Restoring microvascular circulation with diagnostic ultrasound and contrast agent: Rationale and Design of the REDUCE trial.

OBJECTIVES: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure. BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear. METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of two treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for six months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total. CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

Index of Microcirculatory Resistance to predict microvascular obstruction in STEMI: A systematic review and meta-analysis.

BACKGROUND: Microvascular obstruction (MVO) is an independent predictor of adverse cardiac events after ST-elevation myocardial infarction (STEMI). The Index of Microcirculatory Resistance (IMR) may be a useful marker of MVO, which could simplify the care pathway without the need for Cardiac Magnetic Resonance (CMR). We assessed whether the IMR can predict MVO in STEMI patients. METHODS AND RESULTS: We conducted a systematic review and meta-analysis, including articles where invasive IMR was performed post primary percutaneous coronary intervention (PCI) in addition to MVO assessment with cardiac MRI. We searched PubMed, Scopus, Embase, and Cochrane databases from inception until January 2023. Baseline characteristics, coronary physiology and cardiac MRI data were extracted by two independent reviewers. The random-effects model was used to pool the data. Among 15 articles identified, nine articles (n = 728, mean age 61, 81% male) contained IMR data stratified by MVO. Patients with MVO had a mean IMR of 41.2 [95% CI 32.4-50.4], compared to 25.3 [18.3-32.2] for those without. The difference in IMR between those with and without MVO was 15.1 [9.7-20.6]. Meta-regression analyses demonstrated a linear relationship between IMR and TIMI grade (ß = 0.69 [0.13-1.26]), as well as infarct size (ß = 1.18 [0.24-2.11]) or ejection fraction at 6 months (ß = -0.18 [-0.35 to -0.01]). CONCLUSION: In STEMI, patients with MVO had 15-unit higher IMR than those without. IMR also predicts key prognostic endpoints such as infarct size, MVO, and long-term systolic function.

Prophylaxis to Prevent Cardiotoxicity in Patients Receiving Anthracycline for Breast Cancer: A Combined Bayesian and Frequentist Network Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: The benefits in survivorship gained with anthracycline (ANT)-based chemotherapies for breast cancer are unfortunately mitigated for some patients by irreversible cardiotoxicity. Randomised controlled trials (RCTs) have explored multiple cardioprotection options, however, it remains unclear which drug is most effective in preserving left ventricular ejection fraction (LVEF). This study aimed to perform a systematic review and network meta-analysis, using Bayesian and frequentist approaches, of RCTs evaluating cardioprotective agents. METHODS: Two authors searched four databases (CENTRAL, Cochrane Reviews, MEDLINE, SCOPUS), to find RCTs evaluating cardioprotective agents. Trial populations were limited to patients with breast cancer without prior ANT exposure. The primary outcome was mean LVEF change pre and post ANT dosing. Our primary analysis utilised a Bayesian approach, while our sensitivity analysis used frequentist methodology (Prospero registration number CRD42020199580). RESULTS: From 4,007 search results, we identified 12 RCTs, with their various trial arms considered separately-nine beta-blocker (BB), two angiotensin-converting enzyme inhibitor /angiotensin receptor blockers [(AA)+BB=AABB], one AA, one spironolactone, one statin-evaluating 1,126 patients (age 50.5 years). Bayesian network meta-analysis showed no difference in LVEF preservation between AA (1.3%, 95% credible interval [-0.20, 2.9]), BB (0.77, [-0.21, 1.8]), AABB (0.84 [-1.1, 2.8]), spironolactone (0.72, [-2.3, 3.7]) or statin (0.60, [-2.4, 3.6]) when compared against placebo. However, the frequentist analysis showed benefits from using AA (mean difference, 1.32% [0.32, 2.33]) and BB (mean difference, 0.76% [0.12, 1.4]). CONCLUSIONS: There is insufficient evidence to support prophylactic cardioprotection to prevent EF reduction. However, frequentist analysis suggested that AA or BBs provide cardioprotection. Thus, for those already on other anti-hypertensives, switching to AA or BBs could be considered.

The Effect of Obesity on Echocardiographic Image Quality.

BACKGROUND: Increased body mass index (BMI) may reduce transthoracic echocardiogram (TTE) image quality, resulting in increased requirements for ultrasound enhancing agents (UEA), as recommended by the American Society of Echocardiography (ASE), and a greater incidence of non-diagnostic studies. METHODS: Over a 5-month period 1,108 TTEs were analysed as to (1) whether they could answer the clinical question posed by the ordering physician (i.e. were diagnostic vs non diagnostic), and (2) whether they required UEAs according to the ASE guidelines. Patient characteristics were gathered from the medical record. RESULTS: 12.9% of TTEs were non-diagnostic (21.0% of TTEs in the obese population [BMI≥30 kg/m2] vs 7.8% in the non-obese [p<0.001]). Predictors of a non-diagnostic study were BMI (OR 1.09, [95% CI 1.06-1.11], p<0.0001), male gender (OR 1.54, [1.06-2.25], p=0.02), and inpatient status (OR 1.75, [1.20-2.55], p=0.004). Obesity (BMI≥30) was strongly associated with non-diagnostic studies (OR 3.22, [2.23-4.51], p<0.001). Factors associated with increased requirement of UEAs were BMI (OR 1.10, [1.08-1.12], p<0.0001), age (OR 1.02, [1.01-1.03], p<0.0001) and inpatient status (OR 1.7, [1.29-2.24], p<0.05). Obesity (BMI>30) was strongly associated with contrast requirement (OR 3.16, [2.43-4.10], p<0.0001). CONCLUSIONS: Body mass index, male gender and inpatient status were associated with an increased incidence of non-diagnostic studies. Body mass index, age and inpatient status were associated with an increased requirement for UEAs.

Coronary Flow Velocity Reserve Declines After Anthracycline Therapy in Breast Cancer Patients.

Anthracycline therapy (ANT) is associated with cancer therapy-related cardiac dysfunction. Coronary flow velocity reserve (CFVR) has shown prognostic utility in non-cancer cohorts, but no data have been obtained in a cardio-oncology setting. We investigated the acute effect of ANT on CFVR in breast cancer patients. A total of 12 female breast cancer patients undergoing ANT had pre- and post-ANT CFVR assessment. A significant decline in CFVR occurred (baseline: 2.66 ± 0.41 vs post-ANT: 2.47 ± 0.37, P = 0.016). This prospective study is the first to identify ANT-related coronary physiology changes in humans. Further studies are required to determine their clinical significance.

Le traitement par l'anthracycline est associé à une dysfonction cardiaque liée au traitement anticancéreux. La réserve de débit coronaire a démontré son utilité pronostique dans les cohortes sans cancer, mais aucune donnée n'a été obtenue dans un contexte de cardio-oncologie. Nous avons étudié l'effet aigu de l'anthracycline sur la réserve de débit coronaire chez des patientes atteintes d'un cancer du sein. La réserve de débit coronaire a été évaluée avant et après le traitement par l'anthracycline chez un total de 12 femmes atteintes d'un cancer du sein. Un déclin important de la réserve de débit coronaire est survenu (valeur initiale de 2,66 ± 0,41 par rapport à 2,47 ± 0,37 après le traitement par l'anthracycline, p = 0,016). Cette étude prospective est la première à déceler des changements dans la physiologie coronarienne liés à l'anthracycline chez les humains. D'autres études sont nécessaires pour en déterminer la portée clinique.

Cardiac magnetic relaxometry versus ejection fraction in anthracycline-related cardiac changes: a systematic review and meta-analysis.

PURPOSE: The purpose of this meta-analysis is to compare the magnitude of the changes in left ventricular ejection fraction (LVEF) and cardiac magnetic resonance (CMR) relaxometry techniques soon after the completion of anthracycline therapy. Anthracyclines are associated with myocardial functional and morphological changes. LVEF is currently used to identify the functional changes. Anthracyclines can also cause myocardial inflammation and oedema. This can be assessed using CMR relaxometry techniques; T1 and T2 mapping and extracellular volume (ECV) fraction. METHODS: Three databases were systematically searched for studies evaluating CMR relaxometry parameter at baseline and 1±1 months after anthracycline completion (the last search date 17 March 2023). CMR parameters pre and post anthracycline-based chemotherapy were abstracted. A random effects model was used to pool mean difference (MD) in LVEF and ECV. Standardised mean difference (SMD) was also calculated for T1 and T2 mapping due to the variations in techniques, normal ranges and for the comparison among the parameters. RESULTS: A total of 296 patients were included from 10 studies. 84% were female with a mean age of 54.9 years. Statistically significant alterations were observed in LVEF (MD -3.38% (95% CI -5.13%, -1.62%)) and ECV (1.92% (1.30%, 2.53%)). The pooled SMDs were also significant in LVEF, T1, T2 and ECV with -0.61 (-0.91, -0.30), 0.53 (0.16, 0.90), 0.59 (0.22, 0.96) and 0.74 (0.41, 1.06), respectively. CONCLUSIONS: Our meta-analysis demonstrated small but significant alterations in CMR relaxometry parameters soon after anthracycline therapy, where ECV was superior to LVEF and T1 or T2 mapping. However, these short-term MDs were below the minimal detectable differences. PROSPERO REGISTRATION NUMBER: CRD42020196296.

Left ventricular longitudinal systolic dysfunction in children with type 1 diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVE: Children with type one diabetes mellitus (T1DM) may have subclinical myocardial insults but large heterogeneity exists among the reports. This study aimed to compare myocardial strain values of the left ventricle (LV) in paediatric patients with T1DM without overt cardiac disease and healthy controls. METHODS: Five databases (MEDLINE, Embase, Scopus, Web of Science and Cochrane central register of controlled trials) were searched from inception to March 30, 2020. The studies reporting two-dimensional speckle tracking echocardiography in asymptomatic T1DM paediatric patients and control groups were included. Pooled mean strain values in each group and mean difference (MD) between the two groups for LV global longitudinal strain (LVGLS) and LV global circumferential strain (LVGCS) were assessed using a random effects model. RESULTS: Ten studies (755 T1DM and 610 control) with LVGLS were included with 6 studies having LVGCS (534 T1DM and 403 control). Patients with T1DM had overall 3 percentage points lower LVGLS than healthy subjects (18.4 %, 95 % confidence interval [17.1, 19.6] vs 21.5 % [20.3, 22.7], MD = -3.01 [-4.30, -1.71]). A similar result was seen in LVGCS (18.7 % [15.4, 22.0] vs. 21.4 % [18.1, 24.6], MD = -3.10[-6.47, 0.26]) but not statistically significant. Meta-regression identified those with higher Haemoglobin A1c (HbA1c) had worse GLS. CONCLUSIONS: Subclinical LV dysfunction among patients with T1DM occurs as early as in their childhood, while even EF is preserved. The longitudinal cardiac function is altered, but not the circumferential. GLS can be used to detect subclinical LV systolic dysfunction in paediatric population.

Subclinical systolic dysfunction detected by 2D speckle tracking echocardiography in adults with diabetes mellitus: systematic review and meta-analysis of 6668 individuals with diabetes mellitus and 7218 controls.

PURPOSE: Speckle tracking echocardiography (STE) can help to identify subclinical features of diabetic cardiomyopathy (DCM). There is, however, significant heterogeneity in the reported strain values in literature. We performed a systematic review and meta-analysis to compare cardiac systolic strain values assessed by 2D-STE in asymptomatic adults with diabetes mellitus (DM) and healthy controls. METHODS: Five databases were searched, and a total of 41 valid studies (6668 individuals with DM and 7218 controls) were included for analysis. Pooled mean in each group and mean difference (MD) for left ventricular global longitudinal strain (LVGLS), LV global circumferential strain (LVGCS), LV global radial strain (LVGRS), LV longitudinal systolic strain rate (LVSR), left atrial reservoir strain (LARS) and right ventricular GLS (RVGLS) were assessed. RESULTS: Patients with DM had overall 2 units lower LVGLS than healthy subjects 17.5% [16.8, 18.3], vs 19.5 [18.7, 20.4], MD = - 1.96 [- 2.27, - 1.64]. Other strain values were also lower in patients with DM: LVGCS (MD = - 0.89 [- 1.26, - 0.51]); LVGRS (MD = - 5.03 [- 7.18, - 2.87]); LVSR (MD = - 0.06 [- 0.10, - 0.03]); LARS (MD = - 8.41 [- 11.5, - 5.33]); and RVGLS (MD = - 2.41 [- 3.60, - 1.22]). Meta-regression identified higher body mass index (BMI) as the single contributor to worse LVGLS, LVGCS and LVSR. Those with higher Hemoglobulin A1c had worse RVGLS. CONCLUSION: Myocardial strains were reduced in whole heart in patients with DM. The largest reduction was observed in LA reservoir strain, followed by RVGLS and LVGLS. Higher BMI in patients with DM is associated with worse LV strain values.

Coronary perforation incidence, outcomes and temporal trends (COPIT): a systematic review and meta-analysis.

Coronary perforation is a potentially life-threatening complication of percutaneous coronary intervention (PCI). We studied incidence, outcomes and temporal trends following PCI-related coronary artery perforation (CAP). METHODS: Prospective systematic review and meta-analysis including meta-regression using MEDLINE and EMBASE to November 2020. We included 'all-comer' PCI cohorts including large PCI registries and randomised controlled trials and excluding registries or trials limited to PCI in high-risk populations such as chronic total occlusion PCI or cohorts treated only with atheroablative devices. Regression analysis and corresponding correlation coefficients were performed comparing perforation incidence, mortality rate, tamponade rate and the rate of Ellis III perforations against the midpoint (year) of data collection to determine if a significant temporal relationship was present. RESULTS: 3997 studies were screened for inclusion. 67 studies met eligibility criteria with a total of 5 568 191 PCIs included over a 38-year period (1982-2020). The overall pooled incidence of perforation was 0.39% (95% CI 0.34% to 0.45%) and remained similar throughout the study period. Around 1 in 5 coronary perforations led to tamponade (21.1%). Ellis III perforations are increasing in frequency and account for 43% of all perforations. Perforation mortality has trended lower over the years (7.5%; 95% CI 6.7% to 8.4%). Perforation risk factors derived using meta-regression were female sex, hypertension, chronic kidney disease and previous coronary bypass grafting. Coronary perforation was most frequently caused by distal wire exit (37%) followed by balloon dilation catheters (28%). Covered stents were used to treat 25% of perforations, with emergency cardiac surgery needed in 17%. CONCLUSION: Coronary perforation complicates approximately 1 in 250 PCIs. Ellis III perforations are increasing in incidence although it is unclear whether this is due to reporting bias. Despite this, the overall perforation mortality rate (7.5%) has trended lower in recent years. Limitations of our findings include bias that may be introduced through analysis of multidesign studies and registries without pre-specified standardised perforation reporting CMore research into coronary perforation management including the optimal use of covered stents seems warranted. PROSPERO REGISTRATION NUMBER: CRD42020207881.

Management of Multivessel Disease and Physiology Testing in ST Elevation Myocardial Infarction.

For decades, advances in ST elevation myocardial infarction (STEMI) care have been driven by timely reperfusion of the occluded culprit vessel. More recently, however, the focus has shifted to revascularization of nonculprit vessels in STEMI patients. Five landmark randomized trials, all published in the past 7 years, have highlighted the importance of complete revascularization in STEMI treatment. This review focuses on evidence-based management of STEMI in the setting of multivessel disease, highlighting contemporary data that investigate the impact of complete revascularization.

Three-Dimensional Global Left Ventricular Myocardial Strain Reduced in All Directions in Subclinical Diabetic Cardiomyopathy: A Systematic Review and Meta-Analysis.

Background Three-dimensional (3D) speckle tracking echocardiography can identify subclinical diabetic cardiomyopathy without geometric assumption and loss of speckle from out-of-plane motions. There is, however, significant heterogeneity among the previous reports. We performed a systematic review and meta-analysis to compare 3D strain values between adults with asymptomatic, subclinical diabetes mellitus (ie, patients with diabetes mellitus without known clinical manifestations of cardiac disease) and healthy controls. Methods and Results After systematic review of 5 databases, 12 valid studies (544 patients with diabetes mellitus and 489 controls) were eligible for meta-analysis. Pooled means and mean difference (MD) using a random-effects model for 3D global longitudinal, circumferential, radial, and area strain were calculated. Patients with diabetes mellitus had an overall 2.31 percentage points lower 3D global longitudinal strain than healthy subjects (16.6%, 95% CI, 15.7-17.6 versus 19.0; 95% CI, 18.2-19.7; MD, -2.31, 95% CI, -2.72 to -2.03). Similarly, 3D global circumferential strain (18.9%; 95% CI, 17.5-20.3 versus 20.5; 95% CI, 18.9-22.1; MD, -1.50; 95% CI, -2.09 to -0.91); 3D global radial strain (44.6%; 95% CI, 40.2-49.1 versus 48.2; 95% CI, 44.7-51.8; MD, -3.47; 95% CI, -4.98 to -1.97), and 3D global area strain (30.5%; 95% CI, 29.2-31.8 versus 32.4; 95% CI, 30.5-34.3; MD, -1.76; 95% CI, -2.74 to -0.78) were also lower in patients with diabetes mellitus. Significant heterogeneity was noted between studies for all strain directions (inconsistency factor [I2], 37%-78%). Meta-regression in subgroup analysis of studies using the most popular vendor found higher prevalence of hypertension as a significant contributor to worse 3D global longitudinal strain. Higher hemoglobulin A1c was the most significant contributor to worse 3D global circumferential strain in patients with diabetes mellitus. Conclusions Three-dimensional myocardial strain was reduced in all directions in asymptomatic diabetic patients. Hypertension and hemoglobin A1c were associated with worse 3D global longitudinal strain and 3D global circumferential strain, respectively. Registration URL: https://www.crd.york.ac.uk/prospero; unique identifier: CRD42020197825.

Cardiotoxic Effect of Modern Anthracycline Dosing on Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis of Placebo Arms From Randomized Controlled Trials.

Background Anthracyclines are a key chemotherapeutic agent used against hematological and solid organ malignancies. However, their benefits in cancer survival are limited by cumulative, dose-related cardiotoxicity. The impact of anthracyclines on left ventricular ejection fraction (LVEF), in the era of modern chemotherapy regimens, remains unclear. Methods and Results Three databases (CENTRAL, MEDLINE, and SCOPUS) were systematically searched for randomized trials evaluating cardioprotective agents against placebo, in preventing cardiotoxicity. Echocardiography or magnetic resonance measured LVEF pre- and post-anthracycline-based chemotherapy was abstracted from placebo trial arms. The key terms included "anthracycline," "cardiotoxicity" and "randomized." A doxorubicin equivalent anthracycline dose metric was calculated to compare different anthracyclines. A random-effects model was used to pool mean difference in LVEF after anthracycline. Meta-regressions were calculated to identify variation sources. We included 660 patients from 19 trials. The weighted mean baseline LVEF across studies was 62.6%, and follow-up LVEF assessment was performed at 6 months. The pooled mean decline in LVEF among placebo arms was 5.4% (95% CI, 3.5%-7.3%) with a doxorubicin equivalent anthracycline dose of 385 mg/m2. Meta-regression analysis showed no significant difference in LVEF against doxorubicin equivalent anthracycline dose as continuous (P=0.29) or against published cut-offs for cardiotoxicity (250 mg/m2, P=0.21; 360 mg/m2, P=0.40; and 400 mg/m2, P=0.66). The differences in mean LVEF were not associated with sex, adjunct chemotherapy, or cancer type. Conclusions The magnitude of LVEF impairment post-anthracycline therapy appears less than previously described with modern dosing regimens. This may improve the accuracy of power calculation for future clinical trials assessing the role of cardioprotective therapy.

A Systematic Review of Scaling Left Atrial Size: Are Alternative Indexation Methods Required for an Increasingly Obese Population?

BACKGROUND: Left atrial (LA) size indexed to body surface area (BSA) is a clinically important marker of cardiovascular prognosis. However, indexation using a scaling variable such as BSA has inherent flaws, particularly in an obese population. The aim of this study was to determine whether alternative indexation methods may more accurately scale for LA size. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to execute a structured search of medical databases, to identify articles discussing alternative methods of LA indexation in echocardiography. Articles that stratified indexed LA size by obesity class were also included. Two independent reviewers identified relevant articles and extracted baseline characteristics, alternative indexation methods, scaling variables, obesity class characteristics, and correlation coefficients. RESULTS: A total of 3,804 articles were found in the database search after removing duplicates. After abstract and full-text screening, 13 relevant articles were identified. Twelve studies used alternative methods of LA indexation, of which nine reported allometric indices. Seven of the included studies reported LA size by obesity class, of which six reported alternative indices. Correlation coefficients plotted for indexed LA size against absolute measured LA size showed that allometric indices (specifically to height) were more likely to maintain proportionality to body size compared with isometric indices such as BSA. Allometric indices were less likely to overcorrect for body size compared with isometric indices. CONCLUSIONS: Compared with isometric indexation to BSA, allometric indexation (specifically to height) improves scaling of LA volumes to maintain proportionality and avoid overcorrection for body size.

Type B ankle fractures: a retrospective study of longer-term outcomes.

OBJECTIVES: Ankle fractures are common and can be treated with or without surgery. The aim of the present study was to compare patient reported outcomes between patients who sustained an Orthopaedic Trauma Association type 44-B1 ankle fracture who had either surgical or non-surgical fixation. RESULTS: Forty-six people were recruited; 38 were treated non-surgically and 8 were treated surgically. Mean follow-up time was 24 and 25 months for surgical and non-surgical groups respectively. Baseline characteristics were similar between the two groups. On unadjusted analysis, there was no significant difference between the two groups with respect to any outcome. After adjusting for age and gender, the surgical group had a significantly lower outcome score with respect to the FAOQ. Surgical management was associated with a significantly lower patient-reported ankle function compared to non-surgical management for the treatment of patients with type 44-B1 ankle fracture after adjusting for age and gender. However, there was no significant difference between the two groups with respect to the general health outcomes or adverse events. Higher-level evidence is required to inform optimal practice for this common fracture.