Single-photon emission computed tomography as a fundamental tool in evaluation of myocardial reparation and regeneration therapies.

Despite unquestionable progress in interventional and pharmacologic therapies of ischemic heart disease, the number of patients with chronic ischemic heart failure is increasing and the prognosis remains poor. Repair/restoration of functional myocardium through progenitor cell-mediated (PCs) healing and renovation of injured myocardium is one of the pivotal directions in biomedical research. PCs release numerous pro-angiogenic and anti-apoptotic factors. Moreover, they have self-renewal capability and may differentiate into specialized cells that include endothelial cells and cardiomyocytes. Uptake and homing of PCs in the zone(s) of ischaemic injury (i.e., their effective transplantation to the target zone) is an essential pre-requisite for any potential therapeutic effect; thus effective cell tracking is fundamental in pre-clinical and early clinical studies. Another crucial requirement in rigorous research is quantification of the infarct zone, including the amount of non-perfused and hypo-perfused myocardium. Quantitative and reproducible evaluation of global and regional myocardial contractility and left ventricular remodeling is particularly relevant in clinical studies. Using SPECT, our earlier work has addressed several critical questions in cardiac regenerative medicine including optimizing transcoronary cell delivery, determination of the zone(s) of myocardial cell uptake, and late functional improvement in relation to the magnitude of cell uptake. Here, we review the role of single-photon emission computed tomography (SPECT), a technique that offers high-sensitivity, quantitative cell tracking on top of its ability to evaluate myocardial perfusion and function on both cross-sectional and longitudinal bases. SPECT, with its direct relevance to routine clinical practice, is a fundamental tool in evaluation of myocardial reparation and regeneration therapies.

Eligible-and-enrolled vs. eligible-but-not-enrolled patients with chronic ischaemic heart failure in randomized clinical trials of myocardial regeneration.

Introduction: Clinical trial applicability to routine clinical practice is a fundamental consideration. Little is known about factors that determine enrolment (vs. non-enrolment) in chronic ischaemic heart failure (CIHF) interventional randomized controlled trials (iRCT). Aim: To compare clinical characteristics and medical therapy in eligible-and-enrolled (E-E) vs. eligible-but-not-enrolled (E-NE) patients in CIHF myocardial regeneration iRCTs. Material and methods: Clinical characteristics and medical treatment were compared for E-E and E-NE in 4 periods (32 months): P1 (iRCT#1 recruitment), P2 (between iRCT#1 and iRCT#2), P3 (iRCT#2 recruitment), P4 (post iRCT#2). iRCT#1 and iRCT#2 shared inclusion/exclusion criteria. Results: Evaluation involved 5,436 hospitalized patients (P1-P4; CIHF-526). 283 were iRCT eligible (53.8%). The eligibility rate was similar throughout P1-P4 (43.1-58.5%, p = 0.08). Eligible patient characteristics and pharmacotherapy did not differ in recruitment vs. non-recruitment periods. Principal reasons for ineligibility were recent/planned cardiac intervention outside iRCT (22.8%), age above threshold (14.6%) and coexisting disease as the exclusion criterion (12.2%). Primary reasons for eligible patient non-enrolment (n = 89) were other trial participation (52.8%) and no consent (28.1%). E-E patients did not differ from E-NE in characteristics including CIHF medical management and clinical stage; the exception was more severe left ventricular impairment in E-E (LVEF 31.2 vs. 33.9%, p = 0.039; end-diastolic volume 197.8 vs. 160.4 ml, p < 0.0001). Conclusions: CIHF medical management was similar in E-E and E-NE. Ineligibility resulted mainly from recent/planned intervention outside iRCT and age > 80 years. LV impairment was more severe in E-E patients, consistent with higher-risk patient enrolment in CIHF-iRCTs. This contrasts with typical lower-risk patient enrolment in other cardiovascular RCT types and populations.

Acute myocardial infarction reparation/regeneration strategy using Wharton's jelly multipotent stem cells as an 'unlimited' therapeutic agent: 3-year outcomes in a pilot cohort of the CIRCULATE-AMI trial.

Introduction: CIRCULATE-AMI (NCT03404063), a cardiac magnetic resonance imaging (cMRI) infarct size-reduction-powered double-blind randomized controlled trial (RCT) of standardized Wharton jelly multipotent stem cells (WJMSCs, CardioCell Investigational Medical Product) vs. placebo (2 : 1) transcoronary transfer on acute myocardial infarction (AMI) day ~5-7, is preceded by safety and feasibility evaluation in a pilot study cohort (CIRCULATE-AMI PSC). Aim: To evaluate WJMSC transplantation safety and evolution of left ventricular (LV) remodeling in CIRCULATE-AMI PSC. Material and methods: In 10 consecutive patients (32-65 years, peak CK-MB 533 ±89 U/l, cMRI-LVEF 40.3 ±2.7%, cMRI-infarct size 20.1 ±2.8%), 30 × 106 WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCULATE catheter). Other treatment was guideline-based. Results: WJMSC transfer was safe and occurred in the absence of coronary (TIMI-3 in all) or myocardial (corrected TIMI frame count (cTFC) 45 ±8 vs. 44 ±9, p = 0.51) flow deterioration or troponin elevation. By 3 years, 1 patient died from a new, non-index territory AMI; there were no other major adverse cardiovascular and cerebrovascular events (MACCE) and no adverse events that might be related to WJMSCs. cMRI infarct size was reduced from 33.2 ±7.6 g to 25.5 ±6.4 g at 1 year and 23.1 ±5.6 g at 3 years (p = 0.03 vs. baseline). cMRI, SPECT, and echo showed a consistent, statistically significant increase in LVEF at 6-12 months (41.9 ±2.6% vs. 51.0 ±3.3%, 36.0 ±3.9% vs. 44.9 ±5.0%, and 38.4 ±2.5% vs. 48.0 ±2.1% respectively, p < 0.01 for all); the effect was sustained at 3 years. Conclusions: CIRCULATE-AMI PSC data suggest that WJMSC transcoronary application ~5-7 days after large AMI in humans is feasible and safe and it may be associated with a durable LVEF improvement. CIRCULATE-AMI RCT will quantify the magnitude of LV adverse remodeling attenuation with CardioCell/placebo administration.

Trans-endocardial delivery of progenitor cells to compromised myocardium using the "needle technique"and risk of myocardial injury.

Introduction: Recent analysis from CHART-1 study indicated that the therapeutic effects of trans-endocardial cardiopoetic cell transplantation in chronic ischemic heart failure (iCHF) may be lost with an increasing number of injections perfomed to deliver therapeutic cells. Aim: To evaluate global and regional contractility and diastolic function of the left ventricle of patients with iCHF who received trans-endomyocardial cardiopoietic stem cells (CSCs) delivery or sham procedures. Material and methods: The study included patients (mean age: 60.8 ±7.1 years) with iCHF (left ventricular ejection fraction (LVEF) < 35%) and a history of hospitalization for worsening heart failure within 12 months despite optimal medical therapy. The patients underwent transmyocardial CSCs transplantation using perforated needle technique or a sham procedure. The wall motion score index (WMSI), LVEF, transmitral E-velocity, E-wave deceleration time, E/A-ratio, and E/e'-mean value were measured with two-dimensional echocardiography on days 1 and 30. Results: A total of 170 segments were analyzed, including 48 targeted segments where 92 injections of 0.5 ml of CSCs were performed. In the transendocardial injections cohort, a decrease in regional contractility was observed in 30.6% (26/85) and 18.9% (16/85) of the segments on days 1 and 30, respectively. This was accompanied by an increase in WMSI by 0.32 ±0.06 and 0.19 ±0.18 (day 1, p = 0.02, day 30, p = 0.03) and a reduction in LVEF (-3.15 ±1.23%, p = 0.065). Conclusions: Transendocardial injections performed to deliver therapeutic cells were associated with myocardial injury. This adverse effect remained, albeit at a lesser degree, at 30-days. Mechanical injury with trans-endocardial delivery of progenitor cells using the "needle technique" may counterbalance, at least in part, any cell-related benefit(s).

Objective, observer-independent evaluation of myocardial perfusion and function: role of SPECT.

The number of patients with coronary artery disease and ischaemic heart failure - and those with terminal heart failure - is increasing despite improvements in medical and interventional therapies of ischaemic heart disease - and, over the next decades, it is projected to continue to increase further. Observer-independent, reproducible imaging techniques play a fundamental role in objective evaluation of both conventional (such as surgical or percutaneous) myocardial revascularization and novel therapeutic approaches to reduce myocardial ischaemia, improve contractility and prevent adverse myocardial remodelling. To be applicable to clinical practice, the clinical study design and data should best be rooted in everyday clinical practice. Accurate and reproducible assessment of left ventricular ejection fraction, left ventricular volumes, myocardial perfusion and function is one of the most important objectives of cardiac imaging. Current techniques used both in clinical studies and in everyday clinical practice include 2- and 3-dimensional echocardiography, magnetic resonance imaging, single-photon emission computed tomography and positron emission tomography; each of these has its strengths and limitations. We review present evidence on the role of single-photon emission computed tomography as a technique that may offer, through being observer-independent, the most objective evaluation of evolution of left ventricular perfusion, volumes and ejection fraction.

Diffusion-tensor magnetic resonance imaging of the human heart in health and in acute myocardial infarction using diffusion-weighted echo-planar imaging technique with spin-echo signals.

Introduction: Originally thought unsuitable due to proneness to myocardial motion and susceptibility artefacts, spin-echo echo planar imaging (SE-EPI) has gained attention for the cardiac diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) offering higher SNR and lower achievable echo time (TE). Aim: The application of DTI for patients with acute myocardial infarction (AMI) using our methodology developed on the basis of the SE-EPI sequence. Material and methods: Twelve patients with AMI and six healthy controls were enrolled in the preliminary DTI study within the CIRCULATE STRATEGMED 2 project. Our method relied on a pilot ECG-triggered DTI examination, based on which the initial evaluation was possible and allowed proper manipulation of TE (64/47 ms for patients/control), repetition time (TR) and ECG trigger delay in the consecutive DTI. Results: The study demonstrated that by using our algorithm it was possible to obtain DWI images showing infarct zones identified on T1-weighted images with late gadolinium-enhancement (LGE) with division into subtle and severe damage. Quantitative DTI showed increased mean diffusivity (MD) and decreased fractional anisotropy (FA) in the infarct compared to remote tissue. The application of B-matrix spatial distribution (BSD) calibration allowed the improvement of FA. Conclusions: Our algorithm is suitable for qualitative assessment of infarction zones with different severity. The analysis of the quantitative DTI showed that despite the lack of motion compensation blocks in the applied SE-EPI sequence, it was possible to approach the diffusion tensor parameter values reported for the myocardium.