Metabolic Syndrome Definition:

The development of 4 co-morbidities:

1. Hypertension (high blood pressure),
2. High blood glucose,
3. High levels serum lipids (e.g., high cholesterol, high levels of Low-Density Lipoproteins also known as LDLs and low levels of High-Density Lipoproteins also known as HDLs), and
4. being overweight (particularly with apple-shaped deposition of fat also called abdominal obesity).

Risk Factors of Metabolic Syndrome:

• Non-modifiable:
  • age
  • genetics
  • some medical conditions and medications
  • biological sex as menopause increases risks of abdominal obesity, high blood sugar, and low HDLs
• Modifiable:
  • sedentary behaviour,
  • unhealthy diet high in fat and simple carbohydrate sugars (foods with high glycemic index), diet low in fiber and low in vegetables, large portions
  • smoking
  • drinking alcohol
  • night shift work (which may not be modifiable)
  • sleep deprivation (which may not be modifiable – can dependent on socioeconomic status, due to demands of multiple jobs, demands of supporting family members,

Cardiovascular Pathogenesis (Describe effects of hyperglycemia, hyperlipidemia on blood vessels and heart):

1. Development of Atherosclerosis:
   1. Blood vessel damage makes them susceptible to the formation of atherosclerotic plaques. The following can cause blood vessel damage:
      1. Turbulence damages blood vessels – occurs at bifurcations (natural forks in blood vessels) & plaques
      2. Hypertension damages blood vessels

• High levels of blood sugar damage blood vessel endothelial cells in 4 ways
  1. High blood glucose reduces endothelial cells’ ability to synthesize the vasodilator NO (nitric oxide) which leads to the inability to vasodilate can contribute to hypertension which damages blood vessels.
  2. More glucose inside endothelial cells reduces NO (nitric oxide) phosphorylation (activation) which also leads to the inability to vasodilate and hypertension which damages blood vessels.
  3. More glucose inside endothelial cells reduces ROS (Reactive Oxidative Species) neutralizers, so oxidative stress occurs (leading to cell damage, dysfunction and/or death).
  4. More glycation of proteins inside endothelial cells leads to toxic waste build up (causing cell damage, dysfunction and/or death).

Risk Factors for Blood Vessel Damage:

1. Smoking damages blood vessels
2. Hyperlipidemia damages blood vessels
3. Type I and II Diabetes Mellitus due to high blood sugar and high blood lipids
4. Toxins damages blood vessels 
5. Viruses damage blood vessels 
6. Immune Reactions (e.g., Type III Hypersensitivity Reactions that involve vasculitis, for example can occur in Systemic Lupus Erythematosus (SLE)

Blood Vessel Damage Promotes Atherosclerosis:

1. Endothelial injury stimulates Inflammation (signs of inflammation include higher CRP C Reactive Protein which promote Completement Protein activity) and recruitment/migration of WBCs (macrophages
2. Deposition of Fatty Streak in tunica intima (endothelial cell inner lining of blood vessel wall).  Lipid can come from LDLs. Macrophages ingest fat becoming “Foam Cells”
3. Development of Atheroma = mass of fibro fatty material (lipid + fibrin + RBCs + macrophages + platelets)
4. Thickening of intima media (middle layer of blood vessel wall) due to proliferation of smooth muscle. This causes further narrowing of the lumen of blood vessel, which increases blood pressure in the area.
5. Plaque becomes fibrous as fibroblasts in the blood vessel wall produce collagen which can create a collagen cap on the atheroma. Tears (fissures) in the collagen cap can occur.
6. Formation of Thrombus – platelets are activated by damaged site and stick to arterial wall forming thrombus.
7. Calcium can accumulate in area of damage making blood vessel wall weaker, less elastic and more susceptible to bulging (aneurysm) and tears.

• Atherosclerotic Plaques that have a combination of fat, thrombus, collagen and calcium are called Complicated Lesions.
• Atherosclerotic Plaques are susceptible to:
  1. Fully occluding blood vessels causing downstream ischemia
  2. Creating emboli, which would travel downstream, blocking blood vessels & causing ischemia
• Development of weakened blood vessels walls that bulge (forming aneurysms) which are susceptible to tearing
  • Tearing (which would cause internal bleeding/hemorrhaging)

• Development of Arteriosclerosis (loss of blood vessel elasticity), often occurs with aging and leads to narrowing of blood vessels, which can contribute to hypertension.

Development of Hypertension (High Blood Pressure) – There are 3 Types of Hypertension:

1. Primary Hypertension (Essential Hypertension)

1. 1. 1. Idiopathic; 90-95% of all cases of hypertension
      2. Essential hypertension = BP consistently above 140/90

• May be adjusted for age due to arteriosclerosis in elderly

1. ↑ arteriolar vasoconstriction causes ↓ blood flow to kidneys
   • Causes renin-angiotensin-aldosterone response; ↑vasoconstriction & ↑ blood vol = ↑ BP
2. Over period of time – damage to arterial walls & atheromas!

• And walls become hard + sclerotic; may tear or lead to aneurysm
• Can be checked through retina;  Can lead to left-sided CHF (congestive heart failure)
• Blood supply to involved area is reduced – affecting brain, kidney, retina
• Ischemia and necrosis of tissues with loss of function

2. Secondary Hypertension caused by:

1. 1. Renal disease (e.g. glomerular disease such as APSGN, or polycystic kidney disease, diabetic nephrosclerosis – FYI) in which renin is over-produced or
   2. Endocrine disease, (e.g. pheochromocytoma- FYI – rare benign tumor of the adrenal medulla that secretes E and NE), aldosteronism, Cushing’s, hyperthyroidism,

• Aortic coarctation (abnormal narrowing of aorta)

1. Obstructive sleep apnea
2. Drugs or alcohol
3. >At risk for developing malignant hypertension. Treat underlying cause!

3. Malignant or resistant hypertension

• (develop in 1% of people with essential hypertension)
  1. Emergencies!  Uncontrollable, severe, and rapidly progressive form with many complications (damaging organs); idiopathic; other causes include drug or alcohol overdose/withdrawal
  2. Diastolic pressure is extremely high.
• Retinopathy with papilledema; headache; encephalopathy can occur due to hyper-perfusion causing cerebral edema; angina; MI; CHF; pulmonary edema

Hypertension Complications:

1. All forms of hypertension cause damage to kidneys, heart, brain and retina due to vascular damage
   1. Can lead to cerebral aneurysms and subsequent hemorrhagic CVA stroke
   2. Can lead to microaneurysms in retina causing vision impairments

• Can lead to angina pectoris and myocardial infarction

1. Can lead to nephrosclerosis (nephron damage due to blood vessel damage and reduced oxygenation) and kidney failure

Risk Factors for Hypertension:

1. 1. Incidence increases with age.
   2. Biological Males affected more frequently and more severely (due to less protection of vasculature by estrogen)
      • Incidence in women increases after middle age (in part due to menopause).
   3. Genetic factors
   4. Sodium intake, excessive alcohol intake, obesity, smoking, prolonged or recurrent stress

Signs & Symptoms of Hypertension:

1. 1. Asymptomatic – the “silent killer”
   2. Fatigue, malaise, sometimes morning occipital headache

 Treatment of Hypertension:

1. 1. Lifestyle changes – increase cardiovascular fitness
   2. Reduction of sodium, high-fat, and excess alcohol intake
      • Weight reduction
   3. Reduction of stress & stop smoking!
   4. Drugs
   5. Diuretics, ACE inhibitors, alpha-blockers, Ca++ channel blocker, beta blockers

Development of Coronary Artery Disease (CAD) and Peripheral Artery Disease (PAD)

1. 1. Atherosclerosis in coronary arteries and peripheral arteries can contribute to
      1. narrowing of blood vessels
      2. loss of ability to vasodilate

• poor blood flow (therefore poor supply of O2 & nutrients; reduced ability to remove waste products)
• possible full occlusion and/or emboli (that could result in Stroke, Pulmonary Embolism or Myocardial Infarction or damage to other tissues/organs)

Development of Angina Pectoris

Caused by temporary deficit of O₂ in myocardium

1. 1. Risk Factors: coronary artery atherosclerosis, coronary artery spasm, anemia, respiratory disease that negatively affect blood oxygenation, myocardial hypertrophy (in which a heart outgrows its blood supply)
   2. Three types of Angina Pectoris
      1. Classic/Exertional angina = occurs when emotional or physical exertion due to heart’s inability to vasodilate to meet increase in oxygenation needs.  Coronary vessels are damaged by plaque or arteriosclerosis and can not vasodilate.
      2. Variant angina = due to abnormal vasospasm at rest
      3. Unstable angina = characterized by prolonged pain at rest, most likely due to embolus causing full occlusion, emergency! may transition into Myocardial Infarction.

1. Signs & Symptoms =recurrent, intermittent brief episodes of substernal chest pain & possibly left arm, triggered by emotional/physical stress. Attacks typically become more frequent and longer as disease progresses
2. Diagnosis = imaging, angiograms
3. Treatment = nitroglycerin (potent vasodilator, mimics body’s natural NO, nitric oxide), avoid stressors (physical, emotional, big meals), angioplasty, bypass grafts

Development of Myocardial Infarction

Caused by sudden and permanent deficit of O₂ in myocardium

1. 1. Signs & Symptoms
      • Feeling of pressure, heaviness, or burning in chest – especially with increased activity
      • Sudden shortness of breath, weakness, fatigue
      • Nausea, indigestion
      • Anxiety & fear
      • Pain may occur and if present is usually:
        • Substernal, Crushing
        • Radiating –left arm, shoulder, jaw or neck
        • Women – “indigestion pain”
        • Unlike angina, pain is not relieved by rest & nitroglycerin

1. • Diagnostic tests
     1. ECG changes (e.g., disrupted QRS wave)
     2. ↑ Serum enzymes/proteins (e.g., troponin, creatine kinase, myosin) released from necrotic cells
     3. ↑ serum K+ levels
     4. Leukocytosis, elevated CRP and ESR common
     5. Arterial blood gas levels may be altered in severe cases (low O2, high CO2, low pH).
     6. Pulmonary artery pressure measurements helpful (measures remaining strength of left ventricle)

• Complications:
  • Sudden death (1/4) = due to cardiac arrhythmias or hypoxia or acidosis
  • Cardiogenic shock = due to failure of ventricles; ↓CO (Cardiac Output)=poor blood flow, organ failure depicted by:
  • Rapid, weak pulse, hypotension; can lead to death

1. • Congestive heart failure = ↓contractility
   • Within few days or later; acute or chronic deteriorating condition
   • Rupture of necrotic heart tissue and/or cardiac tamponade  – Within 3-7 days when necrotic tissue is breaking down

• • Thromboembolism causing:
  • Emboli in brain (CVA) (with left ventricular MI)
  • Pulmonary embolus (if right ventricular MI)
    • Metabolic acidosis (due to ↑ anaerobic cellular respiration which involves lactic acid production)

• Treatment: Best within 20min
  1. Reduce cardiac demand
  2. O2 therapy
  3. Analgesics (morphine, ASA)
  4. Anticoagulants (heparin, warfarin, streptokinase, urokinase, TPA, ASA)
  5. Thrombolytic agents may be used.
  6. Medication to treat Dysrhythmias (digoxin),
  7. Medication to treat hypertension (e.g., ACE inhibitors, potassium-sparing diuretics, alpha blockers, beta blockers, calcium channel blockers), and congestive heart failure

• By-pass surgery or angioplasty if necessary and possible
• Long-Term Treatment: Cardiac rehab, Regular exercise. Diet, ↓Stress

Development of Type II Diabetes Mellitus Co-morbidities:

Describe how development of insulin resistance exacerbates:

1. Cardiovascular problems,
2. Peripheral vascular disease,
3. Cerebrovascular disease, and can lead to
4. Eye problems, blindness,
5. Neuropathies, and
6. Kidney failure

Type II Diabetes Mellitus results in high blood sugar and high blood lipid levels and as mentioned above, high blood sugar and high lead to atherosclerosis, and therefore CAD, PAD, hypertension, vascular damage and narrowing leading to retinal damage, nephron damage.

Type II Diabetes Signs and Symptoms:

• 3Ps (polydipsia, polyuria, and polyphagia)
• Ketosis, ketonemia, ketonuria
• High Blood Glucose, and Glycogenolysis, Gluconeogenesis (converting protein to glucose = muscle wasting)
• High Blood Lipids (Lipidemia) and Adipocyte Lipolysis
• Excessive thirst, Excessive hunger, fatigue, irritability, wounds heal slowly, blurry vision.

Type II Diabetes Treatment:

1. Diet and exercise:

a) Exercise: reduces blood glucose level as skeletal muscle uses glucose.

• • Also, reduces stress, improves cardiovascular fitness, helps control weight (↓BMI will ↓ insulin resistance)
  • Risk: hypoglycemia can develop during strenuous or prolonged exercise (due to ↑ use of glucose by skeletal muscle; offset risk with carbohydrate snack & monitor blood glucose levels)

b) Diet: should have low glycemic index (more complex carbohydrates in place of simple sugars); appropriate amount of food per day.

Oral medication for T2D:

a) Oral Hypoglycemic Drugs (g. glyburide): stimulate beta cells to increase insulin secretion.

b) Metformin: reduce liver’ production of glucose and lipogenesis, decrease GI absorption of glucose

c) Meds: To reduce insulin resistance (by increasing tissue sensitivity to insulin).

Insulin replacement for T1D & sometimes T2D:

1. a) Injected insulin (not oral) – small continuous pump; options include rapid/slow onset