Atherosclerosis causes myocardial dysfunction through several mechanisms. In its most advanced state, thrombotic closure of an epicardial conduit artery leads to downstream myocardial infarction and replacement of functioning cardiomyocytes with noncontracting fibrous tissue (◘ Fig. 8.3). Just short of infarction, gradual closure of the coronary arteries, usually accompanied by ingrowth of collateral vessels from neighboring coronary branches, leads to chronic cardiomyocyte ischemia. The chronic ischemia results in a noncontracting myocyte that eventually enters a hibernating state [8]. This results in impaired systolic function and impaired diastolic relaxation. Finally, atherosclerosis-associated abnormal vasomotion and constriction of the coronary arteries can lead to both transient loss of cardiomyocyte function and loss of myocytes in the subendocardium.

Atherosclerosis is usually preceded by reduced endothelial control of vascular tone. Since arteries are prone to constrict in the absence of tonic NO production by the endothelium, these arteries are prone to inappropriate constriction at both the micro- and conduit vessel levels. For example, transient sympathetic stimulation that might cause an increase in contractility and blood flow can lead to microvascular constriction [see the heading below, “Stress-Induced Ischemic Cardiomyopathy”] in the face of increased oxygen demand due to the elevated contractile state. This can result in transient myocardial ischemia and dysfunction but usually does not lead to chronic heart failure or loss of pump function.

As atherosclerotic deposits develop within the coronary arteries, the usual initial response to increased coronary wall thickness is for the artery to grow externally (i.e., increase its outer diameter) while preserving the lumen caliber. This “positive remodeling” described by Glagov et al. continues until the wall thickness is increased by about 40 % [9]. Thereafter, the lumen of the artery slowly diminishes in caliber, usually in an eccentric manner. As the conduit coronary lumen narrows, blood flow to the downstream cardiac muscle is maintained by dilation of the microcirculation. Typically, this downstream microvascular dilation is engaged when the cross-sectional area of the large coronary lumen is about 70 % reduced, compared to the original lumen caliber [10].

With this downstream autoregulation, blood flow at rest is preserved. When myocardial oxygen requirements increase, however, capacity for further dilation is limited. This results in demand-induced ischemia. Typical demands that result in ischemia are exercise and elevated heart rate. Although elevated blood pressure also invokes more oxygen demand, it is accompanied by increased driving pressure for coronary flow through the stenotic lesion, which mitigates the effects of the stenosis.

As the arterial lumen narrows further, blood flow at rest diminishes because the downstream microcirculation is fully dilated and cannot further compensate for the upstream obstruction to flow. This occurs when 90 % of the arterial lumen cross-sectional area is obstructed. On the arteriogram, these lesions appear to cause subtotal occlusion of the epicardial artery, and the distal flow of contrast media is slow.

The effects of an upstream stenosis on myocardial blood flow can be mitigated by collateral blood vessel connections between the coronary branches. Small collateral arteries that usually connect the microcirculatory branches exist in most human hearts to a variable degree. The branches are most prominent in the subendocardium but can be found throughout the circulation [11]. In non-ischemic coronary beds, the available collateral blood flow is low: around 0.2–0.4 mL/g/min [12]. Repetitive ischemia can lead to the growth in diameter of collateral blood vessels such that, in some patients, collateral blood supply can nearly reach the level of the original flow from the epicardial artery [13]. Diabetics and patients with microcirculatory disorders appear to have less collateral blood flow [14].

Collateral blood flow can increase rapidly. Typically, hibernating myocardial segments, where the initial coronary occlusion did not result in infarction, have markedly better collateral blood flow. After sudden coronary occlusion, 48 % of patients have angiographically visible collateral support of the occluded coronary risk area at 6 h, whereas by 1–30 days, 92 % had angiographically visible collateral blood flow to the infarct risk area [15].

Most myocardial infarctions are due to a relatively sudden occlusion of an epicardial coronary artery at a site of atherosclerotic plaque rupture. The muscle zone fed by that artery is referred to as the “area at risk.” The larger the risk area, the larger the infarction, and the worse the outcome. Increases in the infarct volume bring a stepwise increase in long-term mortality. Infarction of more than 40 % of the left ventricular mass is generally not survivable [16].

Assessing the impact of therapies on myocardial infarction center on risk area measurements: Effective therapies change the ratio between the area at risk and the area of infarction. Cardiac magnetic resonance imaging (CMRI) with T2 weighting enables measurement of the edema that occurs in the area at risk after a prolonged ischemic episode. Delayed gadolinium (Gd) imaging , where the Gd contrast agent clears slowly from injured myocytes (early infarction) and fibrotic areas (late infarction), allows measurement of the infarct area. Using the two methods, an infarct-to-risk area ratio can be obtained.

When atherosclerotic plaques rupture, the luminal platelets are activated by the collagen and other clot promoters in the plaque, such as tissue factor. This leads to intraluminal thrombosis, which can be highly variable. Patients with enhanced platelet function (such as those with inflammatory diseases or cigarette smokers) develop greater clot volume than others. Pieces of the intraluminal thrombus often break off and embolize downstream, leading to microinfarctions throughout the thickness of the downstream muscle. Activated platelets generate potent vasoconstrictors, such as thromboxane A2 and serotonin, leading to transmural ischemia from microvascular constriction downstream and spasm in the epicardial artery. Moreover, the thrombus in the artery is dynamic. Plasmin gradually dissolves the fibrinogen holding the platelets together, leading to thrombus resorption. Additional platelet activation leads to more clot deposition. As a result, arteries often open and close actively.

All of these factors lead to recurrent bouts of myocardial ischemia.

The ischemic episodes can result in ischemic preconditioning. In clinical studies, ischemic preconditioning can occur quite rapidly. For example, a 1-min coronary occlusion with an angioplasty balloon causes brief preconditioning to subsequent coronary occlusion. The time to ischemic changes showing on an electrocardiogram (ECG) lengthens with each subsequent balloon occlusion. Similarly, patients with prior intermittent angina before infarction have a better outcome and smaller infarction for the area at risk, presumably aided by preconditioning.

When an epicardial coronary artery becomes occluded suddenly, the ischemia is most profound in the subendocardial layers. Infarction occurs first in these layers and proceeds out to the mid- and subepicardial layers with prolonged occlusion. The periphery of the risk area is usually better supplied with nearby collateral blood flow from the surrounding unobstructed arteries. If, however, the surrounding arteries are also occluded or severely narrowed, the availability of collateral blood flow will be diminished, leading to a more extensive and dense infarction in the area at risk.

Advanced IschCM leads to remodeling of the left ventricle. The muscle in infarcted areas has reduced or no contraction, leaving the remainder of the myocardium to sustain stroke volume. As a result of reflexive changes and increased filling pressures, the surrounding non-infarcted muscle becomes hypercontractile. Reduced pump capacity activates the sympathetic nervous system (both neural and through release of catecholamines from the adrenal glands). The prolonged increased load on the remaining muscle can lead to hypertrophy. In many cases, however, the blood supply of the surrounding muscle is also impaired. The increased load on the non-infarcted muscle can lead to chronic ischemia and worsening of the heart failure through deterioration of the contraction of the surviving viable muscle.

Over time, the left ventricle dilates, changing from a prolate ellipsoid to a spherical chamber. This increases the wall stress needed to develop a given intraventricular pressure, further increasing the workload of the remaining myocytes. Unlike many non-ischemic cardiomyopathies, IschCM is usually associated with segmental, nonhomogeneous loss of LV contraction. This further reduces ventricular efficiency by creating “hinge points” between contracting and noncontracting segments [17].

Regional loss of contraction can particularly affect mitral valve function. Akinesis in the areas supporting the papillary muscles leads to mitral regurgitation due to impaired systolic mitral closure. Like all dilated cardiomyopathies, dilation of the ventricle leads to an enlargement of the mitral annulus and reduced tethering of the mitral leaflets (the ventricle enlarges more than the mitral chordae lengthen), leading to mitral insufficiency. The degree of mitral regurgitation (MR) is affected substantially by changes in LV volume and geometry—and it can be quite dynamic.

Eventually, the downward spiral of left ventricular dilation, sympathetic overdrive, secondary left atrial dilation (often inciting atrial fibrillation), pulmonary congestion leading the pulmonary hypertension and right ventricular failure, and fluid retention from inadequate renal perfusion results in death .

The prognosis of all patients with coronary artery disease is related to the presence and volume of myocardial ischemia that can be induced under a stress condition. Whether ischemia is detected by ischemic electrocardiographic changes during stress (ST segment depression), loss of contraction on echocardiographic stress imaging, or a focal reduction in ventricular perfusion (nuclear imaging), the greater the volume of ischemic muscle and the less stress required for induction of ischemia, the worse the prognosis [18]. Not surprisingly, most studies show that the presence and extent of inducible ischemia also predicts, in part, the prognosis of patients with IschCM [19, 20].