Stress Pathways and Heart Failure Kenneth R Chien, M.D., Ph.D.  Cell  Volume 98, Issue 5, Pages 555-558 (September 1999) DOI: 10.1016/S0092-8674(00)80043-4

Figure 1 Distinct Gene Mutations Can Give Rise to Either Hypertrophic or Dilated Forms of Cardiomyopathy Mutations within sarcomeric genes give rise to a hypertrophic cardiac phenotype, whereas mutations within components of the extrasarcomeric cytoskeleton give rise to dilated cardiac phenotypes. Unknown genetic modifiers also can lead to the conversion of hypertrophic to dilated forms of cardiomyopathy. (For a list of mutations, see Seidman and Seidman 1999 and Chen and Chien 1999.) Red, cardiac muscle; beige, valvular structures. Ao, aorta; LA, left atrial chamber; LV, left ventricular chamber. Cell 1999 98, 555-558DOI: (10.1016/S0092-8674(00)80043-4)

Figure 2 Critical Protein Components of the Cytoskeletal Network and Sarcoplasmic Reticulum in Heart Muscle The upper figure is a three-dimensional representation of two myofibrils and associated sarcolemmal, T-tubular, and sarcoplasmic reticular membranes within a cardiomyocyte. The panel on the bottom left depicts the interconnecting pathway between the extracellular matrix (laminin-2) and the nucleus (lamin A/C) via the dystrophin-glycoprotein complex and proteins within the Z line of the sarcomere. Mice that are null for muscle LIM protein (MLP) develop dilated cardiomyopathy. Asterisks denote proteins for which gene mutations have been shown to cause dilated cardiomyopathy. The panel on the bottom right depicts SR calcium pathways within cardiomyocytes. During systolic contraction, extracellular calcium enters the cytosol via the dihydropyridine receptor (DHPR) within the sarcolemmal membrane, and induces Ca release via the ryanodine receptor from the SR. During diastolic relaxation, calcium is taken up into the SR via the SERCA, and is stored in calsequestrin complexes. The amount of calcium taken up via SERCA during diastolic relaxation will determine the extent of relaxation and the quantity of calcium available for subsequent quantal release during systole. Calcium uptake via SERCA is negatively regulated by nonphosphorylated phospholamban. Ablation of phospholamban results in increased cardiac contractility and relaxation; while increased inhibition of SERCA by phospholamban has been documented in human heart failure. Cell 1999 98, 555-558DOI: (10.1016/S0092-8674(00)80043-4)

Figure 3 Biomechanical Stress Can Induce Myocyte Survival, Cell Death, and Hypertrophic Pathways Recent in vivo evidence highlights the importance of gp130 and neuregulin signaling pathways in modulating cardiac hypertrophy or cell death (see text for details). Cell 1999 98, 555-558DOI: (10.1016/S0092-8674(00)80043-4)