Pathology Snapshot: Structure and Function of the Heart in the Circulatory System

The circulatory system comprises two anatomically and functionally integrated components: the cardiovascular system and the lymphatic system. Its central physiological role is mass transport—delivery of O₂, nutrients, and endocrine signals to peripheral tissues simultaneous with removal of metabolic by-products such as CO₂. 1. Cardiovascular system: a closed circuit composed of the heart, arteries, capillaries and veins. 2. Lymphatic system: an open, unidirectional network of lymphatic vessels and organs (lymph nodes, spleen, thymus, etc.) that recovers excess interstitial fluid (lymph), facilitates intestinal lipid absorption and provides immune surveillance.

As the central pump, the heart generates the pressure gradient required to maintain systemic and pulmonary perfusion. Its precise three-dimensional architecture, specialized histological organization and tightly-regulated electro-mechanical coupling collectively guarantee efficient convective transport of blood gases, nutrients and waste products.

 

I. Anatomical fundamentals of the heart

(A) Position and external configuration

The heart lies in the middle mediastinum within the pericardial sac; ~2/3 of its mass is left of the mid-sagittal plane. The base faces right-posterior-superior and receives the great vessels; the apex points left-anterior-inferior and corresponds to the 5^th intercostal space, 1–2 cm medial to the mid-clavicular line, where the apical impulse is palpable.

 

(B) Cardiac chambers and blood flow trajectory

The interatrial and interventricular septa divide the heart into right and left pumps, each composed of an atrium and a ventricle—yielding a “two-atrium–two-ventricle” topology. One-way valves ensure unidirectional flow and prevent regurgitation.

Chamber	Blood source	Outlet valve	Destination	Key anatomical landmarks
Right atrium	Superior & inferior vena cava + coronary sinus	Tricuspid (right atrioventricular) valve	Right ventricle	Right auricle, fossa ovalis (remnant of fetal foramen ovale)
Right ventricle	Right atrium	Pulmonary valve	Pulmonary trunk (deoxygenated blood)	Trabeculae carneae, papillary muscles, chordae tendineae, tricuspid valvular complex
Left atrium	Left & right pulmonary veins (oxygenated blood)	Mitral (left atrioventricular) valve	Left ventricle	Left auricle
Left ventricle	Left atrium	Aortic valve	Aorta (oxygenated blood)	Trabeculae carneae, papillary muscles, chordae tendineae, mitral valvular complex

 

(C) Cardiac skeleton and conduction system

Cardiac skeleton: dense connective tissue comprising the left and right fibrous trigones and the four valvular annuli (mitral, tricuspid, aortic, pulmonary). It serves as the anchoring platform for myocardium and valves and provides electrical insulation between atria and ventricles.

Conduction system: specialized, electrically-autonomous cardiomyocytes organized into five sequential components:

• Sino-atrial (SA) node: subepicardial at the junction of the superior vena cava and right atrium—primary pacemaker.
• Atrioventricular (AV) node: subendocardial in the inter-atrial septum; relays impulse to the His bundle.
• Bundle of His: penetrates the fibrous trigone and descends along the membranous interventricular septum.
• Left & right bundle branches: travel subendocardially along either side of the septum.
• Purkinje fibre network: subendocardial plexus that ensures near-synchronous ventricular excitation.

 

II. Histological architecture of the heart

The wall is arranged from lumen to surface as endocardium, myocardium and epicardium, each layer being structurally and functionally specialized for efficient pumping.

(A) Endocardium

Innermost tunic composed of three sub-layers:

Endothelium: simple squamous epithelium continuous with vascular endothelium; minimizes friction.

Sub-endothelial connective tissue: dense collagenous layer with scattered smooth-muscle cells.

Sub-endocardial layer: loose connective tissue containing blood vessels, nerves and Purkinje fibres.

 

(B) Myocardium

Cardiomyocytes: short, branched cylinders forming a three-dimensional syncytium. Usually one central nucleus. Intercalated discs appear as dark, step-like lines in LM.

① Intercalated disc: EM reveals transverse fascia adherens & desmosomes (mechanical coupling) and longitudinal gap junctions (low-resistance electro-chemical communication).

② Cross-striations: sarcomeric banding pattern less conspicuous than in skeletal muscle.

③ Myofibrils: irregularly arranged compared with skeletal fibres.

 

(C) Epicardium (visceral pericardium)

Serous membrane composed of:

Surface mesothelium (simple squamous epithelium).

Underlying loose connective tissue with adipocytes, vessels, nerves and lymphatics; together with the parietal pericardium it delimits the pericardial cavity whose lubricating fluid reduces friction during the cardiac cycle.

(D) Cardiac valves

Endocardial folds whose core is avascular dense connective tissue lined on both surfaces by endothelium; nutrition via direct diffusion from blood. Their geometry guarantees unidirectional flow—atrioventricular valves prevent back-flow into atria during systole, while semilunar valves block ventricular re-entry during diastole.

 

III. Principal cardiac functions and pathobiological relevance

Pump function: rhythmic sequence of atrial contraction (filling) → ventricular contraction (high-pressure ejection) → ventricular relaxation (diastolic suction) drives two circuits:

• Systemic circulation: left ventricle → aorta → systemic capillaries → superior & inferior vena cava → right atrium (arterial → venous blood).
• Pulmonary circulation: right ventricle → pulmonary trunk → pulmonary capillaries → pulmonary veins → left atrium (venous → arterial blood).

 

Pathological correlates: any structural or functional derangement may precipitate disease:

• Valvular damage (e.g., rheumatic heart disease) → stenosis/insufficiency → hemodynamic disturbance.
• Myocardial pathology (myocarditis, cardiomyopathy) → impaired contractility → heart failure.
• Conduction-system dysfunction → arrhythmias (atrial fibrillation, ventricular premature beats).
• Defects in cardiac skeleton or septa → congenital heart disease.

 

Core mIHC biomarker panel for human cardiac tissue

Multiplex immunohistochemistry (mIHC) permits simultaneous labelling of multiple targets within a single section, enabling spatial mapping of protein expression, cell lineage identification and micro-environmental profiling. The following evidence-based panel is organized into four biological modules: (1) cardiomyocyte injury/necrosis, (2) contractile & structural integrity, (3) inflammation/micro-environment, and (4) vascularization & fibrosis/remodelling.

 

1. Cardiomyocyte injury & necrosis markers

Marker	Target class	Biological/clinical relevance	Sub-cellular/topographic localization	Associated pathologies
Cardiac troponin I (cTnI)	Contractile protein	Gold-standard biomarker of necrosis (specificity >95%); mIHC distinguishes intracellular vs interstitial leakage, delineates injury extent	Cytosol of cardiomyocytes	AMI, myocarditis, cardiotoxicity
Cardiac troponin T (cTnT)	Contractile protein	Functionally equivalent to cTnI; mIHC detects micro-injury in chronic HF	Cytosol of cardiomyocytes	AMI, chronic heart failure
Creatine-kinase MB isoenzyme (CK-MB)	Myocardial enzyme	Useful for dating evolving infarction; mIHC highlights “border-zone” activity	Cytosol of cardiomyocytes	AMI, skeletal muscle cross-injury
Myoglobin (Myo)	Oxygen-binding heme protein	Earliest marker (1–2 h); mIHC identifies necrotic core at ultra-early stage	Cytosol of cardiomyocytes	Hyper-acute MI, rhabdomyolysis

2. Myocardial structural & functional integrity markers

Marker	Target class	Biological/clinical relevance	Localization	Associated pathologies
α-Actinin (sarcomeric)	Cytoskeletal protein	Z-disc anchor; mIHC evaluates sarcomeric disruption	Cross-striated cytosolic pattern	MI, cardiomyopathy, fibrosis
Connexin-43 (Cx43)	Gap-junction protein	Mediates inter-myocyte conduction; mIHC quantifies lateralization vs intercalated-disc retention	Intercalated disc (sarcolemma)	Arrhythmias, conduction block post-MI
Myosin light-chain 1 (MLC-1)	Contractile protein	Early degradation product; mIHC detects sub-clinical injury	Cytosol of cardiomyocytes	Hyper-acute MI, myocarditis
HCN4	Pacemaker channel protein	Specific for Purkinje fibres; mIHC maps conduction-system loss	Subendocardial Purkinje cells	Bundle-branch block, sick-sinus syndrome

 

3. Inflammation & micro-environment markers

Marker	Target class	Biological/clinical relevance	Localization	Associated pathologies
CD68 (pan-macrophage)	Lysosomal glycoprotein	Combined with M1/M2 markers (iNOS/CD206) to profile macrophage polarization	Interstitial space, peri-necrotic zone	Myocarditis, remodelling post-MI
Neutrophil elastase (NE)	Serine protease	Quantifies acute neutrophilic infiltration	Infarct core (hyper-acute phase)	Hyper-acute MI, septic myocarditis
C-reactive protein (CRP)	Pentraxin (acute-phase protein)	mIHC detects local CRP synthesis, reflecting tissue-level inflammation	Interstitium, perivascular	Myocarditis, coronary plaque inflammation
Interleukin-6 (IL-6)	Pro-inflammatory cytokine	Driver of inflammatory cardiomyopathy and fibrosis; mIHC pinpoints cellular source	Cardiomyocyte & macrophage cytosol	Myocarditis, inflammation-driven HF

 

4. Vascularization & fibrosis/remodelling markers

Marker	Target class	Biological/clinical relevance	Localization	Associated pathologies
CD31 (PECAM-1)	Endothelial adhesion molecule	Quantifies neovascular density post-MI	Microvascular endothelium	MI (reparative phase), ischemic cardiomyopathy
α-Smooth-muscle actin (α-SMA)	Contractile microfilament	Identifies activated myofibroblasts; mIHC quantifies fibroblast infiltration	Interstitial & fibrotic foci	Myocardial fibrosis, HF with remodelling
Collagen I / III	Fibrillar ECM proteins	Type I (mature) vs III (early) ratio indicates fibrotic stage	Interstitial collagen bundles	Chronic HF, post-MI remodelling
Endothelin-1 (ET-1)	Vasoactive peptide	Marker of endothelial dysfunction; mIHC localizes ET-1 over-production	Endothelium & cardiomyocyte cytosol	Coronary artery disease, pulmonary hypertension