The heart is a muscular organ and receives its blood supply from two main arteries : the left main coronary artery (LMA) and the right coronary artery (RCA) (◘ Fig. 2.3a). The LM coronary artery originates from the left sinus of Valsalva and is short, 0.5–2 cm length and has a large diameter (3–4 mm). The LM coronary artery bifurcates into the left anterior descending (LAD) coronary artery and the left circumflex (LCx) artery (◘ Fig. 2.3a, b) [19]. The LAD artery courses in the anterior interventricular groove and ascends a short distance following the posterior interventricular groove. The LAD artery has multiple branches including the septal branches, which supply the anterior two-thirds and apical portions of the septum, as well as a number of branches to the anteroapical portions of the left ventricle, including the anterior papillary muscle. The latter branches are called diagonals that vary in size and number. Usually, there are two or three diagonal vessels that are medium to large in size (1–2 mm diameter) (◘ Fig. 2.3b). The second main branch from the LM coronary artery is the LCx coronary artery (◘ Fig. 2.3b). It is usually smaller and courses in the left AV groove and branches into the obtuse marginal (OM1 and OM2) arteries to supply the upper lateral LV wall and the LA. The blood flow to the anterolateral papillary muscle in the LV is from the LAD (typically the diagonal branch) and the left circumflex (obtuse marginal artery) coronary arteries, and the blood flow to the posteromedial papillary muscle in the LV is from the posterior descending coronary artery (PDA), which is a branch of the RCA. This single source of blood supply contributes to posteromedial papillary muscle rupture and acute mitral regurgitation following right coronary artery occlusion [19, 20].

The right coronary artery (RCA) is the other main coronary artery that is responsible for the delivery of blood to the inferior wall of the heart (◘ Fig. 2.3a). The RCA arises from the right coronary sinus of Valsalva of the aorta and courses in the right atrioventricular (AV) groove (◘ Fig. 2.3b). The RCA branch, the posterior descending artery (PDA), courses in the posterior interventricular groove and supplies the posterior third of the interventricular septum [15].

The architecture of the heart is distinctive and functionally important. The myofibers are organized into laminated sheets that are approximately four cells thick. The ventricular myocardium is subdivided into three layers (superficial layer, middle layer, and deep layer) (◘ Fig. 2.4) [15]. The superficial layer is composed of oblique fibers that form a sheet extending from the base and wrapping around the apex. These oblique fibers form a twin helix around the ventricle and cause a wringing effect (similar to wringing the water out of a towel) resulting in optimal ventricular filling and emptying. The middle layer consists of circumferential muscle bundles that are primarily located in the midwall at the base and closer to the epicardium [21]. The deep layer is composed of oblique, circumferential, and longitudinal fibers (◘ Fig. 2.4). Collectively, the left ventricle has continuous fiber geometries with circumferential fibers associated with the upper septum and base and oblique fibers that extend from the midwall to the apex. This architecture of circumferential and oblique fibers results in increased efficiency of the pump (i.e., stress and strain) during the cardiac cycle.

The myocardium comprises the vast majority of the heart’s thickness (◘ Fig. 2.4). It contains both myocytes and connective tissue (◘ Fig. 2.4). Cardiac myocytes represent most of the myocardial mass and accounts for more than half the heart’s weight [22]. About 70 % of the myocardium, however, is connective tissue that maintains the heart’s strength and stiffness. Recently, flow cytometry studies in rodents suggested that the adult mouse heart contained 55 % myocytes and 45 % nonmyocytes, although investigators recognized the possibility of species differences regarding cellular composition. The nonmyocyte constituents include cells such as fibroblasts, myofibroblasts (smooth muscle-like fibroblasts), vascular smooth muscle, and endothelial cells (◘ Fig. 2.4). Several types of myocytes are found in normal hearts, and they are classified based on their location in the atria and ventricles [22, 23]. Atrial myocytes are smaller than ventricular myocytes. Ventricular myocytes are long and narrow in shape. They are approximately 20 μm in diameter, 60–120 μm in length, and have a volume of 15,000–45,000 μm³. Individual contractile myocytes in the atrium are elliptical in shape. The atrial myocytes are 5–6 μm in diameter, 20 μm in length, and have a volume of 500 μm³ [24]. Compared to the ventricular myocytes, the atrial myocytes have bundles of atrial tissue separated by wide areas of collagen. Working myocytes are filled with cross-striated myofibers and mitochondria and usually contain a single centrally located nucleus (◘ Figs. 2.4 and 2.5).

Atrial myocytes contain stores of active natriuretic peptide which functions as natriuretic factors and facilitates the dilation of vascular smooth muscle. The increasing stretch of the cardiac wall caused by vascular congestion with decompensated heart failure is a potent stimulus for the release of these peptides from the atria and ventricles. Cardiomyocytes contain a large number of myofilaments that are organized in a regular array of cross striations (◘ Fig. 2.5). The cross striations of the myocardium reflect the organization of the contractile proteins into thick and thin filaments [22]. The sarcomere is defined as the area between the two Z lines and is considered the fundamental unit of striated muscle (◘ Fig. 2.5).

As schematized in ◘ Fig. 2.5, the sarcomere contains the central A band and the two adjacent I bands. The sarcomere consists of the thick filaments composed largely of myosin that extend the length of the A band and contribute to the dark staining characteristics and its high birefringence. The thin filaments are composed of actin and the associated regulatory proteins—tropomyosin and troponin. Together, they form a complex that extends the length of the I bands and are characterized by the lightly stained striations and decreased birefringence. A broad dense M band is located in the center of each A band, while the I bands are bisected by Z lines (◘ Fig. 2.5).

The parasympathetic (cholinergic) and sympathetic (adrenergic) nerve fibers innervate the heart. The parasympathetic fibers arise from the cardiac components of the cranial neural crest cells and are propagated to the heart via the vagus nerve (◘ Fig. 2.6). The vagus nerve is a mixed nerve that has both sensory and motor nerves. The right and the left vagal nerves course from the medulla to the heart via the carotid sheath and primarily innervate the sinoatrial (SA) and AV nodes.

The sympathetic nerve fibers arise from the medulla and course to the heart from the sympathetic ganglia (◘ Fig. 2.6). The sensory nerves arise from the ectodermal placode of the nodose ganglion and are propagated via the vagus nerve. The nucleus ambiguus, the nucleus solitarius, and the dorsal motor nucleus in the medulla provide autonomic neuronal control for the cardiovascular system via the vagus nerve and the sympathetic ganglia. The nucleus solitarius receives sensory afferent input from chemoreceptors and baroreceptors and is a control center for the baroreflex (as well as exercise-induced reflexes such as the exercise pressor reflex and central command). The nucleus ambiguous and the dorsomedial nucleus (DMN) provide parasympathetic control for the parasympathetic control for the heart.

Sympathetic efferent nerves originate from the cervical and thoracic sympathetic ganglia and course with the blood vessels to innervate the atria and ventricles. The effects of the sympathetic nervous system are mediated by norepinephrine that binds to alpha-adrenoreceptors (to regulate vasoconstriction of the vasculature in response to dehydration) or beta-1 adrenoreceptors to increase chronotropy, lusitropy, inotropy, and conduction velocity. The parasympathetic system mediates its effects by the release of acetylcholine, which binds muscarinic receptors and regulates the SA and AV nodes (◘ Fig. 2.6).

Collectively, the cardiovascular innervation and its global impact on the cardiac output are evident in a number of reflexes (i.e., vasovagal syncope, Bezold–Jarisch reflex, Valsalva maneuver, carotid sinus reflex, etc.). In the failing heart, decreased cardiac output promotes an increase in sympathetic activity resulting in remodeling and is associated with increased arrhythmias and sudden cardiac death. Heart failure symptoms and progression of disease are exacerbated by a hyperadrenergic state. This increase in the sympathetic nervous system results in tachycardia, vasoconstriction, increased afterload, diaphoresis, oliguria, increased myocardial oxygen consumption, and progressive left ventricular remodeling. In short, norepinephrine becomes toxic to the myocardium. In patients with advanced heart failure who receive a cardiac transplant, the graft is denervated (i.e., vagus nerves are severed), and, typically, the heart rate is about 105 bpm.

Tissue hemoglobins are found in diverse organisms including plants, mollusks, and mammals. These tissue hemoglobins include cytoglobin, neuroglobin, and myoglobin [4, 25]. In vertebrates, myoglobin is restricted to striated muscle (cardiomyocytes and oxidative skeletal myofibers ) and is a monomeric cytoplasmic hemoprotein consisting of 154 amino acids [26, 27]. Myoglobin is named because of its functional and structural similarity to hemoglobin. Evolutionarily, myoglobin and hemoglobin arose from a common ancestral gene more than 500 million years ago [26, 28, 29]. In 1958, myoglobin was the first protein to be subjected to definitive structural analysis (◘ Fig. 2.7a) [30]. Subsequently, a number of studies have established that the structure of myoglobin consists of a heme pocket, which is bracketed by histidine residues and has a backbone of eight alpha-helices (◘ Fig. 2.7a). The flanking histidine residues stabilize the heme group and allow for the concentration of ligands (e.g., dioxygen, nitric oxide, carbon monoxide, etc.) to bind to the heme residue of myoglobin (◘ Fig. 2.7a). In this fashion, myoglobin has been shown to have important roles as a facilitator of oxygen transport to mitochondria to maintain oxidative phosphorylation (and the generation of adenosine 5′-triphosphate, ATP) for myocardial contractility, as well as serve as a modulator of nitric oxide (NO) bioavailability and as a scavenger of reactive oxygen species [27, 31].

Previous studies using gene disruption technologies engineered a mouse model that lacked myoglobin (◘ Fig. 2.7b) [32]. While many mutant embryos were nonviable, viable myoglobin null mice had preserved cardiac performance due to a number of adaptive mechanisms including an induction of the hypoxia-inducible molecular program, neovasculogenesis, and increased coronary flow [25, 33]. Collectively, the results of these genetic studies underscore the importance of myoglobin (and its role in oxygen transport and the generation of ATP), the redundancy of other tissue hemoglobins (in the absence of myoglobin), and the role of adaptive mechanisms to promote cardiac function, even in the absence of myoglobin [32].

Cardiac contraction and relaxation : The contractile proteins of the heart—actin and myosin—lie within the cardiomyocytes, which constitute about 75 % of the total volume of the myocardium (◘ Fig. 2.5) [34]. The physical interactions between myosin and actin are activated by calcium and regulated by tropomyosin and troponins (◘ Fig. 2.8) [22, 28]. Troponins have several subtypes (C, I, and T) and are associated with actin thin filaments. The signaling process that initiates cardiac systole, called excitation–contraction (EC) coupling , begins when an action potential depolarizes the plasma membrane [35]. This EC coupling opens L-type voltage-dependent calcium channels during the action potential plateau and allows an influx of calcium to enter the cytosol from the extracellular fluid (◘ Fig. 2.8) [22, 36]. This calcium influx triggers the opening of calcium-release channels in the sarcoplasmic reticulum (via the ryanodine receptor 2, RyR2) that releases a larger pool of this activator to the cytosol from stores within this intracellular membrane system (◘ Fig. 2.8) [5, 37]. This increased cytosolic calcium concentration facilitates the binding of calcium to troponin C and the induction of contraction [38, 39]. Following contraction, the calcium is released from troponin C, and reuptake into the SR is facilitated by the SR calcium-ATPase 2a (SERCA2a) calcium pump (◘ Fig. 2.8). The heart relaxes when calcium is transported out of the cytosol. A smaller amount of calcium is transported from the cytosol into the extracellular space by a plasma membrane calcium pump and sodium/calcium exchanger [22, 36]. The total time period required for cardiomyocyte depolarization, calcium-induced calcium release, contraction, relaxation, and recovery in the adult human heart is about 600 msec [38].

Regulation of cardiac contractile performance : Two mechanisms are traditionally viewed as essential for the regulation of the heart’s contractile performance: the length-dependent regulation (the Frank–Starling law of the heart) and inotropic/lusitropic properties (◘ Fig. 2.9).