Lecture 24 - alternative mechanisms driving cardiovascular remodeling

How do sex differences affect the incidence of cardiovascular disease (CVD) across the lifespan?

Men have a higher incidence of CVD earlier in life, while women are generally protected until menopause, after which their risk increases significantly.

How do testosterone and estradiol levels change with age?

Testosterone in men declines gradually with age, whereas estradiol (17β-estradiol) in women drops sharply during menopause.

What is estradiol (17β-estradiol, E2), and where is it produced?

Estradiol is the primary form of estrogen. It is mainly produced by the ovaries in females, but is also produced in adipose tissue, brain, bone, adrenal glands, and testes.

Why are premenopausal women at lower risk of coronary heart disease (CHD)?

Because circulating estrogen provides strong cardioprotection, reducing the risk of CVD compared to men.

How does estrogen promote cardiomyocyte survival?

By enhancing mitochondrial function, reducing apoptosis, lowering oxidative stress, and increasing fatty acid oxidation, which reduces infarct size and reactive oxygen species (ROS) production.

How does estrogen affect vascular endothelial cells?

It upregulates endothelial nitric oxide synthase (eNOS), leading to increased nitric oxide production, improved vasodilation, anti-inflammatory effects, and antioxidant activity.

What role does estrogen play in angiogenesis?

Estrogen upregulates vascular endothelial growth factor (VEGF), which promotes angiogenesis and improves myocardial perfusion.

How does estrogen protect against pathological cardiac remodeling and fibrosis?

It inhibits fibroblast proliferation, collagen deposition, and fibrosis by suppressing TGFβ1, angiotensin II, and matrix metalloproteinase-2 (MMP-2).

Why does menopause increase the risk of cardiovascular disease in women?

Because the sharp drop in estrogen levels removes its cardioprotective effects, leading to higher CVD risk similar to or greater than men.

How do biological female and male hearts differ in size and structure?

Female hearts are ~26% smaller, with ventricular wall thickness 10% less, and differences in EDV, ESV, and heart mass. Ejection fraction (EF) shows no difference.

By how much does blood volume increase during pregnancy, and what is the total volume?

Increases by up to 45%, reaching 7–8 L.

What causes plasma volume to increase during pregnancy?

Plasma volume rises by ~150%, driven by hormonal changes and RAAS activation

How does systemic vascular resistance change during pregnancy?

It decreases physiologically, due to vasodilation.

What factors activate the RAAS in pregnancy?

Reduced renal perfusion pressure and high estrogen.

What are the roles of aldosterone, ADH, and progesterone during pregnancy?

• Aldosterone: ↑ Na⁺ reabsorption

• ADH: ↑ water reabsorption and thirst

• Progesterone: ↓ Na⁺ reabsorption

What is “hyponatremic hypervolemia” in pregnancy?

A state of high blood volume but relatively low sodium concentration.

How do red blood cell levels change during pregnancy?

RBC mass increases by ~120% (via progesterone-induced EPO), but still less than normal, preventing anemia but leading to relative RBC deficiency.

Why does physiological anemia occur during pregnancy?

Plasma volume increases disproportionately compared to RBCs, lowering hematocrit.

What happens to hematocrit levels during pregnancy?

Drops from ~39% pre-pregnancy to ~34% in the third trimester.

How does cardiac output (CO) change during pregnancy?

Increases gradually by 30–50% (e.g., from 4.6 to 8.7 L/min).

What drives the increase in cardiac output in pregnancy?

Increased stroke volume (via increased blood volume and venous return) and increased HR (~+10 bpm), plus higher sympathetic activity.

Why does cardiac output drop around 35 weeks of pregnancy?

Reduced preload due to uteroplacental blood flow and vena cava compression by the enlarged uterus.

Why is mean arterial blood pressure (MABP) decreased during pregnancy despite increased CO?

Because systemic vascular resistance falls, distributing the larger blood volume more widely.

How much does peripheral vascular resistance (PVR) decline in pregnancy, and why?

Declines by up to 30% due to vasodilatory effects of estrogen, progesterone, and prostacyclin.

How do cardiovascular changes in pregnancy compare to the menstrual cycle?

Pregnancy effects are stronger but resemble the luteal phase, when mild vasodilation occurs.

How does pregnancy cause cardiac remodeling?

Chronic volume overload increases venous return (preload), stretching ventricular walls.

What structural changes occur in cardiac remodeling during pregnancy?

Elongation of cardiomyocytes (sarcomeres in series), eccentric hypertrophy, increased LV mass, chamber dilation, and proportional wall thickening.

Is cardiac remodeling in pregnancy reversible?

Yes, it reverses after pregnancy ends.

What proportion of adults in New Zealand are overweight or obese?

About 67% (two in three adults).

How is obesity classified by BMI?

• Underweight: <18.5

• Normal: 18.5–24.9

• Overweight: 25.0–29.9

• Obese: ≥30.0

  • Mild Obese: 30.0–34.9

  • Severely Obese: 35.0–39.9

  • Morbidly Obese: ≥40.0

How does obesity affect cardiovascular disease risk?

It increases the risk of heart failure and cardiac dysfunction.

What extrinsic mechanisms drive cardiac dysfunction in obesity?

Volume expansion, increased CO, hypertension, increased vascular tone, reduced NO availability, ↑ triglycerides, ↑ free fatty acids (FFAs), and hypoadiponectinemia

What intrinsic mechanisms drive cardiac dysfunction in obesity?

Lipotoxicity and inflammation.

How does increased body mass affect blood flow and CO?

Extra tissue requires 2–3 mL/min/100 g of blood; 100 kg of fat requires ~3 L/min extra flow, increasing CO.

Give examples of CO changes with increasing body weight.

• 70 kg: 6.0 L/min

• 120 kg: 7.5 L/min

• 170 kg: 9.0 L/min

How does obesity affect preload, SV, HR, and sympathetic drive?

Increased mass = ↑ preload, ↑ stroke volume, ↑ HR, and increased sympathetic activity.

Why is obesity described as a “high output–low resistance” state?

Increased body mass requires higher CO, but TPR decreases to maintain MABP.

What type of hypertrophy occurs in obesity-related cardiac remodeling?

• Primarily: Eccentric hypertrophy (volume overload, obesity).

• Secondarily: Concentric hypertrophy (pressure overload, hypertension).

How do obesity and hypertension together affect remodeling?

They produce a spectrum between eccentric (volume) and concentric (pressure) hypertrophy.

What are signs of end-stage cardiac dysfunction in obesity?

Impaired contractility, reduced filling rate, and decreased midwall shortening.

Where is epicardial adipose tissue (EAT) located, and why is it important?

Around the coronary vessels in the interventricular/atrioventricular grooves, in direct contact with myocardium. It is metabolically active, innervated, and has endocrine functions.

What are the normal physiological functions of EAT?

Supports metabolism, provides heating, mechanical cushioning, and immune protection.

What is the threshold for pathological EAT thickness?

>5 mm.

How does excess EAT contribute to cardiac dysfunction?

Enlarged adipocytes, lipid accumulation, immune cell migration, pro-inflammatory and pro-fibrotic secretome, failure to store triglycerides, ↑ lipolysis, ↑ FFAs.

What are key molecules secreted by EAT, and what do they do?

• Adiponectin: Anti-inflammatory, protective.

• Leptin: Harmful, promotes dysfunction.

• TNF-α: Pro-inflammatory, damages cells.

What vascular effects result from NEFA and TNF-α in obesity?

They reduce eNOS signaling, lowering NO production, increasing smooth muscle contraction and vasoconstriction.

How does perivascular adipose tissue contribute to disease?

Disrupts vascular tone and wall integrity, promotes atherosclerosis and complications like CAD, retinopathy, nephropathy, and neuropathy.

How does extracellular myocardial fat infiltration cause dysfunction?

TNF-α and IL-6 cause inflammation, while activin A promotes fibrosis.

How does intracellular myocardial fat infiltration cause dysfunction?

Lipotoxicity → mitochondrial dysfunction, oxidative stress, and cell death, replaced with fibrosis.

How does fat infiltration disrupt myocardial function?

Causes desynchrony of contraction, impairs electrical conduction, increases arrhythmia and heart failure risk.