Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure

Milton Packer

Research output: Contribution to journalReview article

44 Citations (Scopus)

Abstract

The mechanisms underlying the progression of diabetes mellitus and heart failure are closely intertwined, such that worsening of one condition is frequently accompanied by worsening of the other; the degree of clinical acceleration is marked when the 2 coexist. Activation of the sodium-hydrogen exchanger in the heart and vasculature (NHE1 isoform) and the kidneys (NHE3 isoform) may serve as a common mechanism that links both disorders and may underlie their interplay. Insulin insensitivity and adipokine abnormalities (the hallmarks of type 2 diabetes mellitus) are characteristic features of heart failure; conversely, neurohormonal systems activated in heart failure (norepinephrine, angiotensin II, aldosterone, and neprilysin) impair insulin sensitivity and contribute to microvascular disease in diabetes mellitus. Each of these neurohormonal derangements may act through increased activity of both NHE1 and NHE3. Drugs used to treat diabetes mellitus may favorably affect the pathophysiological mechanisms of heart failure by inhibiting either or both NHE isoforms, and drugs used to treat heart failure may have beneficial effects on glucose tolerance and the complications of diabetes mellitus by interfering with the actions of NHE1 and NHE3. The efficacy of NHE inhibitors on the risk of cardiovascular events may be enhanced when heart failure and glucose intolerance coexist and may be attenuated when drugs with NHE inhibitory actions are given concomitantly. Therefore, the sodium-hydrogen exchanger may play a central role in the interplay of diabetes mellitus and heart failure, contribute to the physiological and clinical progression of both diseases, and explain certain drug-drug and drug-disease interactions that have been reported in large-scale randomized clinical trials.

Original languageEnglish (US)
Pages (from-to)1548-1559
Number of pages12
JournalCirculation
Volume136
Issue number16
DOIs
StatePublished - Oct 17 2017

Fingerprint

Sodium-Hydrogen Antiporter
Diabetes Mellitus
Heart Failure
Protein Isoforms
Pharmaceutical Preparations
Neprilysin
Adipokines
Glucose Intolerance
Diabetes Complications
Aldosterone
Drug Interactions
Angiotensin II
Type 2 Diabetes Mellitus
Disease Progression
Insulin Resistance
Norepinephrine
Randomized Controlled Trials
Insulin
Kidney
Glucose

Keywords

  • diabetes
  • heart failure
  • sodium-hydrogen exchanger

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure. / Packer, Milton.

In: Circulation, Vol. 136, No. 16, 17.10.2017, p. 1548-1559.

Research output: Contribution to journalReview article

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