The Physiological Basis of Myocardial Hibernation

Introduction Myocardial hibernation is the active downregulation of myocardial function in response to recurrent episodes of non-lethal ischaemia. It develops as part of an adaptive programme which favours cell survival over contractility, with clear evidence of progressive cellular changes including metabolic switches, regression of the contractile apparatus and glycogen deposition. Early hibernation is reversible if the ischaemic stimulus is removed or reduced; whilst this was traditionally considered specific to revascularisation, emerging evidence suggests that any intervention which favourably alters the balance of myocardial oxygen supply against demand has comparable effects. Due to the potential for functional recovery, hibernation has become a key therapeutic target in ischaemic left ventricular dysfunction. Viability testing refers to the prospective identification of the substrate of myocardial hibernation using a variety of non-invasive imaging methods including cardiac magnetic resonance imaging (CMR), nuclear imaging and stress echocardiography, and has become an important part of the assessment of patients with ischaemic left ventricular dysfunction being considered for revascularisation. All modalities have similar diagnostic performance, though techniques which assess both the viability of the myocardial tissue and the presence of inducible ischaemia have higher specificity for reversibility and functional recovery. However, the need for multiple tests, including invasive coronary angiography and non-invasive viability testing, is a potential barrier to patients undergoing revascularisation and places a significant burden on healthcare resources. Invasive coronary physiology is an established alternative to non-invasive imaging. Assessment of arterial physiology with fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) is the most widely accepted vessel specific surrogate for inducible myocardial ischaemia, and there is emerging evidence that pathophysiological states of the myocardium can be differentiated through assessing myocardial physiology by coronary wave intensity analysis (cWIA), by measuring the magnitude of the myocardial-originating backward compression wave (BCW) and backward expansion wave (BEW). The studies in this thesis have been designed to further our understanding of both the invasive and non- invasive assessment of myocardial viability and ischaemia in patients with ischaemic left ventricular dysfunction (ILVD). Methods Patients with a recent diagnosis of ILVD, defined as the presence of extensive coronary artery disease (British Cardiovascular Intervention Society jeopardy score ≥ 6) and left ventricular dysfunction (ejection fraction ≤ 40%) were enrolled. Those with a recent acute myocardial infarction or severe valvular heart disease were excluded. Participants underwent invasive physiological assessment during cardiac catheterisation, with simultaneous measurement of aortic and distal coronary pressure, and coronary blood flow velocity, measured at rest, during adenosine induced hyperaemia and low dose dobutamine stress. Pressure-based indices of coronary stenosis severity, coronary stenosis resistance, microvascular resistance, and coronary wave intensity analysis were calculated from ensemble-averaged signals. Myocardial viability was determined by CMR using a dark-blood late gadolinium-enhanced phase-sensitive inversion-recovery (PSIR) turbo field echo pulse sequence at either 1.5 or 3-Tesla, with viability defined as scar burden ≤ 25% on quantitative assessment. Stress perfusion data were acquired using a saturation-recovery k-t sensitivity encoding accelerated gradient-echo method at 3-Tesla. Regional left ventricular function was assessed at baseline and 6-month or 12-month follow up after optimisation of medical therapy +/- revascularisation, using transthoracic echocardiography. The primary outcome was functional recovery, defined either regionally (as an improvement in wall motion score index ≥ 0.5 across the subtended territory) or segmentally (as an improvement in wall motion score ≥1). In the first study, hyperaemic stenosis resistance was used as a reference standard to investigate the diagnostic accuracy of FFR and iFR in 40 patients with ILVD who underwent cardiac catheterisation and invasive coronary physiology studies, compared to a control population of 13 patients with normal left ventricular function. The second study assessed the ability of backward-originating coronary wave energy (the BCW and BEW) to predict the presence of hibernation (defined as the observation of functional recovery in the subtended territory): the same forty patients also underwent CMR (the current clinical reference standard viability test) and baseline echocardiography; 25 had follow-up echocardiography. The ability of BCW, BEW and CMR to predict functional recovery were compared by the area under the curve (AUC) on receiver operator characteristic (ROC) analysis. The final study determined whether the combination of ischaemia and viability assessment, with a combined stress perfusion/late gadolinium enhancement (SP/LGE) CMR protocol, would improve the prediction of hibernation (defined as segmental functional recovery) compared to LGE alone, in twenty-nine patients with ILVD who underwent CMR and baseline and follow-up echocardiography. Results In the ILVD group, hyperaemic stenosis resistance was positive in 20 vessels, FFR positive in 26 vessels and iFR positive in 32 vessels: FFR had a sensitivity of 95% and specificity of 83% whilst iFR had a sensitivity of 95% and specificity of 68%. In controls, hyperaemic stenosis resistance was positive in 12 vessels, FFR positive in 13 vessels and iFR positive in 23 vessels; FFR had a sensitivity of 100% and specificity of 93%, and iFR had a sensitivity of 100% and specificity of 21%. However, when FFR and iFR were assessed as a continuum, there was increasing inaccuracy with increasing stenosis resistance, with a tendency to underestimate severity in high grade lesions in ILVD compared to normal controls. Microvascular resistance, wall thickening, and late enhancement were all found to influence FFR results in patients with ILVD. The resting BCW was significantly larger in recovering than non-recovering territories (-5564 ± 4054 vs. -1853 ± 1735 W.m-2.s-1, p <0.001). The BEW did not differ significantly (-6377 ± 4833 vs. -5053 ± 5929 W.m-2.s-1, p = 0.476) (figure 4.3). The BCW was the most effective predictor of functional recovery (AUC 0.814, 95% CI 0.671-0.957), with comparable diagnostic accuracy to LGE-CMR (AUC 0.771, 95% CI 0.617-0.925), difference between AUC 0.0425, 95% CI -0.140-0.225, p = 0.649). A BCW threshold of -2351 W.m2.s-1 had 92% sensitivity and 73% specificity for predicting functional recovery. Dobutamine stress did not improve the diagnostic accuracy of cWIA. The BEW, previously identified as the most effective predictor of functional recovery following an acute coronary syndrome, did not predict functional recovery but was closely related to the regional scar burden at baseline. Microvascular resistance did not differentiate viable from non-viable territories. Four-hundred and fifty-eight segments were included in the analysis. Scar was identified in 162 segments (1-25% in 48, 26-50% in 49, 51-75% in 25 and 76-100% in 40); 296 segments had no evidence of scar. Stress perfusion defects were identified in 166 segments in 26 patients. The primary outcome occurred in 167 of 458 segments (36.5%). On univariate analysis, the demonstration of the full substrate of hibernation (both inducible ischaemia and viability), assessed by a combined SP/LGE-CMR protocol, significantly increased specificity for predicting functional recovery (76.8% vs. 26.8%, p < 0.001) compared to LGE-CMR alone. The increase in specificity came at a significant cost to sensitivity (34.3% with SP/LGE-CMR vs. 78.4% with LGE- CMR alone, p <0.001). Diagnostic accuracy was greatest in segments which exhibited both inducible ischaemia and preserved viability (60.3%), followed by SP-CMR alone (57.9%): both were significantly more accurate than LGE- CMR (45.6%, p < 0.001). On multiple regression analysis, however, scar burden and baseline wall motion predicted segmental recovery, whilst the presence of an inducible perfusion defect and revascularisation status did not. Conclusion The combined assessment of inducible ischaemia and viability during invasive cardiac catheterisation is feasible. Backward expansion wave magnitude measured with cWIA in resting conditions provides an accurate prediction of functional recovery, comparable to LGE-CMR and as an adjunct to coronary angiography may permit timely, streamlined revascularisation for patients with ischaemic left ventricular dysfunction. The addition of pharmacological stress does not improve diagnostic performance. The results of both FFR and iFR are influenced by microvascular function and myocardial pathology in patients with ILVD, producing a less accurate estimation of stenosis resistance. Further validation of pressure-derived indices in ILVD is needed. The addition of ischaemia assessment to LGE-CMR improved overall diagnostic performance, although the diagnostic accuracy was limited with all techniques, with a low observed rate of functional recovery in this population. Adjusted analyses demonstrated that scar burden and baseline wall motion remained the best predictors of functional recovery, and the routine addition of stress perfusion sequences to LGE-CMR in ILVD is unlikely to be beneficial. This thesis advances our understanding of the invasive and non-invasive assessment of ischaemia and viability as integral parts of the physiology of hibernation. In time such detailed phenotyping may provide the key to truly personalised decision making for patients in this high-risk population

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