K. Williams

Reparative Effects of Allogeneic Mesenchymal Precursor Cells Delivered Transendocardially in Experimental Nonischemic Cardiomyopathy

OBJECTIVES This study set out to evaluate the safety and efficacy of allogeneic bone marrow mesenchymal precursor cells (MPC) delivered by multisegmental, transendocardial implantation in the setting of nonischemic cardiomyopathy (NICM). BACKGROUND Prospectively isolated MPC have shown capacity to mediate cardiovascular repair in myocardial ischemia. However, their efficacy in NICM remains undetermined. METHODS Mesenchymal precursor cells were prepared from ovine bone marrow by immunoselection using the tissue nonspecific alkaline phosphatase, or STRO-3, monoclonal antibody. Fifteen sheep with anthracycline-induced NICM were assigned to catheter-based, transendocardial injections of allogeneic MPC (n = 7) or placebo (n = 8), under electromechanical mapping guidance. Follow-up was for 8 weeks, with end points assessed by cardiac magnetic resonance, echocardiography, and histology. RESULTS Intramyocardial injections were distributed similarly throughout the left ventricle in both groups. Cell transplantation was associated with 1 death late in follow-up, compared with 3 early deaths among placebo animals. Left ventricular end-diastolic size increased in both cohorts, but MPC therapy attenuated end-systolic dilation and stabilized ejection fraction, with a nonsignificant increase (37.3 ± 2.8% before, 39.2 ± 1.4% after) compared with progressive deterioration after placebo (38.8 ± 4.4% before, 32.5 ± 4.9% after, p < 0.05). Histological outcomes of cell therapy included less fibrosis burden than in the placebo group and an increased density of karyokinetic cardiomyocytes and myocardial arterioles (p < 0.05 for each). These changes occurred in the presence of modest cellular engraftment after transplantation. CONCLUSIONS Multisegmental, transendocardial delivery of cell therapy can be achieved effectively in NICM using electromechanical navigation. The pleiotropic properties of immunoselected MPC confer benefit to nonischemic cardiac disease, extending their therapeutic potential beyond the setting of myocardial ischemia.

Percutaneous closure of atrial septal defects leads to normalisation of atrial and ventricular volumes.

BackgroundPercutaneous closure of atrial septal defects (ASDs) should potentially reduce right heart volumes by removing left-to-right shunting. Due to ventricular interdependence, this may be associated with impaired left ventricular filling and potentially function. Furthermore, atrial changes post-ASD closure have been poorly understood and may be important for understanding risk of atrial arrhythmia post-ASD closure. Cardiovascular magnetic resonance (CMR) is an accurate and reproducible imaging modality for the assessment of cardiac function and volumes. We assessed cardiac volumes pre- and post-percutaneous ASD closure using CMR.MethodsConsecutive patients (n = 23) underwent CMR pre- and 6 months post-ASD closure. Steady state free precession cine CMR was performed using contiguous slices in both short and long axis views through the ASD. Data was collected for assessment of left and right atrial, ventricular end diastolic volumes (EDV) and end systolic volumes (ESV). Data is presented as mean ± SD, volumes as mL, and paired t-testing performed between groups. Statistical significance was taken as p < 0.05.ResultsThere was a significant reduction in right ventricular volumes at 6 months post-ASD closure (RVEDV: 208.7 ± 76.7 vs. 140.6 ± 60.4 mL, p < 0.0001) and RVEF was significantly increased (RVEF 35.5 ± 15.5 vs. 42.0 ± 15.2%, p = 0.025). There was a significant increase in the left ventricular volumes (LVEDV 84.8 ± 32.3 vs. 106.3 ± 38.1 mL, p = 0.003 and LVESV 37.4 ± 20.9 vs. 46.8 ± 18.5 mL, p = 0.016). However, there was no significant difference in LVEF and LV mass post-ASD closure. There was a significant reduction in right atrial volumes at 6 months post-ASD closure (pre-closure 110.5 ± 55.7 vs. post-closure 90.7 ± 69.3 mL, p = 0.019). Although there was a trend to a decrease in left atrial volumes post-ASD closure, this was not statistically significant (84.5 ± 34.8 mL to 81.8 ± 44.2 mL, p = NS).ConclusionASD closure leads to normalisation of ventricular volumes and also a reduction in right atrial volume. Further follow-up is required to assess how this predicts outcomes such as risk of atrial arrhythmias after such procedures.

A study of the 16-Segment Regional Wall Motion Scoring Index and biplane Simpson's rule for the calculation of left ventricular ejection fraction: a comparison with cardiac magnetic resonance imaging.

Aims: Accurate calculation of left ventricular ejection fraction (LVEF) is important for diagnostic, prognostic and therapeutic reasons. Cardiac magnetic resonance (CMR) is the reference standard for LVEF calculation, followed by real time three‐dimensional echocardiography (RT3DE). Limited availability of CMR and RT3DE leaves Simpsons rule as the two‐dimensional echocardiography (2DE) standard by which LVEF is calculated. We investigated the accuracy of the 16‐Segment Regional Wall Motion Score Index (RWMSI) as an alternative method for calculating LVEF by 2DE and compared this to Simpsons rule and CMR. Methods and Results: The 2D echocardiograms of 110 patients were studied (LVEF range: 7–74%); 57 of these underwent CMR. A RWMS was applied, based on the consensus opinion of two experienced cardiologists, to each of 16 American Heart Association myocardial segments (RWMSI: hyperkinesis = 3; normal regional contraction = 2; mild hypokinesis = 1.25; severe hypokinesis = 0.75; akinesis = 0; dyskinesis =–1). LVEF was calculated by: LVEF(%) =Σ(16segRWMS)/16×30. LVEF was calculated by Simpsons rule and CMR using standard methods. Results were correlated against CMR. Intertechnique agreement was examined. A P value of<0.05 was considered significant. RWMSI‐LVEF correlated strongly with Biplane Simpsons rule (P< 0.001, r = 0.915). RWMSI‐LVEF had a strong correlation to CMR (P < 0.001, r = 0.916); Simpsons rule‐LVEF had a moderate correlation to CMR (P< 0.001, r = 0.647). In patients with LV dysfunction (EF < 55%), on linear regression analysis, RWMSI‐LVEF had a better correlation with CMR than Simpsons rule. Further more Simpsons rule overestimated LVEF compared to CMR (mean difference: –6.12 ± 16.44, P = 0.002) whereas RWMSI did not (mean difference: 2.58 ± 14.80, P = NS). Conclusion: RWMSI‐LVEF correlates strongly with CMR with good intertechnique agreement. In centers where CMR and RT3DE are not readily available, the use by experienced individuals, of the RWMSI for calculating LVEF may be a more simple, accurate, and reliable alternative to Simpsons rule. (Echocardiography 2011;28:597‐604)

Prognostic value of adenosine stress perfusion cardiac MRI with late gadolinium enhancement in an intermediate cardiovascular risk population

BACKGROUND The high diagnostic accuracy of adenosine stress cardiac magnetic resonance (AS-CMR) for detecting coronary artery stenoses, with high sensitivity and specificity, is well documented. Prognostic data, particularly in non-low risk study populations and for greater than 12 months of follow up, is however lacking or variable in its findings. We present prognostic data, in an intermediate cardiovascular risk cohort undergoing adenosine stress perfusion CMR, over approximately 2 years of follow up. METHODS The study population comprised 362 patients referred for a clinically indicated stress CMR and included patients with proven coronary artery disease (CAD; n=157) or unknown CAD status, yet an intermediate cardiovascular risk profile (n=205). Perfusion imaging was performed at stress (adenosine 140 μg/kg/min) and rest on a 1.5 T system. Patient records and state-wide hospital databases were reviewed. Major adverse cardiac events--death, myocardial infarction, revascularisation or ischaemic hospitalisation--were evaluated over a median follow up of 22 months. RESULTS Of the 362 cases, 90 had a stress perfusion CMR positive for ischaemia and experienced a MACE rate of 24%. Of the 272 negative CMR scans, 225 were also negative for late gadolinium enhancement, and in this group MACE was encountered in only 6 (2.7%) patients. Accordingly a negative stress CMR afforded a freedom from MACE of 97.3%. Freedom from death/myocardial infarction was 99.6%. CONCLUSIONS In patients with confirmed coronary artery disease or at intermediate risk for cardiovascular events, a negative stress perfusion CMR is associated with an excellent prognosis over nearly 2 years of follow up.

Diagnostic Accuracy of Adenosine Stress Cardiovascular Magnetic Resonance Following Acute ST-segment Elevation Myocardial Infarction Post Primary Angioplasty

BackgroundAdenosine stress cardiovascular magnetic resonance (CMR) has been proven an effective tool in detection of reversible ischemia. Limited evidence is available regarding its accuracy in the setting of acute coronary syndromes, particularly in evaluating the significance of non-culprit vessel ischaemia. Adenosine stress CMR and recent advances in semi-quantitative image analysis may prove effective in this area. We sought to determine the diagnostic accuracy of semi-quantitative versus visual assessment of adenosine stress CMR in detecting ischemia in non-culprit territory vessels early after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).MethodsPatients were prospectively enrolled in a CMR imaging protocol with rest and adenosine stress perfusion, viability and cardiac functional assessment 3 days after successful primary-PCI for STEMI. Three short axis slices each divided into 6 segments on first pass adenosine perfusion were visually and semi-quantitatively analysed. Diagnostic accuracy of both methods was compared with non-culprit territory vessels utilising quantitative coronary angiography (QCA) with significant stenosis defined as ≥70%.ResultsFifty patients (age 59 ± 12 years) admitted with STEMI were evaluated. All subjects tolerated the adenosine stress CMR imaging protocol with no significant complications. The cohort consisted of 41% anterior and 59% non anterior infarctions. There were a total of 100 non-culprit territory vessels, identified on QCA. The diagnostic accuracy of semi-quantitative analysis was 96% with sensitivity of 99%, specificity of 67%, positive predictive value (PPV) of 97% and negative predictive value (NPV) of 86%. Visual analysis had a diagnostic accuracy of 93% with sensitivity of 96%, specificity of 50%, PPV of 97% and NPV of 43%.ConclusionAdenosine stress CMR allows accurate detection of non-culprit territory stenosis in patients successfully treated with primary-PCI post STEMI. Semi-quantitative analysis may be required for improved accuracy. Larger studies are however required to demonstrate that early detection of non-culprit vessel ischemia in the post STEMI setting provides a meaningful test to guide clinical decision making and ultimately improved patient outcomes.

Cardiac magnetic resonance, transthoracic and transoesophageal echocardiography: a comparison of in vivo assessment of ventricular function in rats

In vivo assessment of ventricular function in rodents has largely been restricted to transthoracic echocardiography (TTE). However 1.5 T cardiac magnetic resonance (CMR) and transoesophageal echocardiography (TOE) have emerged as possible alternatives. Yet, to date, no study has systematically assessed these three imaging modalities in determining ejection fraction (EF) in rats. Twenty rats underwent imaging four weeks after surgically-induced myocardial infarction. CMR was performed on a 1.5 T scanner, TTE was conducted using a 9.2 MHz transducer and TOE was performed with a 10 MHz intracardiac echo catheter. Correlation between the three techniques for EF determination and analysis reproducibility was assessed. Moderate-strong correlation was observed between the three modalities; the greatest between CMR and TOE (intraclass correlation coefficient (ICC) = 0.89), followed by TOE and TTE (ICC = 0.70) and CMR and TTE (ICC = 0.63). Intra- and inter-observer variations were excellent with CMR (ICC = 0.99 and 0.98 respectively), very good with TTE (0.90 and 0.89) and TOE (0.87 and 0.84). Each modality is a viable option for evaluating ventricular function in rats, however the high image quality and excellent reproducibility of CMR offers distinct advantages even at 1.5 T with conventional coils and software.

Tissue injury characterization by pre-contrast T1 mapping post myocardial infarction

Background Myocardial scar and edema can be assessed by late gadolinium enhancement (LGE) and T2W cardiac magnetic resonance (CMR) respectively, but each has important limitations. T1-mapping has emerged as an alternative method to characterize acute ischemic injury and contemporary mapping sequences make this clinically feasible. We assessed the T1 relaxation time in myocardial segments exhibiting varying degrees of ischemic injury in patients after acute MI. Methods T2W, T1-mapping (using Shortened Modified LookLooker Inversion recovery sequence) and LGE imaging was performed 24-72 hours after MI on a 1.5T scanner. Assessment of acute segmental damage, in a 16-segment AHA model, was performed on matched short axis slices. Mean segmental T1 values were calculated for infarcted, adjacent/edema, microvascular obstruction (MVO) or remote segments as defined by LGE. Results

Optimal planimetry location for MRI-derived mitral inflow velocity assessment of diastolic function

Background Diastolic function is almost exclusively assessed using transthoracic echocardiography (TTE), however velocityencoded phase-contrast imaging permits diastolic evaluation with cardiac magnetic resonance (CMR). However, previous studies have utilized heterogeneous planimetric contour locations to measure mitral valve (MV) inflow velocities and the optimal contour is uncertain. We therefore evaluated CMR MV inflow velocities measured at various regions against TTE to identify the optimal method.

ADENOSINE STRESS PERFUSION CMR RELIABLY RISK STRATIFIES PATIENTS WITH PRIOR EXERCISE TREADMILL TESTING

Background ETT is an inexpensive and easily accessible non-invasive test. However it affords only modest sensitivity and specificity for ischaemic heart disease (IHD). Accordingly ETT can often provide results that are either equivocal or which run contrary to clinical suspicion. Therefore, clinicians frequently request an additional non-invasive test to clarify matters. Adenosine stress perfusion CMR has been shown to have a high sensitivity and specificity for the detection of IHD. We sought to evaluate a cohort of patients who had a recent ETT followed by stress perfusion CMR to examine the clinical utility of CMR in risk stratifying these patients.

Stress perfusion CMR reliably risk stratifies patients with prior exercise treadmill testing

Seventy patients (50% male, age 58.4 years ±11.2; mean ±SD) were identified. Twelve (17%) had a history of previous MI or revascularisation. Seventeen had an objectively positive ETT, of which 7 (41%) had a positive stress CMR. Thirty one had an equivocal ETT, of which 8 (26%) had a positive stress CMR. Twenty two had a negative ETT, of which 3 (14%) had a positive CMR. All positive CMRs had stenoses ≥50% at angiography, except for two patients (11%), both from the equivocal ETT group. A negative CMR, irrespective of ETT status, resulted in a 0% MACE rate at median 23 months (IQR 20-27) follow up. No positive CMRs were seen in negative or equivocal ETTs where ≥ 10 metabolic equivalents (METS) were attained. Conclusions Adenosine stress perfusion CMR can reliably risk stratify patients independent of previous ETT result. A negative CMR is associated with an excellent prognosis at a median of 23 months follow up.