title: Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure.
abstract: Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.
authors.affiliation: Department of Medicine (Cardiology) and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Gary L
authors.initials: GL
authors.lastname: Aistrup
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Gupta
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: O'Toole
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Nahhas
authors.forename: Daniel
authors.initials: D
authors.lastname: Schuster
authors.forename: Nimi
authors.initials: N
authors.lastname: Chirayil
authors.forename: Nikhil
authors.initials: N
authors.lastname: Bassi
authors.forename: Satvik
authors.initials: S
authors.lastname: Ramakrishna
authors.forename: Lauren
authors.initials: L
authors.lastname: Beussink
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.forename: Bonnie
authors.initials: B
authors.lastname: Kane
authors.forename: David
authors.initials: D
authors.lastname: Wang
authors.forename: Blake
authors.initials: B
authors.lastname: Randolph
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.forename: Megan
authors.initials: M
authors.lastname: Wu
authors.forename: Lisa
authors.initials: L
authors.lastname: Akintilo
authors.forename: Thitipong
authors.initials: T
authors.lastname: Mongkolrattanothai
authors.forename: Mahendra
authors.initials: M
authors.lastname: Reddy
authors.forename: Manvinder
authors.initials: M
authors.lastname: Kumar
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
authors.forename: Jason
authors.initials: J
authors.lastname: Ng
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D005355:Fibrosis / Q000503:physiopathology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate; D006973:Hypertension / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012508:Sarcolemma / Q000648:ultrastructure*; D014463:Ultrasonography
chemical_list: D002118:Calcium
keywords: T-tubules; calcium transients; heart failure; hypertension; ventricular mechanics