# Preclinical Diastolic Dysfunction in Type 2 Diabetes

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $691,534

## Abstract

PROJECT SUMMARY
The broad objective of the current application is to advance our understanding of the pathophysiological
mechanisms of preclinical left ventricular diastolic dysfunction (PDD) (Stage B heart failure) in humans with
type 2 diabetes mellitus (DM) and to develop novel therapeutic strategies to prevent the progression to
symptomatic heart failure (Stage C heart failure). Centers for Disease Control and Prevention reported that the
number of Americans with DM has grown to 30 million people, or 9.3% of the U.S. population, with 90% to 95%
of cases being type 2 DM. This application will focus only on type 2 DM. DM is strongly associated with the
development of heart failure (HF) which is a major cause of death. We have previously reported that between
23-54% of DM patients have preclinical diastolic dysfunction (PDD) or Stage B heart failure determined by
echo Doppler. More importantly, we determined that diastolic dysfunction was associated with increased risk of
the subsequent development of HF after adjustment for age, sex, body mass index, hypertension, coronary
disease and echo parameters (HR=1.67, 95% CI=1.27-2.23; p<0.001). The cumulative probability of
development of HF for DM patients with PDD was 37% at 5 years compared to 17% at 5 years for DM patients
without diastolic dysfunction (P<0.001). Cyclic guanosine 3',5'-monophosphate (cGMP) is the second
messenger of the natriuretic peptide system and the nitric oxide system. cGMP plays an important role in the
preservation of myocardial, vascular and renal function. Disruption of this signal transduction process may
contribute to the development of cardiorenal dysfunction. Preclinical studies and the applicant's preliminary
clinical data suggest that there is an impaired cGMP generation in response to the activation of the
endogenous natriuretic peptides (NPs) in DM. The mechanism of impaired cGMP generation in DM to
endogenous NPs is not well defined and may be due to the lack of biologically active NPs, increased NPs
degradation or down regulation of NP receptors. Neprilysin is a zinc-dependent metalloprotease that cleaves
peptides at the amino side of hydrophobic residues and inactivates several peptide hormones, including the
NPs. Angiotensin receptor neprilysin inhibitor (ARNI) is a new class of therapeutic agents that combines
neprilysin and angiotensin receptor inhibitor, potentiates the cGMP system and is approved for the
management of Stage C systolic HF. However, the cardiorenal renal action of ARNI in human DM with and
without PDD (Stage B HF) has not been well defined. We have previously demonstrated that neprilysin
inhibition in experimental HF improves cardio-renal function associated with increasing endogenous NPs.
Hence, ARNI may be used as a tool to provide insight into the mechanism of impaired cGMP generation in DM
by inhibition of endogenous NPs degradation. Building on our know-how in protein biology, we have
succeeded in creating a bivalent chimeric peptide t...

## Key facts

- **NIH application ID:** 10077337
- **Project number:** 5R01HL136440-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** HORNG H CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $691,534
- **Award type:** 5
- **Project period:** 2018-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077337

## Citation

> US National Institutes of Health, RePORTER application 10077337, Preclinical Diastolic Dysfunction in Type 2 Diabetes (5R01HL136440-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077337. Licensed CC0.

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