Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes . There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function . Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size,  The mortality gap between individuals with schizophrenia and the general population is growing2, suggesting the need for improved understanding of the factors underlying cardiovascular disease in this group.Compared with the general population, people with schizophrenia are both twice as likely to have a diagnosis of cardiovascular disease (CVD), and die as a consequence of CVD3. Moreover, myocardial fibrosis is implicated in arrhythmogenic sudden cardiac death3, a cause of mortality up to 5-times more likely in patients taking antipsychotic drugs compared with the general population4. Pre-clinical evidence shows that dopamine D2/3 receptor activation plays a key role in regulating cardiac function5 and that antipsychotics impair this by blocking dopamine D2/3 receptors6. Specifically, antipsychotics have been found to reduce cardiac myocyte viability7, increase myocyte apoptosis6 and induce autophagy of cardiac myocytes8, potentially leading to cardiac fibrosis9. Antipsychotics are also associated with development of inflammatory lesions and lymphocytic infiltrates within the myocardium11. D3 knock-out mice show increased interstitial fibrosis in cardiac myocyte samples12, and antipsychotics have also been found to induce interstitial and endocardial fibrosis, as well as myolysis and other changes seen in dilated cardiomyopathy9. Moreover, antipsychotic treatment is associated with impaired cardiac function in preclinical models, including reduced left ventricular ejection fraction9. Antipsychotics have other potentially cardio-toxic effects via potassium (hERG) channel blockade13 and the induction of myocardial oxidative stress and inflammation10, processes which are associated with the development of myocardial fibrosis and functional myocardial impairment14.In various cardiac diseases, myocardial fibrosis predicts both cardiovascular and all-cause mortality18. These have typically shown reductions in left ventricular (LV) ejection fraction in schizophrenia with large effect sizes (d = 0.92–1.17), even in the absence of cardiac symptoms or diagnosed CVD. However, to our knowledge there have been no prior studies examining for myocardial tissue alterations characteristic of a fibrotic/inflammatory process in patients taking antipsychotic drugs, or of cardiac function using MRI, the gold standard for assessing cardiac function22. In view of this, using cardiac MRI we set out to test the hypothesis that, compared with matched healthy controls, individuals with schizophrenia receiving antipsychotic treatment would show evidence of tissue alterations characteristic of myocardial fibrosis and inflammation, indexed by native myocardial T1 time. As secondary analyses, we also set out to examine if patients also showed changes in cardiac structure (LV mass) and function .Despite the wealth of evidence that individuals with schizophrenia are at increased risk of cardiovascular disease, there has been relatively little research directly examining cardiac function in schizophrenia. The studies that do exist have used transthoracic echocardiography (TTE) to assess cardiac function2 of each other). Inclusion criteria for SCZ were: an ICD-10/DSM-IV diagnosis of schizophrenia, and no history or family history of other psychiatric disorders. Exclusion criteria for all participants were: age < 18 or > 65 years, pregnancy or breastfeeding, a past medical history of, or current/past treatment for, any physical health condition that might impact cardiac function ), and history of past/current substance abuse, including alcohol. Exclusion criteria for HV included a personal or first-degree family history of a psychiatric disorder. Subjects were excluded if they had contraindications to MR imaging. Written informed consent was obtained from all volunteers and the study was approved by a local research ethics committee.A total of 17 patients with schizophrenia (SCZ) were recruited from community mental health services from the South London and Maudsley NHS Foundation Trust, London, UK. A total of 17 healthy volunteers (HV) were also recruited. We recruited HV matched 1:1 to SCZ for age (+/− 3 years), ethnicity (1:1 matching of people of Caucasian and non-Caucasian ethnicity), gender , and BMI . Brachial blood pressure measurements were performed following 5 min’ rest in accordance with European Society of Hypertension guidelines (eAppendix 1) using a validated oscillometric device . The first of 3 measures was discarded and the second 2 values averaged. Physical activity grading was based on the Copenhagen City Heart Study Leisure Time Physical Activity Questionnaire (eAppendix 1). Categories of activity were based on participants’ level of activity over the preceding 12 months, ranging from level 1  to level 4 (>5 h of exercise per week). Plasma HbA1c was analysed using the Tosoh G8 HPLC Analyzer . Chlorpromazine equivalent doses and dose-years were calculated as described by Andreasen and colleagues (eAppendix 1)24.Physical assessment, blood tests, study questionnaires, and cardiac MRI were all performed during the same study visit. A diagnosis of schizophrenia and exclusion of other psychiatric co-morbidity was confirmed using the Structured Clinical Interview for DSM-IVFor all participants, CMR imaging was performed on a 3 T Magnetom Prisma  using a combination of an 18-element body matrix coil and 12 elements of the 32-element spine coil. Myocardial tissue alterations were assessed in line with consensus guidelines .The Shapiro-Wilk test of normality was used to assess continuous variables. Depending on the data being normally distributed, SCZ and HV groups were compared using either unpaired d) was calculated as the difference in mean cardiac MRI outcome between patients and controls divided by the pooled standard deviation. In line with international guidelines25, we did not compare mean native T1 values with published normal ranges, as these outcomes are recognised to be scanner-specific.The primary outcome assessed was native myocardial T1 time. In addition, we conducted secondary analyses assessing cardiac structure (left ventricular mass) and function . As these were exploratory, correction for multiple comparisons was not applied. Statistical analyses were performed on volumes and masses indexed to body surface area. Physiological variables were not included as covariates in statistical analysis of cardiac parameters owing to baseline statistical matching of these factors. Where we observed significant alterations in cardiac parameters between patients and controls, for normally distributed variables, the corresponding effect size , we also set out to examine if these parameters were associated with alterations in native myocardial T1 time in patients. Spearman correlation coefficients were employed owing to the measure being robust to the influence of outliers. All statistical analysis was performed using SPSS software , for which statistical significance was defined as p > 0.05). No participant met World Health Organisation criteria for type 2 diabetes mellitus or hypertension. For patients, duration of contact with mental health services ranged from 0.5–15 years. At the time of assessment, 3 patients were receiving aripiprazole, 3 olanzapine, and 8 clozapine  and 17 controls  were included in final analyses. Further subject characteristics are described in Table p = 0.02; Cohen’s d effect size = 0.89). Moreover, compared with HV, SCZ patients presented with lower indexed LV mass , smaller indexed LV end-diastolic volume , smaller indexed LV stroke volume , smaller indexed RV end-diastolic volume (p = 0.02), and smaller indexed RV stroke volume . The difference was not significant in SCZ compared with HV for the following parameters: LV and RV ejection fraction, and indexed LV and RV end-systolic volume . Representative maps demonstrating differences between patients and controls for native myocardial T1 times are shown in Fig. As shown in Fig. p = 0.02).Variation in T1 values between mid-myocardial segments and removal of 3% of ventricular segments (owing to identification of artefact) may have resulted in error in calculation of mean T1 time for some participants. However, re-inclusion of these 6 segments in the analysis did not significantly alter results, with T1 relaxation time remaining significantly longer in SCZ compared with HV (p = 0.12). No significant association was observed between T1 relaxation time and the following 4 variables: antipsychotic dose ; duration of treatment , mean arterial pressure , and HbA1c .Removal of subjects taking aripiprazole (Supplementary Table 2) did not change results, except for indexed LV mass where the difference between patients and controls was no longer significant (d = 0.76–1.11). Subjects were matched for age, gender, ethnicity and BMI, and there were no statistical differences between the groups in terms of smoking status, blood pressure, HbA1c, and physical activity, indicating that our findings are unlikely to be explained by these cardiac risk factors.We observed that, compared with matched controls, native myocardial T1 was longer in antipsychotic-treated individuals with schizophrenia, who also exhibited lower indexed ventricular mass and smaller indexed ventricular and stroke volumes, with large effect sizes 28. Echocardiographic evidence of cardiac disease in the context of metabolic syndrome and smoking (leading to ischaemic heart disease) is characterised by LV hypertrophy and potentially reduced ejection fraction29. Thus, it is little surprise that these studies exhibited outcomes characteristic of a group with increased cardiovascular risk. However, in the current study, we matched patients and healthy volunteers for multiple cardiovascular risk factors and ethnicity, and in this context, absence of LV hypertrophy and EF reductions suggests that previously observed cardiac alterations in schizophrenia were likely the product of increased prevalence of cardiovascular risk factors in the patient group, alongside the added potential confound of different ethnic makeup of the two groups. The current study is also the first to observe reductions in end diastolic and stroke volumes in patients with schizophrenia compared with controls. Beyond the limitations of previous studies in matching patients with healthy volunteer groups, this could relate to differences in the method of assessing cardiac volumes, with MRI recognised as the more accurate measure compared with echocardiography22.The results of our study contrast with previous cardiac imaging studies in schizophrenia19. Moreover, CMR is the gold standard for LV function and mass quantification20, and has been demonstrated to provide better test-retest reliability than echocardiography21, as well as lower inter-operator and intra-operator variability for a range of key measures22. Thus, this study is the first to use the gold standard approach to measure cardiac function in schizophrenia research to date. A further strength is the matching of patients and controls for cardiac risk factors, thereby limiting the influence of confounders on outcome variables. Nevertheless, we cannot exclude residual confounding due to subtle sub-clinical metabolic or other variation32. Moreover, it is recognised that measurement of certain variables  were based on self-reporting. The Copenhagen Physical Activity Score is not specifically designed for psychiatric populations, and individuals with schizophrenia can over-estimate the amount of physical activity in which they engage33. This may have contributed to our finding of no significant difference in patients compared with controls with regards physical activity scores. However, a priori matching of groups in terms of BMI and exclusion of patients with cardiovascular comorbidity may by association have resulted in our observation of similar activity levels in the 2 groups. Future studies may consider including actigraphy to objectively quantify physical activity levels. Finally, although we measured BMI, we did not assess diet/abdominal obesity. However, metabolic alterations seen in schizophrenia or simply associated with poor diet, reduced exercise, and smoking would be expected to result in cardiac dysfunction typical of metabolic disease (such as LV hypertrophy29), the opposite to the pattern observed in this study. Indeed, although not statistically significant, in absolute terms BMI was raised in SCZ compared with HV (p = 0.31). However, increased BMI is associated with LV dilatation34, while we observed the opposite in SCZ relative to HV. This suggests that residual confounding due to metabolic alterations or inaccurate reporting of lifestyle factors was not sufficient to alter outcomes, and indeed may have reduced the effect size magnitude of some parameters observed. Similarly, although patients and healthy volunteers were statistically matched for proportion of males and females (p = 0.50), there was still a relative increase in the proportion of females in the healthy volunteer group compared with patient group. Some35, although not all36, studies have observed prolonged native T1 in females compared with males. Moreover, smaller LV mass and ventricular volumes are observed in females compared with males35. However, with a greater proportion of females in the HV group, one would expect this to result in relatively prolonged native T1 time and reductions in LV mass/volumes in HV, whereas we observed the opposite, suggesting this does not explain our findings. However, future studies with larger sample sizes that employ more assessments of cardiometabolic health  are indicated.A strength of this study is the use of cardiac MRI to visualise the myocardium, which provides volumetric and functional cardiac measures that are not possible to derive from alternative cardiac imaging techniques, including assessments of myocardial tissue behaviourRemoval of 3% of the mid-ventricular segments used to calculate mean T1 relaxation time (owing to identification of artefact) and variation in T1 values between the 6 mid-myocardial segments, may have altered the mean T1 calculation for some participants thereby influencing results. However, we are reassured that re-inclusion of these 6 segments in the analysis was not associated with any change in outcomes.37.It should be recognised that native myocardial T1 time is not a specific marker of fibrosis. Future studies could employ further MRI measurements of myocardial fibrosis, such as post-contrast T1  mapping to provide additional validity, and T2 mapping to examine specifically for myocardial inflammation, although sensitivity for low-level oedema/inflammation is limiting 10. Thus, our observations are compatible with antipsychotic treatment having a similar effect in humans, although future studies are required to examine if this is indeed a global effect of treatment, or specific to only certain drugs. When taken in the context of the broader outcomes of the current study, with longer native T1 times associated with lower ventricular mass, and smaller ventricular and stroke volumes, these findings are more compatible with a diffuse fibrotic process in patients resulting in reduced myocardial compliance, rather than a myocarditic process. Indeed, previous in vivo studies have observed that myocarditis is associated with increased LV mass38, rather than our observation of a relative decrease in LV mass. Furthermore, although myocarditis is a recognised complication of clozapine, and 8/14 patients (57%) included in this sample were prescribed clozapine, patients included in the study were systemically well, with no history suggestive of myocarditis.Longer native myocardial T1 times in patients may reflect an early diffuse myocardial fibrosis and/or sub-clinical myocardial inflammation. Patients were taking a number of different antipsychotics including clozapine. Pre-clinical data suggest that both clozapine and non-clozapine antipsychotics can induce myocardial tissue alterations characteristic of fibrosis and inflammation, in a dose-dependent manner39. These studies, after controlling for metabolic syndrome diagnoses, observe an inverse relationship between myocardial fibrosis and end-diastolic volumes and LV mass. In preclinical models of aging, the mechanism underlying reductions in LV mass in the context of fibrosis seem to relate to myocardial collagen fibre deposition and myocyte cell death occurring at a greater rate than concomitant hypertrophy in remaining myoctes40. Reductions in end diastolic volumes are thought to be a consequence of the accumulation of collagen within the myocardium impacting its elasticity and limiting torsional recoil and ventricular suction.Our findings are in keeping with previous studies examining relationships between interstitial myocardial fibrosis and broader myocardial structure and function in the general population and in systemic inflammatory disease states such as rheumatoid arthiritis16. Thus, the overall findings of this study, compatible with early diffuse myocardial fibrosis and/or sub-clinical myocardial inflammation in medicated patients with schizophrenia even in the absence of metabolic disease, could have significant clinical implications. For example, in various cardiac disease states, including non-ischaemic dilated cardiomyopathy and valvular pathology, myocardial fibrosis independently predicts both cardiovascular and all-cause mortality3. If antipsychotic treatment in schizophrenia is indeed associated with a myocardial fibrotic process, then establishing the mechanism of these myocardial tissue alterations could potentially lead to identification of novel therapeutic approaches to reduce mortality rates in schizophrenia.Compared with the general population, people with schizophrenia are both twice as likely to have a diagnosis of CVD, and die as a consequence of CVD10, the cardiac alterations observed in the current study may be the consequence of antipsychotic treatment. Further studies are therefore required to examine the potential link between antipsychotic medication and myocardial tissue alterations in humans by longitudinally assessing cardiac function in patients over time; when antipsychotic naïve and then during treatment.Taken in the context of previous preclinical studies that have observed myocardial fibrotic and inflammatory changes accompanying antipsychotic administration41, systemic alterations that are associated with myocardial fibrosis and functional myocardial impairment14. Examining myocardial alterations in antipsychotic naïve first episode psychosis would also provide insight into the role of physiological alterations that are putatively intrinsic to psychosis in altering myocardial structure and function.However, the absence of significant correlations between antipsychotic dose/duration of treatment with native myocardial T1 time could be interpreted as suggesting that antipsychotics do not play a major role in the observed CMR alterations, although it is recognised that the study is not powered to examine this dose-response relationship. There is an emerging body of evidence suggesting that psychotic illness is independently associated with increased markers of oxidative stress and inflammation42 and diabetes mellitus43, but also in clozapine treated models44.Finally, studies examining the potential to attenuate accelerated myocardial fibrosis/inflammation in patients with schizophrenia may be required and could provide insight into novel therapeutic avenues with the potential to reduce mortality rates of patients with schizophrenia. Moreover, if antipsychotics are implicated in myocardial tissue alterations, examining antipsychotic dose-related cardiac alterations could guide clinicians with regards best practice in improving mental health without detrimentally impacting the physical health of patients. Furthermore, pharmacological interventions designed to target myocardial fibrosis/inflammation may be of therapeutic worth, and future studies exploring their use in antipsychotic treated individuals warranted. For example, drugs targeting the renin-angiotensin-aldosterone system have been observed to ameliorate myocardial fibrosis not only in preclinical models of hypertensionPatients with schizophrenia taking antipsychotics show myocardial tissue alterations characteristic of an early diffuse fibrotic/inflammatory process that are not explained by other cardiac risk factors. These alterations could contribute to excess cardiac mortality rates observed in schizophrenia.Supplementary Information


Despite ongoing advances in the treatment of patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), they remain a major global public health concern conferring an increased risk of morbidity and mortality in affected individuals. This is, in part, because of the widespread dysfunction imposed by HIV and its treatment on the cardiovascular system, including the myocardium, valvular apparatus, pericardium and coronary, pulmonary and peripheral vasculature. In recent times, cardiovascular magnetic resonance (CMR) imaging has emerged as the gold standard tool for assessment of a variety of indications, allowing comprehensive characterisation of functional, morphological, metabolic and haemodynamic sequelae of several cardiovascular pathologies. Furthermore, continued advancement in imaging techniques has yielded novel insights into the underlying pathophysiology and guides future therapeutic strategies. In this article, we review the various clinical phenotypes of HIV-associated cardiovascular disease and highlight the utility of CMR in their assessment. HIV-associated CVD results from a complex interplay of factors, including, but not limited to, chronic inflammatory processes resulting from HIV infection itself, opportunistic infections, concurrent metabolic changes resulting from the use of ART and conventional risk factors for atherosclerotic CVD.4 Consequently, HIV-associated CVD involves all segments of the cardiovascular tree, commonly affecting the left ventricular (LV) myocardium, valvular apparatus, pericardium and coronary, pulmonary and peripheral vasculature.4As a consequence of the introduction of combination antiretroviral therapy (ART), the survival of people living with HIV infection has improved substantially.Various modalities of cardiovascular imaging are integral to the assessment of CVD, and many are ingrained into the modern practice of cardiovascular medicine. Cardiovascular magnetic resonance (CMR) has emerged as the gold standard technique for many indications, allowing comprehensive characterisation of functional, morphological, metabolic and hemodynamic sequelae of various cardiovascular manifestations. In this article, we review phenotypes of HIV-associated CVD along a clinical continuum and highlight the utility of CMR in their assessment.5 Furthermore, the ability to obtain images in any tomographic plane regardless of body habitus confers significant advantage in patients with limited sonographic acoustic windows.5Several unique properties of CMR contribute to its widespread utility in the assessment of the cardiovascular system. The relatively high spatial and temporal resolution coupled with excellent tissue contrast enables comprehensive assessment of multiple parameters pertaining to cardiovascular morphology and function, without exposure to ionising radiation.5 More recently, native (precontrast) T1 and T2 mapping techniques have allowed direct measurement of myocardial relaxation times on a pixel-wise basis, parameters which have been extensively validated offering similar diagnostic performance and superior sensitivity for inflammation, infiltration, acute injury and fibrosis as compared with delayed enhancement imaging in detecting myocardial pathology.7 T1 maps are most commonly acquired using modified look-locker inversion recovery (MOLLI)-based or saturation recovery single-shot acquisition (SASHA)-based sequences in the short-axis plane at the basal, mid and apical LV levels. The underlying principle involves the application of an inversion or saturation pulse followed by successive sampling of the relaxation curve as myocardial longitudinal magnetisation returns to its original level. The entire relaxation curve is then extrapolated from the acquired data and the native T1 values extracted. For ease of interpretation, these values are displayed as a colour map superimposed on anatomic images, allowing global and segmental quantification of T1 values using targeted regions-of-interest (ROIs). The further acquisition of T1 maps following contrast administration allows for the estimation of myocardial extracellular volume (ECV), a marker of myocardial tissue remodelling which has been shown to be a robust measure of the degree of myocardial fibrosis.7Characterisation of myocardial tissue is a unique feature of CMR, traditionally achieved through late gadolinium-enhanced imaging and based on the relative difference in volume of distribution of intravenously administered contrast [and subsequent alteration of longitudinal relaxation (T1) times] between normal and abnormal myocardium.In addition to the assessment of biventricular function using ejection fraction (EF), several CMR techniques have been developed to quantify myocardial deformation (i.e. strain) throughout the cardiac cycle. In essence, this is achieved using multiple magnetic labels (in the form of black lines or tags) which are superimposed on and embedded into the myocardium at the start of a cine sequence see . The sub9 Conventional indices available for the assessment of LV function include the EF, volumes, wall motion, thickness and mass.5 The measurement of systolic and diastolic strain and strain rate parameters provides more sensitive information about global and regional cardiac function and cardiac deformation properties, and changes in strain parameters often predate the development of overt LV systolic dysfunction.10Left ventricular systolic and diastolic dysfunction are well documented in HIV-infected persons, with most data emerging from echocardiography-based studies.12 In the setting of preserved EF, impairment was detected on CMR as reduced circumferential,10 longitudinal11 and radial12 strain and strain rate measurements.Several studies using CMR have consistently demonstrated the presence of regional LV systolic and diastolic dysfunction in asymptomatic individuals.13 Another study of 129 HIV-infected patients showed a 47% higher median myocardial lipid content and 76% prevalence of myocardial fibrosis, using MR spectroscopic and parametric mapping techniques, respectively, raising suspicion that these morphologic abnormalities may underlie cardiac dysfunction in this subset of patients.11A cross-sectional study of 698 HIV-infected persons showed that 48% had diastolic dysfunction, which was associated with the co-existence of conventional cardiovascular risk factors .14 Direct invasion of cardiomyocytes by HIV has been described, though this occurs in a haphazard fashion with no clear association between viral load and extent of myocardial involvement.15 Worsening immunosuppression predisposes to cardiotropic viral infection  and infection by opportunistic pathogens including Mycobacterium tuberculosis, Toxoplasma gondii, Cryptococcus neoformans and Histoplasma capsulatum.4 It is worth noting, however, that no specific pathogen is identified in up to 80% of affected patients, and clinical presentation is heterogeneous with a large proportion of patients remaining asymptomatic despite ongoing subclinical myocardial oedema and inflammation.16Inflammatory changes within the myocardium have been extensively studied in the context of HIV infection and contribute significantly to the eventual decline in cardiovascular function and the development of cardiomyopathy in affected individuals.Cardiovascular magnetic resonance is a powerful tool for diagnosing myocarditis because of its ability to accurately delineate areas of myocardial oedema, necrosis, infiltration and fibrosis. Standard cine balanced steady-state free precession (bSSFP) sequences may show regional wall motion abnormalities, areas of increased wall thickness associated with acute inflammation and the presence of co-existent pathologies, which includes characterisation of the extent, location and haemodynamic significance of any pericardial effusions.6 The acquisition of post-contrast images yields further insight as regional vasodilation and acute myocardial necrosis result in altered gadolinium kinetics, with an increased uptake and rapid distribution of gadolinium chelates into the expanded interstitial space. The acquisition of T1-weighted images acquired approximately 2–5 min following contrast administration allows for the quantitative assessment of the myocardial early gadolinium enhancement ratio (EGEr), a ratio between myocardial and musculoskeletal enhancement, which highlights the variation in gadolinium distribution resulting from tissue damage . Late gadolinium-enhanced MR images use inversion recovery sequences to null normal myocardium, highlighting areas of retained contrast as high signal areas representative of focal myocardial fibrosis. Findings classically include linear, patchy or nodular areas of enhancement in a non-coronary distribution  with a mid-wall or sub-epicardial pattern17  see , and morrn17 see . Lastly,19 Ntusi et al. looking at 103 HIV-infected individuals, without known CVD, found evidence of subclinical myocardial oedema and an increased incidence of pericardial effusions, providing additional evidence for chronic myocardial inflammation.20Luetkens et al. studied 28 HIV-infected patients, on HAART with HIV RNA < 200 copies/mL, using CMR and found elevated parameters indicating myocardial inflammation  as compared with healthy controls.21Acquired cardiomyopathy in the context of HIV infection represents the final common pathway of a complex and multifactorial process resulting in systolic and diastolic dysfunction and, most often, progression to a dilated cardiomyopathy see . In ‘TheAlthough echocardiography remains the first-line imaging modality for the diagnosis of HIV-associated cardiomyopathy, CMR allows comprehensive, easily reproducible assessment of cardiac morphology and function, with added tissue characterisation techniques allowing the detection and quantification of underlying myocardial fibrosis through late gadolinium enhancement (LGE) and parametric mapping techniques see . This prMycobacterium tuberculosis being the most likely pathogen implicated. Historic studies demonstrated that tuberculous pericarditis accounted for over 80% of causes of pericardial effusion in HIV-infected individuals occurring in sub-Saharan Africa.23 The underlying pathophysiology implicates retrograde lymphatic spread from peribronchial and mediastinal lymph nodes or haematogenous dissemination from primary tuberculous infection. The manifestations of tuberculous involvement of the pericardium may include pericarditis, pericardial effusions with or without associated effusive-constrictive syndromes and progression to calcified pericardial constriction.26The spectrum of pericardial disease associated with HIV is broad with isolated pericardial effusions reported as the commonest manifestation. Although non-specific, their presence supports active inflammation and may add weight to the diagnosis of subclinical myocarditis or point to primary pericardial disease, with 27  playing a role.29 Endothelial cells are thought to alter procoagulant, anticoagulant and fibrinolytic pathways in vivo, while underlying HIV-associated platelet dysfunction and background vasculitis likely contributes to the development of CAD.31 Furthermore, the chronic inflammatory state imposed by HIV infection is associated with an increased risk of spontaneous coronary artery dissection (see 32The association between HIV and accelerated coronary artery disease (CAD) is well described and has been the focus of extensive study in recent years.tion see . In addide novo manifestations of heart disease within the HIV-positive subset of the cohort (518 of 5328 cases), CAD was the primary diagnosis in only 14 patients (2.7%).21 In a cohort of 12 800 HIV-infected patients, Zhang et al. concluded that increasing age was associated with non-AIDS defining illnesses, including CVD.33 The widespread accessibility to ART may, in part, be responsible for the changing spectrum of diseases related to HIV, with an overall shift from AIDS-related illnesses to long-term age-related complications.28Despite the known relationship between HIV infection and accelerated atherosclerosis, the anticipated pandemic of CVD related to CAD has not materialised in sub-Saharan Africa. ‘The Heart of Soweto Study’ showed that, of the 32 In a study of 35 HIV-positive patients, a significant increase in right coronary artery vessel wall thickness was found as compared with healthy controls.34 Another publication showed that the extent of local coronary epicardial adipose tissue was significantly related to coronary endothelial dysfunction as measured on coronary CMR.35 With the ongoing advances in the treatment for HIV and a steadily increasing life expectancy in infected individuals, accelerated CAD is likely to play a more significant role in HIV-related CVD over time, and novel CMR techniques offer insights that may broaden our understanding of this condition and inform future treatment strategies.Coronary angiography has been the gold standard for the assessment of the coronary arteries for several decades, offering high spatial and temporal resolution of coronary flow. A significant limitation has been its inability to provide information about the affected vessel walls themselves, preventing further study of plaque characteristics and vascular remodelling associated with ongoing or subclinical disease. Computed tomography is more recently recognised as a robust tool for the assessment of coronary anatomy and quantification of overall calcified and non-calcified plaque burden, but has limitations in its ability to offer further insights into the underlying properties of tissues being imaged. Ongoing advancements in high field strength coronary MR have shown great promise in accurately gauging the degree of coronary stenosis, allowing coronary vessel wall imaging, measurement of coronary blood flow velocities and further characterisation of non-calcified plaques using delayed enhancement imaging techniques.36 CMR techniques used to study this entity include measurement of reduced aortic distensibility, as demonstrated by cine acquisitions through various aortic planes and increased pulse wave velocity as calculated from phase contrast velocity encoded sequences. Both measures have been shown to be sensitive markers of reduced aortic elastic function, predictive of both future adverse cardiovascular events and mortality in several population-based studies. A study by Rider et al. found that treated HIV infection in patients without concurrent metabolic syndrome was associated with an 11% increase in pulse wave velocity and 14% regional reduction in aortic distensibility as compared with healthy controls.37 This effect was similar in HIV-negative patients with metabolic syndrome and additive in the subset of patients with both illnesses occurring concurrently.37Human immunodeficiency virus-associated vasculopathy encompasses a wide spectrum of conditions including cerebrovascular disease, peripheral arterial thrombosis, arterial aneurysms and deep venous thrombosis. Its epidemiology remains incompletely characterised, with several described histological subtypes and a multifactorial aetiology.38The effects of chronic inflammation and ART-associated lipodystrophy exert similar effects on the entire vascular system, with increased carotid artery intima-media thickness (C-IMT) on B-mode ultrasound shown to be predictive of future stroke and myocardial infarction. C-IMT, as measured by carotid CMR, has been shown to correlate well with sonographic measurements, with the added advantage of preserved resolution along the entire length of the examined arteries and ability to derive novel whole vessel parameters including plaque volume quantification, which may be useful as surrogate markers for longitudinal follow-up of cardiovascular risk in this subset of patients.39 The precise mechanism is uncertain, with both host and viral factors thought to contribute to the underlying pathogenesis. Furthermore, an increased propensity for thromboembolic disease or recurrent pulmonary infections with resulting pulmonary fibrosis likely contributes to the development of PAH and the high mortality associated with this condition.The estimated prevalence of pulmonary arterial hypertension (PAH) in the HIV population is 0.5%, up to 2500-fold greater than that of the general population.40 LGE has been noted at the superior and inferior LV or RV hinge-points in patients with PAH.40 The degree of enhancement has been shown to relate to RV volume and mass, raising suspicion that increased mechanical strain exacerbates structural deformation at the insertion points of the interventricular septum, resulting in architectural distortion and fibrosis of the myocardium in this region.41The imaging findings of HIV-associated PAH are indistinguishable from those of primary PAH, with morphologic abnormalities observed including, dilatation of the pulmonary trunk, main pulmonary arteries and eventually the right ventricle (RV) and right atrium. Cine imaging is used for the quantification of RV indices  and assessment of tricuspid regurgitation, following annular distortion related to RV dilatation.1H-MR spectroscopy (1H-MRS) is broadly accepted as a fast, accurate and reproducible means for the quantification of intra-cellular triglyceride content in the cytosol of non-adipose cells.42 Most commonly, a single volume of interest (voxel) is positioned over the interventricular septum, and myocardial spectra (with and without water suppression) are acquired at end-systole in several cardiac planes using either point-resolved spectroscopy (PRESS) or stimulated echo acquisition mode (STEAM) sequences. Subsequent analysis allows the expression of several myocardial lipid constituents  as a percentage of the overall tissue water content. Two recent studies using 1H-MRS have demonstrated increased myocardial lipid content in patients with HIV, adding weight to the hypothesis that morphologic alterations in myocardial tissue and possible lipotoxicity may underlie subclinical LV dysfunction.43Thrombi represent the most common cardiac mass, with stagnant blood flow in the setting of LV systolic dysfunction, myocardial infarction or aneurysms, and dilated cardiomyopathy coupled with a chronic inflammatory state predisposing to their formation. When large, these may be readily apparent on transthoracic echocardiography; however, suboptimal visualisation of the left atrial appendage and LV apex may compromise their detection with potentially disastrous clinical consequences. Additionally, despite good sonographic visualisation of the LV apex, layered mural thrombi may be difficult to differentiate from underlying myocardium.In contrast, thrombi are readily detected on CMR, largely appearing as low intensity mass lesions that are incompatible with the normal myocardial contour or commonly noted intra-cardiac anatomical structures  on standard cine SSFP sequences. The acquisition of early post-gadolinium inversion recovery sequences, typically 1–2 min following intravenous contrast administration, facilitates detection as the avascular thrombi appear hypointense in contrast to the enhancing blood pool and perfused myocardium.44 resulting in pulmonary or systemic embolisation45 or conduction abnormalities.46 Most cases are of the diffuse large B-cell subtype, presenting as a solid, ill-defined mass typically centred in the right atrium with infiltration along the epicardium and tricuspid annulus, with associated encasement, rather than invasion, of the coronary arteries.47 The relatively low likelihood of concurrent intratumoural haemorrhage or necrosis results in a homogenously hypo- or isointense mass on T1-weighted images, with variable LGE (see There is a substantial increase in the risk of developing non-Hodgkin’s lymphoma in HIV-infected patients, with secondary involvement of the heart found frequently at post-mortem, thought to result from lymphatic, haematogenous or direct extension. Clinical presentation is often heterogeneous with patients remaining asymptomatic until the tumour produces significant mass effect or obstruction of cardiac chambers or great vessels, LGE see .Cardiovascular magnetic resonance thus enables comprehensive characterisation of cardiac masses, with cine imaging allowing characterisation of the size, shape and location of these lesions while allowing review of potential complications, including mass effect on adjacent coronary arteries and infiltration of surrounding structures, that may explain co-existing conduction defects and haemodynamic sequelae related to valvular dysfunction.Human immunodeficiency virus infection affects the entire cardiovascular axis through a complex interplay of multiple host, viral and treatment related factors. The availability of and access to ART have had a significant impact on improving the survival in patients with HIV or AIDS, and it is likely that over time, adverse cardiovascular events are likely to play an increased role in contributing to causes of morbidity and mortality in this subset of patients. CMR offers an opportunity to comprehensively assess the cardiovascular system, allowing detection of subclinical disease or detailed characterisation of known pathologies and informing subsequent clinical practice with the hopes of improving outcomes in affected individuals. Furthermore, the non-invasive and non-ionising nature of CMR make it a robust, flexible research tool well suited to longitudinal follow-up of patients and the development of novel imaging biomarkers that will serve to improve our understanding of disease processes, treatment effects and overall cardiovascular outcomes in HIV-infected individuals over time.


P < 0.001). A decrease in left ventricular torsion rate was significantly correlated with a decrease in right ventricular contractility (end-systolic elastance) , and an increase in right ventricular systolic pressure in pulmonary arterial hypertension kids . In both pulmonary arterial hypertension and control subjects, left ventricular torsion rate correlated with right ventricular ejection fraction  . In the pulmonary arterial hypertension group, interventricular septum curvature demonstrated a strong direct relationship with right ventricular systolic pressure  and inversely with left ventricular torsion rate . Left ventricular torsion rate showed a direct relationship with ventricular vascular coupling ratio , and an inverse relationship with mean pulmonary arterial pressure , and pulmonary vascular resistance . We conclude that in pediatric pulmonary arterial hypertension, reduced right ventricular contractility is associated with decreased left ventricular torsion rate.The right ventricle and left ventricle are physically coupled through the interventricular septum. Therefore, changes in the geometry and mechanics of one ventricle can directly affect the function of the other. In treatment of pediatric pulmonary arterial hypertension, the left ventricle is often overlooked, with clinical focus primarily on improving right ventricular function. Pediatric pulmonary arterial hypertension represents a disease distinct from adult pulmonary arterial hypertension based on etiology and survival rates. We aimed to assess left ventricular torsion rate in pediatric pulmonary arterial hypertension and its role in right ventricular dysfunction. Cardiac magnetic resonance images with tissue tagging were prospectively acquired for 18 pediatric pulmonary arterial hypertension (WHO class I) patients and 17 control subjects with no known cardiopulmonary disease. The pulmonary arterial hypertension cohort underwent cardiac magnetic resonance within 48 hours of clinically indicated right heart catheterization. Using right heart catheterization data, we computed single beat estimation of right ventricular end-systolic elastance (as a measure of right ventricular contractility) and ventricular vascular coupling ratio . Left ventricular torsion rate was quantified from harmonic phase analysis of tagged cardiac magnetic resonance images. Ventricular and pulmonary pressures and pulmonary vascular resistance were derived from right heart catheterization data. Right ventricular ejection fraction and interventricular septum curvature were derived from cardiac magnetic resonance. Left ventricular torsion rate was significantly reduced in pulmonary arterial hypertension patients compared to control subjects (1.40 ± 0.61° vs. 3.02 ± 1.47°,  Thus, a study of the progression of PAH in children, separate from adult pathophysiology, is needed.Pulmonary arterial hypertension (PAH) in children is an incurable and progressive disease, characterized by increasing mean pulmonary arterial pressure (mPAP) and vascular resistance, resulting in right ventricular (RV) hypertrophy, and eventual ventricular failure.7 which interferes with normal left ventricular (LV) geometry and mechanics, thus affecting RV–LV interdependent mechanical and structural function.810 However, the contribution of the left ventricle on RV function is often overlooked in the clinical setting in the management of PAH, in which current therapies primarily focus on RV function improvement.10 A study conducted by Fogel et al. on patients with systemic right ventricles observed differences in ventricular strain, strain rate, and ventricular twisting compared to normal healthy subjects, demonstrating that the lack of normal LV function has a significant effect on RV mechanics.11 Damiano et al. showed that in an electrically isolated, healthy, dog heart, the left ventricle alone contributed to passive RV contraction by inducing 68% of normal RV systolic pressure and 80% of pulmonary arterial flow.12 These studies demonstrate the critical role the left ventricle has in affecting RV systolic function. LV torsion and rotation may reflect the ability of the left ventricle to contract and transfer mechanical energy to the right ventricle, and has been shown to be indicative of LV ejection, filling, and potential energy storage.14 Therefore, we hypothesize that the LV torsion rate is decreased in our sample of children with PAH, and that this reduction is associated with a decrease in RV function (e.g. contractility and ejection fraction), RV–pulmonary arterial decoupling (measured as the ventricular–vascular coupling ratio), and hemodynamic measures of pulmonary arterial and ventricular afterload.During PAH progression, the rise in RV pressure causes alteration in the interventricular septal (IVS) geometry,15 Like CMR, echocardiography can also measure myocardial deformation. However, echo techniques are limited by available acoustic windows and body habitus. Near-field imaging is particularly limited, making the anterior right ventricle often difficult to delineate. CMR approaches are free of these constraints and allow high spatial resolution images without exposure to radiation or sedation in older children.8To test our hypothesis, we prospectively recruited PAH patients undergoing clinically indicated right heart catheterization (RHC) to undergo tagged cardiac magnetic resonance imaging (MRI) within 48 hours. Cardiac magnetic resonance (CMR) imaging tissue tagging is the reference standard for evaluating myocardial deformation.This study was carried out with the approval of the Colorado institutional research board, in accordance with the Declaration of Helsinki. We recruited PAH patients cared for in the pulmonary hypertension program at the Children's Hospital Colorado who were undergoing clinically indicated RHC to undergo CMR within 48 hours. Healthy control subjects were recruited prospectively for CMR alone. The inclusion criteria for this study were any person aged 7–21 years, with mPAP of 25 mmHg or greater established by catheterization or RV pressure of 50% or greater of systemic arterial pressure established by echocardiogram before the age of 18 years for PAH patients. We excluded significant intracardiac shunts defined as a pulmonary:aortic flow of more than 1.2:1. In addition, patients with pulmonary thromboembolic diseases, PAH from left heart disease, veno-occlusive disease, pulmonary capillary hemangiomatosis, or lung disease were excluded from this study. Medical records, including World Health Organization (WHO) functional class, were retrospectively reviewed. Longitudinal disease progression was not considered in this analysis. For any subject, differences in hemodynamic states between sedated RHC and non-sedated CMR were unavoidable. Our institutional protocol calls for RHC under general anesthesia for all children, while our CMR research protocol included older children (>5 years old) without sedation during CMR. Thus, with the youngest subject at age 7 years, no children in either cohort underwent sedation during CMR for this study. Control healthy subjects aged 7–21 years with no known cardiopulmonary disease were recruited by campus advertisement.2 as close to room air as tolerated.RHC was performed under general anesthesia. Pulmonary vascular resistance (PVR = (mPAP – PCWP)/CO) was taken as a measure of resistive afterload, in which PCWP is the pulmonary capillary wedge pressure, mPAP is mean pulmonary arterial pressure, and CO is cardiac output. The cardiac index was measured using Fick's principle at baseline, with FiOes) was used as a measure for RV contractility, which was estimated using the single beat method described by Truong et al.16 Ees was estimated as the ratio of the difference between maximum pressure and end systolic pressure to stroke volume [(Pmax – Pes)/SV]. Arterial elastance (Ea), which represents arterial afterload, was defined as the ratio of end systolic pressure to stroke volume [Pes/SV]. Arterial compliance was defined as the ratio of stroke volume to pulse pressure (PP) [SV/PP]. The ventricular vascular coupling ratio (VVCR) was calculated as the ratio of ventricular contractility (Ees) to arterial afterload (Ea), with higher VVCR values representing increased coupling competency between the pulmonary artery and right ventricle.1719RV end-systolic elastance  with dedicated cardiac receiver coils appropriate for subject size. All subjects were awake during the study. Tagged MRI images are acquired after application of a pre-pulse to nullify signal within defined parallel lines or grids known as ‘tags’ which persist through the cardiac cycle. The low signal intensity lines allow tracking of the myocardium through systole and diastole. This was applied to the horizontal long axis and three short-axis planes . Typical image parameters were 6–8 mm slice thickness, repetition time of 3.9–4.7 ms, echo time of 3.7 ms, flip angle 15°, matrix 144 × 256, voxel size of 1.875 × 1.875 × 8 mm, with a tag spacing of 6–8 mm. Images were acquired in short-axis view at the basal, mid, and apical levels with a minimum of 25 phases throughout the cardiac cycle. The short-axis basal slice was defined as a full circumferential view of the LV chamber as landmarked directly inferior to the mitral valve leaflet tips. The short-axis apical slice was defined as a full circumferential view of the chamber inferior to the papillary muscles but superior to the end of the cavity. The mid-chamber slice was defined as the region of the cavity encompassing the entire length of the papillary muscles.21 The harmonic phase flow method extracts myocardial motion between consecutive tagged CMR image frames by generation of two-dimensional vector fields indicating the position and direction of a point through analysis in the Gabor domain.22 LV rotation in degrees was calculated over the cardiac cycle for basal, mid-ventricular, and apical short-axis views. End-systole was defined by aortic valve closure. Torsion was calculated using the equationThe LV torsion was calculated over the cardiac cycle using harmonic phase flow analysis .rapex and rbase are their respective radii, and D is the length between the base and apex in systole.20 The radius was measured as half the length of the measured distance between the anterior endocardial wall and the inferior endocardial wall of the left ventricle. Torsion rates were calculated as the change in degrees of torsion per length (cm) over one systolic cycle. Cubic spline interpolation was performed on torsion versus percentage systole with an interval of 0.001. The derivative of the torsion curve (top of In equation (1), BR is the rotation of the base, AR is the rotation of the apex, e top of c was take top of c with meThe septal radius of curvature (SROC) was utilized as a metric for the extent of septal flattening through analysis of cine CMR. This was measured by fitting a curve at three points along the LV endocardial septal wall, from anterior to posterior, within the basal level in short-axis view, at end-systole. The corresponding SROC was normalized to the distance between the basal and apical planes of the left ventricle. Larger radii represent an increase in septal flattening.t-test was used to compare the mean LV torsion rate between control and PAH subjects. Univariate linear regression was used to assess relationships between torsion rate and mechanical and hemodynamic vascular/ventricular functional parameters (right ventricular ejection fraction (RVEF), mPAP, PVR, VVCR, RV systolic pressure and RV contractility). Reproducibility, and intraobserver and interobserver agreement for harmonic phase flow analysis and the algorithm used have been verified in previous studies;2022 however, we performed our own independent analysis. Intraobserver and interobserver reproducibility of LV rotation and torsion was assessed in 10 randomly selected PAH patients by two blinded researchers (MJD and PT) utilizing intraclass correlation coefficients (ICCs) and Bland–Altman analysis. Intraobserver variability was assessed by comparison of measurements performed by the same observer (MJD) approximately 10 months apart.All data analyses were performed using MatLab, in which an alpha of 0.05 represented statistical significance, with a 95% confidence interval that any one sample is representative of the population. The mean and standard deviation of LV torsion rate were calculated for control and PAH patients. An unpaired two-tailed Student's Patient demographic details are summarized in P = 0.322).Female patients comprised 66% of the PAH group and 65% of the control group. The median age for the PAH group was 13 (range 9–20) years, compared to 10 (range 7–16) years in the controls. All PAH patients were classified as WHO group I based on medical records. Thirteen of the PAH patients were diagnosed as idiopathic PAH, one patient was diagnosed as PAH due to a connective tissue disease, three had PAH due to congenital heart disease , and two with hereditary PAH. Median mPAP and PVR for the PAH subjects was 49 (range 24–58) mmHg and 8.50 (range 2.32–22.76) Wood units, respectively. RVEF is significantly lower in the PAH subjects compared to controls. RV CO and RV SV were not significantly different between the cohorts. No significant differences were found in left ventricular ejection fraction (LVEF) between PAH  and control subjects  . P = 0.032) and PAH subjects (P = 0.034). The graph depicts a steeper slope of RVEF values in response to a change in LV torsion rate in the PAH cohort compared to the controls. Unlike the PAH group, in the control subjects, the torsion rate did not correlate with RVCO or RVSV. The LV torsion rate also demonstrated a positive relationship with Ees (RV contractility) (P = 0.007), but an inverse relationship with RV systolic pressure (P = 0.021), as shown in r = 0.03, P = 0.909) or PAH subjects .The LV torsion rate for control and PAH patients is displayed in P = 0.001), shown in P = 0.013) and control subjects (P = 0.012).The SROC in the PAH cohort showed a strong relationship with increasing RV systolic pressure (subjects b (P = 0.P = 0.021). The torsion rate correlated highly with invasive hemodynamic parameters including mPAP (P = 0.008) and PVR (P = 0.049), shown in r = 0.39, P = 0.101).VVCR showed a positive relationship with LV torsion rate  LV torsion rate tends to be decreased in PAH subjects compared to controls; and (b) this reduction in torsion rate is concomitant with a reduction in RV contractility. Our results, combined with the current literature on the interventricular mechanical relationship,29 Initial RV dysfunction in PAH is brought on by increasing resistive afterload, thus logically influencing LV twist through IVS alteration. In advanced PAH, where the right ventricle becomes hypertrophied and enlarged, the ability of the right ventricle to affect LV mechanics through this maladaptation may be more significant. Conversely, the subsequent reduction in LV torsion may further drive RV functional decline through reduced assistance from the left ventricle.A decreasing LV torsion rate shows a relationship with decreasing RV contractility a. WhetheRVEF has a steeper and stronger correlation with LV torsion rate in the PAH cohort compared to the controls, as seen in 3032In our study, a lower LV torsion rate demonstrated a relationship with higher RV systolic pressure b. Increa3235The hypothesis that the LV torsion rate decreases with increasing RV pressure – in part due to septal flattening – is supported by 37 and demonstrated a direct relationship with the LV torsion rate in this study. VVCR is an indicative metric for when the patient enters a point of maladaptive remodeling and typically experiences a rapid decline. Our finding that the LV torsion rate is highly correlated to both contractility and VVCR implies the potential role it has in PAH related to contractility and afterload .VVCR has been shown to have enormous prognostic value for PAH,29 LV twist may be indicative of the amount of mechanical energy transferred from the left to the right ventricle, and thus reduced LV torsion may result in reduced mechanical energy transfer from the left to the right ventricle during systole (indicated in the right side of 23 thereby leading to decreased RV contractility. The reduced mechanical energy transferred from the left ventricle results in a decrease in maximum RV functional reserve, allowing the right ventricle eventually to reach a limit where contractility is outmatched by rising afterload. This theory is supported by the relationship of LV torsion with RV contractility (We postulate the following mechanism based on the data from this study: increased afterload causes increased RV systolic pressure, which causes a decrease in LV torsion rate which in turn causes further decrease in RV contractility and ventricular decline. actility a; howeve38 and as such is limited in resolution. In-plane motion is also affected by through-plane motion during ventricular contraction, and this change in through-plane motion was not accounted for. However, a study by Brotman et al. comparing LV rotation calculated with and without through-plane motion demonstrated equal variances between methods, although the methods yielded significantly different values in rotation.39 Therefore, within consistent methods of measurement, torsion and rotation can be relatively compared between two populations without the inclusion of through-plane motion. Hence, the measurement of LV rotation and torsion through conventional methods of short-axis image analysis has been widely accepted as a standard method for tissue-tagged CMR studies.4042 For future analysis, deformation in the sagittal and coronal planes will be calculated and normalized to short-axis torsion. Although the median age of the PAH cohort13 and control subjects10 is not significantly different, variance of age within each cohort may influence the differences in LV torsion, as it has been shown that LV torsion increases with age until adulthood.44The implications of our findings are limited by a small number of study subjects, and thus may not fully represent a spectrum of pediatric PAH patients. Control subjects were unable to undergo RHC, therefore a comparative analysis between control and PAH subjects could not be made for all hemodynamic and single-beat derived metrics. The regional and directional strain of the left ventricle was not analyzed in this study; however, future analysis of ventricular torsion will consider strain to analyze regional differences in myocardial motion. The limits of agreement for intraobserver Bland–Altman analysis are approximately within the magnitude of the standard deviation of the LV torsion rate in control subjects, which indicates a limitation in precision of the measurements, and thus the conclusions presented are speculative and warrant additional analysis. Tagged MRI has a limit of detection that is defined as the size of the voxel,The LV torsion rate within the pediatric PAH population is reduced compared to normal healthy children and is linearly related to RV contractility and ventricular–vascular coupling. This study suggests that LV mechanics is associated with RV functional decline in pediatric PAH, detectable with non-invasive tagged CMR. We provide a speculative explanation of causality on the underlying physiological mechanism of decreased LV torsion induced reduction of RV contractility. Further mechanistic studies are warranted to elucidate fully the role of LV torsion and its potential as a therapeutic target for improvement of RV function.


Cardiac dynamics are traditionally linked to a left ventricle, right ventricle, and septum morphology, a topography that differs from the heart’s five-century-old anatomic description of containing a helix and circumferential wrap architectural configuration. Torrent Guasp’s helical ventricular myocardial band (HVMB) defines this anatomy and its structure, and explains why the heart’s six dynamic actions of narrowing, shortening, lengthening, widening, twisting, and uncoiling happen. The described structural findings will raise questions about deductions guiding “accepted cardiac mechanics”, and their functional aspects will challenge and overturn them. These suppositions include the LV, RV, and septum description, timing of mitral valve opening, isovolumic relaxation period, reasons for torsion/twisting, untwisting, reasons for longitudinal and circumferential strain, echocardiographic sub segmentation, resynchronization, RV function dynamics, diastolic dysfunction’s cause, and unrecognized septum impairment. Torrent Guasp’s revolutionary contributions may alter future understanding of the diagnosis and treatment of cardiac disease. The current approach to understanding cardiac dynamics relies upon movements that adhere to the conventional topographical separation of cardiac muscle into the left ventricle, right ventricle, and septum. Functional analyses have addressed them independently, and this approach has resulted in many suppositions that this report will define and question.Alternatively, cardiac muscle mass is formed by the helix and surrounding circumferential wrap described by Lower in the 1600s , Krehl iFor example, the left ventricular free wall and septum are usually discussed separately, yet both are formed by the same muscle  and theiTreating disease requires restoration of normality, so decisions must be based upon an understanding of anatomic normality. The heart’s functional counterpart involves only six movements; narrowing, shortening, lengthening, widening, twisting, and uncoiling. The helical ventricular myocardial band model of Torrent Guasp  appears This knowledge answers the query about the heart by explaining the only valid definition of heart structure involves describing a mechanical architecture whose motion can account for all dynamic cardiac movements. Misconceptions happen without it. For example, rather than focusing upon cardiac compression, the pivotal role of twisting for mechanical proficiency must be understood . TwistinThe background behind this misunderstanding started 2200 years ago when Erasistratus (280 BC), then Galen (180 AD) and subsequently Borelli (1600s)  describeThe capacity to understand the dynamics of the surrounding wrap and helix is a very different approach from using deductions to explain many ‘accepted cardiac mechanical relationships’. This tactic will lead to questioning of many ‘state of the art’ concepts. They include heart anatomy as LV, RV, and septum, timing of mitral valve opening, the isovolumic relaxation period, structural reasons for torsion/twisting, the term untwisting, structural reasons for circumferential and longitudinal strain, echocardiographic cardiac sub segmentation, resynchronization, RV function dynamics, and diastolic dysfunction’s cause and its unrecognized septum involvement.A heart with two ventricles, separated by a midline muscular septum defines its classic morphologic description. Despite correct topography, no functional insight is provided to define what these three structures do. A different structural guideline has existed for 500 years, whereby heart architecture contains a helix formed by right- and left-handed fibers and a surrounding circumferential wrap ,2,3,5,16Torrent Guasp’s macroscopic anatomic pattern , wherebyControversy and Criticism: MacIver, Anderson’s colleague, recently proposed a report to put “an end to unique myocardial band” approach, because its presence cannot be defined by two- dimensional histology ,23. Our Macroscopic analysis has the limitations of not addressing the microscopic display of the nests of layers and lamellae within individual myocytes that interact with cardiac ejection and filling. LeGrice found sarcomeres clustered in 1–12 groups within their connective tissue netting ,28. WhilThe conceptual understanding of macroscopic cardiac structure is straight forward because only three components need be known. There is a circumferential wrap of transverse fibers that surrounds both ventricles—called a basal loop—which compresses and rotates the global heart, and predominantly forms the RV free wall . The secSimplicity underlies the solution to the structure function relationship, since its three structural components  produce the heart’s six readily apparent dynamic movements of narrowing, shortening, lengthening, widening, twisting, and uncoiling ,7,8. ThiFunctional balance exists between the structural wrap and helix, as the wrap causes counterclockwise motion before ejection, the helix produces twisting, and the wrap triggers clockwise recoil during post ejection interval that includes the isovolumic period .State-of-the-art imaging reports do not recognize this dynamic balance because they do not address the fundamental role of the surrounding wrap ,34,35. TEcho motion recordings amplify the circumferential basal loop’s presence by documenting cardiac lengthening during the pre-ejection isovolumic interval , while MThe anatomy documenting the location of the outer circumferential wrap becomes evident from echo studies showing the smooth reciprocal movement (in different directions) between the contracting inner and outer helical arms . InterpoMacroscopic interlocking of structure and function is aided by the comparison of their dynamic clockwise and counterclockwise helical motions in The plane identifying the mid ventricular overlapping between helical arms  extends These dynamic findings differ from conclusions made from post mortem DT-MRI observations that suggest circumferential fibers exist within the septum mid myocardium due to observations of zero helix angles . Yet phyThe most powerful or dominant muscle amongst these three architectural components governs the direction of movement, and their contraction takes place at different timing intervals . For exaConversely, shortening during ejection emphasizes the dominance of the inner descending helical arm. The ventricle twists as the base rotates clockwise and apex turns counterclockwise from the torque of the outer ascending helical arm’s longer lever radius . The outThe wrap ,7 causesGlobal longitudinal strain measurements match those recorded by sonomicrometry  and the Mitral valve opening (MVO) is a term reflecting the Doppler based echocardiographic recording of initial transmitral inflow into the left ventricle. This passage coincides with left ventricular pressure falling below atrial pressure, and the most rapid anterior mitral leaflet motion . Its desMRI recordings quantify leaflet separation, and The functional dynamics of the wrap and helix establishes the mechanical insight to explain why MVO occurs during systole. This geometric process focuses upon the architectural interaction between the mobile ventricle that uncoils—and the mitral annulus that is fixed. The circumferential wrap causes clockwise recoiling, which rotates the helix that contains the papillary muscles that connect with the mitral leaflets and annulus. Their counterclockwise rotation during ejection allows them to close the fixed annulus by a leaflet flap, and this ‘trap door’ re-opens—as they spring backward during recoil to produce MVO . The dynMVO can only happen when helix’s inner descending contraction has ended, an action that permits initiation of outer ascending helix arm lengthening  as quantOur understanding of diastolic dysfunction is enhanced by a fuller understanding of MVO—since uncoiling cannot begin while torsion is ongoing. Ventricular recoil begins at the inception of negative dP/dt, so that this measurement may become a signpost to determine when unwinding starts. If MVO timing is normal, the hiatus or time gap between the end of the inner and outer helix contraction is ~90 ms—and its disruption will impair uncoiling ,7,58. PrFinally, the traditional identification of MVO is incorrect, so that the physiological term “mitral valve inflow” (MVI) should replace it. MVO is due to anatomic changes that carry vast physiologic implications—as we suspect recoiling will become the centerpiece behind understanding diastolic dysfunction.Isovolumic relaxation time (IVRT) joins MVO in being a universally accepted term . It signThe ventricle is isovolumic, yet the other three components reflect deductions that are incorrect. First, the MVO during clockwise recoil is caused by the wrap—initiating when LV negative dP/pt starts, rather than when a LV pressure falls below left atrial pressure. Second, the entire ventricle does not relax—ongoing strain measurements and sonomicrometer crystal recordings confirm outer ascending helical arm contraction . FinallyRademakers described the impact of the post ejection isovolumic interval on ventricular filling when he defined a dissociation between untwisting and filling, whereby 50–60% of recoil occurs during this isovolumic interval . He reasThe interdependence of torsion and recoiling is a vital interaction because torsion must stop before unwinding can start. The post ejection isovolumic time frame interval is ~90 ms , but diaCurrent thoughts about recoil during isovolumic relaxation imply that the epicardium governs the clockwise rotation of the LV apex, suggesting that it reverses torsion’s apical counterclockwise rotation ,65. The This revision has historic precedence, as Wiggers can now join Harvey (who described compression versus twisting) and Vesalius  as being astounding titans that were not perfect.There is agreement that the spiral architecture of LV muscle fibers produces LV systolic wringing or twisting during ejection by producing differential rotation of the LV base (clockwise) and apex (counterclockwise). This is called torsion by expressing its rotational angle, along the LV longitudinal axis. The responsible muscular mechanisms have important functional implications, yet these have only been deduced.Taber’s bioengineering model has been accepted , as it iEvidence for this structural explanation is supported by architectural and imaging studies. The anatomically unfolded heart reflects an uncoiled rope  that, whDownward shortening of both helical coils cannot cause torsion, because the systolic septum longitudinal strain shows the positive deformation (elongation) of the outer ascending helical arm —a motionTorsion and recoil affect ventricular performance in a way that relates to the contractile patterns of the inner descending and outer ascending helical arms. Torsion ends when the inner descending helical arm stops contracting—since uncoiling cannot begin until that happens. This recoil interval includes the post ejection isovolumic phase and first-third of diastole . ProlongUntwisting during recoil represents the antonym for twisting during ejection. This traditional term is used to describe the clockwise rotation of the apex that counteracts its counter-clockwise motion during twisting for ejection . Yet theEach muscle must return to its starting point, so these anatomic reasons do not counteract the recoil that helix and wrap muscles must develop. Instead, functional aspects of the HVMB explain why recoil’s expected global clockwise and counterclockwise ‘untwisting’ cannot occur. The term ‘untwisting’ should be changed into ‘uncoiling, recoiling, or unwinding’ to capture recoil’s inception point since it may evolve future diastolic dysfunction treatments.Strain measurements define muscle deformation relative to original length by addressing “shortening in circumferential or longitudinal dimensions or thickening in radial dimensions”, but they do not define why deformation happens or what it means. For example, two-thirds of strain is circumferential and only one-third longitudinal, so that it is considered a more robust tool ,68, espeThe functional importance of deformation is linked to its muscular cause. Longitudinal strain reflects coiling downward of the oblique helical spiral fibers to generate the normal ~60% ejection fraction . ConversLongitudinal strain quantifies ventricular shortening, and was thought to reflect how the apical part pulls the ventricular base downward . The helTwo factors explain why circumferential deformation produces ventricular compression or cardiac narrowing. The first is short axis shortening of the wrap or basal loop’s transverse fibers. The second is transverse shortening produced by thickening of the contracting inner helix’s descending arm. Their individual contributions cannot be determined because they are superimposed within the LV free wall. Conversely, the septum does not contain a circumferential wrap so that its longitudinal strain measurement is possible .Longitudinal strain reflects deformation of helical spiral fibers, and is measured by recording mitral annulus excursion toward the apex  . Figure Impaired longitudinal strain is an early finding in dilated hearts  and deveThe surrounding basal loop fibers provide a short axis supporting restraint  that folWorsened longitudinal systolic strain exists when relaxation is altered during diastolic dysfunction . The queRegional echo based structure function analysis is linked to perfusion related changes . RegionaA similar arbitrary concept guides how readers are taught to understand the architecture of the helical muscles in the LV elliptical shape. They are considered to exist within overlapping cones, with “state of the art” reports  showing This designation is incorrect because the outer ascending helical arm forms different parts of the endocardium. An example of this unsuitability is that helical muscle overlap is absent in the septum muscle endocardium below the aortic valve . VelocitExcitation contraction coupling provides the infrastructure behind how twist develops during each HVMB contraction. This process requires the natural flow of electrical impulse from the conduction system into the responsible myocytes. Insight into the HVMB anatomy and interventricular conduction relationship is gained by reviewing the evolution of clinical ‘resynchronization’ therapy (CRT). ‘Synchrony’ is the traditional term used to characterize the coordinated contraction of the LV, RV and septum—observed from two-dimensional echo or ventriculography. They record harmonized “all at once“ movement—mimicking the making of a fist with all fingers squeezing in unison in patients with a normal narrow QRS interval. Conversely, a wide QRS interval defines delayed regional electrical activation, and is associated with uncoordinated contraction that may produce septum bulging or billowing, mitral regurgitation, and raise LV volume.‘Resynchronization’ is achieved by simultaneously pacing the LV and RV with the aim of restoring ‘synchrony’, but its portended treatment goals are only sometimes met . For exaThis change in thinking may be important because normal cardiac motion is not ‘synchronous’. Instead it is a ‘sequential’ motion that evolves when the electrical impulse traverses the natural conduction system and its collagenous cardiac netting matrix to stimulate individual muscle fibers. The clenched fist that is traditionally used to define contractility does not reflect an ‘all at once’ motion. Instead, it represents the ‘chronological closing’ of the little finger, ring finger, middle, and then index fingers, as they create the whirling motion which mirrors the normal heart’s natural twisting movement. Such coordinated torsion develops because the electrical propagation velocity is 10× faster (at 3 m/s) through the natural His-Purkinje fiber conduction system, than via direct ventricular muscle stimulation (at 0.3 m/s) . WiggersTwisting was recently evaluated by recording HVMB motions following either isolated (direct) ventricular, or biventricular stimulation (CRT), and torsion was inconsistent . ConversCRT provides mechanical, but not physiological improvements. For example, a wide QRS interval delays septum activation, so that the earlier LV free wall contraction will make it billow or bulge. The resultant ventricular stretching will tether the posterior papillary muscle (adjacent to septum) connected to the mitral leaflet, and produce mitral regurgitation from poor leaflet coaptation. CRT returns the septum to its midline position to offset papillary muscle tethering and remedy mitral regurgitation—but it does not consistently restore cardiac twisting. Conversely, His-Purkinje pacing rebuilds normal conduction by shortening the QRS interval . It geneRight ventricular failure is difficult to manage because its underlying mechanisms are uncertain. Decision dilemmas follow such incomplete functional knowledge. For example, the RV is considered a passive chamber because early functional recovery follows its exclusion by the Glenn (superior vena cava to pulmonary artery) or Fontan (pulmonary artery to right atrium) procedures ,95. Yet RV cardiac function is determined by myocardial fiber orientation . A thin Investigative studies document the dynamics of RV’s compression and twisting movements. For example, unaltered RV function follows RV free wall exclusion by cauterization, patch replacement ,101 or iThe interplay becomes especially clear following cardiac surgery, where postoperative RV performance remains unimpaired, despite almost 50% of patients developing paradoxical septum motion . But thiTricuspid annular plane systolic excursion (TAPSE) quantifies the extent and rate of helically induced longitudinal strain  by documThe interface between RV helical and circumferential muscle interaction is further clarified from RV function examination following either conventional or catheter based aortic valve replacement (AVR). Longitudinal and circumferential strain is unaltered in catheter based AVR that does not use cardioplegia. In contrast, the use of cardioplegia during surgical SVR results in the commonplace finding of septal damage . This inRV failure sometimes develops in heart failure patients with high PVR following implantation of a left ventricular assist device (LVAD). Ventricular decompression by LVAD changes cardiac geometry by collapsing the LV. This maneuver bows the septum toward the left side, making its helical fibers more transverse and dysfunctional . RV failDiastolic dysfunction is characterized by how impaired ventricular relaxation and increased wall stiffness can limit LV filling in ~50% of patients with heart failure, despite their having normal ejection fraction . NishimuNormal ventricles receive 70% of their filling during the first third of diastole, but uncertainty exists about why this happens. Uncoiling via apical clockwise rotation influences early filling, but this motion begins in the last half of systole and extends to the first third of diastole . DespiteThe alternate mechanism is “active” ventricular suction to aspirate atrial blood, using peak negative dP/dt and the time constant of relaxation (tau) as measurement indexes . UnderstThere is clear-cut understanding of how ventricular pressure increases during filling of a stiff ventricular wall, yet this “compliance mechanism” is absent during normal rapid ventricular filling, where ventricular pressure falls as volume increases . “DiastoThe current term “passive rapid ventricular filling” parallels the prior controversy between twisting or compression for ejection. Background exists, as Galen, in 180 AD described “the overlying heart, at each diastole, robs the vena cava by violence of a quantity of blood”. Wiggers, in 1921, rejected a vis a fronte ventricular filling , and RobConcepts about elastic recoil or systolic ventricular filling are best tested by evaluating the integration of form and performance. Van Dalen’s elegant series of observations ,121,122 Torrent Guasp’s geometric contributions are central to our structure/function approach, but his “systolic ventricular filling” concept  uses onlThe interdependence of torsion and recoil are fundamental concepts behind understanding how HVMB clarifies why diastolic dysfunction develops. The central theme is that recoil cannot start until torsion ends. The recoil process causes the predominance of ventricular filling in the healthy heart, yet 50% of this unwinding exists during the pre-filling phase, reaching 60% after catecholamine infusion ,123. TheThe time-frame between the end of contraction of the inner descending and then, of the outer ascending helix arms, creates a “temporal hiatus” , and thiDisruption of the HVMB dynamics responsible for the interface between torsion and recoil creates diastolic dysfunction in several ways, because prolonged systole during torsion will encroach upon the aforementioned “temporal hiatus” during aortic stenosis , hypertrMost importantly, thoughts of diastolic dysfunction that focus upon an isolated relaxation disorder must be reexamined, since each patient shows combined systolic and diastolic abnormalities . These aMechanism related treatments can reverse diastolic dysfunction, since aortic valve replacement allows regression of LV hypertrophy with resulting return of twisting and recoil to normal . Post isThe LV free wall and septum are formed by the same HVMB muscle mass  and thisDiastolic dysfunction, its sequel, develops in 44% to 75% of patients undergoing coronary grafting or aortic valve procedures ,131,132.This rethinking of the core cardiology values started after learning of the contributions of Francisco Torrent Guasp. His studies exposed the simple design of cardiac architecture by showing that the HVMB contains a helix and a circumferential wrap. These two structures create the functional mechanics behind cardiac motion and thus define ‘what the heart is’. Application of this foothold knowledge reveals that many ‘accepted’ cardiac events are based upon deductions drawn from presumed myocardial structure, rather than from its natural configuration. Torrent Guasp’s revolutionary contribution opens the door toward an exciting future for the understanding, diagnosis, and treatment of cardiac disease.


Influenza virus infection (IVI) was reported to be associated with minor cardiac changes, mostly those detected on electrocardiogram with and without elevated blood markers of myocardial injury; however, the characteristics of myocardial involvement in association with IVI are poorly understood. This study used echocardiographic tissue imaging  to evaluate changes in left atrial (LA) and left ventricular (LV) myocardial function after IVI.We examined 20 adult individuals  at 2 and 4 weeks after diagnosis of IVI. For myocardial functional variables, we obtained LV global longitudinal strain (GLS), LV early diastolic strain rate (e'sr), LA strain, and LA stiffness (E/e’/LA strain), in addition to data on tissue Doppler  and myocardial performance index. Blood markers of myocardial injury were also examined. During follow-up, there were no significant changes in global chamber function such as LV ejection fraction, E/e’, and LA volume. However, significant changes in myocardial function were observed, namely, in s’ , e’ , e’sr , and LA strain , and the myocardial performance index , but not in a’, LA stiffness, or GLS. Cardiac troponin T and creatinine kinase isoenzyme MB were not elevated significantly at any examination.Myocardial dysfunction during IVI recovery appeared to be transient particularly in the absence of myocardial injury. Echocardiographic tissue imaging may be useful to detect subclinical cardiac changes in association with IVI. Influenza virus infection (IVI) results in cardiac involvement up to 12% of cases . StudiesCompared with conventional techniques on echocardiography including tissue Doppler imaging, speckle tracking echocardiography (STE) is more accurate for evaluating subclinical LV dysfunction –12. STE During the period from February 2014 through March 2018, we identified 114 adult individuals who had just recovered from IVI. Either type A or B IVI was diagnosed on the basis of a positive nasal swab specimen, as determined with a commercially available test kit, such as the QuickNavi-Ful kit . Among those individuals infected, 20 who completely underwent echocardiography and blood sampling at 2 and 4 weeks after IVI diagnosis were examined for the current study.The present study was based on the data on our previous study , and thuThis study was approved by the Institutional Ethics Committee of Osaka Medical College, and written informed consent was obtained from all participants.Blood markers of cardiac injury, including CKMB, and high sensitive cardiac troponin T (cTnT) using HBsAgII quantII troponin T hs  were measured. Normal ranges for these markers in our laboratory are CKMB 7–15 U/L; and cTnT <0.014 ng/mL. Complete blood count and some contents of blood chemistry were also obtained.Echocardiography was performed with commercially available ultrasound machines with the phased array probes  at 2 and 4 weeks after IVI diagnosis. All measurements were performed by experienced sonographers blinded to background characteristics of the subjects. LA diameter, LV dimensions, and LV wall thickness were measured with M-mode method under 2-dimensional guidance. LV ejection fraction was calculated by the modified Simpson’s rule in apical 2- and 4-chamber views. LA volume was calculated with the disc method in apical 2- and 4-chamber views . Pulsed We used an EchoPAC workstation  to assess STE variables, including global longitudinal strain (GLS), global strain rate during early diastole (e’sr), and LA strain. The process to calculate STE-derived variables is followings. A couple of cardiac cycle loops for the apical 2-chamber, 3-chamber, and 4-chamber views (frame rate 80 to 100 frames per second) were stored in the workstation. At the end-systolic frame for each image, with the timing of aortic valve closure defined, the STE software algorithm automatically traced LV wall borders and tracked them throughout the cardiac cycle. Ultimately, we obtained longitudinal strain curves for 17 myocardial segments, and the strain (%) for each segment was presented on a bull’s eye display. GLS is an averaged strain value at end-systole for those segments. Because GLS is a negative value, we used its absolute value, |x|, to simplify interpretation; a GLS of <17.3% was considered to be abnormally low . The e’sData are presented as mean ± standard deviation for continuous variables, and as numbers or percentages for categorical variables. Changes in clinical and echocardiographic variables between the first and second assessments were analyzed with the paired t-test. Categorical variables were compared with the chi-square test. McNemar’s test was used to assess changes in categorical variables. All of the statistical calculations were performed with SPSS for Windows ver. 24.0 . A p value of <0.05 was considered to indicate statistical significance.The demographic characteristics of the 20 subjects are presented in Figs The present study found that myocardial function was depressed during recovery from IVI, which was not associated with elevations of the markers of myocardial injury. This finding suggests that cardiac involvement during IVI is transient as long as usual healing course of IVI is taken without any further deterioration of the clinical pictures. On the other hand, our findings indicate that echocardiographic tissue imaging enable to detect subtle and reversible myocardial changes in association with IVI.Few studies have used echocardiography to examine IVI-related cardiac abnormalities. Ison et al examined 30 asymptomatic IVI patients with echocardiography at 2, 11 and 28 days after presentation and found no global or regional wall motion abnormalities in any patients at any point, despite some patients exhibiting slight elevations of CKMB . Among 4MPI is an index of cardiac function that represents both contraction and relaxation of cardiac chambers  and is uLittle is known about the role of STE in the evaluation of IVI-related myocarditis. Han et al evaluated cardiac injury caused by avian-origin influenza A virus (H7N9) infection and observed that patients who developed cardiovascular complications, including overt heart failure, had elevated cardiac troponin I and decreased GLS . With thAnother STE-derived variable we used here, e’sr, may be better than tissue Doppler e’ for assessing abnormalities of LV relaxation , becauseIn the present study, some of the myocardial variables (those derived from tissue Doppler and strain rate) were shown to reach statistical significance but others (GLS and LA strain) did not. This may mostly be related to the small number of subjects. However, we believe that tissue Doppler and strain rate are more sensitive in detecting subclinical disease because they, from a methodological viewpoint, represent dynamic, instantaneous function, whereas GLS represents a stationary condition similar to LV ejection fraction.The cTnT has been found to be a more sensitive maker for detecting biopsy-proven myocarditis than conventional markers including CKMB . In thisWith sepsis, wherein a variety of inflammatory cytokines go around within the human body, there have been several reports on myocardial dysfunction with otherwise normal chamber function as assessed by echocardiographic tissue imaging –32. AmonNevertheless, most of our subjects were asymptomatic and did not seem to have significant hemodynamic or inflammatory findings. Thus, the aforementioned mechanisms were unlikely to exert on the myocardial function, although there was a possibility that certain myocardial depressant factors circulating had an influence on cardiac function far beyond the acute phase. Also, reduction of platelet count during follow-up  might coThis study has limitations inherent to a single-center, observational study with the small sample size. Particularly, the study population was too small to represent the entire spectrum of cardiac dysfunction and patterns of recovery associated with IVI. Also, it was hard to explain the clinical implications of our study and how information obtained could be used in clinical practice. We did not obtain the data set at the time of (or before) IVI diagnosis . Only thOther biomarkers for detecting myocardial injury such as cardiac troponin I and myosin light chain I were not measured in this study. However, most of the previous studies of IVI-related myocarditis found no positive response to troponin I or T ,8, and mDespite those limitations, our results may indicate that especially in terms of the need of biopsy to diagnose myocarditis, echocardiographic tissue imaging becomes a noninvasive diagnostic tool for identifying myocardial dysfunction in IVI patients.We used echocardiographic tissue imaging to evaluate myocardial function in adult individuals with IVI. During early recovery from IVI, myocardial function was depressed without alteration of global chamber function. Given that no evidence of myocardial injury was observed, this finding appeared to exhibit subtle myocardial changes that are reversible. Further studies, recruiting a larger number of participants, are necessary to confirm our results and identify thresholds at which any abnormal values on echocardiographic tissue imaging alter the clinical management in IVI patients.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.