransporter SLC34a1 on vascular smooth myocytes, thereby permitting intracellular accumulation of phosphate ions.

After its uptake into vascular smooth myocytes, phosphate primes synthesis of proteins involved in matrix mineralization and bone formation and downregulates vSMC-specific transcription factors. Vascular smooth myocytes subsequently evolve from a contractile into osteochondrogenic phenotype, and release membrane-enclosed matrix vesicle-like structures (size 100–400 nm) from the plasma membrane [127]. Furthermore, phosphate can induce apoptosis in vascular smooth myocytes, which subsequently release apoptotic bodies. Moreover, Ca $^{2+}$ supports liberation of matrix vesicle-like particles of living vSMCs and apoptotic bodies from apoptotic vSMCs that act as nuclei for extracellular calcium–phosphate precipitation [127]. Calcium also reduces the expression of calcification inhibitors by vascular smooth myocytes.


Myocardial Hypertrophy

Elevated FGF23 levels cause maladaptive left ventricular hypertrophy via vascular stiffening and subsequent elevated cardiac afterload, in addition to calcifications. Maladaptive cardiac hypertrophy results from the activation of the PP3–NFAT pathway [127]. Moreover, elevated phosphatemia triggers secretion of FGF23 to raise phosphaturia, but in parallel activates cardiomyocytes, thereby further exaggerating maladaptive cardiac hypertrophy. In addition, intake of calcium supplements for bone protection against osteoporosis can cause myocardial infarction [127].


Nutrition and Regulator Hormones

The arcuate nucleus of the hypothalamus controls the metabolic rate, hunger, and satiety. It contains two cell types: (1) hunger NPY/AgRP8 cell and (2) satiety POMC cell.9 Ghrelin and leptin are two major hormonal controllers of hypothalamic hunger and satiety cells. They are antagonistic and complementary, responding to acute and chronic changes in energy balance. Their effects are mediated by hypothalamic neuropeptides, such as neuropeptide-Y and agouti-related peptide. Endocrine and nervous (vagal afferent) signals contribute to actions of ghrelin and leptin.

The hunger hormone, ghrelin, a member of the motilin-related category of regulatory peptide10 and a ligand of the G-protein–coupled growth hormone secretagogue (GHS) receptor,11 is a 28-amino acid hunger-stimulating hormone. In addition to stimulating GH secretion and gastric motility, ghrelin wakes up appetite and induces a positive energy balance with body’s weight gain. This orexigenic and adipogenic peptide is produced mainly by endocrine P/D1 cells of oxyntic glands12 in the fundus of the stomach and ϵ cells of the pancreas. It circulates (plasma concentration 117 ± 37 fmol/ml) and is conveyed to the hypothalamus where it activates hunger cells and inhibits satiety cells. Although about 90 % of ghrelin is made in the stomach, duodenum, and jejunum, it is also synthesized in the pancreas, pituitary gland, kidney, and various regions of the brain such as hypothalamus.

The satiety hormone, leptin, is produced by adipocytes. Once it is liberated into blood, it travels to the hypothalamus where it activates satiety cells and inhibits hunger cells. High leptin concentrations in combination with high insulin levels prevent ghrelin production. Low ghrelin concentrations render hunger cells hypersensitive to ghrelin. On the other hand, high leptin concentrations cause insensitivity to leptin of satiety cells. Obestatin, a preproghrelin-derived peptide, is a hormone that stops the hunger sensation. This anorectic peptide is produced by ghrelin-producing cells of the gastrointestinal tract. It antagonizes growth hormone secretion and food intake induced by ghrelin [131].

Ghrelin improves memory and concentration. Moreover, ghrelin favors restorative sleep and dreams that preclude leptin production.


2.3.2 Inflammatory Intestine, Gut Microbiome, and Cardiovascular Disease


The intestinal barrier determines the nutrient uptake. The intestinal microbiota within the alimentary canal influences the intestinal barrier and hence the nutritional and metabolic status of the organism.


2.3.2.1 Intestinal Microbiota


The gut microbiome (1000–1500 bacterial species) interacts with the intestinal mucosa and may affect the function of other organs, such as the heart, lung, and lymphatic circuit [132]. Diet, bacterial composition of the environment, and host genetics, influence the composition of the microbiome in a given subject.

The commensal biota provides numerous nutrients and small molecules. In addition, certain bacterial species such as Firmicutes contribute to a higher uptake of molecules such as short-chain fatty acids. Moreover, these commensals contribute to immunity, as it directly influences the cytokine production of epitheliocytes and innate immunocytes.

Many acute and chronic disorders that affect the heart, such as obesity and metabolic syndrome, are linked to inadequate postnatal microbiome acquisition or environmental microorganism exposure during early childhood [132]. In obese patients, the gut contains different bacterial species, especially Firmicutes. Transplantion of the microbiome of obese mice in lean mice provokes a weight gain in the absence of diet change (but the transplantation of the microbiome of lean mice into obese mice does not engender a weight loss).


2.3.2.2 Oral Drugs and Alimentary Tract


The gut determines not only nutrient uptake but also absorption of drugs after oral administration. Conversely, drugs influence the intestinal function. Macrolide antibiotics inhibit the cytochrome-P450 isozyme CyP3a that is constitutively expressed in small intestinal villi and contributes to prehepatic metabolism of drugs [132]. Statins are metabolized by CyP3a4 and CyP3a5, hence influencing their pharmacokinetics; conversely, they increase CyP3a expression [132].


2.3.2.3 Altered Intestinal Barrier and Bacteria


An altered intestinal barrier with elevated permeability for bacterial products (lipopolysaccharide, bacterial DNA with CpG motifs, and peptidoglycans [e.g., muramyl dipeptide]) can contribute to atherosclerosis and chronic heart failure. An acute prominent inflammatory response to bacteria facilitates innate immune defense, but can increase the risk of atherosclerosis. Microbial components (toxins and DNA) as well as factors secreted by intestinal epithelial and dendritic cells can intervene in the pathogenesis.

Conversely, impaired cardiac function in chronic heart failure impacts intestinal microcirculation and can cause a barrier defect of the intestinal mucosa, thereby favoring bacterial invasion. Toll-like receptor-4, the receptor for lipopolysaccharide of Gram− bacteria, is expressed on cardiomyocytes and foam cells, among other cell types. Once they are recognized by Toll-like receptors, microbial products signal to neutrophils, activating NF ${\upkappa}$ B and transcription of proinflammatory genes. Single nucleotide polymorphism in the Tlr4 gene replacing Asp299 with Gly (D299G) and Thr399 with Ile (T399I) in TLR4 causes lipopolysaccharide hyporesponsiveness. These two genetic variants are linked to various infectious and noninfectious diseases.13 Carriers of 1 or 2 alleles with TLR4 polymorphisms (Asp299Gly and Thr399Ile) are more susceptible to bacterial infections. In particular, patients with the Asp299Gly TLR4 allele have lower levels of certain proinflammatory cytokines (e.g., IL6), acute-phase reactants, and adhesion molecules. On the other hand, the Asp299Gly TLR4 polymorphism that attenuates TLR4 signaling and inflammatory response to Gram− bacteria decreases risk of atherosclerosis [134].

In addition, bacterial lipopolysaccharides can interact with low-density lipoproteins, hence influencing lipoprotein metabolism and contributing to the development of atherosclerosis [132]. Furthermore, lipopolysaccharides damage endotheliocytes and support the production and release of superoxide anions and the oxidation of low-density lipoproteins.


2.3.2.4 Inflammatory Bowel and Risk for Cardiovascular Diseases


The intestine is associated with metabolic diseases. The autoimmune disorder of the small intestine celiac disease and the regional immunity-related chronic enteritis Crohn syndrome (caused by a combination of environmental, immune, and bacterial factors in genetically susceptible individuals) disturb the absorption of nutrients and drugs in the small intestine. In addition, celiac disease is characterized by a decreased expression of some cytochrome-P450 isozymes such as CyP3a. Patients with inflammatory bowel diseases have a higher risk for coronary artery disease, despite a lower exposure to classical risk factors [132].

The metabolism by the gut flora of phosphatidylcholine that generates three metabolites, choline, trimethylamine ${}^{\mathrm{N}}$ oxide, and betaine, predicts risk for cardiovascular disease [132].

Patients with chronic heart failure, a state of chronic inflammation, have elevated levels of soluble CD14 (shed from the plasma membrane), a component of the bacterial lipopolysaccharide receptor. Chronic heart failure favors bacterial migration through a congestive intestinal mucosa. The altered mucosal perfusion indeed raises intestinal mucosal permeability, hence facilitating the penetration of bacteria and their product. Lipopolysaccharides trigger catecholamine release by granulocytes and phagocytes [132].

Moreover, CHF patients have morphological and functional alterations of the intestine. The large bowel wall thickens. The mucosal permeability for the sugar alcohol mannitol, nondigestible lactulose, and artificial sucralose increases in both the small and large intestine [132]. The passive carrier-mediated transport for ${}^{\mathrm{D}}$ xylose lowers. In addition, the bacterial density in the sigmoidal mucosal biofilm and the extent of their adherence heighten with respect to healthy subjects.

The small and large intestine is affected by hypoxia caused by chronic heart failure. Hypoxia raises sympathetic activity and production of inflammatory cytokines, leukotrienes, and prostaglandins, thereby engendering intestinal dysfunction. Increased sympathetic tone and resulting vasoconstriction redistribute blood flow away from the splanchnic circulation. Moreover, the venous stasis further increases mucosal hypoxia [132].


2.3.3 Psychological Context


Depression, acute stress, phobia, and anxiety increase the probability of fatal coronary heart disease. This psychological context favors inflammation induced by secretion of cytokines by immunocytes. Myocardial infarction indeed has a strong inflammatory component. Conversely, laughter, happiness, and self-esteem lower the expression of some proinflammatory cytokines.


2.3.4 Smoking


Smokers have a two to threefold higher risk of developing arterial disease than nonsmokers. Smokers have a higher risk to develop heart failure than ex-smokers and nonsmokers. Ex-smokers have a 30 % lower mortality than smokers 2 years after smoking cessation.

Nicotine, the addictive ingredient of tobacco, stimulates the sympathetic nervous system, thus increasing blood flow rate, and causes endothelial dysfunction. Cardiac frequency determines myocardial O $_2$ consumption. An increased resting cardiac frequency reduces cardiac performance and ischemic threshold.

Nicotine also exaggerates postinjury intimal hyperplasia and contributes to the formation of intracranial [135] and abdominal aortic aneurysm [136]. Smoking is a major risk factor in abdominal aortic aneurysm, because of oxidation of serpin-A1 (or ${\upalpha}$ 1-antitrypsin), which is carried by high-density lipoproteins at low levels in dyslipidemia, among other factors.

Smoke exposure also provokes damage of nuclear and mitochondrial DNA. Mitochondrial DNA damage can precede atherogenesis and, then, be exacerbated by impaired antioxidant activity [137]. Moreover, cardiac adenine nucleotide translocase activity needed for ATP synthesis can decrease.

Smoking can contribute to endothelial dysfunction with a disturbed balance between nitric oxide and oxygen free radicals. Like hypertension, smoking alters the expression of endothelins. Like hypertension, hypercholesterolemia, and oxidative stress, smoking promotes NF ${\upkappa}$ B activation. As with other cardiovascular risk factors (diabetes, dyslipidemia, hypertension, and renal disease), smoking is associated with a decreased number and function of bone marrow-derived endothelial progenitor cells, which participate in endothelial regeneration and angiogenesis. Smoking (1) increases levels of proinflammatory compounds (e.g., tumor-necrosis factor- ${\upalpha}$ and endothelial intercellular adhesion molecule-1), and reactive oxygen species, (2) decreases concentrations of anti-inflammatory, antioxidant HDL–cholesterol (HDL $^{\mathrm{Cs}}$ ), which promotes reverse cholesterol transport, and adiponectin, and (3) activates leukocytes and platelets.

Tobacco smoke elicits production of intra- and extracellular superoxide (O $_2^{{\bullet}-}$ ) as well as peroxynitrite (ONOO $^-$ ) and causes oxidation (inactivation) of nitric oxide NOS3 synthase [138]. Smokers have a drop of endothelium-mediated vasodilation.

Proliferation of vascular smooth myocytes results from hypoxia, arterial injury, and stimulation by angiotensin-2, which lead to activation of early growth response EGR1 factor [139]. Factor EGR1 stimulates transcription of proinflammatory genes, such as those that encode the cytokines TNFSF1 and IL2, chemokine CCL2, and adhesion molecule ICAM1, as well as expression of growth factors, such as FGF2, PDGF, and TGF ${\upbeta}$ , and tissue factor [140].

Proatherosclerotic and prorestenotic nicotine increases vascular smooth myocyte proliferation via nonneuronal nicotinic acetylcholine receptors,14 ERK1 and ERK2, and phosphorylated ELk1 factor, which in turn upregulates the EGR1 expression [139].


2.3.5 Resting Tachycardia


An increased, sustained resting heart frequency reduces cardiac performance. Moreover, resting tachycardia is an accelerator of atherosclerosis development [141].

When the cardiac frequency is reduced, the sensitivity of the baroreflex increases (Table 2.7). The baroreflex is aimed at short-term controlling sympathetic activity, cardiac frequency and flow rate, as well as blood pressure via the vasomotor tone.


Table 2.7
Baroreflex. The processing nervous path from arterial baroreceptors in the carotid body and aortic arch to the medulla, spinal cord, and blood vessel walls (sympathetic nerve activity; Source: [142]). When arterial blood pressure increases, baroreceptors are activated and stimulate the nucleus of the solitary tract (NTS) that activates the caudal ventrolateral medulla (CVLM), an inhibitory medullary site, which, in turn, inhibits the sympathoexcitatory site rostral ventrolateral medulla (RVLM), thus inhibiting the sympathetic branch of the autonomic nervous system via the intermediolateral nucleus of the spinal cord (ILNSC), thereby decreasing arterial blood pressure. Conversely, a low arterial blood pressure increases the sympathetic tone via disinhibition, i.e., activation of the rostral ventrolateral medulla. The NTS also sends excitatory fibers to the nucleus ambiguus (vagal component) that regulates the parasympathetic nervous system, assisting decreasing sympathetic activity during hypertension. Baroreceptor activation thus inhibits the sympathetic nervous system and stimulates the parasympathetic nervous system. The baroreflex maximizes arterial blood pressure reduction, as it couples sympathetic inhibition and parasympathetic activation in response to hypertension. Conversely, sympathetic activation coupled with parasympathetic inhibition enables the baroreflex to elevate arterial blood pressure in response to hypotension. Nitric oxide reduces sympathetic nerve activity, hence modulating the sympathetic effect on arterial blood pressure








































Afferents and central processors

1
Arterial baroreceptors

2
Excitatory (glutamatergic) afferents neurons

3
Excitatory (glutamatergic) neurons of NTS

4
Inhibitory (gabaergic) neurons of CVLM

5
Excitatory (glutamatergic) neurons of RVLM

Efferents

6
Sympathetic preganglionic (cholinergic) neurons of ILNSC

7
Sympathetic postganglionic (noradrenergic) neurons

8
Adrenergic receptors of vascular endothelial and smooth muscle cells
 
Adrenergic receptors of cardiac cells
 
Adrenergic receptors of renal cells

Activation of endothelial ${\upbeta}$ 2-adrenergic receptor raises endothelial cytosolic concentration of free calcium ion and NOS3-dependent NO production and release. ${\upbeta}$ 1-adrenoceptor does not reside on endothelial cells [143].

Nitric oxide exerts a stronger effect on the regulation by the baroreflex of cardiac frequency than on the renal sympathetic nerve activity aimed at regulating blood volume to normalize arterial blood pressure.


2.3.6 Hypertension


Arterial hypertension is a major cardiovascular risk factor. Arterial blood pressure is a complex genetic trait with heritability estimates of 30–50 %. Arterial hypertension affects at least 25 % of adults in industrialized societies.

Arterial blood pressure ( $p_a~=~{\tt R}\,q$ ) is controlled by peripheral vascular resistance ( ${\tt R}$ ) and blood flow rate (q).15 Vascular resistance depends on the vasomotor tone under local and remote control. Blood flow rate depends on cardiac performance and blood volume, itself related to salt content.

Constitutive and environmental factors that influence blood pressure include sympathetic tone, dietary salt intake, alcohol consumption, age, body mass index, and physical activity. Arterial hypertension depends in particular on the renal sodium handling, steroid hormone metabolism, and mineralocorticoid receptor activity.

Treatment of hypertension involves numerous types of drugs. Blockers of ${\upbeta}$ -adrenergic and angiotensin AT $_1$ receptors abolish the action of adrenaline and angiotensin-2. ${\upbeta}$ -blockers inhibit ${\upbeta}$ -adrenergic receptors, thereby decreasing cardiac frequency and contractility. ${\upbeta}$ -adrenoceptors initiate signaling cascades upon phosphorylation by AMPK, CamK2, PKA, PKB, and TOR kinases. These enzymes target in particular ion channels such as K $_{\mathrm{V}}$ 7.1 and transporters that mediate ion fluxes at high cardiac frequency [144]. G-protein-coupled receptors that regulate myocardial contractility are also substrates. Inhibitors of angiotensin-converting enzyme prevent formation of angiotensin-2. Diuretics hinder increase in plasma volume. Calcium antagonists treat vasoconstriction.

High salt intake raises blood volume and vascular smooth myocyte contraction, thereby increasing heart load. Natriuresis with increased glomerular filtration and inhibited sodium reabsorption restores normal osmotic pressure.

The midbrain produces natriuretic signals that operate via: (1) the adrenal gland, which produces cardioactive steroids, and (2) the heart, which synthesizes atrial natriuretic peptide.

The vascular smooth myocyte tone determines the total peripheral vascular resistance and arterial blood pressure. Most forms of hypertension result from vasoconstriction. Hormone levels increase in response to a high-salt diet. Hormone binding to GPCRs located in caveolae of smooth myocytes with Na $^+$ –K $^+$  ATPase triggers Ca $^{2+}$ -dependent and -independent pathways.

Calcium-dependent mechanism functions via Gq/11, PLC ${\upbeta}$ , and IP $_3$ , thereby inducing Ca $^{2+}$ release from intracellular stores and myosin light chain phosphorylation by activation of myosin light chain kinase.

Calcium-independent process impedes phosphorylated myosin light chain degradation via subunits of the G12/13 subclass, RhoGEF12 guanine nucleotide-exchange factor,16 Rho GTPase, and RoCK kinase that inhibits myosin light chain phosphatase. Phosphorylated myosin light chain allows myosin to interact with actin and generate smooth myocyte contraction.

The dual regulation of myosin light chain phosphorylation using both signaling cascades produces vasoconstriction. The Gq/11 pathway is responsible for the maintenance of basal blood pressure and intervenes in the development of salt-induced hypertension [145]. The G12/13 subunit-primed pathway only yields salt-induced hypertension. In response to sodium, hormones may bind to Na $^+$ –K $^+$  ATPase and launch Ca $^{2+}$ influx, as well as inhibit myosin light chain dephosphorylation via Rho GTPase to prevent smooth muscle relaxation.


2.3.7 Diabetes



Diabetes mellitus,17 or simply diabetes, is a chronic disease associated with hyperglycemia. Three types of diabetes mellitus exist. Type-1 diabetes (a.k.a. insulin-dependent and childhood-onset [juvenile] diabetes) in which the pancreas fails to produce the proper amount of insulin, an hormone that assists glucose uptake by cells to yield energy. This autoimmune disease is characterized by loss of insulin-producing ${\upbeta}$ cells of islets of Langerhans in the pancreas. Type-2 diabetes (a.k.a. insulin-independent, obesity-related, and adult-onset diabetes) results from insulin resistance, as cells do not respond to the insulin. Sometimes, it combines resistance to insulin action, inadequate insulin secretion, and inappropriate glucagon secretion. Gestational diabetes occurs when pregnant women develop hyperglycemia. Classical symptoms include polyuria, polydipsia, and polyphagia. Long-term complications include microangiopathy, diabetic neuropathy, chronic renal failure, diabetic retinopathy, and cardiovascular disease such as aggravated atherosclerosis.

Diabetes mellitus is also characterized by endothelial dysfunction. In gestational diabetes, the adenosine– ${}^{\mathrm{L}}$ arginine–nitric oxide pathway is activated [146]. Second messengers involved in adenosine signaling include PKC, ERK1, and ERK2 that activate ${}^{\mathrm{L}}$ arginine ingress through SLC7a1,18 but preclude adenosine import through the SLC29a1 carrier.19 Subsequent extracellular accumulation of adenosine activates the A $_{\mathrm{2A}}$ receptor, increases transcription of the Nos3 and SLC7A1 genes, hence NO synthesis. Cultured human umbilical vein endotheliocytes from gestational diabetic pregnancies or subjected to hyperglycemia produce higher NO levels. However, the NO-dependent downregulation of the SLC29A1 gene transcription lowers uptake of vasodilatory adenosine [146]. Nitric oxide supports formation of the complex made of DNA-damage-inducible transcript DDIT3, or CCAAT/enhancer-binding protein (C/EBP) homologous protein-10 (CHOP or CHP10),20 and C/EBP ${\upalpha}$ factor [147].21 In the nucleus, like the transcription factor Specific protein SP1 in hyperglycemia, the DDIT3–C/EBP ${\upalpha}$ heterodimer represses Slc29a1 gene transcription (as well as glucose transporter GluT4) [147].


2.3.8 Metabolic Syndrome



Metabolic syndrome is the set of risk factors that includes hyperlipidemia, hypertension, chronic inflammation, obesity, and type-2 diabetes; Vol. 8—Chap. 2. Metabolic Syndrome). These perturbations that cause atherosclerosis result from failure to sense and respond to metabolic cues properly.

Elevated circulating lipids, especially low-density lipoproteins, is a major risk factor. Transfer of LDLs into the vessel wall and subsequent oxidation by intracellular lipoxygenases or action of reactive oxygen species initiate atherogenesis.

The heart and blood vessels are surrounded by epicardial22 and perivascular adipose tissues, respectively, which secrete numerous adipokines, or adipocytokines. In addition to storage of energy, adipose tissue actually acts as a metabolic sensor and endocrine organ that participates in the regulation of glucose and lipid metabolism as well as insulin sensitivity, among other roles.

Adipokines function as endo- and paracrine messengers that support the adipocardiovascular axis, as they mediate interferences (crosstalk) between adipose tissue depots, heart, and vasculature. Some adipokines are proinflammatory, others protect the cardiovascular apparatus.

Adipokines secreted by adipocytes include: (1) hormones, such as adiponectin, angiotensin-2, apelin, chemerin, hepcidine, leptin, omentin, resistin, retinol-binding protein RBP4, vaspin, and visfatin; (2) chemokines such as CCL2; (3) cytokines, either proinflammatory, such as interleukin-6 and tumor-necrosis factor- ${\upalpha}$ , in addition to IL1 ${\upbeta}$ , IL4, IL8, and IL18, or anti-inflammatory such as interleukin-10; (4) serpins; such as serpin-E1, or plasminogen activator inhibitor PAI1, and serpin-F1, or pigment epithelium-derived factor (PEDF); (5) fatty acid-binding proteins (FABPs) such as adipocyte FABP (aFABP, or FABP4); (6) lipocalin-2; and (7) adhesion glycoproteic molecules such as thrombospondin-1.

Many adipokines, such as TNFSF1, resistin, aFABP, and lipocalin-2, are proinflammatory, thereby causing endothelial and cardiac dysfunction.

On the other hand, adiponectin has beneficial effects, especially during caloric restriction and improvement of left ventricular function as well as antiapoptotic activity and reduction of infarct size. Adiponectin activates AMPK and PKB kinases as well as ceramidase, thus producing antiapoptotic sphingosine 1-phosphate and subsequently inhibiting caspase-8 (Table 2.8) [148]. Adiponectin also stimulates lipoprotein lipase via the RhoA–RoCK axis and actin remodeling as well as VEGF production.


Table 2.8
Cardioprotection ensured by adiponectin. Adiponectin is synthesized mainly by adipocytes, but also by cardiomyocytes, triggers multiple actions via adiponectin receptors AdipoR1 and AdipoR2, which both lodge on cardiomyocytes, and cadherin-13: (1) an antiapoptotic effect by activating ceramidase, PKB, and AMPK, ceramidase producing antiapoptotic sphingosine 1-phosphate (S1P); (2) an antioxidative and -nitrative stress effect via decreased synthesis of inducible NOS2 and NOx2 subunit of NADPH oxidase; (3) an anti-inflammatory effect by activating sphingosine kinase-1 (SphK1) and cyclooxygenase-2 (COx2); (4) lipid uptake stimulation via AMPK-mediated upregulation of ScaRb3 scavenger receptor; and (5) glucose uptake promotion via PKB-dependent translocation to the plasma membrane of glucose GluT4 transporter; (6) angiogenesis via VEGF. (Source: [148])




























Process
Pathway and effect

Angiogenesis
VEGF

Apoptosis
AMPK, ceramidase–S1P

Inhibition of caspase-8

Glucose uptake
PKB

GluT4 transfer to the plasma membrane

Inflammation
SphK1–COx2

Inhibition of TNFSF1

Lipid uptake
AMPK–ScaRb3

Oxidative and nitrative stresses
Inhibition of NOS2

Inhibition of NOx2

Obesity is associated with the production of proinflammatory molecules and recruitment of immunocytes to metabolic organs, particularly adipose tissue, liver, pancreas, and hypothalamus [149, 150]. Resulting derangements of local metabolism lead to insulin resistance, type-2 diabetes, nonalcoholic fatty liver disease, and dyslipidemia.

Obesity increases JNK activity in adipose tissue and liver. Obesity-induced stress response in adipose tissue depends partly on JNK1 in adipocytes. In fact, adipocyte hypertrophy and hyperplasia enable JNK1 and JNK2 activation in resident macrophages. In adipose tissue and muscle (but not liver), JNK1 intervenes during the development of insulin resistance. In hepatocytes, JNK1 reduces hepatic steatosis and insulin resistance [149]. Tissue-resident macrophages belong to 2 main populations. Classically activated macrophages (M1) induced by interferon- ${\upgamma}$ or endotoxin promote interleukin-12-mediated helper T $_{{\mathrm{H}}1}$ lymphocyte-based immunity. Activated macrophages by IL4 or IL13 (M2a), immune complexes (M2b), and anti-inflammatory cytokines IL10 or TGF ${\upbeta}$ (M2c) support T $_{{\mathrm{H}}2}$ -based immunity implicated in wound healing, tissue repair, and resolution of inflammation. Obesity favors macrophage polarization to the proinflammatory M1 phenotype [150]. Kinase JNK is required for the differentiation of proinflammatory macrophages. In myeloid cells, JNK1 and JNK2 are involved in obesity-induced recruitment of macrophages and inflammation in adipose tissue, without affecting other myeloid cell populations (eosinophils and neutrophils) [150].

Metabolic syndrome can be caused by mutation in the Lrp6 gene that encodes LDLR-related protein-6, a coreceptor of the Wnt pathway, thus impairing Wnt signaling [151]. The cellular metabolic sensor PAS domain-containing protein Ser/Thr kinase (PASK, or STK37) integrates multiple cues to monitor cellular energetic status. Nutrient-responsive PASK is activated by glucose. Activated PASK contributes to insulin secretion in pancreatic ${\upbeta}$  cells, increases the synthesis and storage of triglycerides in hepatocytes, and decreases ATP generation both from carbohydrate and fatty acid oxidation in skeletal muscle [152].


2.3.9 Altered Sleep


Sleep is constituted of two main stages, rapid eye movement (REM) and nonrapid eye movement (NREM) sleep. More precisely, sleep is characterized by three (formerly four) stages of increasingly deep dreamless sleep and a stage of dreaming and REMs.
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Jul 10, 2016 | Posted by in CARDIOLOGY | Comments Off on Context of Cardiac Diseases

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