10.1 Clinical Pathophysiology: Cardiovascular and Endocrine

Cardiovascular Pathophysiology

Hypertension

Hypertension (HTN) is sustained arterial blood pressure ≥130/80 mmHg per ACC/AHA. Primary (essential) HTN accounts for ~90-95% of cases with no identifiable cause; pathogenesis involves increased sympathetic nervous system (SNS) activity, renin-angiotensin-aldosterone system (RAAS) activation, sodium retention, and vascular remodeling. Secondary HTN has identifiable causes: renal artery stenosis, primary aldosteronism, pheochromocytoma, obstructive sleep apnea, aortic coarctation, CKD. Chronic pressure elevation produces end-organ damage: left ventricular hypertrophy (LVH), heart failure, ischemic stroke, intracerebral hemorrhage, CKD, hypertensive retinopathy.

Heart Failure

Heart Failure (HF) is a clinical syndrome of impaired ventricular filling or ejection. Heart Failure with reduced Ejection Fraction (HFrEF) (LVEF ≤40%) features systolic dysfunction — weak pump. Heart Failure with preserved Ejection Fraction (HFpEF) (LVEF ≥50%) features diastolic dysfunction — stiff ventricle with impaired relaxation. Heart Failure with mildly reduced EF (HFmrEF) (41-49%) sits between. Compensatory neurohormonal activation (RAAS, SNS, arginine vasopressin) initially supports perfusion but drives maladaptive cardiac remodeling: myocyte hypertrophy, interstitial fibrosis, chamber dilation, worsening function. Natriuretic peptides (ANP, BNP) counter-regulate but are overwhelmed.

Coronary Artery Disease and Acute Coronary Syndrome

Atherosclerosis begins with endothelial injury (lipids, hypertension, smoking, hyperglycemia), LDL infiltration, oxidative modification, macrophage uptake forming foam cells and fatty streaks. Smooth muscle migration and collagen deposition produce a fibrous plaque with a lipid-rich core. Inflammatory thinning of the fibrous cap leads to plaque rupture, exposing thrombogenic contents to platelets and coagulation factors. The acute coronary syndrome (ACS) spectrum spans unstable angina (ischemia without biomarker elevation), NSTEMI (subendocardial infarction, troponin positive, no ST elevation), and STEMI (transmural infarction, ST elevation, urgent reperfusion required).

Arrhythmias

Atrial fibrillation (AF) features chaotic atrial depolarization with an irregularly irregular ventricular response and increased stroke risk from left atrial thrombus. Supraventricular tachycardia (SVT) originates above the ventricles. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are life-threatening and require immediate defibrillation. Conduction abnormalities (AV block, bundle branch block) impair impulse propagation. QT prolongation predisposes to torsades de pointes — many drugs (macrolides, fluoroquinolones, antipsychotics, methadone, ondansetron) extend QT and require monitoring.

Dyslipidemia

Elevated low-density lipoprotein (LDL) is the principal atherogenic particle; high-density lipoprotein (HDL) mediates reverse cholesterol transport; triglycerides (TG) contribute modestly but very high levels (>1,000 mg/dL) risk acute pancreatitis. The LDL:HDL ratio, non-HDL cholesterol, and apolipoprotein B refine cardiovascular risk assessment, particularly in metabolic syndrome and diabetes where atherogenic remnant particles abound. Familial hypercholesterolemia (LDL receptor or PCSK9 mutations) produces severely elevated LDL and premature ASCVD, illustrating the causal role of LDL in atherogenesis.

Hypertensive Urgency and Emergency

Hypertensive urgency is BP ≥180/120 without acute end-organ damage and is managed with gradual oral lowering. Hypertensive emergency features acute target-organ damage (encephalopathy, intracerebral hemorrhage, acute pulmonary edema, aortic dissection, acute renal failure, eclampsia) and requires titratable IV therapy (nicardipine, labetalol, clevidipine, esmolol) with controlled reduction (no more than 25% in the first hour). Distinguishing urgency from emergency is essential because overly rapid correction risks ischemic stroke and acute kidney injury from autoregulation failure.

Venous Thromboembolism

Deep vein thrombosis (DVT) and pulmonary embolism (PE) arise from Virchow's triad: venous stasis, endothelial injury, and hypercoagulability. Risk factors: immobility, surgery, malignancy, pregnancy, estrogen therapy, inherited thrombophilias (factor V Leiden, prothrombin gene mutation, antithrombin deficiency).

Endocrine Pathophysiology

Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) is autoimmune destruction of pancreatic beta-cells producing absolute insulin deficiency; it presents with polyuria, polydipsia, weight loss, and risk of diabetic ketoacidosis (DKA). Type 2 diabetes mellitus (T2DM) begins with insulin resistance in muscle, liver, and adipose; compensatory hyperinsulinemia eventually fails as beta-cell function declines. Chronic hyperglycemia drives complications through sorbitol accumulation (aldose reductase), advanced glycation end-products (AGEs), and protein kinase C (PKC) activation. Microvascular complications: diabetic nephropathy (glomerulosclerosis, albuminuria), retinopathy (pericyte loss, neovascularization), neuropathy (distal symmetric sensorimotor, autonomic). Macrovascular complications: coronary artery disease, stroke, peripheral arterial disease.

Thyroid Disorders

Hypothyroidism most commonly arises from Hashimoto's thyroiditis (anti-thyroid peroxidase antibodies) — fatigue, cold intolerance, bradycardia, weight gain, delayed reflexes. Hyperthyroidism commonly reflects Graves' disease (thyroid-stimulating immunoglobulin activating the TSH receptor) — heat intolerance, tachycardia, weight loss, exophthalmos. Thyroid storm is life-threatening thyrotoxicosis with hyperthermia, tachyarrhythmia, heart failure, and altered mental status requiring beta-blockade, thionamides, iodine, and glucocorticoids.

Adrenal Disorders

Cushing's syndrome reflects excess cortisol from pituitary adenoma (Cushing's disease), adrenal tumor, or exogenous steroids; central obesity, moon facies, purple striae, hyperglycemia, osteoporosis. Addison's disease is primary adrenal insufficiency from autoimmune destruction — fatigue, hypotension, hyperpigmentation, hyponatremia, hyperkalemia. Pheochromocytoma is a catecholamine-secreting tumor causing episodic hypertension with headache, diaphoresis, and palpitations.

Metabolic Syndrome and PCOS

Metabolic syndrome clusters abdominal obesity, atherogenic dyslipidemia (high TG, low HDL), hypertension, and insulin resistance, multiplying cardiovascular and diabetes risk. Polycystic ovary syndrome (PCOS) features hyperandrogenism, oligo-anovulation, polycystic ovaries, and insulin resistance, increasing T2DM and endometrial cancer risk.