Dr Kapur began his talk by describing the global burden of heart failure (HF), which affects over 23 million individuals worldwide. Acute decompensated HF is currently the leading cause of hospital admissions and rehospitalisation for persons over the age of 65 years in the US.1,2 Approximately 1.8 million people are admitted for HF each year, with annual treatment and readmission costs of US$31 billion and US$7 billion, respectively.3–6 Patients who have a heart attack are at high risk for developing HF, generating a major healthcare burden.
Rapid coronary reperfusion or opening a blocked artery after acute MI can reduce the risk of HF. However, the size of the infarct impacts the magnitude of potential benefit from reperfusion. Larger infarcts drive mortality and HF. Data from patients receiving primary reperfusion after a heart attack indicate that 18% of total left ventricular mass remains infarcted after reperfusion.7 The same dataset also demonstrated that 1-year all-cause mortality and hospitalisation for HF increase by approximately 20% for every 5% increase in myocardial infarct size.
Time to treatment is also critical for ST-segment elevation MI (STEMI). Every minute of delay from symptoms of chest pain to the point that a coronary artery is opened with angioplasty counts towards mortality, as well as infarct size. Every 30-minute delay in total ischaemic time, or time from symptom onset to reperfusion, is associated with a 7.5% increase in 1-year mortality and a 30% increase in infarct size.8,9
Rapid reperfusion is one option to try to terminate ischaemic injury, yet may contribute to approximately 50% of myocardial damage in the setting of a heart attack.10 As a result, a significant volume of research has been conducted to identify the molecular mechanism(s) of reperfusion injury. Activation of the reperfusion injury salvage kinase and survivor activating factor enhancement signalling pathways prevents reperfusion injury in cardiac muscle cells by protecting mitochondria.11 Mitochondria provide energy to the cell, thus protection of mitochondria prevents energy loss and subsequent cell death. Ischaemia disrupts these pathways, reducing mitochondrial structural and functional integrity to produce reperfusion injury.12 Clinical trials to identify cardioprotective pharmacological agents targeting the ischaemia–reperfusion injury cascade remain inconclusive.13
Dr Kapur’s research hypothesis is that primary mechanical unloading could be a potential cardioprotective strategy to reduce ischaemia–reperfusion injury. In the past 15 years, his team demonstrated that mechanical devices, such as the Impella CP transvalvular pump, unload the heart, decreasing stress during a heart attack and reduce infarct size by approximately 50% in preclinical models.
Dr Kapur also demonstrated that 30 minutes of left ventricular (LV) unloading before reperfusion is necessary and sufficient to reduce infarct size.14 In addition, a meta-analysis of preclinical studies from around the world over the past 40 years established that LV unloading reduces infarct size using a variety of different pump configurations.15
Reperfusion without unloading is the current MI standard of care. Dr Kapur’s STEMI-Door-to-Unload (DTU) pilot clinical trial was designed to assess whether mechanical unloading for 30 minutes prior to reperfusion would increase or decrease infarct size.16 Fifty anterior STEMI patients received an Impella CP device to assess device safety and feasibility during a heart attack. The patients were randomised to receive unloading with immediate reperfusion or unloading for 30 minutes prior to reperfusion. The results confirmed the safety, feasibility and technical performance of the Impella CP in STEMI patients, and demonstrated that unloading with delayed reperfusion by 30 minutes limits infarct size, irrespective of the MI area at risk.
Additional data from the STEMI-DTU pilot trial indicated that mechanical unloading reduces myocardial ischaemia prior to reperfusion. Increased exposure time to unloading prior to reperfusion time correlated with a decrease in infarct size in patients with large anterior MI.16,17 These data correlate with anecdotal evidence of chest pain resolution and decreased ST-segment elevation after mechanical unloading. These encouraging data from the STEMI-DTU pilot trial enabled the initiation of Dr Kapur’s currently enrolling STEMI-DTU pivotal randomised clinical trial to compare the impact of unloading and delayed reperfusion against reperfusion without unloading on infarct size in a larger patient population.
Dr Kapur’s team is currently investigating the mechanism by which LV unloading improves blood flow, reduces ischaemic injury and protects cell function to promote heart recovery after infarction. Hypoxia, or lack of oxygen, characterises the ischaemic phase of a heart attack before reperfusion. Dr Kapur’s team demonstrated that, LV unloading with Impella CP prior to reperfusion in a preclinical ischaemic model of coronary artery occlusion, improves myocardial oxygen delivery by decreasing levels of hypoxia-inducible factor-1 alpha.17 Further data, pending publication, indicate that mechanical unloading reduces infarct size, both with and without subsequent reperfusion. Mitochondrial function is also improved with or without reperfusion, as indicated by retention of mitochondrial structural integrity, increased levels of critical complex I proteins, increased adenosine triphosphate production and stabilised calcium handling.17 LV unloading also increases microcirculatory collateral flow and reduces the area at risk in acute MI models pre-reperfusion.18
Interestingly, the protective effects of mechanical unloading against ischaemia–reperfusion injury differ according to pump type. Comparison of the Impella CP transvalvular pump to the venoarterial (VA)-extracorporeal membrane oxygenation (ECMO) pump demonstrated that use of ECMO was associated with increased infarct size and did not provide mitochondrial structural protection prior to reperfusion.17 This suggests that transvalvular unloading with Impella protects mitochondrial function in acute MI, whereas VA-ECMO does not. Unpublished data from Dr Kapur’s laboratory, in collaboration with Dr Divaka Perrara, also suggest that VA-ECMO decreases coronary blood flow and increases myocardial oxygen consumption, resulting in increased infarct size, vascular pressure, vascular injury and poor myocardial recovery.
Dr Kapur’s laboratory will continue to advance the field of mechanical circulatory support and LV unloading as a vital approach to prevent ischaemia–reperfusion injury. At the forefront of these efforts is the STEMI-DTU pivotal trial, a landmark study to further understand the benefits of transvalvular unloading in patients with acute MI.