An ongoing loss of cardiomyocytes via apoptotic and necrotic cell death pathways contributes to the progressive nature of heart failure. As depicted in Figure
, apoptotic cells are rapidly scavenged by macrophages; they neither disintegrate nor lose their contents to stimulate the immune system. As a result, serum troponin levels are not elevated and a wound healing response is not invoked.1–3
Dying necrotic cells, on the other hand, release troponins and other intracellular contents, which serve as danger signals to the immune system and chemoattractants that promote invasion of inflammatory cells to the site of injury. These cells, together with myofibroblasts, account for subsequent tissue repair. Foci of microscopic scarring are the final outcome. Hence, elevations in serum troponins and cardiac fibrosis are each footprints of cardiomyocyte necrosis. Scattered foci of fibrosis are found throughout both ventricles of the explanted failing human heart and are considered the major component of the pathological structural remodelling of myocardium.4
This would not only implicate the importance of cardiomyocyte necrosis, but would also suggest it to be an ongoing process. The loss of cardiomyocytes and their replacement with stiff fibrillar collagen each contribute to the progressive failure of this muscular pump. Elevations in serum troponins are found in patients hospitalized because of their congestive heart failure (CHF) and are associated with an increased risk of morbidity and mortality from cardiovascular events.5–14
In ambulatory asymptomatic elderly men, followed for 11 years in a community in Sweden, the appearance of elevated serum troponin predicted an increased risk of heart failure.15
Factors other than overt ischaemia with a segment of infarcted myocardium can account for cardiomyocyte necrosis (vide infra). An understanding of pathophysiological mechanisms involved becomes essential to the optimal evaluation and management of these patients. Towards this end, the origins of the CHF syndrome provide crucial insights.
Heart failure involves an ongoing loss of cardiomyocytes to apoptosis and necrosis. See text.
Congestive heart failure has its origins rooted in inappropriate neurohormonal activation. This includes the hypothalamic–pituitary–adrenal axis (HPA), the adrenergic nervous (ANS), and renin–angiotensin–aldosterone (RAAS) systems. Their effector hormones are cytotoxic to cardiomyocytes.16–18
Some 50 years ago, Albrecht Fleckenstein and coworkers at the University of Freiburg im Breisgau hypothesized that hyperadrenergic state which accompanies stressor states, such as CHF, would lead to catecholamine-mediated excessive intracellular Ca2+
accumulation (EICA), particularly involving cardiac mitochondria. The ensuing dysfunction of Ca2+
overloaded mitochondria, coupled with the diminished synthesis of high-energy phosphate and structural degeneration of these organelles, would lead to cardiomyocyte necrosis. They validated their hypothesis using isoproterenol-induced cardiac injury in rodents in which cotreatment with a calcium-channel blocker, verapamil, proved cardioprotective.19,20
Later, others confirmed this paradigm and provided further insights into the adverse consequences of elevated plasma epinephrine levels (5000 pg/mL) comparable with those found in man during acute and chronic stressor states.18,21–24
Today, the importance of catecholamine excess that accompanies marked emotional stress or acute stressor states, such as head trauma or subarachnoid haemorrhage, is now recognized as leading to stress-related cardiomyopathy syndromes (e.g. apical ballooning or Takotsubo cardiomyopathy).25
In recent years, two other factors, together with EICA, were identified to be major participants in a signal–transducer–effector pathway to cardiomyocyte necrosis during acute or chronic hyperadrenergic states (see Figure ). This includes the genesis of oxidative stress, where the rate of reactive oxygen and nitrogen species generation overwhelms their rate of elimination by endogenous antioxidant defences, invoked in response to EICA. Second, the role of the mitochondrial inner membrane permeability transition pore (mPTP) opening which leads to organellar dysfunction, osmotic swelling, and ultimate structural degeneration of these organelles. Other pathophysiological responses that accompany catecholamine excess and which extend beyond the importance of Ca2+ overloading can also be cytotoxic. They cannot be overlooked and include a dyshomeostasis of essential cations which are manifested as hypokalaemia, ionized hypomagnesaemia and hypocalcaemia, hypozincaemia, and hyposelenaemia. Herein, we introduce and highlight this broader perspective of cation dyshomeostasis in revisiting the Fleckenstein hypothesis and cardiomyocyte necrosis.
Figure 2 Catecholamine-mediated cellular and subcellular Ca2+ overloading with induction of oxidative stress and reactive oxygen species generation and opening of the mitochondrial inner membrane permeability transition pore that leads to solute entry, osmotic (more ...)