Cardiac arrhythmias have been linked to mutations in the cardiac ryanodine receptor (RYR2). Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary autosomal dominant disease that typically presents in childhood as exercise-induced tachycardia, which can progress to arrhythmias during exercise or stress, potentially resulting in sudden death. Roughly 40% of CPVT patients have a defect in RYR2, which has been associated with an increased release of calcium from the sarcoplasmic reticulum (SR). This mutation in RYR2 may involve a substitution of a highly conserved amino acid, distinguishing it from malignant hyperthermia where splicing errors or deletions within RYR have been reported. The hypothesis is that during exercise or stress, elevated levels of intracellular calcium (due to the combined effects of β-adrenergic stimulation and increased activity of the mutated RYR2) promote the development of delayed afterdepolarizations and consequently arrhythmias. The elevation of intracellular calcium during diastole is believed to facilitate the development of delayed afterdepolarizations through the activation of the 3Na+-Ca++ antiporter. This results in calcium extrusion during diastole, leading to a net inward current sufficient to depolarize the cell to the threshold for an action potential. Treatment for CPVT involves antiadrenergic therapy with β-adrenergic antagonists or, for unresponsive patients, the implantation of a defibrillator.

In vivo and in vitro, stretching of the heart enhances the force of contraction and is an intrinsic mechanism for regulating contractile force. In contrast, skeletal muscle typically exhibits maximal tension at rest. The stretching of the heart in vivo occurs when there is an increased venous return of blood to the heart, such as during exercise or when the heart rate slows down, or both. The Frank-Starling law of the heart refers to the heart's ability to increase its force of contraction when it is stretched. This occurs during times of increased venous return. Sympathetic stimulation of the heart leads to an increase in cytosolic cyclic adenosine monophosphate (cAMP) levels, which in turn phosphorylates several proteins through protein kinase A (PKA). An A kinase anchor protein (AKAP) located near the L-type calcium channel facilitates the phosphorylation of this channel and potentially nearby sarcoplasmic reticulum calcium channels. Other proteins phosphorylated by PKA include phospholamban (PLN) and troponin I. On the other hand, muscarinic agonists, like acetylcholine (ACh), inhibit this sympathetic cascade by suppressing the production of cAMP by adenylate cyclase (AC). The sympathetic stimulation of the heart results in an increase in cytosolic cAMP levels and phosphorylation of various proteins by PKA. The β-adrenergic receptor (β-AR), ATP (adenosine triphosphate), inhibitory G protein (Gi), muscarinic acetylcholine M2 receptor (M2Rec), and regenerating gene receptor (Reg) are all involved in this process.
Mutationsinthecardiacryanodinereceptor(RYR2)havebeenassociatedwithcardiacarrhythmias.Specifically,catecholaminergicpolymorphicventriculartachycardia(CPVT)isaninheritedautosomaldominantdiseasethatistypicallymanifestedduringchildhoodasanexercise-inducedtachycardiathatcanprogresstoarrhythmiasduringexercise(orstress)andresultinsuddendeath.Approximately40%ofpatientswithCPVTexhibitadefectinRYR2thathasbeenassociatedwithincreasedreleaseofCa++ fromtheSR.ThemutationinRYR2mayinvolvesubstitutionofahighlyconservedaminoacid,whichdiffersfrommalignanthyperthermia,inwhichsplicingerrorsordeletionswithinRYRhavebeenreported.Itishypothesizedthatduringperiodsofexerciseorstress,increasedlevelsofintracellularCa++ (becauseofthecombinedeffectsofβ-adrenergicstimulationandincreasedactivityofthemutatedRYR2)promotethedevelopmentofdelayedafterdepolarizationsandhencearrhythmias.Elevationofintracellular[Ca++]duringdiastoleisthoughttopromotethedevelopmentofdelayedafterdepolarizationsthroughactivationofthe3Na+-Ca++ antiporter,whereinCa++ extrusionduringdiastoleresultsinanetinwardcurrentsufficienttodepolarizethecelltothethresholdforanactionpotential.TreatmentofCPVTinvolvesantiadrenergictherapy(withβ-adrenergicantagonists)or(forunresponsivepatients)animplanteddefibrillator.
Stretching of the heart increases the force of contraction both in vivo and in vitro and is an intrinsic mechanism for regulating contractile force. In contrast, skeletal muscle typically exhibits maximal tension at resting length. Stretching of the heart in vivo occurs during times of increased venous return of blood to the heart (e.g., during exercise or when the heart rate is slowed, or both). The Frank-Starling law of the heart refers to this ability of the heart to increase its force of contraction when stretched, which occurs at •Fig. 13.4 Sympatheticstimulationoftheheartresultsinanincreaseincytosoliccyclicadenosinemonophosphate(cAMP)andhencephosphorylationofseveralproteinsbyproteinkinaseA(PKA).AnAkinaseanchorprotein(AKAP)adjacenttotheL-typecalciumchannelfacilitatesphosphorylationofthischannelandpossiblynearbysarcoplasmicreticulumcalciumchannels.OtherproteinsphosphorylatedbyPKAincludephospholamban(PLN)andtroponinI.Muscarinicagonists(e.g.,acetylcholine[ACh]),ontheotherhand,inhibitthissympatheticcascadebyinhibitingtheproductionofcAMPbyadenylatecyclase(AC).β-AR,β-adrenergicreceptor;ATP,adenosinetriphosphate;Gi,inhibitoryGprotein;M2Rec,muscarinicacetylcholineM2receptor;Reg,regeneratinggenereceptor.(RedrawnfromBersDM.Cardiacexcitation-contractioncoupling.Nature 2002;415:198.) times of increased venous return (Fig. 13.6A
The importance of this mechanism is that it helps the heart pump whatever volume of blood it receives. Thus when the heart receives a lot of blood, the ventricles are stretched, and the force of contraction is increased, which ensures ejection of this extra volume of blood. Stretching of cardiac muscle also increases passive tension, which helps prevent overstretching of the heart. This passive resistance in the heart is greater than that in skeletal muscle and is attributed to both extracellular matrix (connective tissue) and intracellular elastic proteins (titin).