Anatomy and Histology

Heart

The muscular wall of the heart is composed of cardiac muscles. The heart consists of four chambers: two
atria, which receive blood, and two ventricles, which discharge blood from the heart. The superior and
inferior venae cavae return systemic venous blood to the right atrium of the heart. From here, the blood
passes through the right atrioventricular valve into the right ventricle. As the ventricles contract, blood
from the right ventricle is pumped out the pulmonary trunk, a large vessel that bifurcates into the right
and left pulmonary arteries to deliver deoxygenated blood to the lungs for gaseous exchange.
Oxygenated blood from the lungs returns to the heart via the pulmonary veins, which empty into the
left atrium. From here, the blood passes through the left atrioventricular valve to enter the left
ventricle. Again, ventricular contraction expels the blood from the left ventricle into the aorta, from
which many branches emanate to deliver to the tissues of the body.

Layers of the Heart Wall

The three layers that constitute the heart wall are the endocardium, myocardium, and epicardium,
homologous to the tunica initima, tunica media, and tunica adventitia, respectively, of the blood vessels.

Endocardium

It is composed of of an endothelium, consisting of a simple squamous epithelium and an underlying

layer of fibroelastic connective tissue with scattered fibroblasts. Lying deeper is a layer of dense
connective tissue heavily endowed with elastic fibers interspersed with smooth muscle cells. Deep to
the endocardium is a subendocardial layer of loose connective tissue that contains small blood vessels,
nerves, and Purkinje fibres from the conduction system of the heart. The subendocardial layer forms the
boundary of the endocardium as it attaches to the endomysium of the cardiac muscle.

Myocardium

The myocardium, the middle and thickest of the three layers of the heart, contains cardiac muscle cells
arranged in complex spirals around the orifices of the chambers. Certain cardiac muscle cells attach the
myocardium to the fibrous cardiac skeleton, others are specialized for endocrine secretions, and still
others are specialized for impulse generation or impulse conduction.

The heart rate is controlled by the sinoatrial node located at the junction of the superior vena cava and
the right atrium. These specialized nodal cardiac muscle cells can spontaneously depolarize 70 times per
minute, creating an impulse that spreads over the atrial chamber walls by intermodal pathways to the
atrioventricular node, located in the septal wall just above the tricuspid valve. Modified cardiac muscle
cells of the atrioventricular node, regulated by impulses arriving from the sinoatrial node, transmit
signals to the myocardium of the atria via the atrioventricular bundle (bundle of His). Fibers from the
atrioventricular bundle pass down the interventricular septum to conduct the impulse to the cardiac
muscle, thus producing a rhythmic contraction. The atrioventricular bundle travels in the subendocardial
connective tissue as large, modified cardiac muscle cells, forming Purkinje fibers, which transmit
impulses to the cardiac muscle cells located at the apex of the heart. It should be noted that although
the autonomic nervous system does not initiate the heartbeat, it does modulate the rate and stroke
volume of the heartbeat.

Epicardium

Epicardium, the outermost layer of the heart wall, is also called the visceral layer of the pericardium. The
subpericardial layer of loose connective tissue contains the coronary vessels, nerves, and ganglia. It also
is the region where fat is stored on the surface of the heart. At the roots of the vessels entering and
leaving the heart, the visceral pericardium becomes continuous with the serous layer of the parietal
pericardium. These two layers of the pericardium encloses the pericardial cavity, a space containing a
small amount of serous fluid for lubricating the serous layer of the pericardium and the visceral
pericardium.

Valves

The four cardiac valves (tricuspid, pulmonary, mitral, and aortic) maintain unidirectional blood flow
through the heart. Their function depends on the mobility, pliability, and structural integrity of their
delicate flaps, called leaflets (in the tricuspid and mitral valves) or cusps (in the aortic and pulmonary
valves, also known as the semilunar valves). All four valves have similar, layered architecture: a dense
collagenous core close to the outflow surface and continuous with valvular supporting structures, a
central core of loose connective tissue, a layer rich in elastin below the inflow surface, and an
endothelial covering. The collagen is responsible for the mechanical integrity of a valve. The valve is
populated throughout by interstitial cells, which produce and continuously repair the extracellular
matrix, allowing the valve to respond and adapt to changing mechanical conditions.

Structure and Function of Blood Vessels

The basic constituents of the walls of the blood vessels are endothelial cells and smooth muscle cells,
and extracellular matrix, including elastin, collagen, and glycosaminoglycans. The three concentric
layers- intima, media, and adventitia- are most clearly defined in the larger blood vessels, particularly
arteries. In normal arteries, the intima consists of a single layer of endothelial cells with minimal
underlying subendothelial connective tissue. It is separated from the media by a dense elastic
membrane called the internal elastic lamina. The smooth muscle cell layers of the media near the vessel
lumen receive oxygen and nutrients by direct diffusion from the vessel lumen, facilitated by holes in the
internal elastic membrane.
Response of Vascular Wall Cells

All vessels are lined by endothelium. Endothelial cells form a specialized lining for blood vessels. Although
all endothelial cells share certain homeostatic properties, endothelial cells in specific vascular beds have
special features that allow for tissue-specific functions (e.g., fenestrated endothelial cells in renal
glomeruli).

Endothelial cells can respond to various stimuli by adjusting their steady-state (constitutive) functions and
by expressing newly acquired (inducible) properties—a process termed endothelial activation. Inducers of
endothelial activation include cytokines and bacterial products, which elicit inflammation and, in severe
cases, septic shock; hemodynamic stresses and lipid products, critical to the pathogenesis of
atherosclerosis; advanced glycation end-products; as well as viruses, complement components, and
hypoxia. Activated endothelial cells, in turn, express adhesion molecules and produce cytokines and
chemokines, growth factors, vasoactive molecules that result either in vasoconstriction or in vasodilation,
major histocompatibility complex molecules, procoagulant and anticoagulant factors, and a variety of
other biologically active products.

Basal and activated endothelial cell states. Normal blood pressure, laminar flow, and low growth factor
levels promote a basal endothelial cell state that maintains a nonthrombotic, nonadhesive surface with
appropriate vascular wall smooth muscle tone. Injury or exposure to certain mediators result to
endothelial activation, a state where endothelial cells develop a procoagulant surface that can be adhesive
for inflammatory cells, and also express factors that cause smooth muscle contraction and/or proliferation
and matrix synthesis. VEGF, vascular endothelial growth factor.

Endothelial cells influence the vasoreactivity of the underlying smooth muscle cells through the
production of both relaxing factors (e.g., nitric oxide [NO]) and contracting factors (e.g., endothelin).
Normal endothelial cell function is characterized by a balance of these responses.

Endothelial cell function is tightly regulated in both the basal and activated states. Various physiologic
and pathophysiologic stimuli induce endothelial activation and dysfunction that alter the endothelial cell
phenotype (e.g., procoagulative vs. anticoagulative, proinflammatory vs. antiinflammatory, and
nonadhesive vs. adhesive).

Injury (of almost any type) to the vessel wall results in a stereotyped healing response involving smooth
muscle cell proliferation, extracellular matrice deposition, and intimal expansion.

The recruitment and activation of the smooth muscle cell involves signals from cells (e.g., endothelial cells,
platelets,
and macrophages), as well as mediators derived from coagulation and complement cascades.

Excessive thickening of the intima may result in luminal stenosis and vascular obstruction.

Vascular smooth muscle cells are the predominant cellular element of the vascular media, playing
important roles in normal vascular repair and pathologic processes such as atherosclerosis. Smooth
muscle cells have the capacity to proliferate when appropriately stimulated; they can also synthesize
collagen, elastin, and proteoglycans and elaborate growth factors and cytokines. Smooth muscle cells are
also responsible for the vasoconstriction or dilation that occurs in response to physiologic or
pharmacologic stimuli.