Ventricular Performance
Ventricular Performance
Dr. Martin LeWinter has had a longstanding interest in ventricular and myocardial function. Current areas of interest include mechanoenergetics of the myocardium in acquired heart failure and genetic models of cardiomyopathy. The goal is to use whole heart mechanoenergetic, skinned strip and in vitro motility and force analyses to provide a comprehensive understanding of abnormalities of the myofilament in disease. Illustration: a ventriculogram from the first patient treated with t-PA.
A second area is diastolic left ventricular function, in particular the role of the giant cytoskeleton protein titin as a determinant of left ventricular stiffness and restoring forces. A third area is the effect of diabetes on myocardial function, both calcium handing and the myofilament. These studies utilize samples of human myocardium obtained in the operating room.
Recent Grant Support
Separate NIH RO1 grants currently support each of these areas, as well as a collaborative grant with Dr. David Maughan.
Representative Publications
Wu Y, Bell SP, Trombitas K, Witt CC, Labeit S, LeWinter MM, Granzier H., Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation. 2002 Sep 10;106(11):1384-9.
VanBuren P, Alix SL, Gorga JA, Begin KJ, LeWinter MM, Alpert NR. Cardiac troponin T isoforms demonstrate similar effects on mechanical performance in a regulated ontractile system. Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1665-71.
Mulieri LA, Barnes W, Leavitt BJ, Ittleman FP, LeWinter MM, Alpert NR, Maughan DW. Alterations of myocardial dynamic stiffness implicating abnormal crossbridge function in human mitral regurgitation heart failure. Circ Res. 2002 Jan 11;90(1):66-72.
Noguchi T, Chen Z, Bell SP, Nyland L, LeWinter MM. Activation of PKC decreases myocardial O2 consumption and increases contractile efficiency in rats. Am J Physiol Heart Circ Physiol. 2001 Nov;281(5):H2191-7.
McCurdy DT, Palmer BM, Maughan DW, LeWinter MM. Myocardial cross-bridge kinetics in transition to failure in Dahl salt-sensitive rats. Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1390-6.
LeWinter MM. Titin: the "missing link" of diastole. J Mol Cell Cardiol. 2000 Dec;32(12):2111-4.
Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H, LeWinter MM. Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res. 2000 Aug 4;87(3):235-40.
Kameyama T, Chen Z, Bell SP, VanBuren P, Maughan D, LeWinter MM. Mechanoenergetic alterations during the transition from cardiac hypertrophy to failure in Dahl salt-sensitive rats. Circulation. 1998 Dec 22-29;98(25):2919-29.
Blanchard E, Seidman C, Seidman JG, LeWinter M, Maughan D. Altered crossbridge kinetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. Circ Res. 1999 Mar 5;84(4):475-83.
Bell SP, Fabian J, LeWinter MM. Effects of dobutamine on left ventricular restoring forces. Am J Physiol. 1998 Jul;275(1 Pt 2):H190-4.
Recent Grant Support
Grant Title: Familial Hypertrophic Cardiomyopathy: Sarcomeric Disease
Sponsor: National Institutes of Health
Co-Investigator: Peter VanBuren
Grant Title: Contractile Dysfunction in Ischemic Heart Disease
Sponsor: National Institutes of Health
Principal Investigator: Peter VanBuren
Grant Title: Mechanoenergetics of Hypertrophy and Failure
Sponsor: National Institutes of Health
Co-Investigator: Peter VanBuren
Representative Publications
VanBuren P, Work SS, Warshaw DM. Enhanced force generation by smooth muscle myosin in vitro. Proc Natl Acad Sci USA.1994; 91: 202-205.
VanBuren P, Waller GS, Harris DE, Trybus KM, Warshaw DM, Lowey S. The essential light chain is required for full force production by skeletal muscle myosin. Proc Natl Acad Sci USA 1994;91:12403-12407.
VanBuren P, Harris DE, Alpert NR, Warshaw DM. Cardiac V1 and V3 myosins differ in their hydrolytic and mechanical activities in vitro. Circ Res 1995;77:439-444.
VanBuren P, Begin K, Warshaw DM. Fluorescent phalloidin enables visualization of actin without effects on myosin's actin filament sliding velocity or hydrolytic properties in vitro. J Mol Cell Cardiol 1998;30:2777-83.
VanBuren P, Palmiter KA, Warshaw DM. Tropomyosin directly modulates actomyosin mechanical performance at the level of a single actin filament. Proc Natl Acad Sci USA. 1999;96:12488-12493.
VanBuren P, Alix SL, Gorga JA, Begin KJ, LeWinter MM, Alpert NR. Cardiac Troponin T Isoforms Demonstrate Similar Effects on Mechanical Performance in a Regulated Contractile System Am J Physiol Heart Circ Physiol 2002;282:H1665-1671.
Noguchi T, Kihara Y, Begin KJ, Gorga JA, Palmiter KA, LeWinter MM, VanBuren P. Altered Myocardial Thin Filament Function in the Failing Dahl Salt Sensitive Rat Heart: Amelioration by Endothelin Blockade. Circulation In press.
Noguchi T, Camp P, Alix SL, Gorga JA, Begin KJ, Leavitt BJ, Ittleman FP,Alpert NR, LeWinter MM, VanBuren P. Myosin from Failing and Non-Failing Human Ventricles Exhibit Similar Contractile Properties. J Mol Cell Cardiol In press.
