High-Frequency Echocardiography　- Transformative Clinical and Research Applications in Humans, Mice, and Zebrafish.

Echocardiography is an invaluable tool for characterizing cardiac structure and function in vivo. Technological advances in high-frequency ultrasound over the past 3 decades have increased spatial and temporal resolution, and facilitated many important clinical and basic science discoveries. Successful reverse translation of established echocardiographic techniques, including M-mode, B-mode, color Doppler, pulsed-wave Doppler, tissue Doppler and, most recently, myocardial deformation imaging, from clinical cardiology into the basic science laboratory has enabled researchers to achieve a deeper understanding of myocardial phenotypes in health and disease. With high-frequency echocardiography, detailed evaluation of ventricular systolic function in a range of small animal models is now possible. Furthermore, improvements in frame rate and the advent of diastolic strain rate imaging, when coupled with the use of select pulsed-wave Doppler parameters, such as isovolumic relaxation time and E wave deceleration, have enabled nuanced interpretation of ventricular diastolic function. Comparing pulsed-wave Doppler indices of atrioventricular inflow during early and late diastole with parameters that describe the simultaneous myocardial deformation (e.g., tissue Doppler é and á, global longitudinal strain rate and global longitudinal velocity) may yield additional insights related to myocardial compliance. This review will provide a historical perspective of the development of high-frequency echocardiography and consider how ongoing innovation will help future-proof this important imaging modality for 21st century translational research.

Impact of New-generation Hybrid Imaging Technology on Radiation Dose during Percutaneous Coronary Interventions and Trans-femoral Aortic Valve Implantations: A comparison with conventional flat-plate angiography.

BACKGROUND: Technological advancements in newer-generation catheterisation laboratories may reduce patient and occupational radiation exposure. METHODS: We compared fluoroscopy time and dose-area product (DAP) between a Philips Allura X-PER FD20 and Siemens Artis Zeego Hybrid systems for 47 single-vessel percutaneous coronary interventions (PCI) and 35 transcatheter aortic valve implantations (21 Corevalve, 14 Edwards Sapien TAVI) using the FD20, versus 30 PCI and 28 TAVI (15 Corevalve, 13 Sapien) with the Zeego over a 24-month period. RESULTS: Multivariate analysis revealed that, adjusting for patient weight and fluoroscopy time, DAP (median, interquartile range) was 26% lower for PCI with the Zeego than the FD20 [55.6 (27.0-91.5) vs 77.6 (51.2-129.1) Gy.cm(2), P=0.03)] and using tomographic imaging with the Zeego did not increase DAP for TAVI procedures [98.1 (65.9-136.6) vs 112.4 (64.9-156.2) Gy.cm(2) (P=NS). Although fluoroscopy times were longer for TAVI procedures than PCI with both systems (23.5-24.4 vs 7.3-9.2mins, p<0.0001), there was a significant difference in DAP between PCI and combined TAVI with the Zeego (55.6 vs 112.4Gy.cm(2), P<0.006) but not with the FD20 (77.6 vs 98.1Gy.cm(2), P=NS). CONCLUSION: Specific dose-reducing features of the new-generation system reduced DAP more for PCI than TAVI, as valve replacement procedures use additional cine-acquisition not necessary for PCI.

Radiation dose during percutaneous treatment of structural heart disease.

BACKGROUND: With the increased application of structural heart intervention techniques, there is concern over increasing radiation dose, especially during lengthy procedures. METHODS: We compared data from 91 consecutive single-vessel percutaneous coronary interventions, 69 patent foramen ovale closures, 25 atrial septal defect closures, 49 percutaneous transluminal mitral valvuloplasties, 57 balloon aortic valvuloplasties, 53 trans-catheter aortic valve implantations (TAVI), 21 left atrial appendage occlusions and 7 MitraClip procedures. RESULTS: The following fluoroscopy times and dose-area product (median, interquartile range) were recorded: patent foramen ovale closure (7.8, 5.3-10.9 minutes; 16.9, 7.5-30.6 Gycm(2)), atrial septal defect closure (10.1, 7.3-13 minutes; 15.5, 11.6-30.5 Gycm(2)), percutaneous transluminal mitral valvuloplasty (14.3, 11.4-24.2 minutes; 37.4, 19.8-87.0 Gycm(2)), balloon aortic valvuloplasty (8.4, 5.2-13.2 minutes; 19.8, 10.2-30.0 Gycm(2)), Edwards Sapien TAVI (24.0, 19.3-34.4 minutes; 86.4, 64.0-111.4 Gycm(2)), Medtronic CoreValve TAVI (19.4, 15.0-26.0 minutes; 101.9, 52.6-143.2 Gycm(2)), left atrial appendage occlusion (18.5, 15.7-29.1 minutes; 84.1, 36.4-140.0 Gycm(2)), Mitraclip procedures (37.2, 14.2-59.9 minutes; 89.1, 26.2-118.7 Gycm(2)), coronary angiography and single vessel percutaneous coronary intervention (6.6, 5.1-11.0 minutes; 62.5, 37.0-95.8 Gycm(2)). CONCLUSION: For structural heart interventions, dose-area product was not significantly greater than for coronary angiography with single-vessel percutaneous coronary artery intervention. This should be reassuring to patients and staff attending prolonged structural heart interventions.

Splinters in the fingernails, heart and brain: thromboembolic complications of non-bacterial thrombotic endocarditis despite treatment with a direct-acting oral anticoagulant.

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition characterized by non-infectious vegetations affecting the cardiac valves. Although systemic thromboembolism is a commonly associated condition, antiphospholipid syndrome is less common. Nevertheless, treatment generally involves long-term anticoagulation. We report a case of a patient with previously undiagnosed NBTE who suffered systemic thromboembolic events despite pre-existing treatment with a direct-acting oral anticoagulant.

Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies.

BACKGROUND: Cardiovascular disease is the leading cause of death after kidney transplant. Screening for coronary artery disease is integral to pretransplant evaluation, although the relative performance of different tests is uncertain. STUDY DESIGN: Systematic review of diagnostic test accuracy studies using hierarchical summary receiver operating characteristic analysis. SETTING & POPULATION: Kidney transplant candidates undergoing pretransplant assessment. SELECTION CRITERIA OF STUDIES: Studies evaluating the accuracy of screening tests for detecting coronary artery disease. INDEX TESTS: Any non- or minimally invasive test used to diagnose coronary artery disease. REFERENCE TEST: Coronary angiography. RESULTS: 11 studies (690 participants) evaluated dobutamine stress echocardiography; 7 (317 participants), myocardial perfusion scintigraphy; 2 (129 participants), exercise stress electrocardiography; and 2 (121 participants), other tests. Dobutamine stress echocardiography had pooled sensitivity of 0.80 (95% CI, 0.64-0.90) and specificity of 0.89 (95% CI, 0.79-0.94). Myocardial perfusion scintigraphy had pooled sensitivity of 0.69 (95% CI, 0.48-0.85) and specificity of 0.77 (95% CI, 0.59-0.89). Head-to-head comparison of dobutamine stress echocardiography and myocardial perfusion scintigraphy (2 studies; 116 participants) showed that dobutamine stress echocardiography had higher specificity and at least equivalent or higher sensitivity. Indirect comparison suggested dobutamine stress echocardiography may have improved accuracy over myocardial perfusion scintigraphy (P = 0.07). LIMITATIONS: Power to detect differences in accuracy between tests is limited due to sparse data. Absence of significant coronary artery disease may not necessarily correlate with cardiac event-free survival after transplant. CONCLUSIONS: Dobutamine stress echocardiography may perform better than myocardial perfusion scintigraphy; however, additional studies directly comparing dobutamine stress echocardiography and myocardial perfusion scintigraphy are needed. Further research should focus on assessing the ability of functional tests to predict postoperative outcome.

Cardiac testing for coronary artery disease in potential kidney transplant recipients.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of coronary artery disease (CAD) and adverse cardiac events. Screening for CAD is therefore an important part of preoperative evaluation for kidney transplant candidates. There is significant interest in the role of non-invasive cardiac investigations and their ability to identify patients at high risk of CAD.  OBJECTIVES: We investigated the accuracy of non-invasive cardiac screening tests compared with coronary angiography to detect CAD in patients who are potential kidney transplant recipients. SEARCH METHODS: MEDLINE and EMBASE searches (inception to November 2010) were performed to identify studies that assessed the diagnostic accuracy of non-invasive screening tests, using coronary angiography as the reference standard. We also conducted citation tracking via Web of Science and handsearched reference lists of identified primary studies and review articles.   SELECTION CRITERIA: We included in this review all diagnostic cross sectional, cohort and randomised studies of test accuracy that compared the results of any cardiac test with coronary angiography (the reference standard) relating to patients considered as potential candidates for kidney transplantation or kidney-pancreas transplantation at the time diagnostic tests were performed.  DATA COLLECTION AND ANALYSIS: We used a hierarchical modelling strategy to produce summary receiver operating characteristic (SROC) curves, and pooled estimates of sensitivity and specificity. Sensitivity analyses to determine test accuracy were performed if only studies that had full verification or applied a threshold of ≥ 70% stenosis on coronary angiography for the diagnosis of significant CAD were included. MAIN RESULTS: The following screening investigations included in the meta-analysis were: dobutamine stress echocardiography (DSE) (13 studies), myocardial perfusion scintigraphy (MPS) (nine studies), echocardiography (three studies), exercise stress electrocardiography (two studies), resting electrocardiography (three studies), and one study each of electron beam computed tomography (EBCT), exercise ventriculography, carotid intimal media thickness (CIMT) and digital subtraction fluorography (DSF). Sufficient studies were present to allow hierarchical summary receiver operating characteristic (HSROC) analysis for DSE and MPS. When including all available studies, both DSE and MPS had moderate sensitivity and specificity in detecting coronary artery stenosis in patients who are kidney transplant candidates [DSE (13 studies) - pooled sensitivity 0.79 (95% CI 0.67 to 0.88), pooled specificity 0.89 (95% CI 0.81 to 0.94); MPS (nine studies) - pooled sensitivity 0.74 (95% CI 0.54 to 0.87), pooled specificity 0.70 (95% CI 0.51 to 0.84)]. When limiting to studies which defined coronary artery stenosis using a reference threshold of ≥ 70% stenosis on coronary angiography, there was little change in these pooled estimates of accuracy [DSE (9 studies) - pooled sensitivity 0.76 (95% CI 0.60 to 0.87), specificity 0.88 (95% CI 0.78 to 0.94); MPS (7 studies) - pooled sensitivity 0.67 (95% CI 0.48 to 0.82), pooled specificity 0.77 (95% CI 0.61 to 0.88)]. There was evidence that DSE had improved accuracy over MPS (P = 0.02) when all studies were included in the analysis, but this was not significant when we excluded studies which did not avoid partial verification or use a reference standard threshold of ≥70% stenosis (P = 0.09).   AUTHORS' CONCLUSIONS: DSE may perform better than MPS but additional studies directly comparing these cardiac screening tests are needed. Absence of significant CAD may not necessarily correlate with cardiac-event free survival following transplantation. Further research should focus on assessing the ability of functional tests to predict postoperative outcome.

Coronary artery embolism and culture-negative endocarditis post Bentall's procedure.

Infective endocarditis is an important cause of morbidity and mortality, which classically presents with fevers and nonspecific symptoms. Afebrile infective endocarditis with negative blood cultures makes diagnosis more challenging and delays in treatment can occur increasing the likelihood of complications. The presence of prosthetic heart valves places patients at an increased risk of infective endocarditis and the case described below highlights the importance of considering this diagnosis even if classic clinical features such as fever and raised inflammatory markers are not present, as well as discussing an unusual complication of infective endocarditis; coronary artery embolism leading to myocardial infarction.

Impact of Pump Speed on Hemodynamics With Exercise in Continuous Flow Ventricular Assist Device Patients.

At fixed speed, the spontaneous increase in pump flow accompanying exercise in patients with continuous flow left ventricular assist devices (cfLVADs) is slight in comparison to normal physiologic response, limiting exercise capacity. We systematically exercised 14 patients implanted with an isolated HeartWare HVAD undergoing routine right heart catheterization at baseline and at maximal safe pump speed. In addition to hemodynamics, mixed venous oxygen saturation (SvO2), echocardiography and noninvasive mean arterial pressure, and heart rate were measured. Significantly greater pump flows were achieved with maximum pump speed compared with baseline speed at rest (mean ± standard deviation [SD]: 5.0 ± 0.7 vs. 4.6 ± 0.8 L/min) and peak exercise (6.7 ± 1.0 vs. 5.9 ± 0.9 L/min, p = 0.001). Pulmonary capillary wedge pressure was significantly reduced with maximum pump speed compared to baseline pump speed at rest (10 ± 4 vs. 15 ± 5 mmHg, p < 0.001) and peak exercise (27 ± 8 vs. 30 ± 8 mmHg, p = 0.002). Mixed venous oxygen saturation decreased with exercise (p < 0.001) but was unaffected by changes in pump speed. In summary, although higher pump speeds synergistically augment the increase in pump flow associated with exercise and blunt the exercise-induced rise in left heart filling pressures, elevated filling pressures and markedly diminished SvO2 persist at maximal safe pump speed, suggesting that physiologic flow increases are not met by isolated cfLVADs in the supported failing heart.

A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance.

Background Truncating variants in the TTN gene ( TTNtv) are common in patients with dilated cardiomyopathy (DCM) but also occur in the general population. Whether TTNtv are sufficient to cause DCM or require a second hit for DCM manifestation is an important clinical issue. Methods We generated a zebrafish model of an A-band TTNtv identified in 2 human DCM families in which early-onset disease appeared to be precipitated by ventricular volume overload. Cardiac phenotypes were serially assessed from 0 to 12 months using video microscopy, high-frequency echocardiography, and histopathologic analysis. The effects of sustained hemodynamic stress resulting from an anemia-induced hyperdynamic state were also evaluated. Results Homozygous ttna mutants had severe cardiac dysmorphogenesis and premature death, whereas heterozygous mutants ( ttnatv/+) survived into adulthood and spontaneously developed DCM. Six-month-old ttnatv/+ fish had reduced baseline ventricular systolic function and failed to mount a hypercontractile response when challenged by hemodynamic stress. Pulsed wave and tissue Doppler analysis also revealed unsuspected ventricular diastolic dysfunction in ttnatv/+ fish with prolonged isovolumic relaxation and increased diastolic passive stiffness in the absence of myocardial fibrosis. These defects reduced diastolic reserve under stress conditions and resulted in disproportionately greater atrial dilation than observed in wild-type fish. Conclusions Heterozygosity for A-band titin truncation is sufficient to cause DCM in adult zebrafish. Abnormalities of systolic and diastolic reserve in titin-truncated fish reduce stress tolerance and may contribute to a substrate for atrial arrhythmogenesis. These data suggest that hemodynamic stress may be an important modifiable risk factor in human TTNtv-related DCM.

Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models.

The zebrafish (Danio rerio) is an increasingly popular model organism in cardiovascular research. Major insights into cardiac developmental processes have been gained by studies of embryonic zebrafish. However, the utility of zebrafish for modeling adult-onset heart disease has been limited by a lack of robust methods for in vivo evaluation of cardiac function. We established a physiological protocol for underwater zebrafish echocardiography using high frequency ultrasound, and evaluated its reliability in detecting altered cardiac function in two disease models. Serial assessment of cardiac function was performed in wild-type zebrafish aged 3 to 12 months and the effects of anesthetic agents, age, sex and background strain were evaluated. There was a varying extent of bradycardia and ventricular contractile impairment with different anesthetic drugs and doses, with tricaine 0.75 mmol l-1 having a relatively more favorable profile. When compared with males, female fish were larger and had more measurement variability. Although age-related increments in ventricular chamber size were greater in females than males, there were no sex differences when data were normalized to body size. Systolic ventricular function was similar in both sexes at all time points, but differences in diastolic function were evident from 6 months onwards. Wild-type fish of both sexes showed a reliance on atrial contraction for ventricular diastolic filling. Echocardiographic evaluation of adult zebrafish with diphtheria toxin-induced myocarditis or anemia-induced volume overload accurately identified ventricular dilation and altered contraction, with suites of B-mode, ventricular strain, pulsed-wave Doppler and tissue Doppler indices showing concordant changes indicative of myocardial hypocontractility or hypercontractility, respectively. Repeatability, intra-observer and inter-observer correlations for echocardiographic measurements were high. We demonstrate that high frequency echocardiography allows reliable in vivo cardiac assessment in adult zebrafish and make recommendations for optimizing data acquisition and analysis. This enabling technology reveals new insights into zebrafish cardiac physiology and provides an imaging platform for zebrafish-based translational research.