Cardiovascular Disease - Part 1: Risk Factors, Myocardial Infarction, and Hypertension Effects

Introduction

This lecture serves as an introduction to common mechanisms involved in heart disease, with a focus on structural adaptations that occur. Specifically, it will cover:

Common risk factors associated with cardiovascular disease (CVD).
The immediate and chronic effects of myocardial infarction (heart attack) on the circulation and the heart muscle.
The myocardial response to chronic hypertension (high blood pressure).

Cardiovascular Disease: A Global and Local Problem

Global Impact: Cardiovascular disease is the leading cause of death globally, accounting for an estimated 17.9 million deaths per year (WHO Global Health Estimates, 2016 data showed 31.4% of all deaths). Mortality rates are highest in low and middle-income countries. In 2020, an estimated 244.1 million people were living with heart disease.
Local Impact (Wales, UK):
- Wales (along with Scotland) has among the lowest life expectancy rates in the UK.
- In 2020/21, NHS expenditure on heart and circulatory diseases in Wales was £622 million.
- Monthly statistics for Wales illustrate the significant burden: ~790 deaths from heart or circulatory disease (around 240 of whom are younger than 75), ~330 deaths from coronary heart disease, and ~400 hospital admissions due to heart attack.
- Approximately 340,000 people in Wales are living with heart and circulatory diseases, and about 16 babies are diagnosed with a heart defect each month.

Risk Factors for Cardiovascular Disease (CVD)

CVD development is multifactorial, involving a combination of modifiable and nonmodifiable risk factors:

Modifiable Risk Factors:
- Hypertension (High Blood Pressure): A major, often asymptomatic, contributor.
- Dyslipidaemia: Abnormal levels of lipids (e.g., high LDL cholesterol, low HDL cholesterol, high triglycerides) in the blood.
- Smoking: Damages blood vessels and promotes atherosclerosis.
- Diabetes Mellitus: Increases risk due to effects on blood vessels and lipid metabolism.
- Obesity: Particularly central/abdominal obesity.
- Unhealthy Diet: High in saturated/trans fats, salt, and sugar; low in fruits and vegetables.
- Physical Inactivity: Lack of regular exercise.
- Alcohol Misuse: Excessive alcohol consumption.
Nonmodifiable Risk Factors:
- Aging: Risk increases significantly with age.
- Gender: Men generally have a higher risk at younger ages, but risk increases in women after menopause.
- Genetic Predisposition: Family history of CVD.
- Race/Ethnicity: Certain ethnic groups have higher predispositions to specific CVDs.
Other Contributing Factors:
- Psychosocial Factors: Stress, depression, socioeconomic status.

Atherosclerosis: The Major Underlying Cause of CVD

Definition: Atherosclerosis is a chronic inflammatory disease characterized by the build-up of fatty material (plaques, atheromas) within the walls of arteries, leading to their narrowing (stenosis) and stiffening.
Consequences:
- Restricted Blood Flow: Leads to reduced oxygen and nutrient supply to tissues downstream.
  - In coronary arteries (heart): Can cause angina (chest pain on exertion).
  - In peripheral arteries (e.g., legs): Can cause limb ischaemia (pain on walking, claudication).
  - In cerebral arteries (brain): Can lead to transient ischemic attacks (TIAs) or stroke.
- Plaque Rupture and Thrombosis: Atherosclerotic plaques can become unstable and rupture, exposing thrombogenic material that triggers blood clot (thrombus) formation. This clot can occlude the artery.

Myocardial Infarction (MI) / Heart Attack

Cause: Typically occurs when an atherosclerotic plaque in a coronary artery ruptures, leading to the formation of a blood clot (thrombus) that completely occludes one or more arteries supplying the myocardium (heart muscle).
Pathophysiology:
- The occlusion deprives the region of myocardium supplied by that artery of oxygen and nutrients, leading to ischemia and, if prolonged, cell death (necrosis).
- This results in a reduced active area of contracting tissue during systole.
- The location and size of the blockage determine the extent and severity of the infarct.
Immediate Consequences:
- Circulatory Collapse: Decreased myocardial contraction (due to infarcted tissue) leads to a fall in cardiac output and blood pressure.
  - If severe, this can result in cardiogenic shock.
  - Immediate cardiopulmonary resuscitation (CPR) and defibrillation (if ventricular fibrillation occurs) are critical to maintain some circulation and prevent death.
Survival and Reperfusion:
- Survival rates for out-of-hospital cardiac arrests are low (e.g., only 1 in 10 people survive).
- The time to reperfusion (restoration of blood flow) of the blocked vessel is a critical determinant of infarct size and patient outcome.
  - The longer the occlusion time, the larger the infarct size (e.g., studies show infarct size increases from very small at 30 mins occlusion to ~12-13% of ventricle at 24h).
  - Patients who receive reperfusion therapy within <2 hours of MI onset have significantly better long-term cardiac survival compared to those reperfused later (e.g., 2-4 hours, 4-6 hours, or >6 hours).
Reperfusion Strategies:
- Thrombolytic Drugs ("Clot-busters"): Medications (e.g., tissue plasminogen activator - tPA) that break down fibrin, the main component of blood clots.
- Percutaneous Coronary Intervention (PCI) / Angioplasty: A balloon-tipped catheter is inserted into the blocked artery and inflated to compress the plaque and restore blood flow. Often, a stent (a small mesh tube) is deployed to keep the artery open.
- Coronary Artery Bypass Graft (CABG) Surgery: A blood vessel (graft) from another part of the body (e.g., saphenous vein from leg, internal mammary artery from chest) is used to bypass the blocked segment of the coronary artery.

Acute and Chronic Effects of MI on the Heart

A. Acute Effects (Immediate to Early Days):

Tissue Hypoxia and Necrosis: Myocardial cells downstream of the blockage are deprived of oxygen and die (necrosis).
- The extent of necrosis increases with the duration of ischemia before reperfusion (e.g., TUNEL staining, a marker of apoptosis/necrosis, shows significantly more necrotic cells after 24h of ischemia compared to 1h ischemia followed by reperfusion).
Impaired Contractility:
- Loss of rhythmic contractions in the infarcted area.
- Decreased overall cardiac output and blood pressure.
Limited Renewal of Cardiomyocytes:
- Adult heart muscle cells (cardiomyocytes) are largely terminally differentiated and have very limited capacity to proliferate and regenerate.
- Studies using 14C dating (from atmospheric nuclear bomb testing) have shown that cardiomyocyte turnover is very slow (e.g., ~1% per year at age 25, decreasing to <0.5% per year by age 75). At age 50, about half of an individual's cardiomyocytes were present at birth.
- This means lost cardiomyocytes are primarily replaced by non-contractile scar tissue.
Inflammatory Response:
- An immediate and intense pro-inflammatory response is triggered in the infarct region to clear necrotic cells and debris.
- Inflammatory Phase (Early):
  - Cardiomyocyte death.
  - Upregulation of cellular adhesion molecules on endothelium.
  - Neutrophil infiltration (peaks within 1-3 days).
  - Monocyte recruitment and differentiation into pro-inflammatory macrophages (e.g., Ly-6C<sup>high</sup> cells in mice).
  - Secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6).

B. Chronic Effects (Weeks to Months - Post-Infarction Remodeling): The healing process after MI involves several phases that lead to structural and functional changes in the heart, collectively known as ventricular remodeling.

Proliferative and Repair Phase:
- Resolution of Inflammation (Partial): Pro-inflammatory signals decrease.
- Macrophage Polarization: Macrophages shift towards a reparative phenotype (e.g., Ly-6C<sup>low</sup> in mice, often called M2-like macrophages).
- Myofibroblast Proliferation: Fibroblasts are activated and differentiate into myofibroblasts, which are specialized in producing large amounts of extracellular matrix (ECM) components, primarily collagen.
- Collagen Deposition: Leads to the formation of a collagen-based scar tissue in the infarcted area.
Scar Maturation Phase:
- Extracellular matrix cross-linking occurs, strengthening the scar.
- Myofibroblasts may become quiescent or undergo apoptosis.
- The scar tissue is non-contractile and stiffer than healthy myocardium.
Adverse Ventricular Remodeling:
- Widespread Inflammation and Fibrosis: Inflammation and fibrosis can extend beyond the infarct core into the remote, non-infarcted myocardium.
- Infarct Scar Expansion and Thinning: The scar tissue can thin and stretch over time.
- Ventricle Dilation (Enlargement): The left ventricular chamber (and sometimes the right) can dilate.
  - Laplace's Law: Wall stress = (Pressure × radius) / (2 × wall thickness). As the radius of the ventricle increases (dilation), the wall tension (stress) required to generate a given internal pressure also increases.
  - This increased wall stress can further drive maladaptive remodeling.
- Hypertrophy: The remaining viable myocardium (remote myocardium) may undergo hypertrophy (increase in cardiomyocyte size) as a compensatory mechanism to maintain cardiac output against increased workload. This can initially be adaptive but often becomes maladaptive chronically.
- Consequences: Reduced systolic pressure (impaired contractility), reduced cardiac output, and progression to heart failure.

Summary of Immediate and Chronic Effects of MI:

Immediate Effects (Hours to Days)	Chronic Effects (Weeks to Months/Years)
Tissue hypoxia & necrosis	Widespread inflammation (can persist in remote areas)
Arrhythmic/impaired rhythmic contractions	↑ Fibrosis (scar formation and interstitial fibrosis)
↓ Blood pressure & cardiac output	↑ Ventricle stiffness
Inflammation in infarct region (neutrophils, MΦ)	↑ Hypertrophy (of remaining viable myocardium)
	↑ Ventricle dilation
	↓ Systolic pressure (impaired ejection)
	↓ Cardiac output (progression to heart failure)

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Myocardial Response to Chronic Hypertension

Systemic hypertension (chronically elevated blood pressure) imposes a sustained pressure overload on the left ventricle.

Definition of Hypertension Categories (Example guidelines):
- Normal: <120 mmHg systolic AND <80 mmHg diastolic
- Elevated: 120-129 mmHg systolic AND <80 mmHg diastolic
- High Blood Pressure (Hypertension) Stage 1: 130-139 mmHg systolic OR 80-89 mmHg diastolic
- High Blood Pressure (Hypertension) Stage 2: ≥140 mmHg systolic OR ≥90 mmHg diastolic
- Hypertensive Crisis: >180 mmHg systolic AND/OR >120 mmHg diastolic (consult doctor immediately)
Prevalence: Affects about 1 in 4 adults globally.
Causes of Hypertension: Can be multifactorial.
- Increased Cardiac Output: Due to hypervolemia (e.g., renal artery stenosis, renal disease, hyperaldosteronism, hypersecretion of ADH, aortic coarctation, preeclampsia) or stress/sympathetic activation (e.g., pheochromocytoma leading to increased catecholamines).
- Increased Systemic Vascular Resistance (SVR/TPR): Due to atherosclerosis, constriction of vascular smooth muscle cells (e.g., in diabetes), renal artery disease (increased angiotensin II), pheochromocytoma, thyroid dysfunction, cerebral ischemia, or stress/sympathetic activation.
Vascular Resistance and Poiseuille's Equation: Small changes in vessel radius (r) have a large impact on resistance (R), as Rpropto1/r4. A halving of radius increases resistance 16-fold.
Mean Arterial Pressure (MAP): MAP=textCardiacOutputtimestextTotalPeripheralResistance(TPR). Increased MAP is a risk factor for Coronary Artery Disease (CAD).

Effects of Increased Load (Pressure Overload) on the Heart:

The left ventricle must work harder (generate higher pressure) to eject blood against the increased afterload (systemic vascular resistance).
Early Compensatory Adaptations: Initially, the heart may adapt to maintain or even increase contractility (e.g., via Frank-Starling mechanism, sympathetic drive).
Chronic Maladaptations (leading to Hypertensive Heart Disease and Heart Failure):
- Left Ventricular Hypertrophy (LVH): Increase in LV mass due to the growth (hypertrophy) of existing cardiomyocytes. This is an attempt to normalize wall stress according to Laplace's Law.
  - Mechanical and hormonal stress (e.g., from neurohumoral activation) increases myofilament protein synthesis within cardiomyocytes.
  - Concentric Hypertrophy: In response to pure pressure overload, new sarcomeres are predominantly added in parallel within cardiomyocytes. This increases the cross-sectional area (CSA) of the muscle cells and thus the wall thickness, without significant chamber dilation initially. Force is proportional to CSA.
- Chamber Dilation: Over time, especially if hypertrophy is insufficient or becomes pathological, the LV chamber may dilate.
- Fibrosis: Increased deposition of collagen in the interstitial space (between cardiomyocytes) and potentially replacement fibrosis if cell death occurs. This increases ventricular stiffness and impairs diastolic function (relaxation and filling).
- Impaired Cardiomyocyte Function: Cellular changes (covered in Lecture 2/3) can lead to contractile dysfunction.

Hypertrophic Signaling Pathways:

Physiological Hypertrophy (e.g., "Athlete's Heart" in response to exercise): Often associated with activation of pathways like the Insulin-like growth factor-1 (IGF-1) → Akt → mTORC1 pathway. mTORC1 promotes protein synthesis and inhibits autophagy.
Pathological Hypertrophy (e.g., in response to pressure overload/hypertension):
- Often involves neurohumoral activation (e.g., sympathetic nervous system, renin-angiotensin-aldosterone system).
- Calcineurin/NFAT Pathway:
  - Neurohumoral factors (e.g., catecholamines, angiotensin II) can increase intracellular Ca2+ levels in cardiomyocytes.
  - Increased Ca2+ activates calcineurin, a Ca2+-dependent phosphatase.
  - Calcineurin dephosphorylates NFAT (Nuclear Factor of Activated T-cells) transcription factors in the cytoplasm.
  - Dephosphorylated NFAT translocates to the nucleus, where it promotes the expression of genes involved in cardiomyocyte growth, including a switch towards a "fetal gene program" (re-expression of fetal isoforms of contractile proteins), which is often a hallmark of pathological hypertrophy.
- Other pathways involving stress signals (e.g., via AMPK, which can inhibit mTORC1 and protein synthesis but also has complex roles) are also implicated.