In the Edler lecture, delivered during the Opening Ceremony later today (16:00 – 17:30, Room Trianti), Genevieve Derumeaux will explore the role for imaging in cardioprotection studies.
“I’ll explain how in order to demonstrate any beneficial effect you need to use the right tools for the job, and also have an idea of the underlying factors influencing infarct size,” says Professor Derumeaux, from the Hôpital Louis Pradel, Lyon, France.
While in the last decade there have been significant improvements in outcome following MI, left ventricular remodeling still occurs in more than 30% of patients.
The serious consequences of such remodeling are that around 25% of patients who suffer an MI go on to develop heart failure, and half of these patients are likely to be dead within five years.
Although prompt reperfusion of ischaemic myocardium is critical for salvaging the heart, restoration of blood flow can have the paradoxically deleterious consequences of myocardial ischaemia reperfusion injury. The result is further endothelial and microvascular dysfunction, impaired blood flow, metabolic dysfunction, cellular necrosis and apoptosis.
| || ||Myocardial reperfusion injury accounts for up to 50% of the final size of the myocardial infarct.|
Credit: Figure is inspired from Garcia-Doarado D, Piper HM; Cardiovasc Res 2006; 69: 1-3
“With studies clearly demonstrating that infarct size represents an important determinant of prognosis after MI, avoidance of reperfusion injury has become a major therapeutic target,” explains Derumeaux.
One of the cardioprotective strategies currently being explored is post-conditioning, defined as brief periods of reperfusion alternating with re-occlusion applied during the early minutes of reperfusion. Ultimately, it is thought that the mechanism whereby post-conditioning exerts its positive influence is through keeping the mitochondrial permeability transition pore (mPTP) closed. The mPTP is believed to remain in a largely closed state during ischaemia, but to open during reperfusion, triggered by increases in free radical generation and intracellular calcium.
“Like Jekyll to Hyde, mitochondria can change from acting as the cell’s powerhouses to become merciless killers,” says Derumeaux.
The central role for mPTP in reperfusion injury has been demonstrated by Andrew Halestrap in a study showing that hearts of genetically engineered mice lacking the mPTP mechanism are resistant to pathological damage (Nature, 2005, 434:578-579). The central significance of mPTP has led to the development of pharmacological interventions, such as adenosine, cyclosporine and erythropoietin to prevent opening of mPTP.
The first demonstration of the cardio protective effects of post-conditioning was made in 2003 by Jakob Vinten-Johansen and colleagues from Emory University, Atlanta, Georgia. Working in an open chest dog model the team reported that brief episodes of ischaemia (three cycles of 30 seconds reperfusion followed by 30 seconds occlusion) performed at the onset of reperfusion following a prolonged ischaemic insult, reduced infarct sizes by 44% compared with controls (American Journal of Physiology, 2003, 285:579-588). The reduction in infarct size, they reported, was comparable to that observed in dogs treated with ischaemic pre-conditioning, considered the gold standard of cardioprotection.
“But for obvious reasons pre-conditioning is impossible to achieve in patient populations,” says Derumeaux.
Subsequent studies confirmed infarct size reductions using post-conditioning could be achieved in rat and murine models of MI.
For meaningful studies of post-conditioning, the scar resulting from reperfusion injury requires assessment with good and reproducible imaging modalities.
For animal models examined at post-mortem, triphenyltetrazolium chloride (TTC) staining has been the most commonly used method for measuring infarct size. “But clearly such approaches can’t be used in patient studies or longitudinal follow-up,” says Derumeaux.
More recently MRI has emerged as the leading technique for measuring MI size. Stein Ørn, from Stravanger University Hospital, demonstrated the role of contrast enhanced cardiac magnetic resonance (CMR) imaging in assessing left ventricular remodeling following MI (A J Cardio 2007, 99:1109-1114). Using MRI the team showed that the size and weight of the left ventricular scar was inversely related to ejection fractions.
But one drawback for MRI, says Derumeaux, is that the area of hyper-enhancement after gadolinium can vary by nearly 30% between day five and month five, reflecting the different phases of infarct healing and scar formation
More recently global longitudinal peak systolic strain (GLPSS) has been used to reflect LV systolic function. This approach, pioneered by Derumeaux, has involved sonomicrometry, where distances between piezoelectric crystals embedded in the myocardium provide measures of segmental shortening, correlating with systolic strain.
In murine models of MI, Derumeaux and colleagues have been able to show how systolic strain rates correlate with MI scars.
“At the time it was quite a technical challenge to adapt the machines for mice,” recalls Derumeaux.
Furthermore in the mouse model, Derumeaux and colleagues have demonstrated that mice who receive ischaemic post-conditioning (in comparison to control group mice) showed decreased end diastolic volumes, and increased functional shortenings (a way of expression LV ejections fractions) and decreased strain rate (Circ Cardiovasc Imaging, 2011, 5: 550-557).
These experimental observations extended the pioneering clinical work from Michel Ovize’s group showing that ischaemic post-conditioning reduced MI size and improved long term left ventricular remodeling (Circulation, 2008, 117:1037-1044).
However, a major setback has been the findings of a recent study in 79 patients by Xavier Frexia showing that in comparison to controls, patients who underwent post-conditioning for a first STEMI derived no beneficial effects with regard to infarct size, myocardial salvage and LVEF assessed by cardiac MRI (EHJ 2012, 33: 103-112).
From this study it is clear that the concept of cardio protection may need to be critically re-evaluated. One possible explanation for the negative effects observed in this study, suggests Derumeaux, is that a number of co-morbidities which are frequently present in patients suffering from AMI (including hypercholesterolemia, diabetes, obesity and hypertension) may have led to loss of protection by ischaemic post-conditioning, or that concomitant medications (such as beta blockade, statins and anti-diabetic drugs) might have interfered with cardio protection.
Equally protection may have inadvertently occurred in control subjects, thereby minimizing differences between treatment and control groups. For example, says Derumeaux, it is known that medications such as adenosine, nitroglycerin, and ACE inhibitors all recruit cardioprotection.
The CARIM cohort study, currently being undertaken by Derumeaux and colleagues, is recording echocardiography and CMR images of the hearts of 2 000 patients who have experienced MI (with no particular intervention). The patients, for whom baseline characteristics such as other illnesses and medications are recorded, will be followed up for 10 years.
“From this we hope to acquire an idea of the way different baseline factors influence scar size, which should ultimately help us devise fairer studies that show the true effects of post-conditioning,” says Derumeaux.