Mechanism of ventricular premature beats elicited by left stellate ganglion stimulation during acute ischaemia of the anterior left ventricle

Aims Enhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the non-ischaemic myocardium. This ‘injury’ current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the ‘injury’ current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion. Methods and results In nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization. Conclusion LSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.

P2238Prognostic value and incremental benefit of ischaemic myocardial burden subtended by non-invasive CT-derived fractional flow reserve (FFRCT) significant stenoses

Background Fractional flow reserve derived from CT-coronary angiography (FFRCT) accurately identifies ischaemic vessels which may be associated with clinical outcomes. Its predictive value in grey zone FFRCT values between 0.7–0.8 is not defined. The technique permits estimation of burden of ischaemic myocardium subtended by FFRCT significant vessels. Purpose To evaluate the prognostic value and incremental benefit of FFRCT defined ischaemic myocardial burden when compared to FFRCT alone. Methods This is a subanalysis of NXT (Analysis of Coronary Blood-Flow Using CTA:Next-Steps), a prospective study of stable coronary artery disease (CAD) patients referred for invasive angiography (ICA) undergoing invasive FFR, CTA and FFRCT in whom treating physicians had been blinded to FFRCT results. Primary endpoint, defined as a composite of non-fatal myocardial infarction and any revascularisation, was determined in 206 patients (age 64±9.5 years, 64% male) and 618 vessels. Burden of ischaemic myocardium was defined as percentage of myocardium subtended beyond the point at which a vessel's FFRCT becomes ≤0.8 as estimated by APPROACH score (FFRCT-APPROACH). In significant FFRCT vessels, the predictive value and incremental benefit of FFRCT-APPROACH was compared with significant FFRCT (≤0.8) for primary endpoint as measured by area under the receiver operator characteristic curve (AUC). Significant ischaemic myocardial burden was defined as >10%. The incidence and relationship between the primary endpoint with each 10% increase in FFRCT-APPROACH and 0.05-unit decrease in FFRCT values ≤0.8 was determined. Results Significant FFRCT was identified in 52.9% of patients (109/206) and 29.3% of vessels (181/618). At 4.7 years median follow-up the incidence of the primary endpoint in vessels with significant FFRCT-APPROACH was 58.9% (96/163) which was comparable with vessels with significant FFRCT (55.2%,100/181; P=0.50). The predictive value of FFRCT-APPROACH for the primary endpoint was comparable with FFRCT (AUC 0.72 [95% CI 0.65–0.79] vs 0.71 [0.63–0.78], P=0.79). When combined, there was significant predictive improvement compared with FFRCT alone (AUC 0.77 [0.70–0.84]; P=0.01). The largest incremental benefit upon FFRCT was observed in vessels with FFRCT values in the grey zone between 0.70–0.80 (AUC 0.76 [0.65–0.86] vs 0.62 [0.48–0.74]; P<0.01). Each 10% increase in FFRCT-APPROACH (Adjusted-HR 1.36; 95% CI 1.16–1.60; P<0.001) and each 0.05-unit FFRCT decrease (Adjusted-HR 1.42; 1.19–1.70; P<0.001) were independently associated with significant increase in the incidence of the primary-endpoint. Conclusion In patients with stable CAD referred for ICA, the burden of ischaemic myocardium subtended by FFRCT significant vessels predicted non-fatal myocardial infarction and future revascularisation. This provided significant incremental benefit when used in combination with FFRCT particularly at FFRCT values in the grey zone between 0.7 to 0.8.

miR-19a-3p containing exosomes improve function of ischaemic myocardium upon shock wave therapy

Aims As many current approaches for heart regeneration exert unfavourable side effects, the induction of endogenous repair mechanisms in ischaemic heart disease is of particular interest. Recently, exosomes carrying angiogenic miRNAs have been described to improve heart function. However, it remains challenging to stimulate specific release of reparative exosomes in ischaemic myocardium. In the present study, we sought to test the hypothesis that the physical stimulus of shock wave therapy (SWT) causes the release of exosomes. We aimed to substantiate the pro-angiogenic impact of the released factors, to identify the nature of their cargo, and to test their efficacy in vivo supporting regeneration and recovery after myocardial ischaemia. Methods and results Mechanical stimulation of ischaemic muscle via SWT caused extracellular vesicle (EV) release from endothelial cells both in vitro and in vivo. Characterization of EVs via electron microscopy, nanoparticle tracking analysis and flow cytometry revealed specific exosome morphology and size with the presence of exosome markers CD9, CD81, and CD63. Exosomes exhibited angiogenic properties activating protein kinase b (Akt) and extracellular-signal regulated kinase (ERK) resulting in enhanced endothelial tube formation and proliferation. A miRNA array and transcriptome analysis via next-generation sequencing were performed to specify exosome content. miR-19a-3p was identified as responsible cargo, antimir-19a-3p antagonized angiogenic exosome effects. Exosomes and target miRNA were injected intramyocardially in mice after left anterior descending artery ligation. Exosomes resulted in improved vascularization, decreased myocardial fibrosis, and increased left ventricular ejection fraction as shown by transthoracic echocardiography. Conclusion The mechanical stimulus of SWT causes release of angiogenic exosomes. miR-19a-3p is the vesicular cargo responsible for the observed effects. Released exosomes induce angiogenesis, decrease myocardial fibrosis, and improve left ventricular function after myocardial ischaemia. Exosome release via SWT could develop an innovative approach for the regeneration of ischaemic myocardium.

Chronic ischaemic cardiomyopathy

Ischaemic cardiomyopathy is the most common cause of chronic heart failure. It is associated with several diagnostic and therapeutic challenges. They include mainly the detection of viable and ischaemic tissue amenable to improvement after revascularization. Revascularization is useful in patients with a critical mass of viable ischaemic myocardium. Provided that full revascularization is possible, percutaneous coronary intervention might be a valid alternative to surgical revascularization. Contrast-enhanced cardiac magnetic resonance is an important emerging tool to adequately detect viable myocardium. Right ventricular function and functional mitral regurgitations are important prognostic factors in ischaemic cardiomyopathy. Next to reshaping surgery, dedicated devices to restore left ventricular geometry, and stem cell therapy, are under clinical investigation.

Chronic ischaemic cardiomyopathy

Ischaemic cardiomyopathy is the most common cause of chronic heart failure. It is associated with several diagnostic and therapeutic challenges. They include mainly the detection of viable and ischaemic tissue amenable to improvement after revascularization. Revascularization is useful in patients with a critical mass of viable ischaemic myocardium. Provided that full revascularization is possible, percutaneous coronary intervention might be a valid alternative to surgical revascularization. Contrast-enhanced cardiac magnetic resonance is an important emerging tool to adequately detect viable myocardium. Right ventricular function and functional mitral regurgitations are important prognostic factors in ischaemic cardiomyopathy. Next to reshaping surgery, dedicated devices to restore left ventricular geometry, and stem cell therapy, are under clinical investigation.

Inflammation and repair in the ischaemic myocardium

SummaryShortly after myocardial infarction, various circulating leukocyte subsets accumulate in the heart. Leukocyte recruitment is highly coordinated and relies on cell production in the bone marrow, mobilization to the blood, and chemokine-mediated infiltration to the destination tissue. Neutrophils, which are phagocytic and inflammatory, are among the first leukocytes to accumulate in large numbers. Within a day, neutrophils disappear and are replaced by a subset of monocytes that further contribute to inflammation and phagocytosis. After a few days, monocyte-derived reparative macrophages accrue, quell inflammation, and foster angiogenesis and tissue remodelling. Studies suggest a wellbalanced response comprising these three waves is essential to optimal infarct healing.