To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury.P < 0.01) and increases in left ventricular dimensions  compared to healthy controls. Infarcts were small with few large infarcts  and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass].One hundred and fifty-eight angiographically confirmed SCAD-survivors  were phenotyped by CMR and compared in a case–control study with 59  healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts. The extent of myocardial infarction following SCAD using state-of-the-art CMR techniques has not been reported except in one small case series.Cardiac magnetic resonance imaging (CMR) is the reference standard for The study was conducted in accordance with the Declaration of Helsinki. Consecutive patients and healthy controls were recruited from the UK Spontaneous Coronary Artery Dissection Registry to the SCAD Deep Phenotyping Study (ISRCTN42661582). Patients with SCAD in the registry are recruited from across the UK by self-referral, primary care physician referral and referral from the clinical team at the index presenting hospital. Healthy controls were recruited by open advertisement targeted to match the age/sex profile of the SCAD cohort. All participants provided fully informed signed consent to both the SCAD Registry and Deep Phenotyping Study. Comparator patients with atherosclerotic STEMI were consented female patients age <75 years undergoing follow-up CMR imaging following their index event. The protocol was approved by the UK National Research Ethics Service (14/EM/0056) and the UK Health Research Authority.To be included in the UK SCAD registry, all patients must have had an angiographically confirmed diagnosis of SCAD. Patients with atherosclerotic, traumatic or iatrogenic dissection (except where the latter complicates definite SCAD) were excluded. Angiographic analysis was conducted by two experienced SCAD clinicians (A.A.-H. and M.G.G.) with adjudication of any differences by a third experienced SCAD clinician (D.A.). All angiographic analysis was conducted blinded to the results of the CMR analysis and images classified using a modified Yip and SawDemographic information, medical history, and a detailed history of the SCAD event were obtained during the patient visit and clinical assessment including the measurement of a Beighton score . STEMI female controls were recruited from research studies from three UK centres  having been imaged using similar protocols as previously published.Quantitative and qualitative analysis was performed offline blinded to patient details using Circle CVi42 software  by experienced observers (A.A.-H. and A.K.A.) with differences adjudicated by a third experienced reporter (G.P.M.). Left ventricular (LV) volumes and function were calculated as previously described.t-tests were performed to compare infarction in the SCAD patients to both the healthy control and STEMI controls.Summary statistics including counts and percentages are provided for categorical variables and both means and standard deviations and medians and interquartile ranges (IQR) are provided for continuous variables. Independent P-values are provided for all variables. For those who had measurable infarction (>0%), linear regression was performed to investigate the associations between potential correlates and the magnitude of infarction, when this was present on LGE. Two levels of adjustment were considered, one including and one excluding left mainstem (LMS). Univariately, means, 95% CIs, and P-values are provided for categorical variables. For the continuous variables and the multivariable results, estimated model coefficients (β), 95% CIs, and P-values are provided. Variables significant at the 5% level were retained in the final models. All statistical analyses were performed using the R environment for statistical computing.Specifically for the female SCAD individuals, infarction was modelled in three ways. The correlates of the presence of any infarction (>0% compared to 0%) and large infarct size (10+% compared to <10%) were assessed using logistic regression. Odds ratios, 95% confidence intervals (CIs), and Table 1. The SCAD cohort was predominantly female and ethnically Caucasian with a mean age at the time of SCAD of 45.8 years. Fifteen (9.5%) cases were P-SCAD. A third of SCAD patients presented with STEMI whilst 6.9% presented with primary ventricular arrhythmia leading to cardiac arrest.One hundred and fifty-eight SCAD patients, 59 healthy controls, and 56 female Type-1 STEMI patients were recruited to the study. Subject characteristics are listed in Angiographic findings are shown in Fifty-six (35.8%) SCAD patients were managed with PCI with two-thirds of these managed with stenting. Of the patients managed with PCI 25 (44.6%) had a complication as a result of the procedure. The majority (20/25) were due to haematoma extension, with the remaining (5/25) cases due to distal coronary or branch occlusion resulting from PCI. A small number of patients (3.8%) were referred for emergency coronary artery bypass grafting (CABG), half after an initial attempt at PCI.Figure 1. A qualitative variation in the pattern of infarction with relative sparing of the subendocardium was noted as a characteristic feature of SCAD  and an associated increase in end-diastolic  and end-systolic  volumes in SCAD compared to matched healthy controls, SCAD-infarcts were small  with 60 (39%) patients having no demonstrable LGE  and only 6.4% having >20% infarct size.Patients with SCAD underwent follow-up CMR a median of 423 days (IQR 179–1045) following the index event. Eight patients were noted to have had recurrent SCAD. Exemplar images of patients with large and small infarcts coupled with coronary angiographic findings at the time of acute SCAD are shown in  of SCAD Figure SAP = 0.0094) and higher end-diastolic volume  compared to female Type 1 STEMI patients.The comparison of infarct characteristics due to STEMI in female SCAD-survivors with female patients <75 years with atherosclerotic Type 1 STEMI is shown in Figure 3 and The effect of a range of factors on infarct size is shown in Table 2. Univariately, increasing age at SCAD; left anterior descending SCAD; proximal vessel involvement; multivessel involvement; multisegment involvement; TIMI 0/1 vs. TIMI 2/3 flow; STEMI vs. NSTEMI presentation; and patients undergoing revascularisation compared to conservative management and patients with a Beighton score 4 compared to those with a score <4 were associated with >10% LV mass. Multivariably, STEMI presentation; initial TIMI flow 0/1 vs. 2/3; Beighton score 4+ vs. <4, and multivessel involvement were associated with infarction >10% of LV mass being present on LGE.Univariate predictors of infarction >10% LV mass are shown in Table 2. Univariately, TIMI 0/1 vs. TIMI 2/3 flow; STEMI vs. NSTEMI presentation; and patients with a Beighton score 4 compared to those with a score <4 were associated with >0% LV mass. Multivariably, STEMI presentation; Beighton score 4+ vs. <4 and multivessel involvement were associated with infarction >0% of LV mass being present on LGE.Univariate predictors of infarction >0% LV mass are shown in Supplementary material online, Table SC and multivariable predictors are shown in Univariate predictors of magnitude of infarction in SCAD-survivors with measurable infarction (>0%) are shown in P = 0.5482).No significant difference in infarct size was observed between 16 PCI and 16 conservative cases matched for ACS status  TIMI flow (six TIMI 0/1 and 10 TIMI 2/3) and angiographic appearance . Thirdly, that revascularization by PCI is not independently associated with reduced infarct size.,Although the initial presentation of SCAD is far from benign, with a third of patients presenting with STEMI and 6.9% with cardiac arrest, we have shown that a large proportion of patients (39%) have no detectable infarction and only a minority (6.4%) had very large infarction (>20%). Overall SCAD patients had a very small reduction in ejection fraction, but well within the normal range, in keeping with echocardiographic data which have suggested well preserved cardiac function in most cases.Modelling of covariates confirmed previous echocardiographic data that STEMI presentation is associated with increased chronic infarct size.,,We provide novel insights into the role of revascularization in the management of SCAD. It is well-established that conservatively managed SCAD usually heals and that PCI is associated with high failure rates or suboptimal outcome, in part, due to extension of the false lumen due to tracking of the haematoma during stent deployment.However, this study also identifies higher risk SCAD cases such as those presenting with STEMI, poor TIMI flow or multivessel disease. Percutaneous coronary intervention was not independently associated with infarct size. This may be due, in part, to the fact that PCI complications did not appear to be associated with significantly increased chronic infarct size or to the confounding effect of other covariates such as STEMI presentation and TIMI flow interact and are themselves associated with adoption of PCI. Furthermore, in cases propensity matched for STEMI/NSTEMI presentation, TIMI flow, and angiographic appearance, there was no difference in % infarct mass between conservative and PCI managed cases. However, it should be noted that most of the cases included will be ‘grey zone’ cases, as those where management appears clear-cut will not be readily matched. Therefore, in the absence of randomized data, these data appear to support the currently recommended strategy of conservative management where possible in SCAD, reserving PCI for presentations at high risk of incurring large myocardial injuries . Such high-risk patients could form the basis for a future randomized controlled trial, perhaps with infarct size as the primary outcome, especially as we have shown no difference in infarct size in the STEMI cases vs. those with atherosclerotic type 1 STEMI.Comparison of female Type 1 STEMI with SCAD STEMI suggests the different pathological aetiology underlying myocardial infarction in this population does not significantly impact on infarct size. One potential explanation is that this may result from balanced mechanisms with opposing effects on infarct size. For example, SCAD STEMI is associated with less true lumen thrombus than Type 1 STEMI.This is an observational study and, therefore, we cannot conclude that the associations demonstrated are causative. Our data are derived from a SCAD-survivor cohort. Infarcts may be larger in those that died before assessment, although post-discharge mortality following SCAD is reportedly very low. Furthermore, the fact that patients recruited to the UK SCAD registry are retrospectively consented from national patient and clinician referrals may introduce selection bias. Although this might be expected to favour inclusion of more severely affected patients, there is also the potential that patients with a more severe clinical condition might not be prepared to consent to the rigorous phenotyping protocol. Although declined consent was not observed in practice, these factors have the potential to introduce bias. Additionally, because Type 1 atherosclerotic STEMI is uncommon in the demographic group affected by SCAD, it proved to be impossible to age-match the two groups. The comparison made should, therefore, be viewed in this context. The propensity-matched data are underpowered but are included to demonstrate a lack of any large differences in infarct size in equivalent cases managed by PCI or conservatively. Finally, our primary assessment in this study was with CMR, which is a surrogate of clinical outcome as infarct size is strongly related to subsequent clinical outcomes in myocardial infarction.The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fractions when assessed on follow-up CMR. Patients presenting with STEMI, reduced TIMI flow, multivessel SCAD, and those with features of connective tissue disorders are more likely to have bigger infarcts on CMR. PCI, while frequently associated with complications, appears not to induce larger infarcts.ehz895_Online_Supplementary_DataClick here for additional data file.


Soccer players revealed higher amounts of left ventricular mass  than triathletes. Moreover, they showed a greater decrease in left and right ventricular longitudinal strain (p < 0.05 and p < 0.05) as well as in radial left ventricular strain (p < 0.05) in comparison to triathletes. An increase in left ventricular mass correlated significantly with a decrease in longitudinal  and radial  strain. In athletes, attenuation of strain values is associated with cardiac hypertrophy and differ between soccer players and triathletes. Further studies are needed to investigate whether it is an adaptive or maladaptive change of the heart induced by intense athletic training.The purpose of this prospective study was to analyze the relationship between ventricular morphology and parameters of cardiac function in two different athletic groups and controls, using feature tracking cardiac magnetic resonance (FT-CMR). Twenty-three professional soccer players (22 ± 4 years), 19 competitive triathletes (28 ± 6 years) and 16 controls (26 ± 3 years) were included in the study. CMR was performed using a 1.5 T scanner. Cardiac chamber volumes, mass and biventricular global myocardial strain were obtained and compared. In comparison to the control subjects, athletes were characterized by a higher cardiac volume ( Morphological changes of the heart associated with exercise are well studied by both echocardiography and cardiac magnetic resonance (CMR) imaging –5. HowevThe ethics committee of the general medical council approved the study. The subjects were recruited between 2014 and 2017 and gave their written informed consent. Twenty-three male professional soccer players  were recruited during their competitive season in the center for athletic medicine. Nineteen male amateur triathletes  were contacted through advertisement at local triathlon clubs and were included if they had participated in at least 10 h of weekly training and regular participation in triathlon competitions in the past 3 years. Sixteen male control subjects  with < 3 h exercise per week were recruited through local advertisement. Study exclusion criteria were contraindications for CMR or any disease. All subjects were instructed to arrive rested with no exercise in the preceding 72 h. Food and caffeine intake were restricted in the preceding 3 h.3, reconstructed voxel size (RVS) 1.36 × 1.36 × 6 mm3, gap 4 mm, 9–10 slices for full LV coverage, echo time = 1.67 ms, repetition time = 3.34 ms, flip angle = 60°, parallel acquisition technique = SENSE.Non-contrast CMR was performed using a 1.5T Achieva scanner equipped with a 5-channel cardiac phased array receiver coil . The protocol included ECG-triggered steady-state free-precession cine CMR in short axis and 2-, 3- and 4-chamber views with the following imaging parameters: acquired voxel size (AVS) 1.98 × 1.80 × 6 mm®, Cambs, UK) [Two investigators independently and blindly analyzed each CMR using cvi42 software . CMR parameters were indexed to body surface area (BSA) and are given as the mean of two observers. Evaluation of ventricular volumes and LV mass was performed in standard fashion on short axis cine images . Left  . Brieflymbs, UK) , 18. Thembs, UK) , 19.χ2 test or Fischer’s exact test as appropriate. Statistical significance was defined as p < 0.05.Statistical analysis was performed using GraphPad Prism version 6.00  and MedCalc for Windows, version 13.3.3.0 . Continuous data are presented as mean ± standard deviation (SD) and categorical data are presented as absolute numbers and percentages. Continuous data were compared using the two-sided Student's t-test and categorical variables were compared using the p < 0.05). The soccer players were younger than the triathletes (p < 0.05), but weight, height, BMI and BSA did not differ  septal/lateral wall thickness ratio did not differ between groups (p = 0.643 Table 2 than in controls with 67 ± 7 g/m2 (p < 0.001). The indexed end-diastolic LV volume (LVEDVi) was significantly higher in athletes than in controls , which was also true for the indexed end-diastolic RV volume . Furthermore, IVS thickness of soccer players was higher compared to triathletes  and − 18 ± 1% (p < 0.05) respectively (Table p < 0.01). Global circumferential LV (p = 0.141) and RV (p = 0.899) strain values were similar between groups (Table p < 0.05) and − 17 ± 2% (p < 0.05), respectively. Soccer players had a lower RV global longitudinal strain with − 18 ± 2% than triathletes with − 20 ± 3%  and RV (p = 0.101) strain values were similar between groups  and RV  diastolic longitudinal strain rates were lower in athletes compared to controls. LV and RV diastolic circumferential strain rates showed a tendency for lower values in athletes compared to controls (Table p = 0.221) did not differ. LV diastolic longitudinal strain rate  was lower in soccer players compared to triathletes. Concordantly, RV diastolic longitudinal strain rate (p = 0.065) showed a tendency for lower values in soccer players, but other diastolic strain rates values did not differ  leading to higher PFRR in athletes compared to the controls . No differences in EPFRi (p = 0.835), APFRi (p = 0.756) and PFRR (p = 0.504) were found between soccer players and triathletes as shown in Table Passive LV filling was similar between athletes and controls with comparable EPFRi values  and circumferential strain , but not with longitudinal strain  athletes had significantly reduced global radial and longitudinal strain compared to controls, while global circumferential strain did not differ, (2) professional soccer players had significantly higher LV mass and reduced biventricular global myocardial strain values in comparison to triathletes, (3) an increase in LV mass correlated with a decrease in radial and longitudinal strain.In line with findings of previous studies, we observed larger ventricular dimensions in professional soccer players and competitive triathletes than in sedentary controls , 20. BotAnalysis of diastolic parameters showed significant increase of PFRR in athletes compared to controls. This was driven primarily by lower APFR, which is in line with previously described decrease in A-wave peak velocity in echocardiographic studies –35. EPFRE/e′, measurement of tricuspid regurgitation velocity, e′ velocity and pulmonary vein doppler velocity is missing and would be required to fully understand changes of diastolic function in CMR [Some limitations need to be addressed. Currently, no longitudinal data is available to study the prognostic implications of the observed decreased LV longitudinal and radial strain parameters in subjects involved in professional or competitive sports. We cannot exclude presence of the myocardial fibrosis in our study cohort and its potential influence on LV strain parameters. Our cohort included male subjects only. Therefore, our findings can only be extended to healthy male athletes . The numn in CMR . FurtherIn conclusion, our study revealed that attenuation of longitudinal and radial strain values is associated with the level of sport induced myocardial hypertrophy in athletes and differ between soccer players and triathletes. Further studies are needed to investigate the impact of increased hypertrophy in athletes on cardiac function.


Intensive care of patients on left ventricular assist device (LVAD) support is compounded by the peculiar physiological consequences of circulatory assistance.,2. The key principles determining the RV mechanical alterations are series circulatory effects, ventricular interdependence, and ventriculoarterial coupling  function is often encountered post-LVAD implantation, with an incidence of 9.4-44% and is associated with an elevated risk of mortalitycoupling . FirstlyInterestingly, the principle of ventriculoarterial coupling is central to the post-LVAD RV dynamics, with any degree of elevation in pulmonary vascular resistance proving to be detrimental in such scenario. This explains the rationale behind the administration of phosphodiesterase inhibitors and other non-pharmacological and ventilatory manipulations aimed at attenuating an elevated RV afterload.. The coexistent systemic venous congestion compounds the situation furthermore. In the most extreme form, the clinical situation mandates biventricular assistance. Therefore, the echocardiographic predictors of post-LVAD RV failure continue to be actively investigated in order to adequately and consistently define the involved risk. However, the role of serial echocardiography in assessing the degree of septal shift on LVAD support, tricuspid valvular competency, pulmonary arterial pressure, and the concomitant RV function with the titration of inotropic support cannot be overemphasized.The mortality attributable to post-LVAD RV failure is largely a consequence of decreased flow to the LVAD, leading to a significant reduction in pump output, compromising the endorgan perfusion.The aforementioned elucidation of the impact of altered RV mechanics on clinical outcomes post-LVAD insertion highlights the importance of a sound understanding of the underlying pathomechanisms as the basis of echocardiographic surveillance and subsequent therapeutic measures. This discussion is particularly pertinent in the current era of mechanical circulatory assistance, wherein LVAD support continues to evolve as a bridge to transplantation, destination therapy, or as a temporary circulatory support with an expectant recovery of the cardiac function for the ever-growing cohort of patients with advanced heart failure, exceeding the availability of potential organ donors by a considerably wide margin


Takotsubo cardiomyopathy is a reversible cardiomyopathy with a unique morphological feature of the left ventricle characterized by an apical ballooning appearance known for approximately known 25 years. Catecholamine drive plays an essential role in the pathogenesis and pathophysiology of Takotsubo cardiomyopathy; hence, it is also called stress cardiomyopathy. Physical stress could also have an impact and leads to a greater variety of characteristics in Takotsubo cardiomyopathy.Supportive and symptomatic medication remains the mainstay therapy with priority to improving the function of the left ventricle for several days and full recovery in 3-4 weeks. Due to its similarity with myocardial infarction, Takotsubo cardiomyopathy requires careful diagnosis and management for the best possible outcome. Takotsubo cardiomyopathy (TC) is defined by a temporary and reversible systolic abnormality of the left ventricle's apical area resembling myocardial infarction (MI) in the nonexistence of coronary artery disease (CAD) . This clVarious papers from Pubmed in relation to Takotsubo cardiomyopathy were thoroughly selected and appraised. The results from those papers are discussed and summarized to complete the current review paper.The well-accepted TC diagnosis criteria is from Mayo Clinic and consists of four components: 1) temporary hypokinesis, dyskinesis or akinesis in LV segments with or without apical involvement; aberration in regional wall motion exceeding past a single vascular distribution; the existence of stress elicitation; 2) the lack of significant coronary artery disease; 3) recent changes detected in the electrocardiogram (ECG) (ST-segment elevation and/or T-wave inversion) or significant elevation of serum cardiac troponins; and 4) non-existence of pheochromocytoma or myocarditis . The sumIn-line with ECG findings, TC also shows an elevated level of cardiac biomarkers showing myocardial disturbance . In 90% The pathognomonic finding of TC during echocardiography is apical ballooning involving LV. This unique morphology was reported to appear in 75% of patients . In 25% The precise cause, pathogenesis, and pathophysiology of TC are still uncertain. Many hypotheses have been linked with the occurrence of TC. Recently, the most accepted theories are catecholamine-induced cardiotoxicity and microvascular dysfunction, in addition to the complex and integration of neuroendocrine physiology, eventually involving the cognitive centers of the brain and hypothalamic-pituitary-adrenal axis ,18.A study by Wittstein et al. revealed that the plasma levels of epinephrine were critically elevated in TC patients, with emotional stress as its major precipitating factor. In addition, the study also indicated that the serum catecholamine concentration was two to three folds higher in TC than MI patients . MoreoveIt is important to note that a recent body of evidence also revealed that there is a higher prevalence of TC due to physical triggers than that of an emotional trigger. In addition, it was generally agreed that the absence of an isolated trigger should not exclude the diagnosis of this disorder. Due to a large number of possible causes that remain unknown until now, TC may manifest a wide variety of features.Patients with TC also constantly demonstrated microvascular dysfunction features . These fRisk factors of TC include estrogen deficiency, emotional or physical stress, and genetic factors. Most of the patients with TC are postmenopausal women. A study conducted by Ueyama et al. reported that rats who were subjected to stressful conditions and then underwent ovariectomy demonstrated lower LV function than rats with estradiol supplementation . In addiEmotional stress is also playing a major role as a precipitating factor in the occurrence of TC. Stress promotes the response of the sympathetic system, which can be linked to the occurrence of TC . GeneticIn more detail, several emotional or psychological stressors have been known to initiate the onset of TC, and the structures that mediate these responses are found in central and autonomic nervous systems . The strMost common clinical characteristics of patients with TC are chest pain and dyspnea . One stuDue to its resemblance to MI, first management should focus on the treatment of CAD. Hence, one of the diagnostic criteria of TC is theexclusion of CAD. Therefore, initial therapy includes oxygen inhalation, intravenous heparin, aspirin, and b-blockers . After eHowever, when patients with TC come to the hospital in the acute phase, supportive and symptomatic treatment should be given. Hemodynamically unstable patients may need cardiopulmonary support, continuous venovenous hemofiltration, and intra-aortic balloon pump -39. OtheThe in-hospital mortality rates varied from 0-8% with recurrence rate range from 0-15% , 40-44. TC is a transient and reversible cardiomyopathy with good prognosis. The hallmark feature of TC is apical ballooning in LV similar in its outlook with the so called ‘Takotsubo’, which is a pot for octopus fishing used in Japan. Due to its similar features to MI, a careful diagnosis and management should be performed. Catecholamine levels play a vital role in pathogenesis and pathophysiology of TC, hence it is also called stress cardiomyopathy. TC risk factors include estrogen deficiency, emotional and physical stress, and genetic factors. The mainstay therapy is supportive treatment and is reported to be effective as TC patients’ LV function generally begins to restore in several days and fully recuperates in 3-4 weeks.The authors confirm that there are no conflicts of interest.


Background: Currently, normal values of the cardiac chambers' volumes are adjusted only for gender and body surface area (BSA). We aim to investigate the association between the heart rate and the volume of each of the four cardiac chambers using cardiac-gated computed tomography angiography (CCTA).Methods: A total of 350 consecutive patients without known cardiac diseases or significant (>50%) stenosis undergoing CCTA between January 2009 and June 2014 for suspected coronary artery disease were included. Cardiac chamber volumes adjusted to BSA were calculated using automated model-based segmentation analysis software of the CCTA data and correlated with patients' mean heart rate during the scan.Results: There were 240 men and 110 women, median interquartile range age was 55 years (47–61). Women were older 59.0 years (53.7–64) versus 52.0 years (45.0–59.0), had higher prevalence of hyperlipidemia, diabetes mellitus, anemia, and hypothyroidism, and higher median heart rates 64.0 (59.7–66.0) versus 60.0 (55.0–65.0) (p < 0.001). Men had a negative correlation between the volume of each cardiac chamber and the heart rate , whereas such a correlation was not found in women. The multivariate analysis showed that a decrease of five beats per minute was associated with an increase of 4%–5% in volume of each chamber in men. There was no such association among females.Conclusions: Lower heart rate is associated with an increase of each cardiac chamber volume by CCTA in men. This association is not found in women. More extensive studies are required to further elaborate on these gender differences. Volumetric measurements of both ventricles and atria have become part of the routine in cardiac imaging. Currently, the assessment of the volumes of the cardiac chambers, in every modality, including echocardiography as well as cardiac magnetic resonance (CMR), is adjusted to gender and body surface area (BSA) only.3 in which patients with reduced LV size had faster heart rates.4 This can be explained by cardiac physiology: shorter duration of the LV filling phase with increasing heart rate leads to a decrease in the end-diastole volume (EDV) of the ventricle. None of the mentioned studies, however, investigated the correlation between heart rate and the alteration in each of the four cardiac chamber volumes according to gender.Previous studies, mostly done using echocardiography, showed a correlation between the left ventricle (LV) size and the heart rate,5 One of the advantages of 4CVA technology is its capability to provide the volumes of all four cardiac chambers automatically and simultaneously. Thus, this study aimed to assess the relationship between the volumes of the four cardiac chambers based on the analysis of CCTA data and cardiac heart rate according to gender. We believe that the establishment of the relationship between heart rate and each cardiac chamber volume may contribute to refining the definitions of the normal volume of each chamber by additional adjustment to the heart rate.During the past few years, a computed tomography (CT)-based 4-chamber volumetric analysis software (4CVA) was applied to automatically assess the cardiac chambers' volumes in patients who underwent cardiac-gated CT angiography (CCTA).7 In this cross-sectional study, all consecutive ambulatory patients who underwent CCTA for the assessment of coronary artery disease (CAD) from January 2009 to June 2014 were included. Patients with known cardiac disease, that is, congestive heart failure, atrial fibrillation, and other arrhythmias, have been excluded. The medical history of each patient was documented through individual questionnaires and collected into a dedicated database. All the enrollees signed a written informed consent for participation in the study, which was approved by the institutional ethics committee.The data in this investigation constitute a part of the Tel Aviv Prospective Angiographic Survey (TAPAS). The TAPAS is a prospective single-center registry that enrolls all patients undergoing any cardiac test  at the Tel Aviv Medical Center.via 4CVA were included. Patients with evidence of significant CAD (≥50% stenosis in one or more coronary arteries), according to the present CCTA, were excluded.Patients with data on their BSA and accurate cardiac chamber volumetric segmentation CCTA was performed with a 128 × 2 × 0.625 mm or 64 × 0.625 mm detector rows scanner  using our routine coronary arteries assessment protocol. In brief, an average of 70 to 90 mL of iodinated contrast material at a concentration of 400 mg iodine per mL  and rates of 5 to 6 mL/sec were injected and timed using an automated bolus-tracking technique, placed at the descending aorta. To permit visualization of the right heart, we use three injection phases: first is the phase of contrast only (55–70 mL), second is the phase of mixed 50% contrast and 50% saline , and the third phase of 40 mL of saline flush. We used a prospective (step and shoot) mode scan for every patient with a heart rate <70 bpm or retrospective gating with dose modulation in patients with higher heart rates. During image acquisition, all patients were in sinus rhythm. Data were reconstructed at a slice thickness of 0.8 mm with an increment of 0.4 mm.n = 175) in case of a heart rate >60 bpm.Oral β-blockers (metoprolol 50 mg) were given to patients who were not pretreated with β-blockers , right atrium (RA), LV, and the left atrium (LA) of the CCTA scans were obtained using fully automatic software . The software adapts an anatomical model of the heart chambers to the CT image volume.ructures . The vol2.The volumes of the four cardiac chambers were calculated at mid-diastole, which occurs at 75% or 78% of the cardiac cycle. All volumetric measurements were divided by the BSA and reported as mL/mAlso, using dedicated coronary analysis software of the same workspace unit, the coronary arteries were evaluated for the presence of CAD using the phase that had the least motion artifacts. Obstructive CAD was defined as evidence of ≥50% reduction of the diameter in one or more of the coronary arteries on CCTA.t-test or Mann–Whitney test, as appropriate. Associations between continuous variables were assessed by Pearson product–moment correlation coefficient or Spearman's rank correlation coefficient, as appropriate. Association between each chamber volume and pulse while controlling for the effect of age was assessed using partial correlation. Univariate and multivariate linear regressions were used to evaluate the percentage change in chamber volume for a five-beat change in pulse. The covariates included in the multivariate regression were age, gender, and variables with p < 0.2 in the univariate analysis. All linear regressions were evaluated to meet the regression assumptions: linear relationship and homoscedasticity using scatter plot, normality of the errors using a histogram and Q–Q plot, and no or little multicollinearity using variance inflation factor (VIF <5 was considered as no or little multicollinearity). A two-tailed p < 0.05 was considered statistically significant. Analyses were performed with SPSS .Categorical variables were expressed as numbers and percentages. The distribution of continuous variables was assessed using a histogram and Q–Q plot. Normally distributed continuous variables were described using mean and standard deviation, and non-normally distributed continuous variables were expressed using median and interquartile range (IQR). To account for the right-skewed distribution of chamber volumes, we used natural logarithm transformation in all statistical analyses. Categorical variables were compared using the chi-square test or Fisher's exact test, and continuous variables were compared using independent samples Out of 480 patients referred for elective CCTA for suspected CAD, 130 patients (27%) were excluded due to known cardiac disease or significant (>50%) coronary stenosis on their CCTA, or inaccurate segmentation. Thus, the final cohort included 350 patients without a significant CAD, median age 55 years , 240 men (68%).p < 0.001). Women had a higher prevalence of comorbidities, including hyperlipidemia (p = 0.037), diabetes mellitus (p < 0.001), anemia (p = 0.011), and hypothyroidism (p < 0.001). Women had also higher median heart rates 64.0 (59.7–66.0) than men 60.0 . Other baseline characteristics are given in p < 0.001).Women were older with a median age of 59 years  compared with men, 52 years , (rage_adj = (−0.4)–(−0.27), p < 0.001 for all cardiac chambers), whereas there was no correlation in women.p ≤ 0.2 in univariate analysis. Hypertension, diabetes mellitus, hyperlipidemia, hypothyroidism, overweight, chronic obstructive pulmonary disease, anemia, smoking, and β-blocker were considered as potential confounders for inclusion in multivariate analysis. Among men, each chamber volume indexed to BSA was negatively associated with the heart rate; for every increase of 5 beats/min of the heart rate, there is a decrease in heart chambers volume of 4% in the volume of the LV/BSA; 4.9% in the volume of the LA/BSA; 4.5% in the volume of the RV/BSA; and 4.9% in the volume of the RA/BSA .11 However, according to the best of our knowledge, none of the previous studies investigated the relationship between heart rate and the alteration in all four cardiac chamber volumes simultaneously at rest using CCTA. In addition, despite the presence of observations regarding the effect of alterations in heart rate on LV volumes, these studies were done mainly among men and did not provide viable information on the effect of heart rate increase on heart chamber volumes among women.11–18The ability of alterations in heart rate to influence LV volumes and ejection fraction has been well recognized for many years.19 The same imaging study may provide in addition data on the volumes of each of the cardiac chambers, including the LA, RV, and RA, which can be valuable. This software was trained to identify the various cardiac compartments based on a prelearned anatomical model, thus enabling efficient workflow by automated cardiac chamber volume calculation. The output of the automated calculations was compared with the results from labor-intensive manual segmentation and found to be highly reproducible and accurate.5 Normal values for mid-diastolic LV and LA volume have been proposed previously by Walker et al.,20 showing a good correlation between mid-diastolic volumes compared with the maximum volumes of these chambers. Other methods like echocardiography have limited ability for the assessment of the right heart chambers due to the complex shape of the RV, and restrictions of the field of view and the limited acoustic window.CCTA is nowadays widely used for the assessment of CAD.21–23 This study, which contains a relatively large number of women, shows that although among men there is a significant negative correlation between heart rate and cardiac chamber volumes, such a correlation does not present among women. It is well known from the literature that gender differences exist in normal heart structure and function.24–28 Salton et al.24 defined gender-specific normal LV CMR reference values in 142 subjects free of clinically apparent cardiovascular disease or clinical history of hypertension  and Lorenz et al.25 reported normal LV CMR values in relatively young 75 healthy subjects . Both investigators reported higher LV volume in men, before and after adjustment for height and BSA. Other studies supported those results and showed that men have higher EDV and ESV, greater mass, and lower LV ejection fraction than women.27 Similar findings were observed by Robbers-Visser et al.28 in the pediatric population , supporting the hypothesis that cardiac volumes are related to gender more than to other factors such as body size.Investigations of the effect of increased heart rate on LV volume during physical exercise as opposed to resting are numerous but are mostly performed on men only.29 which can explain the larger LA volume in women.30 Smaller LV EDV indexed and LV ESV indexed have been found to be early changes of the cardiac structure in patients with diabetes with the use of cardiac MRI, without significant changes in LV ejection fraction measures.31 Another large prospective study found that the chronic influence of diabetes may manifest with LV dilatation .32 However, patients included in this study referred for coronary CTA; therefore, they do not have echocardiography, and the diastolic function was not evaluated for the patients included.In this investigation, there was no significant difference in the LV volume between men and women, and women had larger LA. A possible explanation for this could be that in our cohort study population, women were older with a higher prevalence of comorbidities, such as diabetes mellitus, than men. It has been shown in previous studies that diastolic dysfunction is one of the findings in diabetic cardiomyopathy,33–35Regarding the right heart, similar to our findings, previous studies have shown that women have lower RV volumes and higher RV ejection fraction than men.36–39 but to the best of our knowledge, gender difference with regard to the relationships between the cardiac volumes and the heart rate was not reported. Some studies showed that cardiac contractility is greater in healthy women than in age-matched men,40 and hormone replacement therapy withdrawal in women decreases contractility.41 Gender affects cardiac electrophysiological properties: women have a faster heart rate that men, estrogen increases the number of β-adrenergic receptors in the myocardium. It has been shown before that the sinus cycle length, i.e. QRS duration and HV interval, are longer in men.42 Hormonal influences could explain these findings.43–45In this study, men had a negative correlation between the volume of each of the four cardiac chambers and the heart rate, whereas such a correlation was not found in women. Extensive literature demonstrating gender differences in cardiovascular disease exists,46Another possible factor that may have contributed to the high gender-related difference of the cardiac chambers' volumes in association with the individual's heart rate in our research might be related to the difference in the age and background diseases between the subjects' gender, since women were older with more comorbidities, which comprises one of the major limitations of this study. Only 2 (3%) of the women in our study had hyperthyroidism, and 11(15%) of the women had hypothyroidism. Hypothyroidism can have effects on heart function such as a reduction in heart rate, decrease in myocardium contractility, and alteration in the diastolic function by slowing the isovolumic relaxation phase.47 Differences in gender response to β-blockers have also been reported, women have higher peak plasma levels of some β-blockers than men, because of enhanced absorption. This could lead to a greater reduction in heart rate in women.48 Since CT technology is still associated with radiation exposure, there is, however, no legitimate use of large series of volunteers for the purpose of research only; thus, we consequently had to take advantage of the CT scans that were done for clinical purposes. Nevertheless, the obtained volumes were correlated to the actual heart rate during CT acquisition itself, even if it was slowed down by the premedication, and thus they still reflect the actual association between the heart rate and the volume of each of the four cardiac chambers. In addition, the rate of β blocker use was similar between genders. Thus they are likely not influencing the finding related to gender differences.Another drawback is the use of β-blockers. Since the purpose of the CCTA was the evaluation of CAD, β-blockers were used in patients with prescan heart rate >60 bpm, to obtain the sharpest images of the coronary arteries. By using β-blockers in half of the patients, we artificially changed, that is, slowed down, the normal physiological heart rate of those patients. β-Blockers can increase LV ejection fraction by reducing ESV and optimizing ventricular filling.In summary, using the 4CVA technology, this study shows that among men, for every increase of 5 beats/min of the heart rate, there is a decrease in volume of each of the heart chambers in 4%–5%, whereas in women such an association does not exist. Thus, for establishing accurate normal limit values of heart chamber volumes, additional adjustment to heart rate in men should be considered. Since this association was not found in women, more extensive studies are required to elaborate on these gender differences further.


Heart failure is the leading cause of death worldwide, and the most common cause of heart failure is ventricular dysfunction. It is well known that the ventricles are anisotropic and viscoelastic tissues and their mechanical properties change in diseased states. The tissue mechanical behavior is an important determinant of the function of ventricles. The aim of this paper is to review the current understanding of the biomechanics of ventricular tissues as well as the clinical significance. We present the common methods of the mechanical measurement of ventricles, the known ventricular mechanical properties including the viscoelasticity of the tissue, the existing computational models, and the clinical relevance of the ventricular mechanical properties. Lastly, we suggest some future research directions to elucidate the roles of the ventricular biomechanics in the ventricular dysfunction to inspire new therapies for heart failure patients. Despite the advances in modern management, heart failure (HF) leads to high mortality and morbidity in the United States. More than 5 million Americans have HF, and around 550,000 new cases occur every year ,2. It isVentricle dysfunction is the most common cause of heart failure, including left-sided HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), as well as right-sided HF secondary to pulmonary hypertension and congenital heart disease (CHD) ,12,13,14It is generally accepted that the mechanical property of the myocardium is an important determinant of the ventricular function ,20. IndeThe ventricular free wall is known as an anisotropic and viscoelastic material, which means it has different mechanical behaviors in different directions and presents both elastic and viscous features in dynamic deformations . DependiAs needed in other biological tissues’ mechanical tests, preconditioning is often performed prior to the data acquisition to ensure a constant and accurate mechanical behavior of the tissue . This prResidual stress is the stress that remains in the tissue after all external loads are removed . The preUniaxial and biaxial mechanical tests are the most common methods to investigate the ventricular mechanical property after tissue harvest . While tFurthermore, when the entire cycle of stress–strain data is used , the ventricular viscoelastic behavior can be derived from the hysteresis stress–strain loop . HoweverStress relaxation and creep tests are traditional methods to measure the viscoelasticity of soft tissues such as tendon, cartilage, and heart valves ,51,52,53The ex vivo measurement discussed above can provide better controls of the experimental conditions  and eliminate the interference of physiological factors  in the mechanical properties of the ventricle tissues. However, the ex vivo tests require tissue removal and are often limited by the contractile state of cardiomyocytes (passive only) and the configuration of the tissue . Therefore, the in vivo measurements could provide useful information of the tissue mechanical behavior that is absent in the ex vivo conditions.systolic stiffness of the ventricle [At the whole-organ level, pressure–volume (PV) loop measurement  is the gentricle ,60.Non-invasively, cardiovascular magnetic resonance (CMR) and speckle-tracking echocardiography (STE) are alternative methods to measure the myocardial performance ,66,67. DThe direct non-invasive measurement of ventricular stiffness  can be obtained by magnetic resonance elastography (MRE) ,76. MRE Finally, with the combination of medical imaging and computational modeling such as finite element methods, it is also possible to estimate the ventricular material properties using ‘inverse modeling’ ,80,81,82The viscoelasticity of ventricles has been occasionally reported with the measurement of cyclic stress–strain relations. Some early studies measured the viscoelasticity of the LV from healthy canine and human hearts by individual measurements of pressure and volume in vivo ,87,88. BThe characterization of the anisotropic behavior of ventricles is highly dependent on the definition of the biaxial coordinate system. To date, there are two main types of coordinate systems: the main fiber and cross-fiber coordinate system ,30,44, aUsing the second coordinate system, Valdez-Jasso et al. found that the rat RV had greater stiffness in the outflow tract direction compared with the cross-outflow tract direction , and HilThe viscoelastic property of a material is manifested by the non-overlapping of loading and unloading stress–strain curves over an entire cycle . Such beBoth empirical models and constitutive models have been applied to characterize the nonlinear, biaxial mechanical behavior of ventricles. Because of the nonlinear, ‘J’-shaped stress–strain curve, the use of an exponential component is common in empirical models. However, these models provide little information on the relations of physical quantities or physiological conditions of the tissue, and thus constitutive models are developed to better describe the myocardium tissue mechanics . With cenon-cardiovascular tissues [Classic empirical models to describe the tissue viscoelasticity are composed of springs and dashpots that represent the elastic and viscous behaviors, respectively. The two basic models of these are also known as the Maxwell model (consisting of a spring and a dashpot in series) and Kelvin–Voight model . Different combinations of the spring and dashpot elements have been used to describe the ventricle and papillary muscle viscoelasticity. For example, a spring connected to two Maxwell elements in parallel was used to form a 1D viscoelastic model for the papillary muscle of the LV . An elas tissues ,94,95,96 tissues ,97,98.Heart failure is associated with extensive remodeling of the tissue involving changes in extracellular matrix (ECM) , recruitment of inflammatory cells , upregulated oxidative stress , and altered metabolic activity  ,101,102.The myocardium ECM consists of proteins such as collagen, elastin, fibronectin, proteoglycan, and laminin. Among these molecules, collagen is the most abundant ECM protein in the adult heart, with at least five different types of collagen  that have been identified . Types IVentricular fibrosis  is frequently observed in cardiac remodeling in both LV failure and RV failure ,108,109,While these previous studies investigated the role of fibrosis in the HF progression, the link of collagen deposition to the mechanical changes is another open area of research. Some biomechanical studies have quantified both biaxial mechanical properties and collagen/myo-fiber orientation in the ventricle  ,29,45. HIn chronic heart diseases, the myocardial structure and morphology changes lead to the stiffening of the ventricles ,120,121.In addition, the increased passive stiffness could result in an increase in stiffness during the systolic contraction, which is why the age-related increases in Ees  and EDPVR are correlated, regardless of the changes in arterial load . While EFinally, the stiffening of LV could impact on the pulmonary circulation as well. Pulmonary edema and elevation in pulmonary venous pressures are observed as a result of the backward transmission of elevated left-sided pressures into the pulmonary circulation. This leads to the development of post-capillary pulmonary hypertension (PH), which is commonly found in HFpEF patients . TherefoRV stiffening is consistently observed in a variety of PH etiologies as well as left-sided heart failure. Using non-invasive echocardiography, reduced RV longitudinal strains have been reported in pre-capillary PH  patients and PH patients with other etiologies ,129,130.The viscoelastic properties of the ventricle can impact the in vivo function. To date, the discussion of the relevance of ventricular viscoelasticity is mainly restricted to the diastolic function. Firstly, because the viscoelastic property is strain-rate dependent and because the early and later diastole have different filling rates, the diastolic function of the ventricle is time-dependent ,132,133.It is well accepted that the passive mechanical properties of the ventricle are important for the diastolic function, and thus heart diseases with a change in myocardial mechanical properties are often associated with diastolic dysfunction ,137,138.


To use velocity vector imaging (VVI) technology to evaluate the correlation between the apical four-chamber view and short-axis myocardial movement in rats.We used 25 10-week-old male Sprague-Dawley rats to measure the myocardium peak systolic velocity , peak diastolic velocity , peak systolic strain , peak systolic strain rate , and peak diastolic strain rate  from the apical four-chamber view of the left ventricle (LV) and the parasternal mitral valve (PMV)-level short-axis view, and to analyze the correlation between myocardial motion in corresponding views of the two sections.Comparing the myocardial motion between the lateral wall’s basal segment in the apical four-chamber view of the LV and the lateral wall of the PMV-level short-axis view revealed that the Vd was positively correlated , as was SRs . Comparing the myocardial motion between the lateral wall’s middle segment in the apical four-chamber view of the LV and the lateral wall of the PMV-level short-axis view demonstrated that Vd, SRs, and SRd were positively correlated . Our comparison of myocardial motion between the posterior septum’s basal segment in the apical four-chamber view of the LV and the posterior septum of PMV-level short-axis view showed that Vd and SRs were positively correlated . Comparing the myocardial motion between the posterior septum’s middle segment in the apical four-chamber view of the LV and the posterior septum of the PMV-level short-axis view revealed that Vs, Vd, SR, and SRd were positively correlated , and the SRs also had a significant positive correlation .VVI technology could be a valuable tool for evaluating the myocardial walls motion of the apical four-chamber view of the rat LV. Velocity vector imaging (VVI) technology, an ultrasound technology that has progressed recently, is a non-Doppler optical method using speckle tracking that enables the quantification of myocardial movement with frame-by-frame tracking of bright myocardial areas. These natural acoustic markers can be identified on 2D echocardiographic images and tracked by frame to provide velocity and displacement data . The VVITwenty-five 10-week-old healthy male Sprague-Dawley (SD) rats weighing 180–200 g were purchased from the Yanbian University Experimental Animal Center. The rats were reared for 4 weeks in ventilated cages and constant-temperature rat cages and given a quantitative standard rat feed and unlimited water. The animal experiments were approved by the Animal Experimental Ethics Committee of Yanbian University  (Protocol No. 2020175). The animal protocols were performed according to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health. We used a Siemens Acuson SC2000 color Doppler ultrasound system which was equipped with VVI technology  and a 10V4 probe (frequency 10 MHz) to examine the rats.At the end of the 4-week protocol, all rats were anesthetized with an intraperitoneal injection of 20% urethane . A physician experienced in making cardiac ultrasound-based diagnoses performed the echocardiography and VVI dynamic image collection on the rats through the apical four-chamber view of the left ventricle and the parasternal mitral valve-level short-axis view. The color Doppler system automatically analyzed the data of each segment, including the lateral wall and posterior septum of the left ventricle of the apical four-chamber view and the lateral wall and posterior septal segment of the parasternal short-axis mitral valve. The parameters of the target segment were collected five times to calculate the average values of the following: the myocardium peak systolic velocity , the peak diastolic velocity , the peak systolic strain , the peak systolic strain rate , and the peak diastolic strain rate . We used the absolute values in the comparisons of the measured values, and we conducted a Pearson correlation analysis . The measurement data are expressed as the mean±SD, and the correlation analysis was performed by the Pearson method, P-values <0.05 were accepted as significant .Our comparison of the myocardial motion between the basal segment of the lateral wall of the apical four-chamber view of the left ventricle and the lateral wall of the parasternal mitral valve-level short-axis view revealed that the index Vd was positively correlated , as was the index SRs . Our analysis of myocardial motion between the middle segment of lateral wall of the apical four-chamber view of the left ventricle and the lateral wall of the parasternal mitral valve-level short-axis view demonstrated that the indexes Vd, SRs and SRd were positively correlated . This is similar to the results reported by Wang Yafe  in a cliThe results of our comparison of myocardial motion between the basal segment of the posterior septum of the apical four-chamber view of the left ventricle and the posterior septum of the parasternal mitral valve-level short-axis view showed that the indexes Vd and SRs were positively correlated . Lastly, our analysis of myocardial motion between the middle segment of the posterior septum of the apical four-chamber view of the left ventricle and the posterior septum of the parasternal mitral valve-level short-axis view showed that the indexes Vs, Vd, SR, and SRd were positively correlated , and the index SRs also had a significant positive correlation . This is similar to the results of an earlier investigation , indicatWe observed that the Vd, SR, SRs, and SRd were well compared in the correlation of the same segment in two different aspects, which is consistent with previous reports , 14. OurIn summary, our present results demonstrated that it is feasible to use the VVI technique to study the left ventricular myocardial motion and cardiac function in the apical four-chamber view of the rat heart. VVI technology can be used to explore the characteristics of left ventricular segment movement in normal rats, and it provides a basis for experimental research on the movement and cardiac function of various segments of the heart and myocardium in rats.S1 File(ZIP)Click here for additional data file.


KoRV is unique among retroviruses in that one strain (KoRV-A) is undergoing endogenization, whereas the other main subtype (KoRV-B) and another subtype (KoRV-C) are reportedly exogenous strains. Its transmission and pathogenesis are of interest in the study of retroviruses and are crucial for any conservation strategy geared toward koala health. This study provides new evidence on the modes of KoRV transmission from parent koalas to their joey. We found vertical transmission of KoRV-A, confirming its endogenization, but with closer conservation between the joey and its sire than its dam . This is also the first report of a KoRV-B-negative joey from KoRV-B-positive parents, contrasting with the few previous reports of 100% transmission of KoRV-B from dams to joeys. Thus, the results in this study give some novel insights for the transmission mode of KoRV. Phascolarctos cinereus) genome. Although KoRV has frequently been isolated in wild and captive koala populations, its pathogenesis and transmission remain to be fully characterized, and most previous research has concentrated on adult koalas rather than on joeys. Here, we characterized KoRV isolates obtained from a deceased male joey and its parents  to investigate KoRV transmission mode and pathogenesis. We sequenced the KoRV long terminal repeat (LTR) and envelope genes isolated from the joey and its parents and found KoRV-A and KoRV-C in genomic DNA from both the parents and the joey. Notably, both parents were also positive for KoRV-B, whereas the joey was KoRV-B negative, further confirming that KoRV-B is an exogenous strain. The KoRV LTR sequence of the joey was considerably closer to that of its sire than its dam. For further characterization, total KoRV, KoRV-A, KoRV-B, and KoRV-C proviral loads were quantified in peripheral blood mononuclear cells from the parents and in blood samples from the joey. Total KoRV, KoRV-A, and KoRV-C proviral loads were also quantified for different tissues  from the joey, revealing differences suggestive of a distinct tissue tropism . The amount of KoRV-C in the parents was less than that in the joey. Our findings contribute to an improved understanding of KoRV pathogenesis and transmission mode and highlight useful areas for future research.Koala retrovirus (KoRV) is of an interest to virologists due to its currently active endogenization into the koala (IMPORTANCE KoRV is unique among retroviruses in that one strain (KoRV-A) is undergoing endogenization, whereas the other main subtype (KoRV-B) and another subtype (KoRV-C) are reportedly exogenous strains. Its transmission and pathogenesis are of interest in the study of retroviruses and are crucial for any conservation strategy geared toward koala health. This study provides new evidence on the modes of KoRV transmission from parent koalas to their joey. We found vertical transmission of KoRV-A, confirming its endogenization, but with closer conservation between the joey and its sire than its dam . This is also the first report of a KoRV-B-negative joey from KoRV-B-positive parents, contrasting with the few previous reports of 100% transmission of KoRV-B from dams to joeys. Thus, the results in this study give some novel insights for the transmission mode of KoRV. Gammaretrovirus in the family Retroviridae. KoRV is endemic in both wild and captive populations, and it represents a major threat to koala health  is from the genus a health –6. KoRV  health –, 8.A total of nine KoRV subtypes (KoRV-A to -I) have been identified up to the present , among wThe mode of transmission has been investigated for both subtypes. As with other endogenous retroviruses, KoRV-A is integrated into the germ line of the host and transmitted vertically to offspring. Reportedly, this vertical transmission apparently occurs between dams and their offspring , 10. In We previously reported on KoRV infection dynamics , and in The koala population at Hirakawa Zoo in Kagoshima, Japan, was among those targeted in our previous KoRV research. Staff at the zoo recently found a 6-month-old joey which had died and been ejected from its dam’s pouch. The KoRV statuses of the deceased joey’s sire and dam (both KoRV-A and KoRV-B positive) were known from our previous studies. Further examination of the parents and the deceased joey represented an opportunity to expand our knowledge on the disease and its transmission between parents and offspring. Accordingly, in this study, we aimed to improve the understanding of KoRV transmission mode and pathogenesis in joeys by investigating the KoRV status of the parents and their joey and by characterizing KoRV in blood and tissues from the joey.The hematology results for the parents are shown in 3; total protein [TP], 3.4 g/dl; fibrin deposit, +) and peritoneal  cavities  isolated from peripheral blood mononuclear cells (PBMCs) for the determination of KoRV proviral copy numbers in the parents and joey, with normalization against koala β-actin. Various proviral copy numbers were found in these koalas . We measTo investigate the tissue tropism of KoRV in the joey, the following organs/tissues were collected at necropsy : heart , lung F, spleen Reverse transcription-quantitative PCR (RT-qPCR) was performed to determine viral load in plasma. The viral copy numbers were 1,070,526/ml of plasma in the sire and 1,147,045/ml of plasma in the dam  and coulPCR amplification of sequences with primers U3F and U5R  resultedenv gene sequences (GenBank accession numbers MK605477 and MK605481)  from the joey and performed multiple-sequence alignment with the parents’ KoRV-A K605481) . MultiplK605481) . One poiK605481) , we alsoK605481) .In the present study, we investigated the subtype status, tissue tropism, and transmission mode of KoRV in a deceased joey koala from parents previously established to be KoRV-A and KoRV-B positive in our previous studies , 11.For KoRV-A, we speculated that vertical parent-to-offspring transmission had occurred in this case, which is in line with previous findings of 100% vertical KoRV-A transmission in regional koala populations in Australia and the inheritance of KoRV after its endogenization into the genome . Notablyde novo) infection from their dams. Such transmission could occur through uterine fluids, milk, or pap, which probably originates in the dam’s cecum. KoRV-B-negative joeys with KoRV-B-positive sires have been featured in these reports; however, to our knowledge, this is the first report of a KoRV-B-negative joey from a KoRV-positive dam. As an understanding of transmission is key to any strategy for species conservation, further research on KoRV prevalence and transmission in joeys would appear to be necessary.Our findings for KoRV-B are of particular interest. The joey was found to KoRV-B negative, although both of its parents were found KoRV-B positive (in both this study and our previous study). Although adult-to-adult transmission of KoRV reportedly occurs at a low rate, the previous (limited) reports on parent-to-offspring transmission suggested that 100% of joeys contract this subtype through horizontal   , 17, 18.Overall, our study confirms that KoRV-B is an exogenous variant of KoRV, and that KoRV-A is inherited by vertical transmission, as has been previously widely reported. However, we suggest that previous assumptions about the 100% dam-to-joey transmission rate for KoRV-B may need to be reexamined. A fuller understanding of transmission and pathogenesis is required to develop any conservation strategies, such as vaccination programs for wild animals, and will be also be of interest to virologists studying the exogenous and endogenous subtypes of this disease. In future research on the koala populations in Japanese zoos, we hope to further expand our knowledge of KoRV and provide answers to some of the questions raised by recent research.The joey was a 6-month-old male found dead and ejected from its dam’s pouch by staff at the Hirakawa Zoo in Japan ; its cadEDTA-treated whole-blood samples were collected by venipuncture from two the adult koalas (sire and dam) housed at the Hirakawa Zoological Park in Kagoshima, Japan, in accordance with the protocols of the Institutional Animal Care and Use Committee of the Joint Faculty of Veterinary Medicine, Kagoshima University. Tissue samples  were collected at necropsy from the dead joey at Hirakawa Zoological Park and stored at −80°C for further characterization. We collected whole-blood samples with heparin or EDTA by venipuncture from 2 koalas (parents) and tissue samples  from their dead joey at Hirakawa Zoological Park, in accordance with the Institutional Animal Care and Use Committee protocols.To determine the health status of the parent koalas, a hematological panel was obtained with standard protocols, and this panel included white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).Whole-blood samples (EDTA treated) were centrifuged at 3,000 rpm and 20°C for 5 min to obtain plasma samples, which were then stored at −80°C. To measure viral plasma load, viral RNA was isolated from plasma using an Isogen-LS kit , according to the manufacturer’s instructions. To remove any contaminating DNA, extracted RNA was treated with RQ1 RNase-free DNase (Promega), according to the manufacturer’s instructions.Genomic DNA (gDNA) was isolated from EDTA-treated whole-blood samples using a Wizard genomic DNA purification kit (Promega), according to the manufacturer’s instructions. gDNA was isolated from frozen tissue samples using a phenol-chloroform extraction method. The extracted gDNA was used for further characterization.Taq polymerase. The resulting target PCR fragments were subcloned into the pCR2.1 TOPO vector (Invitrogen) and sequenced.PCR was performed using gDNA as a template to amplify the envelope genes of KoRV-A, -B, and -C with genotype-specific primer sets , as descenv region of KoRV-C, using gDNA as the template. The sequence data of KoRV-C env were submitted to GenBank (accession no. MT134110). Tissue was isolated from koala blood or tissue samples using the primer sets in A nested PCR was performed to determine the nucleotide sequence of the long terminal repeat (LTR) for KoRV-A and the env gene nucleotides and LTR nucleotides was performed using the MEGA7 software .The sequence data for the KoRV-A envelope gene and KoRV LTRs are available in the GenBank database (accession numbers


Up to 24 February 2020, there have been 77,269 officially reported confirmed cases of 2019 novel coronavirus (nCoV) infection in China. Circulatory dysfunction is considered to have a late onset in severe cases of nCoV pneumonia, which is often ignored in clinical treatment. The main causes of acute respiratory failure and subsequent circulatory dysfunction include the rapid progress of lung injury, fluid overload, lung consolidation, and mechanical ventilation for hypoxemia. Most injuries are related to fluid overload, acute lung injury, and long-term hypoxia. Echocardiographic is an important part of critical ultrasonography, which helps to quickly identify the hemodynamic status. We summarized the echocardiographic features of critically ill COVID-19 patients and its clinical use in the treatment of nCoV pneumonia.The echocardiographic features of COVID-19 are mainly related to the severity of disease and cardiovascular complications. Abnormal findings include (1) hyperdynamic cardiac function, presented as the increase of cardiac output (CO) and ejection faction (EF) of the left ventricular (LV), with/without the decrease of peripheral vascular resistance, which is often seen in the early stage following the systemic inflammatory response; (2) acute stress-induced (takotsubo) cardiomyopathy, characterized as LV segmental contraction abnormalities and apical ballooning [Echocardiography can help to quickly identify the circulatory status of nCoV pneumonia patients and guide hemodynamic management. Five basic views of echocardiography  long and short axis view) should be measured, which help to quickly understand the patient’s volume status, cardiac function, and organ perfusion and help to develop hemodynamic management plans. It is suggested to measure the diameter of IVC, EF, velocity-time integral of the left ventricular outflow during continuous and dynamic evaluation of patients’ volume state and fluid responsiveness, left ventricular systolic function, and left ventricular output effect. If necessary, hemodynamic management can follow the “5P” principle, i.e., lower central venous pressure, optimized pulse/heart rate, appropriate pump function and blood pressure, and organ perfusion as the final goal.According to the pathophysiological mechanism of shock, it can be divided into 4 types: distributed shock, cardiogenic shock, hypovolemic shock, and obstructive shock. Critical ultrasonography is of great significance in fast identifying the types of shock and guide hemodynamic management. Since the focused cardiac ultrasound (FOCUS) was proposed in 2010 , fluid aNovel coronavirus pneumonia may cause the increase in pulmonary vascular resistance due to hypoxia, pulmonary vasospasm, hypercapnia, and inflammation, which further affect the right heart function. Mechanical ventilation itself, especially when lung protective ventilation is not implemented properly, will further increase pulmonary artery pressure and aggravate right heart dysfunction. Right heart dysfunction can be detected by echocardiography, therefore providing important information for circulatory and respiratory management strategies in patients with nCoV pneumonia.Novel coronavirus pneumonia is different from severe acute respiratory syndrome (SARS) in that severe lung injury occurs at the beginning. Some critically ill patients suffer from multiple organ failure, which worsen dramatically in the late stage of disease. It could be a kind of like the “inflammatory storm” with uncontrolled inflammatory reaction in the body. During hypoxia, respiratory distress, intense stress status, and inflammation, the left heart may go through the following abnormalities: segmental dyskinesia, overall hyperdynamic, and diffuse cardiodepression. Diffuse cardiodepression often occurs during lethal hypoxia, in the process of intubation, or after cardiopulmonary resuscitation. The long term of anoxia and inflammation should also be considered. The circulatory failure is often caused by diffuse cardiodepression after arrest and the decrease of vascular tension caused by lactic acidosis. Sepsis or myocardial infarction can also lead to these changes. Left heart function can be evaluated by rapid qualitative and quantitative methods using echocardiography. Critical ultrasonography can also provide etiological evaluation and treatment guidance for patients with systolic dysfunction.As an important part of critical ultrasonography, echocardiography is a useful tool for the fast screen of circulatory status, identifying the types of shock, monitoring during the respiratory and hemodynamic management, and guiding the treatment of nCoV pneumonia patients, which is especially feasible, convenient, and advantageous in critically ill patients.


Myocardial involvement induced by SARS-CoV-2 infection might be important for long-term prognosis. The aim of this observational study was to characterize the myocardial effects during SARS-CoV-2 infections by echocardiography.n = 20). The most prevalent finding was a reduced longitudinal strain observed predominantly in more than one basal LV segment . This pattern reminded of a “reverse tako-tsubo” morphology that is not typical for other viral myocarditis. Additional findings included a biphasic pattern with maximum post-systolic or negative regional radial strain predominantly basal ; the absence or dispersion of basal LV rotation ; a reduced or positive regional circumferential strain in more than one segment ; a net rotation showing late post-systolic twist or biphasic pattern ; a net rotation showing polyphasic pattern and/or higher maximum net values during diastole .An extended echocardiographic image acquisition protocol was performed in 18 patients with SARS-CoV-2 infection assessing LV longitudinal, radial, and circumferential deformation including rotation, twist, and untwisting. Furthermore, LV deformation was analyzed in an age-matched control group of healthy individuals (Myocardial involvement due to SARS-CoV-2-infection was highly prevalent in the present cohort—even in patients with mild symptoms. It appears to be characterized by specific speckle tracking deformation abnormalities in the basal LV segments. These data set the stage to prospectively test whether these parameters are helpful for risk stratification and for the long-term follow-up of these patients. Coronavirus disease 2019 (COVID-19) is a systemic viral infection caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) which may lead to life-threatening severe acute respiratory syndromes, especially in high-risk patients . COVID-1In addition, residual myocardial damage after recovery of the acute phase of the disease might have a significant impact on the patients’ prognosis probably due to SARS-CoV-2 induced myocardial fibrosis.Currently, cardiac magnetic resonance (CMR) imaging represents the gold standard for the detection of AM , 18. HowThe present paper describes the experience at the Leipzig University Hospital in detecting myocardial involvement in SARS-CoV-2-infected patients by echocardiography using a specialized extended imaging and analysis protocol to analyze different components of myocardial deformation . The autn = 4) and severe symptoms .During the acute stage of the pandemic in April 2020, transthoracic echocardiography (TTE) was performed in 18 patients with SARS-CoV-2 infection at the Leipzig University Hospital and the Community Hospital Halle . Symptoms of SARS-CoV-2 patients varied from mild/moderate to severe respiratory symptoms requiring long-term mechanical ventilation. Thus, subgroup analyses were performed in patients with mild/moderate symptoms .Furthermore, LV deformation was analyzed in an age-matched control group of healthy individuals .E and A waves , E/A ratio, E/E′ ratio  of the basal mitral annulus), isovolumetric relaxation time (IVRT) obtained by pulsed-wave (PW) tissue Doppler imaging, and left atrial (LA) volumes determined by biplane LA planimetry [TTE was performed using a Vivid S70 or Vivid q ultrasound system with an M5 or M5-S phased array probe . Echocardiographic analyses were performed with the EchoPac software  using the quantitative analysis software package. LV dimensions (M mode and/or 2D measurements), LV volumes and LVEF (by biplane LV planimetry by the modified Simpson´s rule), relative wall thickness (RWT), LV mass (LVM) (by the Devereux formula), and LV mass index (LVMI) as well as LV remodeling index (LVRI) were assessed [animetry . Right-vGlobal (GLS) and regional (rLS) longitudinal deformation was assessed by determination of layer strain in all apical views. Global (GCS) and regional (rCS) circumferential layer strain and global (GRS) and regional (rRS) radial strain were determined in apical, mid, and basal parasternal short-axis views. For analysis of rotation and rotation rate (twist and untwisting), only apical short -axis views were accepted, which definitively were within the apical third of the LV. Basal short-axis views required documentation of the LV wall during the complete cardiac cycle. In addition, RV GLS was assessed in apical four-chamber views (4-chV). The endocardial contour was manually adjusted, whereas only segments with accurate tracking by carefully visual evaluation were accepted to exclude imaging artifacts. Tracking areas were adjusted to enable full myocardial tracking excluding epicardial as well as valvular or atrial structures. Complete deformation analysis could be performed in 14 patients—one patient was excluded due to left bundle branch block (LBBB) and three due to insufficient image quality. All excluded patients belonged to the patient group with severe symptoms Table .t test. Statistical significance was accepted for p value < 0.05. Intra-observer variability and inter-observer (by another investigator blinded to each other’s results) variability were assessed in five patients.All statistical analyses were performed using SPSS Statistics version 24.0 . Continuous variables were expressed as mean value ± standard deviation (SD) and were compared between groups using Student’s d-dimer were significantly increased in patients with severe in comparison to those with mild/moderate symptoms  revealed several interesting findings potentially documenting myocardial involvement in SARS-CoV-2-infected patients with mild/moderate and severe symptoms .rLS was reduced in more than one of the basal LV segments—predominantly within the subepimyocardium documented by layer-strain analysis .rRS curves showed biphasic pattern with maximum post-systolic rRS  or a negative systolic rRS  .Absence or dispersion of basal rotation was observed .rCS was severely reduced or was positive in more than one of LV segments—predominantly in the mid and basal LV segments .The net rotation showed a late post-systolic twist or a biphasic pattern .The net-rotation curve showed an undulating polyphasic pattern during systole and/or higher maximum net values during diastole than during systole (= “chaotic” undulating diastolic pattern) .The last two criteria can only be used, if rotation of the apical segments could have been correctly analyzed. Thus, the first four criteria can be classified as major criteria. Pathological deformation (> 2 major criteria) was observed in 13 of 14 (93%) SARS-CoV-2-infected patients and in all patients with severe symptoms  COVID-19 patients, the qualitative pattern of rRS was abnormal showing no alteration of LV wall thickness or in some cases even wall thinning  . CS was abnormal in 90% of patients with severe symptoms (n = 9/10), mostly with transmural involvement.Abnormal rCS was most often observed in the inferior, and infero- and anterolateral basal LV segments showing lengthening of the respective LV segments during systole , echocardiographic findings could be confirmed by CMR Fig.  illustran = 20) showing normal findings of LV deformation in all healthy individuals  in four patients with severe and two patients with mild/moderate symptoms in comparison to reported normal mean vales of RV GLS (28.5 ± 4.8), RV GLS was at least in line with the lowest expected value for patients < 50 years in all 18 patients with SARS-CoV-2-infection , 33. It The analysis of LV deformation including circumferential strain and rotation may improve the echocardiographic diagnostic approach in AM , 27, 28.The present study suggests that SARS-CoV-2-induced AM may be detected by deformation abnormalities using speckle tracking echocardiography. SARS-CoV-2-induced myocardial involvement often shows specific LV deformation patterns due to pronounced edema and/or myocardial damage in basal LV segments. Normal global longitudinal deformation and abnormal basal rLS underline the assumption that the early stage of SARS-CoV-2-induced myocarditis is characterized by a subepimyocardial involvement. Furthermore, abnormalities of basal rRS and rCS suggest a primarily basal subepimyocardial involvement. Transmural myocardial involvement obtained by circumferential strain analysis may indicate an advanced stage of the disease at the time of investigation. Comparable to Fabry and Friedreich disease , 39, SARInterestingly, abnormal LV deformation patterns were still observed in all three patients after recovery from the acute stage indicating residual myocardial involvement. Furthermore, CMR showed late enhancement predominantly in the basal inferolateral/anterolateral LV segments indicating myocardial fibrosis or scars, respectively. Myocardial fibrosis might serve as potential arrhythmogenic substrates in long-term follow-up of SARS-CoV-2-induced AM patients. In consequence, CMR follow-up may be considered for patients after SARS-CoV-2-infection, who still show at least two major criteria of LV deformation abnormalities to assess residual scar formation or myocardial fibrosis.The observations of pathological mid basal rotational LV deformation patterns in a high percentage of SARS-CoV-2-infected patients seem to be important, but are obviously not a proof of a specific myocardial involvement in these patients.The main limitation of the present study is the relatively small number of patients. 3D echocardiography could not routinely be performed at the isolation wards. Due to the evolving situation, the data of follow-up and CMR are limited and should be considered hypothesis generating. The strengths of the present study are the new findings of myocardial involvement due to abnormalities of LV deformation obtained by modern echocardiography in patients with SARS-CoV-2. However, the data about patients with SARS-CoV-2-infection should be interpreted carefully, because differences between percentage observations within the respective (sub)groups cannot show statistical significance.Myocardial involvement due to SARS-CoV-2-induced AM might be characterized by specific LV deformation patterns—even in patient with mild/moderate symptoms. The detection of myocardial involvement by speckle tracking echocardiography is feasible at the acute stage of COVID-19 which may improve the early detection of myocardial involvement, risk stratification, and potentially cardio-protective treatment. Speckle tracking echocardiography might also be suitable to detect residual myocardial involvement after acute stage of SARS-CoV-2-infection. The present study sets the stage for follow-up studies to determine the prognostic value of these alterations in patients with SARS-CoV-2 infection.


Acute myocarditis represents a challenging diagnosis as there is no pathognomonic clinical presentation. It is rare to see heart block as the first-and-only presentation of infectious myocarditis. We report the case of a young healthy patient who presented with syncope secondary to a complete heart block. It was caused by acute presumed viral myocarditis. The diagnosis was confirmed with cardiac magnetic resonance imaging. With close monitoring, the EKG abnormalities resolved over the following 5 days. In this case report, we present the importance of several imaging tools to diagnose a rare and reversible cause of conduction disturbances. In at-risk individuals, clinicians should rule out a treatable cause of heart block before proceeding with permanent pacemaker implantation due to enormous clinical and cost implications involved. Acute myocarditis represents a challenging diagnosis as there is no pathognomonic clinical presentation . It rang3 with 48% lymphocytes, and elevated C-reactive protein at 90mg/L. Serum electrolytes, kidney and liver functions were within normal limits. A chest X-ray showed an appropriate cardiac size. The initial transthoracic echocardiography (TTE) showed a normal global left ventricular function (left ventricular ejection fraction (LVEF) 60%) and wall motion abnormalities , with reduced left ventricular global longitudinal strain (LV GLS= -14.1%)  showed grade III atrioventricular (AV) bloc with a ventricular rate of 38 beats per minute . Laborat -14.1%) .Cardiac magnetic resonance (CMR) showed increased signal intensity at the mid-lateral wall on T2-weighted images. Late enhancement revealed a patchy subepicardial hyperenhancement of the medio-distal segments of the anterior and anterolateral walls which confirm the diagnosis of myocarditis . The patAcute myocarditis represents a challenging diagnosis as there is no pathognomonic clinical presentation . The truCommon causes of acquired AV block that need to be ruled out when considering a diagnosis of myocarditis in young patient include ischemic heart disease and acute myocardial infarction, cardiomyopathies including hypertrophic obstructive cardiomyopathy, infiltrative myocardial processes , hyperkalemia, collagen vascular disease , increased vagal tone , thyroid disease, and drugs  . Most ofHigh-degree AV blocks have been related to higher morbidity and mortality in all patients with myocarditis . The patEchocardiography is useful as an initial diagnostic tool to detect the presence and severity of regional or global ventricular dysfunction and chamber dilation in children with acute viral myocarditis. Speckle tracking echocardiography is a quantitative, objective technique for intrinsic cardiac deformation in real time, providing accurate assessment of abnormal regional wall contractility as in myocarditis. Several studies have shown the superiority of strain imaging over the conventional methods used for assessment of regional myocardial dysfunction . CMR imaComplete heart block is usually an ominous finding that might require placement of a permanent pacemaker. Infectious myocarditis is a reversible cause of cardiac conduction abnormalities that should definitely be considered in the differential diagnosis of heart block before resorting to permanent pacemaker implantation, especially in young healthy patients. A suggestive history and physical exam, coupled with abnormal echocardiographic findings and positive CMR helps in the diagnosis.