Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction
Abstract Background Inhibiting both type 1 and 2 sodium–glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide...
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doaj-d68f6091161a4bff8438d79f3ae7c14a2020-11-24T20:57:17ZengBMCCardiovascular Diabetology1475-28402018-07-0117111310.1186/s12933-018-0741-9Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarctionKim A. Connelly0Yanling Zhang1Jean-François Desjardins2Kerri Thai3Richard E. Gilbert4Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s HospitalKeenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s HospitalKeenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s HospitalKeenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s HospitalKeenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s HospitalAbstract Background Inhibiting both type 1 and 2 sodium–glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide 1 secretion. However, beyond the kidney and gut, SGLT1 is expressed in a range of other organs particularly the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, the present study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the normal and diseased heart. Methods Fischer F344 rats underwent ligation of the left anterior descending coronary artery or sham ligation before being randomized to receive the dual SGLT1/2 inhibitor, T-1095, the selective SGLT2 inhibitor, dapagliflozin or vehicle. In addition to measuring laboratory parameters, animals also underwent echocardiography and cardiac catheterization to assess systolic and diastolic function in detail. Results When compared with rats that had received either vehicle or dapagliflozin, T-1095 exacerbated cardiac dysfunction in the post myocardial infarction setting. In addition to higher lung weights, T-1095 treated rats had evidence of worsened systolic function with lower ejection fractions and reduction in the rate of left ventricle pressure rise in early systole (dP/dtmax). Diastolic function was also worse in animals that had received T-1095 with prolongation of the time constant for isovolumic-pressure decline (Tau) and an increase in the end-diastolic pressure volume relationship, indices of the active, energy-dependent and passive phases of cardiac relaxation. Conclusions The exacerbation of post myocardial infarction cardiac dysfunction with T-1095 in the experimental setting suggests the need for caution with the use of dual SGLT1/2 inhibitors in humans.http://link.springer.com/article/10.1186/s12933-018-0741-9Sodium–glucose linked cotransporterMyocardial infarctionSystoleDiastole |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kim A. Connelly Yanling Zhang Jean-François Desjardins Kerri Thai Richard E. Gilbert |
spellingShingle |
Kim A. Connelly Yanling Zhang Jean-François Desjardins Kerri Thai Richard E. Gilbert Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction Cardiovascular Diabetology Sodium–glucose linked cotransporter Myocardial infarction Systole Diastole |
author_facet |
Kim A. Connelly Yanling Zhang Jean-François Desjardins Kerri Thai Richard E. Gilbert |
author_sort |
Kim A. Connelly |
title |
Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction |
title_short |
Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction |
title_full |
Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction |
title_fullStr |
Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction |
title_full_unstemmed |
Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction |
title_sort |
dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction |
publisher |
BMC |
series |
Cardiovascular Diabetology |
issn |
1475-2840 |
publishDate |
2018-07-01 |
description |
Abstract Background Inhibiting both type 1 and 2 sodium–glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide 1 secretion. However, beyond the kidney and gut, SGLT1 is expressed in a range of other organs particularly the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, the present study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the normal and diseased heart. Methods Fischer F344 rats underwent ligation of the left anterior descending coronary artery or sham ligation before being randomized to receive the dual SGLT1/2 inhibitor, T-1095, the selective SGLT2 inhibitor, dapagliflozin or vehicle. In addition to measuring laboratory parameters, animals also underwent echocardiography and cardiac catheterization to assess systolic and diastolic function in detail. Results When compared with rats that had received either vehicle or dapagliflozin, T-1095 exacerbated cardiac dysfunction in the post myocardial infarction setting. In addition to higher lung weights, T-1095 treated rats had evidence of worsened systolic function with lower ejection fractions and reduction in the rate of left ventricle pressure rise in early systole (dP/dtmax). Diastolic function was also worse in animals that had received T-1095 with prolongation of the time constant for isovolumic-pressure decline (Tau) and an increase in the end-diastolic pressure volume relationship, indices of the active, energy-dependent and passive phases of cardiac relaxation. Conclusions The exacerbation of post myocardial infarction cardiac dysfunction with T-1095 in the experimental setting suggests the need for caution with the use of dual SGLT1/2 inhibitors in humans. |
topic |
Sodium–glucose linked cotransporter Myocardial infarction Systole Diastole |
url |
http://link.springer.com/article/10.1186/s12933-018-0741-9 |
work_keys_str_mv |
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