What is the clinical evidence from this study?

Study design: Other. Population: Myocardial Infarction. Intervention: Pinacidil vs. Control conditions / Fibroblasts from normal hearts. Primary outcome: Pinacidil-induced reduction of action potential duration at 70% repolarization (APD70) (p=<0.0001).

February 23, 2013AJP Heart and Circulatory Physiology25 citationsOpen Access

Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts

Q: What are the key findings of this study?

Fibroblasts from the scar and border zones of infarcted hearts express functional KATP channels, and their activation by pinacidil significantly reduced action potential duration in co-cultures.

NBNajate Benamer CVCarolina Vásquez VMVanessa M. Mahoney

Key Result

Fibroblasts from the scar and border zones of infarcted hearts express functional KATP channels, and their activation by pinacidil significantly reduced action potential duration in co-cultures.

PICO

Population

Male Wistar-Hannover rats subjected to left anterior descending coronary artery ligation to study fibroblast KATP currents in infarcted hearts.

Intervention / Comparator

Pinacidil vs Control conditions / Fibroblasts from normal hearts (100 μmol/l)

Primary Outcome

Pinacidil-induced reduction of action potential duration at 70% repolarization (APD70), p=<0.0001

Main Result

Absolute Event Rate: 32.3% vs 14%

p-value: p=<0.0001

Limitations

Isolated fibroblasts were maintained in culture for 4 days, during which their electrophysiological phenotype could have changed.
Neonatal myocytes were used instead of adult myocytes to evaluate the effects of fibroblast KATP currents on myocyte electrical properties.
In vitro changes do not provide direct evidence of interactions between adult cardiomyocytes and fibroblasts in the intact heart.

Abstract

Cardiac metabolism remains altered for an extended period of time after myocardial infarction. Studies have shown fibroblasts from normal hearts express KATP channels in culture. It is unknown whether fibroblasts from infarcted hearts express KATP channels and whether these channels contribute to scar and border zone electrophysiology. KATP channel subunit expression levels were determined in fibroblasts isolated from normal hearts (Fb), and scar (sMI-Fb) and remote (rMI-Fb) regions of left anterior descending coronary artery (LAD) ligated rat hearts. Whole cell KATP current density was determined with patch clamp. Action potential duration (APD) was measured with optical mapping in myocyte-only cultures and heterocellular cultures with fibroblasts with and without 100 μmol/l pinacidil. Whole heart optical mapping was used to assess KATP channel activity following LAD ligation. Pinacidil activated a potassium current (35.4 ± 7.5 pA/pF at 50 mV) in sMI-Fb that was inhibited with 10 μmol/l glibenclamide. Kir6.2 and SUR2 transcript levels were elevated in sMI-Fb. Treatment with Kir6.2 short interfering RNA decreased KATP currents (87%) in sMI-Fb. Treatment with pinacidil decreased APD (26%) in co-cultures with sMI-Fb. APD values were prolonged in LAD ligated hearts after perfusion with glibenclamide. KATP channels are present in fibroblasts from the scar and border zones of infarcted hearts. Activation of fibroblast KATP channels could modulate the electrophysiological substrate beyond the acute ischemic event. Targeting fibroblast KATP channels could represent a novel therapeutic approach to modify border zone electrophysiology after cardiac injury.

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