Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness

I. Falcão-Pires, N. Hamdani, A. Borbely, C. Gavina, C.G. Schalkwijk, J. van der Velden, L. van Heerebeek, G.J.M. Stienen, H.W.M. Niessen, A.F. Leite-Moreira, W.J. Paulus

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Abstract

BACKGROUND: Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.

METHODS AND RESULTS: Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F(passive)). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm(2) versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher F(passive) (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F(passive) and normalization of F(passive) after in vitro treatment with protein kinase A.

CONCLUSIONS: Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F(passive), which was related to hypophosphorylation of the N2B titin isoform.

Original languageEnglish
Pages (from-to)1151-1159
Number of pages9
JournalCirculation
Volume124
Issue number10
DOIs
Publication statusPublished - 6 Sep 2011

Cite this

Falcão-Pires, I. ; Hamdani, N. ; Borbely, A. ; Gavina, C. ; Schalkwijk, C.G. ; van der Velden, J. ; van Heerebeek, L. ; Stienen, G.J.M. ; Niessen, H.W.M. ; Leite-Moreira, A.F. ; Paulus, W.J. / Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. In: Circulation. 2011 ; Vol. 124, No. 10. pp. 1151-1159.
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title = "Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness",
abstract = "BACKGROUND: Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.METHODS AND RESULTS: Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F(passive)). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1{\%} versus AS-DM, 18.2±2.6{\%}; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm(2) versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher F(passive) (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F(passive) and normalization of F(passive) after in vitro treatment with protein kinase A.CONCLUSIONS: Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F(passive), which was related to hypophosphorylation of the N2B titin isoform.",
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author = "I. Falc{\~a}o-Pires and N. Hamdani and A. Borbely and C. Gavina and C.G. Schalkwijk and {van der Velden}, J. and {van Heerebeek}, L. and G.J.M. Stienen and H.W.M. Niessen and A.F. Leite-Moreira and W.J. Paulus",
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Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. / Falcão-Pires, I.; Hamdani, N.; Borbely, A.; Gavina, C.; Schalkwijk, C.G.; van der Velden, J.; van Heerebeek, L.; Stienen, G.J.M.; Niessen, H.W.M.; Leite-Moreira, A.F.; Paulus, W.J.

In: Circulation, Vol. 124, No. 10, 06.09.2011, p. 1151-1159.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness

AU - Falcão-Pires, I.

AU - Hamdani, N.

AU - Borbely, A.

AU - Gavina, C.

AU - Schalkwijk, C.G.

AU - van der Velden, J.

AU - van Heerebeek, L.

AU - Stienen, G.J.M.

AU - Niessen, H.W.M.

AU - Leite-Moreira, A.F.

AU - Paulus, W.J.

PY - 2011/9/6

Y1 - 2011/9/6

N2 - BACKGROUND: Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.METHODS AND RESULTS: Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F(passive)). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm(2) versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher F(passive) (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F(passive) and normalization of F(passive) after in vitro treatment with protein kinase A.CONCLUSIONS: Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F(passive), which was related to hypophosphorylation of the N2B titin isoform.

AB - BACKGROUND: Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified.METHODS AND RESULTS: Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F(passive)). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm(2) versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher F(passive) (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F(passive) and normalization of F(passive) after in vitro treatment with protein kinase A.CONCLUSIONS: Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F(passive), which was related to hypophosphorylation of the N2B titin isoform.

KW - Aged

KW - Aortic Valve Stenosis

KW - Biopsy

KW - Collagen

KW - Connectin

KW - Coronary Circulation

KW - Diabetes Mellitus, Type 2

KW - Echocardiography, Doppler

KW - Female

KW - Fibrosis

KW - Glycation End Products, Advanced

KW - Heart Rate

KW - Humans

KW - Male

KW - Middle Aged

KW - Muscle Proteins

KW - Protein Kinases

KW - Sarcomeres

KW - Ventricular Dysfunction, Left

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1161/CIRCULATIONAHA.111.025270

DO - 10.1161/CIRCULATIONAHA.111.025270

M3 - Article

VL - 124

SP - 1151

EP - 1159

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 10

ER -