Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling

Cameron Donaldson, Bradley M. Palmer, Michael Zile, David W. Maughan, John S. Ikonomidis, Hendrikus "Henk" Granzier, Markus Meyer, Peter VanBuren, Martin M. LeWinter

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background-Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. Methods and Results-Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 μm and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca2+] (pCa =6.5) in HTN patients. Analysis of protein phosphorylation revealed ̃25% reduction in phosphorylation of troponin I in HTN patients (P<0.05). Conclusions-Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca2+] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.

Original languageEnglish (US)
Pages (from-to)803-811
Number of pages9
JournalCirculation: Heart Failure
Volume5
Issue number6
DOIs
StatePublished - Nov 2012

Fingerprint

Ventricular Remodeling
Myosins
Hypertension
Phosphorylation
Troponin I
Cyclic GMP-Dependent Protein Kinases
Sarcomeres
Myofibrils
Left Ventricular Hypertrophy
Cyclic AMP-Dependent Protein Kinases
Detergents
Stroke Volume
Heart Failure
Biopsy

Keywords

  • Diastole
  • Heart failure
  • Hypertrophy
  • Myocardium
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling. / Donaldson, Cameron; Palmer, Bradley M.; Zile, Michael; Maughan, David W.; Ikonomidis, John S.; Granzier, Hendrikus "Henk"; Meyer, Markus; VanBuren, Peter; LeWinter, Martin M.

In: Circulation: Heart Failure, Vol. 5, No. 6, 11.2012, p. 803-811.

Research output: Contribution to journalArticle

Donaldson, C, Palmer, BM, Zile, M, Maughan, DW, Ikonomidis, JS, Granzier, HH, Meyer, M, VanBuren, P & LeWinter, MM 2012, 'Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling', Circulation: Heart Failure, vol. 5, no. 6, pp. 803-811. https://doi.org/10.1161/CIRCHEARTFAILURE.112.968925
Donaldson, Cameron ; Palmer, Bradley M. ; Zile, Michael ; Maughan, David W. ; Ikonomidis, John S. ; Granzier, Hendrikus "Henk" ; Meyer, Markus ; VanBuren, Peter ; LeWinter, Martin M. / Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling. In: Circulation: Heart Failure. 2012 ; Vol. 5, No. 6. pp. 803-811.
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abstract = "Background-Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. Methods and Results-Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 μm and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca2+] (pCa =6.5) in HTN patients. Analysis of protein phosphorylation revealed ̃25{\%} reduction in phosphorylation of troponin I in HTN patients (P<0.05). Conclusions-Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca2+] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.",
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T1 - Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling

AU - Donaldson, Cameron

AU - Palmer, Bradley M.

AU - Zile, Michael

AU - Maughan, David W.

AU - Ikonomidis, John S.

AU - Granzier, Hendrikus "Henk"

AU - Meyer, Markus

AU - VanBuren, Peter

AU - LeWinter, Martin M.

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N2 - Background-Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. Methods and Results-Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 μm and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca2+] (pCa =6.5) in HTN patients. Analysis of protein phosphorylation revealed ̃25% reduction in phosphorylation of troponin I in HTN patients (P<0.05). Conclusions-Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca2+] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.

AB - Background-Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. Methods and Results-Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 μm and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca2+] (pCa =6.5) in HTN patients. Analysis of protein phosphorylation revealed ̃25% reduction in phosphorylation of troponin I in HTN patients (P<0.05). Conclusions-Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca2+] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.

KW - Diastole

KW - Heart failure

KW - Hypertrophy

KW - Myocardium

KW - Remodeling

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