ICS 2012 Report – A novel biomarker and potential treatment for diastolic dysfunction and heart failure

by Edel O’Connell reporting on the presentation by Dr. Stephen Horgan, winner of the 2012 Irish Cardiac Society Young Investigator’s Award.

Dr. Stephen Horgan, SpR in Cardiology is currently a Research Fellow at the Conway Institute, UCD, Dublin 4.

A Serum Amyloid P component is showing great potential for the treatment of diastolic dysfunction and heart failure.

There is growing awareness of the importance of the syndrome of heart failure with preserved ejection fraction (HFPEF) which contributes to approximately 20-50% of the heart failure population.

Excessive myocardial fibrosis results in stiffness and reduced compliance of the left ventricle which leads to left ventricular diastolic dysfunction (LVDD) and eventual HFPEF

While the principal cause of these abnormalities remains unclear, initial data from several studies  indicate that myocardial hypertrophy and excessive fibrosis in the cardiac interstitium lead to reduced compliance, or increased stiffness, of the left ventricle  and  hence, diastolic dysfunction (DD).

A primary cause of HFPEF is hypertensive heart disease.

Experimental and clinical data have demonstrated serological and morphometric evidence of increased myocardial fibrosis and myocyte size in Hypertensive Heart Disease (HHD).  These observations have been directly linked to abnormalities in diastolic function and myocardial stiffness.

“In an attempt to identify molecules associated with the progression of cardiac fibrosis and hypertrophy we have recently completed a proteomic analysis of coronary sinus serum from HHD patients,” explained Dr Stephen Horgan, research fellow at the Conway Institute in UCD.

“We investigated the role of an innate immune system recognition molecule, as a biomarker for LVDD and HFPEF, and assessed its potential as a treatment for cardiac fibrosis.

The Serum Amyloid P component shows great potential for the treatment of diastolic dysfunction and heart failure” he added.

A previous proteomic discovery study carried out at the Conway Institute demonstrated on 2D differential in-gel electrophoresis a number of proteins of interest, one of which was Serum Amyloid P component- the research showed a 1.7 fold decrease of SAP in hypertensive patients at high risk,

“This was an interesting finding,” said Dr Horgan.

“We know that Serum Amyloid P levels fall in patients with worsening renal functions and I came across a number of animal models which showed SAP also had anti-fibrotic properties, so I went on to perform some biomarker analysis. I wanted to see if SAP could detect various disease stages of ventricular dysfunction in heart failure,” he added.

The research looked at 40 asymptomatic hypertensive patients and compared them to 36 patients with heart failure and preserved ejection fraction which showed a very significant production in SAP levels in patients with HFPEF.

“Then we wanted to determine whether SAP could predict disease progression- so we took at group of 30 patients with evidence of progression of diastolic dysfunction – what we showed was SAP seemed to fall with progression of diastolic dysfunction,” he said.

The study also found SAP prevalent in the perivascular and interstitial regions where you’d expect to find collagen.

At this point Dr Horgan went on to perform an animal study on 30 rats, the echo data from which showed a significant reduction in left ventricular mass index in the animals treated with SAP compared to the SHR vehicle.

Dr Horgan also found a decrease in cardio myocyte area and perivascular collagen in the SAP treated animals.

The research shows SAP levels are lower in patients with HFPEF and become depleted in asymptomatic patients with echocardiographic evidence of progressive diastolic dysfunction.

“This means SAP may serve as a biomarker reflecting the left ventricular remodelling responsible for worsening diastolic function and may have a role as a marker to track deterioration,” explained Dr Horgan.

Treatment with SAP reduces left ventricular mass and myocyte hypertrophy and inhibits deposition of perivascular collagen in spontaneously hypertensive rats.

Reduced CD68 staining and a lower chemotactic protein concentration in SAP treated animals may reflect the ability of this peptide to prevent recruitment of profibrotic macrophages.

“Our results show SAP may have potential as a biomarker and as an antifibrotic therapy in diastolic dysfunction and HFPEF,” said Dr Horgan

This is the first study to observe the effects of chronic SAP therapy on a model of solid organ fibrosis. It is also the first study to investigate the effects of SAP on a pre-clinical model of HHD; and to examine the role of SAP as a biomarker across a spectrum of LV remodelling in patients with hypertension.

“The fact that administration of SAP induces anti-inflammatory responses in our study indicates that a functional deficiency of SAP exists in the hearts of hypertensive rats. The theory suggesting SAP consumption through recruitment to the site of injury may also explain why serum concentrations fall in patients with progressive LVDD and HFPEF. Our findings support a role for SAP as a treatment for HHD and perhaps as a biomarker in progression of LV remodelling,” commented Dr Horgan.