The effect of neprilysin inhibition on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction

Docherty, Kieran Francis (2022) The effect of neprilysin inhibition on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction. PhD thesis, University of Glasgow.

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Abstract

Background

The development of heart failure and reduced ejection fraction (HFrEF) in survivors of myocardial infarction occurs as a result of progressive left ventricular dilatation and a reduction in systolic function, a process commonly referred to as adverse left ventricular remodelling. One of the earliest advances in the management of myocardial infarction was the finding that the angiotensin converting enzyme (ACE) inhibitor captopril which inhibits the maladaptive activation of the renin-angiotensin system (RAS) promoting the process of adverse remodelling, reduced the risk of heart failure and mortality by attenuating progressive ventricular enlargement. Subsequently, the angiotensin receptor blocker valsartan (in a dose of 160 mg twice daily) was shown to be as effective as captopril in preventing adverse clinical outcomes after myocardial infarction. Beta-blockers are believed to have similar benefits as a result of attenuating the harmful actions of excessive activation of the sympathetic nervous system (SNS).

Not all neurohumoral activation following myocardial infarction (and in heart failure) is harmful. The natriuretic peptides are released in response to increased left atrial and ventricular wall stress and counteract the harmful effects of RAS and SNS activation through natriuretic, vasodilatory, anti-fibrotic and sympatholytic effects. Endogenous levels of the natriuretic peptides (along with a range of other potentially cardioprotective peptides) can be increased by preventing their breakdown by the enzyme neprilysin.

In patients with symptomatic HFrEF, the combined angiotensin receptorneprilysin inhibitor sacubitril/valsartan (dosed 97/103mg twice daily), compared with the gold-standard ACE inhibitor enalapril, has been demonstrated to reduce the risk of worsening heart failure and cardiovascular death. It may be that part of the clinical benefits of sacubitril/valsartan (i.e., the addition of neprilysin inhibitor), relate to a favourable reverse remodelling effect. Therefore, the addition of a neprilysin inhibition to a RAS inhibitor in high-risk patients following myocardial infarction may result in greater attenuation of adverse left ventricular remodelling than RAS inhibition alone, and potentially reduce the attendant risk of the development of HFrEF.

Aim

To examine the effect of neprilysin inhibition on left ventricular remodelling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction using the gold-standard method, cardiac magnetic resonance imaging (MRI).

Methods

I performed a prospective, randomised, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients at least 3 months following an acute myocardial infarction with a left ventricular ejection fraction (LVEF) less than, or equal to 40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association (NYHA) functional classification II or greater were excluded. The primary endpoint was change from baseline to 52-weeks in left ventricular endsystolic volume index (LVESVI) measured using cardiac MRI. Secondary endpoints included other MRI measurements of left ventricular remodelling, change in NTproBNP (a marker of left ventricular wall stress) and hs-TnI (a marker of myocardial injury), and a patient global assessment of change questionnaire. In exploratory analyses, I also examined the effect of neprilysin inhibition on a range of circulating biomarkers relating to substrates for neprilysin and myocardial fibrosis.

Results

In the 93 randomised patients, mean age was 60.7±10.4 years, median time from myocardial infarction 3.6 years (interquartile range [IQR] 1.2-72), mean LVEF 36.8%±7.1, median NT proBNP 230pg/ml (IQR 124-404) and a beta-blocker was taken by 94% of patients.

Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; between-group difference -1.9ml/m2 (95%CI -4.8, 1.0); p=0.19. A reduction in LVESVI was seen with sacubitril/valsartan in those with NT-proBNP levels greater than or equal to the median than those below (interaction p=0.036). There were no significant between-group differences in NT-proBNP, hs-TnI, left ventricular end-diastolic volume index, left atrial volume index, LVEF, left ventricular mass index, or patient global assessment of change.

Sacubitril/valsartan, compared with valsartan, significantly increased levels of atrial natriuretic peptide (ANP) (p=0.013), a substrate for neprilysin, and its intracellular secondary messenger urinary cyclic guanosine monophosphate (cGMP) (P=0.001), indicating increased natriuretic peptide bioactivity. Midregional pro-atrial natriuretic peptide (MR-proANP), which is not a substrate for neprilysin, was significantly reduced with sacubitril/valsartan (P=0.009) and may reflect a reduction in left ventricular filling pressures. No significant increase in B-type natriuretic peptide (BNP) was observed which was consistent with the greater affinity neprilysin has for ANP relative to BNP. Midregional proadrenomedullin (MR-proADM) (P<0.001), glucagon-like peptide-1 (GLP-1) (P<0.001) and galectin-3 (P=0.045) were increased with sacubitril/valsartan, as compared with valsartan. No significant favourable changes were seen with the addition of a neprilysin inhibitor in biomarkers of profibrotic processes.

Conclusion

In patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan compared with valsartan alone (i.e., the addition of a neprilysin inhibitor) did not have a significant reverse remodelling effect and did not reduce biomarkers of left ventricular wall stress (NT-proBNP) or myocardial injury (hs-TnI) despite augmenting natriuretic peptide activity.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Supervisor's Name: McMurray, Professor John and Petrie, Professor Mark and Jhund, Professor Pardeep
Date of Award: 2022
Depositing User: Theses Team
Unique ID: glathesis:2022-82817
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 20 Apr 2022 09:40
Last Modified: 20 Apr 2022 09:40
Thesis DOI: 10.5525/gla.thesis.82817
URI: http://theses.gla.ac.uk/id/eprint/82817
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