Cell death Reversibly injured myocyte Ischemia leading to cell injury Adapted myocyte (hypertrophy) Adaptation: response to increased load
Fig. 2.21 Therelationshipamongnormal,adapted,reversiblyinjured,anddeadmyocardialcells.Thecellularadaptationdepictedhereishypertrophy,thecauseofreversibleinjuryisischemia,andtheirreversibleinjuryisischemiccoagulativenecrosis.Intheexampleofmyocardialhypertrophy(lower left),theleftventricularwallisthickerthan2cm(normal,1–1.5cm).Reversiblyinjuredmyocardiumshowsfunctionaleffectswithoutanygrossorlightmicroscopicchanges,orreversiblechangessuchascellularswellingandfattychange(shown here).Inthespecimenshowingnecrosis(lower right) thetransmurallightareaintheposterolateralleftventriclerepresentsanacutemyocardialinfarction.Allthreetransversesectionsofmyocardiumwerestainedwithtriphenyltetra-zoliumchloride,anenzymesubstratethatcolorsviablemyocardiummagenta.Failuretostainisduetoenzymelossaftercelldeath.
stress. Myocardium subjected to a persistently increased workload, as in hypertension or with a narrowed (stenotic) valve, adapts by undergoing hypertrophy to generate the required higher contractile force. If, on the other hand, the myocardium is subjected to reduced blood flow (ischemia) due to an occluded coronary artery, the muscle cells may undergo injury.
The mechanisms driving cardiac hypertrophy involve at least two types of signals: mechanical triggers, such as stretch, and soluble mediators that stimulate cell growth, such as growth factors and adrenergic hormones. These stimuli turn on signal transduction pathways that lead to the induction of a number of genes, which in turn stimulate synthesis of many cellular proteins, including growth factors and structural proteins. The result is the synthesis of more proteins and myofilaments per cell, which increases the force generated with each contraction, enabling the cell to meet increased work demands. There may also be a switch of contractile proteins from adult to fetal or neonatal forms. For example, during muscle hypertrophy, the α-myosin heavy chain is replaced by the fetal β form of the myosin heavy chain, which produces slower, more energetically economical contraction.
An adaptation to stress such as hypertrophy can progress to functionally significant cell injury if the stress is not relieved. Whatever the cause of hypertrophy, a limit is reached beyond which the enlargement of muscle mass can no longer compensate for the increased burden. When this happens in the heart, several degenerative changes occur in the myocardial fibers, of which the most important are fragmentation and loss of myofibrillar contractile elements. Why hypertrophy progresses to these regressive changes is incompletely understood. There may be finite limits on the abilities of the vasculature to adequately supply the enlarged fibers, the mitochondria to supply ATP, or the biosynthetic machinery to provide sufficient contractile proteins or other cytoskeletal elements. The net result of these degenerative changes is ventricular dilation and ultimately cardiac failure.
Hyperplasia is an increase in the number of cells in an organ that stems from increased proliferation, either of differentiated cells or, in some instances, less differentiated progenitor cells. As discussed earlier, hyperplasia takes place if the tissue contains cell populations capable of replication; it may occur concurrently with hypertrophy and often in response to the same stimuli.
Hyperplasia can be physiologic or pathologic; in both situations, cellular proliferation is stimulated by growth factors that are produced by a variety of cell types.