Dilated cardiomyopathy (DCM) represents one of the most common causes of non-ischemic heart failure, characterised by ventricular dilation alongside systolic dysfunction. Despite advances in therapy, DCM mortality rates remain high, and it is one of the leading causes of heart transplantation. It was recently recognised that many patients present minor structural cardiac abnormalities and express different arrhythmogenic phenotypes before overt heart-failure symptoms. This has raised several diagnostic and management challenges, including the differential diagnosis with other phenotypically similar conditions, the identification of patients at increased risk of malignant arrhythmias, and of those who will have a worse response to medical therapy. Recent developments in complementary diagnostic procedures, namely cardiac magnetic resonance and genetic testing, have shed new light on DCM understanding and management. The present review proposes a comprehensive and systematic approach to evaluating DCM, focusing on an improved diagnostic pathway and a structured stratification of arrhythmic risk that incorporates novel imaging modalities and genetic test results, which are critical for guiding clinical decision-making and improving outcomes. DCM, also sometimes referred to as dilated non-ischaemic cardiomyopathy, encompasses a group of aetiologically heterogeneous myocardial disorders defined by left ventricular (LV) or biventricular dilation alongside systolic dysfunction, defined by abnormal left ventricle ejection fraction (LVEF), not otherwise explained by abnormal loading conditions such as hypertension, valvular, or coronary artery disorders . DCM is Considering the broad spectrum of disorders that cause DCM, a systematic approach helps to identify and manage this condition, especially the more uncommon but clinically significant forms of DCM. A dedicated diagnostic workup  will leaThe clinical workup starts with family and personal history and a physical examination which considers the patient’s age . The pedInitial laboratory testing should always include a complete blood count, renal function, liver function tests, urine analysis for proteinuria, creatine kinase (CK), serum iron, ferritin, calcium, phosphate, natriuretic peptides, and thyroid-stimulating hormone . In addiImaging is crucial for diagnosing DCM, risk stratification, management, and treatment monitoring. Echocardiography should be the first imaging method performed, as it provides information on chamber dimensions and morphology, systolic and diastolic function, the severity of valve disease, and non-invasive hemodynamic assessment in a broadly available, non-invasive, and cost-effective manner . CardiacIdentifying clinical features suggestive of specific diseases should lead to a second-level diagnostic workup that may include more specific biochemical analyses, endomyocardial biopsy, and genetic testing.In the differential diagnosis of DCM, it is mandatory to exclude the most frequent causes of LV dysfunction, such as coronary artery disease and valvular disease, where LV dilatation can occur due to adverse remodelling. The exclusion of epicardial coronary artery stenosis is carried out using invasive coronary angiography, the gold standard, or by computerised tomography in patients not at high risk of atherosclerosis. Valvular disease should be systematically sought through various imaging methods . Other less-common cardiomyopathies can have phenotypic similarities with DCM. They must also be considered in the differential diagnosis, such as left ventricular non-compaction cardiomyopathy (LVNC) and peripartum cardiomyopathy (PPCM). LVNC is an unclassified cardiomyopathy that, in advanced cases, can present findings similar to DCM (dilated and impaired LV function) . EchocarPPCM is an idiopathic cardiomyopathy with HF, secondary to LV systolic dysfunction, usually seen in the last months of pregnancy or the first five months after delivery. A reduction in LVEF is required to establish the diagnosis, but the left ventricle may or may not be dilated ,13. Despite the distinct classification, DCM and LV hyper trabeculation often overlap due to LV remodelling, and DCM and PPCM may share the same genetic background . Findings of extracardiac manifestations, namely neuromuscular involvement, should alert for other rarer syndromic or metabolic cardiomyopathies . Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterised by the replacement of the ventricular myocardium with fibrofatty tissue. Although initially defined as a condition that distinctively affected the right ventricle (RV), more recent post mortem and contrast-enhanced CMR investigations revealed that the left ventricle is often involved ,16. ACM Conduction system disease and frequent atrial or ventricular arrhythmias (VA), especially with a near-normal LVEF, should raise suspicion of ACM . Low volWhile the typical phenotype of DCM consists of LV dilatation with systolic dysfunction, the ALVC remodelling pattern may present with a normal or only slightly depressed LV function ,20. In dRMB20, and SCN5A. In DCM, the most frequent genes involved encode cytoskeleton, muscular sarcomere, and nuclear envelope proteins. Nonetheless, significant genetic overlap exists [In more advanced stages of ALVC, fibrofatty tissue can deposit in multiple segments of the LV free wall and septum, with transmural involvement, leading to severe systolic dysfunction . Demonstp exists ,23,25.DCM is a heterogeneous disease encompassing various underlying causes, including genetic and acquired disorders. A positive family history can be detected in up to 30–50% of DCM cases, and a causative genetic mutation can be identified in up to 40% of DCM cases ,6,26. InThe interaction between a genetic disorder and an acquired disease has been the focus of recent research, which suggests that environmental factors affect the expression of the genetic background. This knowledge may lead to a better assessment of these patients and new therapies in the future. Despite advances in DCM treatments, 10-year survival remains less than 60%, with death preceded by numerous HF exacerbations. Remarkably, the clinical course of DCM patients varies widely, ranging from rapidly progressive HF or SCD to LVRR, denoting high complexity in assessing the individual risk ,4,5. VarA fragmented QRS, longer QRS duration, antero-lateral T-wave inversion and low QRS voltage in the ECG are associated with a higher risk of major arrhythmic outcomes, including death due to arrhythmia, appropriate implantable cardioverter-defibrillator (ICD) therapy, documented VT/VF, and all-cause mortality . PreviouThe 24-h Holter monitoring demonstrates NSVT in 40–60% of patients and polymorphic PVC in up to 90% of DCM patients. The presence of NSVT and frequent PVC (≥1000 PVC or ≥50 couplets/24 h) increases the arrhythmic risk, mainly when combined with a family history of malignant VA or SCD ,30. There is still some debate about whether an electrophysiology study (EPS) can accurately discriminate between high- and low-risk patients concerning SCD. Nonetheless, despite EPS not being routinely used in current clinical practice to assess the risk of SCD in DCM patients, the inducibility of sustained monomorphic VT in EPS was considered a risk factor for the decision to carry out ICD implantation in the latest guidelines of the European Society of Cardiology (ESC) . Imaging with echocardiography is not only indispensable in diagnosing DCM, but it also provides multiple prognostic indicators. LV systolic function is one of the most critical evaluations. It has been considered the primary determinant of prognosis, guiding patient management and subsequent treatment, including the indication for ICD, cardiac resynchronisation therapy (CRT), or the discontinuation of cardiotoxic chemotherapy. For a more accurate LV function assessment, it is recommended that a 3-dimensional (3D) echocardiography should be performed to determine LVEF, when available in experienced laboratories, as it can overcome some of the limitations inherent to a 2-dimensional (2D) LVEF measurement . Multiple echocardiographic findings are associated with an increased risk of death or hospitalisation, such as left atrium (LA) enlargement, RV dilatation, and RV contractile dysfunction, which may be due to intrinsic disease or develop secondary to left HF ,31,32,33Left ventricular strain measurement should also be included in every echocardiographic evaluation. Global longitudinal strain is a valuable tool for the identification of subtle systolic dysfunction before an overt drop in LVEF, given its higher sensitivity, and it has shown an incremental value in SCD and all-cause mortality risk prediction compared to conventional evaluation, independent of LVEF and the presence or extent of LGE, in DCM patients ,37. AddiStress echocardiography (SE) is another technique that can provide helpful information, by assessing the presence of contractile reserve and coronary flow reserve, predicting LVRR and functional recovery. Contractile reserve, irrespective of stressor dobutamine/exercise, is associated with a better prognosis .Cardiac magnetic resonance allows for a unique non-invasive tissue characterisation which adds important prognostic markers to LV functional parameters.Myocardial fibrosis occurs due to collagen accumulation resulting in interstitial expansion without myocardial necrosis  and from cardiomyocyte death (replacement fibrosis). There is a good histological correlation between LGE and replacement fibrosis, but LGE has a low sensitivity for interstitial fibrosis . Late gadolinium enhancement is present in around 30% of patients with DCM, typically in a mid-wall pattern. It has been associated with the occurrence of major VA consistently across all subgroups, regardless of LVEF. Besides the association with a four-fold increased risk of SCD or aborted SCD, LGE is an independent predictor of cardiovascular mortality and HF hospitalisation. Prognostic value is added with LGE beyond LVEF, NHYA class, and common baseline cardiovascular covariates ,41,42.Fibrosis extent has been proposed as a predictor of clinical outcomes in several studies. However, there is still a lack of consensus on specific cut-off values. Nonetheless, mid-wall LGE extent in the left ventricle walls appears to be inversely correlated with prognosis ,43. In aDespite the improved LV remodelling rate and lower arrhythmic risk in the absence of LGE, some patients without LGE still develop VA. Interstitial fibrosis, usually not detected with LGE, probably plays a role in these cases, where it could act as a substrate for re-entry circuits, potentially leading to malignant arrythmias .Differences in the etiological substrate and scar microstructure may explain the observed variation in risk based on LGE location. Idiopathic DCM is typically associated with septal mid-wall LGE . The locThe simultaneous occurrence of multiple LGE pattern types  increases the risk of all-cause mortality, heart transplantation, LV assist device implantation, and SCD events .DSP and FLNC genotypes. This scar pattern was associated with more regionality in LV impairment, while the other DCM genotypes had more impaired LVEF and GLS with the same degree of LV dilatation. Acknowledging such CMR patterns in patients should thus raise suspicion of ALVC [A correlation between LGE patterns and genetic variants was also recently documented. In a study with 89 patients with DCM-associated mutations, a subepicardial, ring-like scar pattern was associated with  of ALVC ,23,24,45Further work is required to investigate the relationship between the extent, location, and pattern of LGE and SCD events and determine whether there are reproducible amounts of LGE that reliably predict hard adverse arrhythmic events with the most accuracy.The study of interstitial fibrosis using T1 mapping and extracellular volume (ECV) estimation is an expanding area of CMR. Techniques for calculating T1 mapping have shown a good correlation with histologically graded myocardial fibrosis and, as such, may allow for a more sensitive detection of the early disease process, and initiation of respective treatment before overt pathology . In addiExtracellular volume has been shown to hold prognostic value incremental to LGE or native-T1 mapping . A stronFeature-tracking (FT) strain analysis is a promising tool for improving DCM patients’ risk stratification. Evidence suggests that survival prediction and risk stratification in DCM may be strengthened by FT parameters, independently of clinical parameters, biomarkers, LVEF, and LGE. For example, a preserved GLS determined by CMR carried a good prognosis, even in patients with LVEF < 35% and those with LGE .DCM has a recognisable genetic background that significantly overlaps with other cardiomyopathies, which could partially explain its wide heterogeneity. Current evidence suggests that 30% to 40% of DCM cases are caused by pathogenic or likely-pathogenic gene variants that occur in more than 40 genes associated with the condition ,51,52. GHowever, multiple factors have limited the widespread adoption of genetic testing. Indeed, on one hand it is still associated with substantial costs, and on the other hand the current yield of genetic testing for clinically meaningful variants in DCM is only around 30% ,53. To fBAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN, DSP and the genes ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL, respectively [The 2022 European Heart Rhythm Association consensus recommends that the initial pool of genes to be tested for DCM should include genes with definitive evidence of pathogenicity, and may already include genes with moderate evidence of pathogenicity: this includes the genes ectively . TTNtv) account for 15–25% of all DCM cases, making it the most common cause of genetic DCM [TTNtv, it is likely to be exacerbated by environmental factors such as alcohol consumption [TTNtv seem to respond well to optimal medical therapy (OMT), with high rates of LVRR and similar outcomes to patients with idiopathic DCM. Recognising the TTNtv likelihood of LV function improvement may be significant in everyday clinical practice, especially when deciding on cardiac device implantation [Recent studies have shown that truncating mutations in titin  and confer a worse prognosis concerning conduction disturbances, VA, SCD, response to treatment, death, and transplantation [Lamin A/C is a protein encoded by the antation ,61.LMNA mutations often develop early atrioventricular conduction disturbances, including high-grade atrioventricular block, atrial fibrillation and malignant VA, with simultaneous progression to heart failure [Patients with  failure . Moreove failure ,24. LMNA mutation must undergo an early genetic evaluation for a timely ICD implantation [LGE often demonstrates extended fibrosis, consistent with the disease’s high-risk arrhythmic profile. Therefore, patients suspected of carrying an antation ,24. LMNA carriers, NSVT, male gender, LVEF < 45% at presentation, and non-missense mutations were independent predictors of malignant VA [LMNA mutation if the estimated 5-year risk of life-threatening VA is ≥10% , and in the presence of either NSVT or LVEF < 50%, or AV conduction delay [In gnant VA . The curon delay .LMNA subgroup [Carriers of desmosomal variants also have a risk of arrhythmic events similar to the subgroup . Interessubgroup ,61.Mutations in desmosomal can cause skeletal and heart myopathies, and are associated with DCM, ALVC, and classical arrhythmogenic right ventricular cardiomyopathy (ARVC) with conduction disturbances and a high risk of VA and SCD .FLNC gene mutations in DCM are linked to high VA, SCD, heart transplantation, and LV fibrosis rates [At an early age, is rates . FLNC variants [FLNC variants cause DCM to share a histological and ultrastructural overlap with ACM, and present with a consistent arrhythmogenic phenotype and low rates of LVRR [FLNC and desmoplakin appear to be associated with a distinctive ring-like subepicardial LGE on CMR associated with NSVT [FLNC mutation, an LVEF ≤ 50%, and another risk factor  [A recent study showed fibrofatty infiltration of the LV and interstitial fibrosis of the VD among patients with truncating variants . Truncat of LVRR . FLNC anith NSVT . Due to ulation) .RBM20 is a splicing factor that controls the expression of many genes linked to DCM, including TTN. The RBM20 mutations have recently been found to have high penetrance and to produce an arrhythmogenic phenotype [RBM20 mutation, an LVEF ≤ 50%, and another risk factor) [Recent observations suggest that henotype ,69. In ahenotype . Indicat factor) .PLN genes that control calcium handling may influence arrhythmic risk, independently of structural changes [PLN gene are also associated with ACM, characterised by low-voltage ECG complexes and frequent VA events, with SCD often being the index presentation at a young age [Mutations in the  changes . Mutatiooung age .PLN mutation has the same indication for ICD implantation as previously described in other mutations with high arrhythmogenic risk  [A patient who is positive for  factor) .DSP gene have been recognised as e associated with the pathogenesis of ARVC, but recent data suggest that they more frequently cause ALVC. Variants in DSP are associated with a high prevalence of left ventricular (LV) fibrosis, systolic dysfunction and a significant predisposition for VA. Carriers of DSP mutations can develop sustained VA in the absence of severe LV systolic dysfunction, alerting the need for lower thresholds for ICD implantation to be considered in this group [Mutations in the is group .SCN5A are typically associated with conduction disease and Brugada syndrome. Some specific mutations, including the R222Q, may express a DCM phenotype that is associated with atrial arrhythmia, frequent PVC, and SCD [SCN5A DCM, arrhythmias are reported in over 90% of patients [Mutations in  and SCD . In thespatients . Interespatients .DCM is a dynamic disease, with up to 40% of patients experiencing LVRR, defined as an improvement in LVEF and reduction in ventricular volumes on OMT . PatientEarly diagnosis and treatment intervention is key in promoting LVRR in DCM patients, given recent findings underscoring the rapid and irreversible changes denoted in patients with a prolonged symptomatic-disease course ,77.Recent studies identified hypertension, absence of a family history of DCM, symptom duration <90 days, LVEF < 35%, and QRS duration < 116 ms, as independent clinical predictors of LVRR in patients with DCM .LBBB and longer QRS duration at baseline suggest a low probability of future LVRR . FurtherAn improvement in diastolic function, RV function, and functional MR is also associated with a higher likelihood of LVRR. However, the relationship with MR is complex, and it is debated whether functional MR should be considered a bystander .The extent of LGE is a robust independent predictor of LVRR, with a lower extent of LGE predicting a higher LVRR rate, regardless of the severity of LV dysfunction or dilation ,80. In aTTN variants are independently associated with LVRR, despite a lower baseline LVEF [LMNA variants showed high baseline LVEF with less frequent LVRR. Rare variants of the structural cytoskeleton Z-disk gene are independently associated with a lower rate of LVRR [Regarding genetic testing, ine LVEF . Compare of LVRR ,84.However, despite the existing evidence for the above techniques, more than each one alone is needed to predict LVRR accurately. Therefore, an integrated approach considering the imaging parameters as complementary to each other, and using them in combination with clinical observations, can lead to a better prediction model of LVRR and long-term outcomes.The current ESC guidelines recommend ICD for primary prevention as a Class IIA indication in patients with non-ischaemic DCM, symptomatic HF, and LVEF ≤ 35% after three months of OMT . HoweverPrevious studies have described a low rate of appropriate ICD therapies among patients with DCM . FurtherFurthermore, a significant proportion of DCM patients experience LVRR under OMT at a median of 2 years of follow-up, foreseeing a favourable long-term outcome ,43, and Of all the risk factors, LGE appears to have the strongest association with the arrhythmic outcome among studies that included only patients with primary prevention ICDs . In a meTherefore, incorporating LGE status into the criteria for primary-prevention ICD may allow for the selection of a subgroup of patients that have a higher arrhythmic risk (LGE positive) while sparing others who are without LGE the risk of complications from a device that is unlikely to improve their prognosis ,89,90,91Based on current evidence, a waiting period for ICD implantation longer than three months might be considered in selected cases. This decision will depend mainly on individual predictors of LVRR, a favourable genetic background, absence of a familial history of SCD, and NSVT and ECG findings not suggestive of increased arrhythmic risk . LMNA, PLN, FLNC, and RBM20 mutations and an LVEF ≤ 50%, and another risk factor, have an indication for ICD implantation [Patients with a low probability of LVRR at baseline or high arrhythmic risk may warrant prior re-evaluation and consideration for earlier ICD implantation ,88. As pantation . UnfortuThe clinical response to CRT depends on the optimal lead position and the viable cardiac muscle to be depolarized. Therefore, it is reasonable to hypothesise that LGE can help predict clinical response to CRT and therefore select patients more likely to benefit or guide the lead placement away from areas of scar tissue .Multiparametric scores for the arrhythmic stratification of patients with DCM need to be improved. Identifying such integrated models appears essential in selecting the best candidate for ICD implantation to guarantee greater quality-adjusted year of life and reduce complications in the DCM setting.Despite multiple imaging and genetic improvements, several challenges persist concerning the diagnosis, genetics, prognosis, and even the definition of DCM. Nevertheless, evidence suggests that imaging quantification of myocardial fibrosis, and mapping and strain measurements provided by CMR, should go hand in hand with genotyping in determining high-risk subtypes of DCM.In this era of precision medicine, the future holds great promise in improving risk stratification by incorporating clinical, imaging, and genetic factors in combined-score variables. We expect that future randomised prospective studies in DCM cohorts will address these problems, further improving the quality of care and outcomes.


BackgroundIt is important to consider left ventricular hypertrophy (LVH) and carotid intima-media thickness (CIMT) in assessing hypertensive patients’ global cardiovascular risk profile, as LVH and arterial wall changes occur concurrently. This study aimed to assess the relationship between CIMT and left ventricular geometry and function in hypertensive patients.MethodologyThis cross-sectional study included 200 hypertensive individuals and sought to correlate their CIMT with left ventricular geometry and function in Lagos University Teaching Hospital. Hypertension was defined as blood pressure ≥140/90 mmHg or on treatment for hypertension presenting at the outpatient clinics. Patients who satisfied the inclusion criteria were recruited. Abnormal CIMT was defined as >0.9 mm. Patients’ demographic data were obtained in addition to general characteristics, physical examination, transthoracic echocardiography, and CIMT. The statistical relationship between CIMT and left ventricular geometry and function was obtained and analyzed.Results2 = 31.688, p < 0.001). Furthermore, the mean left ventricular mass index was statistically different between abnormal and normal CIMT . Regarding left ventricular function, there was no significant difference in E-point septal separation, left ventricular fractional shortening, and left ventricular ejection fraction in abnormal versus normal CIMT groups. However, there was a significant association of CIMT with grades of diastolic dysfunction . Additionally, individual parameters of diastolic dysfunction such as left atrial volume index and septal mitral were significantly different (p < 0.001).Normal geometry and LVH were observed in 50.5% and 15.5%, respectively. Left ventricular geometry was associated with abnormal CIMT (χConclusionsThere was an association between age, left ventricular geometry, diastolic function, and CIMT in hypertensive individuals. Therefore, it is beneficial to evaluate CIMT and for these patients to receive more targeted blood pressure control which may reduce the risk of cardiovascular diseases. Systemic hypertension is the most common cause of cardiovascular disease which is the leading cause of mortality worldwide . The preCardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels which include coronary heart disease, heart failure, hypertension, cerebrovascular disease, and peripheral artery disease ,6. The sLVH is an increase in left ventricular (LV) mass and a complication of hypertension ,11. LVH Increased CIMT is highly associated with atherosclerosis and may be regarded as a marker of generalized subclinical atherosclerosis ,17. MeasCIMT is not routinely assessed but plays an important role in cardiovascular risk stratification . StudiesThis was a cross-sectional study conducted among hypertensive individuals. The participants were recruited from Lagos State University Teaching Hospital in the outpatient clinic of the cardiology department. The study was conducted for six months. A total of 200 participants were recruited in the study to achieve an estimated sample size using Fisher’s formula . A conveEthical approval was obtained from the Lagos State University Teaching Hospital Health Research Ethics Committee) .A structured questionnaire that contained the patient’s demographics, clinical variables, and the current antihypertensive therapy was administered to each patient. Physical examination, carotid ultrasound, and echocardiography were also conducted for each patient. Investigations done in the last three to six months needed to profile patients were extracted from case notes to aid inclusion and exclusion. We included patients who provided informed consent, were aged ≥18 years, and had a confirmed diagnosis of hypertension. We excluded patients aged <18 years; patients with diabetes mellitus; smokers; those with a previous history of coronary artery disease, chronic kidney disease (estimated glomerular filtration rate <60 mL/minute), stroke, or transient ischemic attack; pregnant women; those with high carotid artery bifurcation; and those with a short neck. These exclusion criteria have been shown to have increased CIMT and/or LVH -26.The left ventricular ejection fraction (LVEF) was calculated automatically by the machine using the Teicholz method . LV diasCarotid ultrasound was conducted bilaterally on each patient, and IMT values of more than 0.9 mm (ESC) were considered abnormal .Data were imputed and analyzed using SPSS version 25.0 . Categorical data were presented as frequencies, percentages, or proportions, while continuous data were presented as means and standard deviation or median and interquartile range when skewed. The Kolmogorov-Smirnov test was used to assess normal distribution.Mean comparisons between two groups were performed by independent Student’s t-test for continuous variables, while the association between CIMT categories and other categorical variables was assessed using the chi-square and Fisher exact test. The Pearson correlation coefficient was used to assess the linear relationship between numeric variables. A p-value of less than 0.05 was considered statistically significant at a 95% confidence interval. Charts were used for data presentation where appropriate.Demographic characteristics of hypertensives2 = 11.386, p = 0.023); thus, the frequency of abnormal CIMT was 2 (7.7%) in those aged <40 years and 4 (15.4%) in those aged >70 years. There was no significant difference in mean CIMT between male and female hypertensive as well as their body mass index (BMI) status. However, the prevalence of abnormal CIMT was higher in males  than in females  but did not achieve statistical significance (p = 0.395). Moreover, the prevalence of abnormal CIMT was the highest in obese patients but did not attain statistical significance (p = 0.245). Similarly, hypertension duration and hypertension control status were also significantly associated with abnormal CIMT   had normal CIMT and 45 (22.5%) had abnormal CIMT. Increasing age was strongly associated with abnormal CIMT  participants had normal geometry, whereas others had the following abnormal geometries: LV remodeling, LV concentric hypertrophy, and LV eccentric hypertrophy at 68 (34%), 18 (9%), and 13 (6.5%), respectively , as summarized in Table The mean systolic function parameters of E-point septal separation (EPSS) of 0.39 ± 0.1 cm, fractional shortening of 39.64 ± 5.1%, and ejection fraction of 70.23 ± 6.2% were within normal limits. No statistically significant difference was found between males and females (p > 0.05). The calculated mean left atrial volume index (LAVI) of 30.35 ± 8.0 mL/mLV geometry and CIMT in hypertensivesAbnormal CIMT occurred only in 45 (15.8%) hypertensive participants with normal LV geometry, with abnormal CIMT occurring mainly in participants with eccentric LVH and concentric LVH. Overall, 68 had concentric LV remodeling, with 58 85.3%) having normal CIMT. There were 13 hypertensives with eccentric LV hypertrophy and 18 hypertensives with concentric LV hypertrophy, of whom 5 (38.5%) and 7 (38.9%) had normal CIMT, respectively, as illustrated in Table % having LV diastolic function of hypertensives with normal and abnormal CIMT2, mitral E/A at 0.97 ± 0.4, septal mitral e at 7.84 ± 1.8 cm/second, and mitral E/e at 8.56 ± 2.2  , left ventricular mass index (LVMI) (p = 0.001), and interventricular septal wall thickness (p < 0.001), which was statistically significant, but there was also a positive correlation with left ventricular end-diastolic diameter (LVEDD) (p = 0.112), which was not statistically significant. LVEF p = 0.625), LV fractional shortening (p = 0.350), and EPSS (p = 0.510) had a positive correlation with CIMT which was not statistically significant. There was a relationship with left atrium (p = 0.001), LV volume index (p < 0.001), and mitral E/A (p = 0.029) but no significant relationship with mitral E/e (p = 0.340) . The results of other studies have also indicated a positive correlation between age and CIMT. Umeh et al.  also indConcerning blood pressure and CIMT, some studies showed only systolic blood pressure correlated with increased CIMT while other studies found both systolic and diastolic blood pressure being correlated with CIMT. In this study, there was a significant positive correlation between systolic blood pressure (p < 0.001) and CIMT but not with diastolic blood pressure (p = 0.224). This is similar to Nand et al.  who obseThere are different reasons why this correlation occurred. Some authors have suggested that the status of blood pressure control can contribute to this finding. Hypertension is a major driver of arterial remodeling and atherosclerosis. The observation that systolic blood pressure was only significantly related to CIMT in this study may be due to the impact of age, where the elderly tend to have more isolated systolic hypertension. In this study, there was no significant correlation between CIMT and BMI . Oluwagbemiga et al.  also didThe pattern of LV geometry in hypertensivesLVH is an independent risk factor for CVDs . In thisKaraye et al.  reportedThe LVH demonstrated in this study was 15.5%, which is similar to the 20% Hammond et al.  observedLV geometry of hypertensive patients with abnormal and normal CIMTIn this study, 22.5% of the hypertensives had abnormal CIMT while 77.5% had normal CIMT. This study observed that 84.5% with normal geometry had normal CIMT. This was in contrast with Saragih et al.  who repoIn our study, the prevalence of CIMT was higher in hypertensive participants with LVH compared with normal or concentric LV remodelling. This is similar to the Khutan et al.  study thThe study involved hypertensives not on medications and no elderly hypertensives such as the Khutan et al. study . Interes2.7 vs. 31.4 g/m2.7) and they were not on antihypertensives. This may be due to the common pathophysiologic pathway of CIMT and LVMI and neurohumoral and atherosclerotic influences. Moreover, LVMI is an independent predictor of cardiovascular morbidity and mortality.The mean LVMI in this study seen in hypertensive participants with abnormal CIMT was 97.84 ± 30.5 and with normal CIMT was 80.75 ± 15.6, which was statistically significant (p < 0.001). Similarly, Khutan et al.  also fouLV systolic function of hypertensives with abnormal and normal CIMTIn this study, there was no statistical difference between CIMT and LV systolic parameters such as EF (p = 0.916), EPSS (p = 0.334), and LVFS (p = 0.565) of hypertensive participants with normal or abnormal CIMT. This study observed that the mean EF with normal CIMT was 70.20 ± 5.9 and the mean EF with abnormal CIMT was 70.31 ± 7.3 (p = 0.916). Saragih et al.  similarlLV diastolic function of hypertensive patients with abnormal and normal CIMT2 = 7.069, p = 0.029). Notably, some diastolic parameters were significantly different among normal and abnormal CIMT, such as LAVI  and septal mitral e . Meanwhile, others had no statistical significance, such as mitral E/A , DT , and mitral E/e . However, Saragih et al. [In this study, the grading of diastolic dysfunction and CIMT showed a significant association . However, multivariate eccentric LV geometry indicated a relationship (p = 0.005).In this study, the relationship of LV geometry to CIMT was evaluated using univariate and multivariate analyses. Regarding LV geometry, the univariate analysis demonstrated a strong relationship between CIMT with the following individual variables: LAD , IVSD , LVM , LVMI . However, on multivariate, only IVSD (p = 0.017) maintained a significant relationship. Concerning LV geometry, a strong association was noticed between CIMT and the different grades of geometry  in this study. Similarly, in the study by Khutan et al. , there wCorrelation of LV function and CIMTCorrelation of univariate and multivariate CIMT with different parameters of systolic function did not show any correlation: LVEF , LV fractional shortening , and EPSS . However, Yarynkina et al.  studied Correlation of univariate and multivariate CIMT with different parameters of diastolic function showed varying correlation: LAVI , mitral E/A , DT , mitral E/e , septal mitral e . However, on multivariate analysis, only DT (p = 0.025) maintained a significant relationship. Systemic hypertension is associated with diastolic dysfunction and CIMT. This study showed a significant correlation between the left atrium and CIMT . Similarly, Yarynkina et al.  also obsLimitationsIn this study, CIMT measurements were done manually. Automated edge detection is preferred and more accurate as the manual method is operator-dependent. Additionally, as the study was hospital-based in a single tertiary hospital, the results might not be generalizable to all hypertensives in society.This study described CIMT assessment and correlation with echocardiographic LV geometry and function in hypertensive patients. Hypertensives are at risk of hypertension-mediated organ damage which includes LVH and abnormal CIMT. Abnormal CIMT has been shown to be higher in hypertensives with concentric and eccentric LVH, which can further increase their risk of cardiovascular events. LVH, which is an independent risk factor for cardiovascular events, has been shown to be associated with abnormal CIMT which further increases the risk of CVDs.


Albeit that cardiac magnetic resonance feature tracking (CMR-FT) has enabled quantitative assessment of global myocardial strain in the diagnosis of suspected acute myocarditis, the cardiac segmental dysfunction remains understudied. The aim of the present study was using CMR-FT to assess the global and segmental dysfunction of the myocardium for diagnosis of suspected acute myocarditis.Ni), segments with edema (SE), and segments with both edema and late gadolinium enhancement (SE+LGE). 272 healthy segments served as the control group (SHCs).Forty-seven patients with suspected acute myocarditis (divided into impaired and preserved left ventricular ejection fraction [LVEF] groups) and 39 healthy controls (HCs) were studied. A total of 752 segments were divided into three subgroups, including segments with non-involvement  and SE , compared with SHCs. The area under the curve (AUC) values of GLS (0.723) and GCS (0.710) were higher than that of global peak radial strain (0.657) in the diagnosis of acute myocarditis, but the difference was not statistically significant. Adding the Lake Louise Criteria to the model resulted in a further increase in diagnostic performance.Compared with HCs, patients with preserved LVEF showed impaired global circumferential strain (GCS) and global longitudinal strain (GLS). Segmental strain analysis showed that the peak radial strain (PRS), peak circumferential strain (PCS), and peak longitudinal strain (PLS) values significantly reduced in SGlobal and segmental myocardial strain were impaired in patients with suspected acute myocarditis, even in the edema or relatively non-involved regions. CMR-FT may serve as an incremental tool for assessment of cardiac dysfunction and provide important additional imaging-evidence for distinguishing the different severity of myocardial injury in myocarditis.The online version contains supplementary material available at 10.1186/s12872-023-03201-2. As an important cause of cardiac morbidity and mortality, myocarditis has been reported in up to 12% of young adults with sudden death . HoweverThis retrospective study was approved by the Institutional Review Boards of our hospital (No.2022-L-128). Forty-seven patients  were retrospectively enrolled from 2015 to May 2019 in our hospital. All the patients had been clinically suspected acute myocarditis  and underwent CMR examination. They were diagnosed with myocarditis for having clinical symptoms and according to the corresponding clinical criteria based on 2013 ESC guidelines . ClinicaCMR was performed on a 3.0-T MR system  using a standard 16-element cardiac phased array coil and a four-lead vectorcardiogram. For functional analysis, electrocardiography-gated balance turbo field echo (b-TFE) cine images were obtained in the short-axis, four-chamber, three-chamber, and two-chamber views . Edema-sensitive black-blood T2-weighted images with fat saturation (triple inversion recovery turbo spin echo sequences with inversion pulses for fat and blood suppression) were acquired in the short-axis orientation covering the entire left ventricle . Late gadolinium enhancement (LGE) imaging was performed 10 min after the injection of 0.1 mmol/kg gadobutrol  with inversion time (300–340 mm) adjusted according to a Look-Locker inversion recovery-prepared T1-weighted phase-sensitive inversion recovery sequence  in the short-axis, four-chamber, three-chamber, and two-chamber views, which corresponded with cine images. CMR scanning was performed according to the standardized protocols recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) .Two radiologists experienced in CMR diagnosis blindly analyzed the data, performed the measurements, and reached agreement regarding the consequences. Prior to FT analysis, a random cohort of 15 patients was chosen to assess intra- and interobserver reproducibility.n = 12) and the preserved-LVEF group  [Cardiac function analysis was performed offline based on the acquired b-TFE cine images by using dedicated software . Endocardial and epicardial contours of the left ventricle were manually delineated at the end-systolic and end-diastolic phases in short-axis views to calculate volume changes and left ventricular ejection fraction (LVEF). Based upon the body surface area, LV end-diastolic volume index, LV end-systolic volume index, and myocardial mass index were quantified. Patients with acute myocarditis were divided into two subgroups according to LVEF, including the impaired-LVEF group  .Image analysis of the updated LLC was performed using the CVI 42 software . The myocardium was divided into 16 segments according to the American Heart Association segmentation . Every sNi; n = 509), segments with edema , and segments with both edema and LGE . The SE subgroup was localized using T2-weighted images; the SE+LGE subgroup was localized using both T2-weighted images and LGE images; and the SNi subgroup was considered as normal in comparison with the two preceding subgroups. A cohort of segments of HCs  served as the control group.CMR diagnosis of myocarditis was based on the edema-sensitive CMR (T2-weighted images or T2 mapping) and at least one additional T1-based tissue characterization technique . As T1 aCMR-FT was performed offline based on the acquired b-TFE cine images using CVI 42 software . Endocardial and epicardial contours were drawn manually in the end-diastolic phases, and myocardial strain was automatically tracked by CVI 42 throughout the cardiac cycle. Global peak longitudinal strain (GLS) was averaged from the measurements of the two-, three-, and four-chamber views. Circumferential (GCS) and radial (GRS) peak strain parameters were determined in the short-axis view covering the entire left ventricle Fig. . Every sp < 0.050. Statistical analysis was performed using SPSS software .Normality was tested with the Kolmogorov–Smirnov test. Continuous variables were presented as means ± standard deviations and compared using the Student’s t-test for normally distributed data or the Mann–Whitney U-test for non-normally distributed data. The inter- and intra-observer variability was assessed with the intraclass correlation coefficient (ICC) and Bland–Altman plot. Parametric data of more than two groups were compared using one-way analysis of variance testing. Post-hoc testing was performed with the least significant difference test (homogeneity of variance) or Dunnett’s T3 test (heterogeneity of variance). Categorical group data presented as percentages were compared using the chi-squared test or Fisher’s exact test, as appropriate. Diagnostic performance of the strain parameters was analyzed by plotting receiver operating characteristic curves and comparing the areas under those curves. Cutoff values were defined by calculating the Youden index for the predictive variables, and sensitivity, specificity, and accuracy were calculated. To combine the single predictive variables, scores were derived from logistic regression analysis. The level of statistical significance was set to The reproducibility was good for global and segmental stain parameters, with ICC of inter-observer ranges from 0.882 to 0.983 for global parameters and 0.837 to 0.883 for segmental parameters, the ICC of intra-observer ranges from 0.986 to 0.996 for global parameters and 0.877 to 0.977 for segmental parameters. The detailed ICC and 95% CI of inter- and intra-observer agreement for different strain parameters and the Bland–Altman plots are listed in Additional file This study included forty-seven patients with suspected acute myocarditis and 39 HCs. Clinical symptoms of the patients are given in Table p = 0.001), GCS , and GLS  , GCS , and GLS  as compared with HCs  and GLS  as compared with HCs, whereas their GRS values were not significantly different from that of the HCs. The three global strain parameters significantly decreased in patients with impaired-LVEF as compared with that in the preserved-LVEF group (p < 0.010)  and SE  groups as compared with that in SHCs group. However, SNi and SE groups were not significantly different from each other in their PRS, PCS, and PLS  being 0.723 and 0.710, respectively. The diagnostic performance of GRS had an AUC of 0.657  myocardium in suspected acute myocarditis. Lastly, GLS and GCS derived from CMR-FT showed good performance in diagnosis of patients with suspected acute myocarditis.Strain parameters like GLS and GCS were considerably reduced in patients with suspected acute myocarditis and even in those with preserved LVEF as compared with that in HCs. However, there was no difference in GRS between patients with preserved LVEF and HCs, which is in agreement with the results of previous CMR and echocardiographic studies , 22–24. As it is known that different myocardial segments are not equally affected by inflammatory processes in acute myocarditis. Histopathological features of acute myocarditis include cellular infiltration, edema, necrosis, and fibrotic scars , 30. ComIn recent years, given the highly variable natural history and prognosis of myocarditis (ranging from complete recovery to severe cardiomyopathy or sudden death), there is great interest in techniques for predicting the risk of future adverse outcomes. LGE and abnormalities of GLS have been shown to be powerful predictors of adverse events in myocarditis , 37–40. The current CMR criteria (updated LLC) for diagnosis of myocarditis use tissue characteristics. The evaluation of cardiac function has only supportive character in the updated LLC. However, as many myocarditis patients show impaired cardiac strains despite their preserved LVEF, the assessment of cardiac deformation has a potential to tap for improving diagnosis of myocarditis of these patients. The current study was intended to investigate the diagnostic performance of strain parameters of the preserved-LVEF group. Although GLS and GCS showed moderate diagnostic potential  for suspected acute myocarditis, they also revealed a considerable overlap between HCs and patients with suspected myocarditis. GRS presented a slightly lower diagnostic performance AUC: 0.693), which supports previous studies , 14. We 93, whichThe present study has several limitations of its own. Firstly, we used a clinical reference standard for suspected myocarditis patients as subjects without endomyocardial biopsy. However, we carefully defined the patient cohort based on clinical criteria similar to that of other studies , 7. NeveGlobal and segmental myocardial strain were impaired in patients with suspected acute myocarditis, even in the edema or relatively non-involved regions. CMR-FT may serve as an incremental tool for assessment of cardiac dysfunction and provide important additional imaging-evidence for distinguishing the different severity of myocardial injury in myocarditis.Additional file 1:Supplementary Table. Intra-observer and inter-observer variability of different strain parameters. Appendix Fig. Bland-Altman plot of intra-(a) and inter-observer(b) reproducibility, for three segmental strain types. The horizontal green line depicts the mean; the 2 red lines depict the upper and lower 95% limit of agreement. PRS, segmental radial strain; PCS, segmental circumferential strain; PLS, segmental longitudinal strain.


Background: Fabry disease cardiomyopathy (FDCM) has manifested some resistance to enzyme replacement therapy (ERT), particularly in its advanced phase. Recently, myocardial inflammation of autoimmune origin has been demonstrated in FDCM. Aims: The objective of this study was the assessment of circulating anti-globotriaosylceramide (GB3) antibodies as potential biomarkers of myocardial inflammation in FDCM, defined by the additional presence of ≥CD3+ 7 T lymphocytes/low-power field associated with focal necrosis of adjacent myocytes. Its sensitivity was based on the evidence of overlapping myocarditis at left ventricular endomyocardial biopsy. Methods and Results: From January 1996 to December 2021, 85 patients received a histological diagnosis of FDCM in our department and 48 (56.5%) of them had an overlapping myocardial inflammation with negative PCR for common cardiotropic viruses, positive antiheart, and antimyosin abs. The presence of anti-GB3 antibodies was evaluated with an in-house ELISA assay , along with antiheart and antimyosin abs, in the FDCM patients and compared with control healthy individuals. The correlation between levels of circulating anti-GB3 autoantibody myocardial inflammation and FDCM severity was assessed. Anti-Gb3 antibodies were above the positivity cut-off in 87.5% of FDCM subjects with myocarditis (42 out of 48), while 81.1% of FDCM patients without myocarditis were identified as negative for Gb3 antibodies. Positive anti-Gb3 abs correlated with positive antiheart and antimyosin abs. Conclusions: The present study suggests a potential positive role of anti-GB3 antibodies as a marker of overlapping cardiac inflammation in patients with FDCM. Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by mutations in the α-galactosidase A gene encoding the lysosomal hydrolase alpha-galactosidase A  ,2. The mFabry disease cardiomyopathy (FDCM) is a major determinant of patients’ survival, and its management actually represents a major therapeutic challenge. Indeed, the impact of enzyme replacement therapy (ERT) on FDCM is still controversial, and while there is agreement that early ERT administration, particularly in the pre-hypertrophic phase, prevents the progression of the disease, the advanced form is believed to be irreversible ,5. The mechanisms of resistance to ERT are, however, still unclear.In Fabry disease, as in other lysosomal storage disorders, substrate deposits in lysosomes fuel multiple pathogenic cascades that ultimately lead to an inflammatory response . This maFurther studies showed that inflammatory and cardiac remodeling biomarkers are elevated in the sera of patients with Fabry disease and positively correlated with Mainz Severity Score Index scores, left ventricular hypertrophy, late gadolinium enhancement at cardiac magnetic resonance, and renal dysfunction . From a However, both TNF and IL-6 plasma levels are nonspecific markers that are elevated in several conditions of chronic heart failure and correlate with a decreasing functional status as well as with all mortality causes . These oWe enrolled all the patients with biopsy-proven and genetical diagnosis of FDCM in the study. Circulating levels of anti-GB3 autoantibodies were compared between patients with the histological presence (group A) or absence (group B) of myocardial inflammation (negative PCR for the cardiotropic viruses and positive antiheart and antimyosin antibodies).The study complies with the Declaration of Helsinki; the locally appointed ethics committee approved the research protocol and informed consent was obtained from all subjects.In all patients, cardiac investigations included noninvasive  and invasive  studies after receiving written informed consent. Our institution is a tertiary referring center for the diagnosis and treatment of cardiomyopathies, myocarditis, and heart failure and obtained permission from the local ethical committee ). EMB is regularly performed in our institution whenever a symptomatic heart muscle disease remains undiagnosed by noninvasive procedures including echocardiography and cardiac magnetic resonance. Biopsy samples, 5–8 per patient, were cut and stored at −80 °C, or processed for histology, immunohistochemistry, and electron microscopy. Two frozen samples per patient were processed for real-time PCR for the most common cardiotropic viruses in case of observation of overlapping myocarditis at histology.The study complies with the Declaration of Helsinki, the locally appointed ethics committee (opinion number 6/2019) approved the research protocol, and informed consent was obtained from all subjects. The patients were strongly motivated to clarify the origin of symptoms and gave their written consent for the procedure.Pathologists, echocardiographers, and CMR investigators were blind to the patients’ clinical and genetic background. They were informed after their report.CMR exams were performed on a 1.5 Tesla scanner . The CMR protocol included: (i) cine CMR sequence acquired during breath holds in the short-axis, 2-chamber, and 4-chamber; (ii) black blood T2-weighted short tau inversion recovery images on short-axis planes covering the entire left ventricle during 6 to 8 consecutive breath holds for myocardial edema detection; (iii) late gadolinium-enhanced imaging performed 15 min after injection of 0.2 nmol/kg of gadoterate meglumine and signal intensity value 2 SDs above the mean signal intensity of the remote normal myocardium were considered suggestive of myocardial fibrosis; (iv) native T1 mapping imaging was performed, when available, using the MOLLI sequence on three short-axis views ; (v) a T2 map was obtained using a T2-prepared True-FISP prototype sequence producing 3 single-shot images with 3 different T2 pulse preparations. A nonrigid registration algorithm and the two-parametric automatic curve fitting were automatically applied to generate the map. CMR image analysis was performed as previously described, extending the analysis method for T1 maps also to T2 maps. In particular, the values of T1 and T2 global were defined as normal, reduced, or increased compared to a reference range developed on a multiage sample of 100 healthy subjects of both sexes . Cardiac catheterization with left ventricular and coronary angiography was obtained in all patients. EMB was performed in the septal–apical region of the left ventricle. Endomyocardial samples were blindly evaluated by the same pathologist. He was informed of clinical and genetic characteristics after morphological examination.For histological analysis, the endomyocardial samples were fixed in 10% buffered formalin and paraffin-embedded. Five-micron-thick sections were stained with hematoxylin and eosin and Masson trichrome. For electron microscopy studies, additional samples were fixed in 2% glutaraldehyde in a 0.1 M phosphate buffer at pH 7.3, post-fixed in osmium tetroxide, and processed following a standard protocol for embedding in Epon resin. Ultrathin sections were stained with uranyl acetate substitute and lead hydroxide. Controls for the morphological study consisted of surgical LV endomyocardial biopsies from patients with mitral stenosis, that, although not obtained from healthy individuals, were derived from a chamber without overload and were considered the samples nearest to normal endomyocardial tissue.The histological diagnosis of myocarditis was based on the evidence of leukocyte infiltrates (≥14 leukocytes/2 mm) associated with necrosis of the adjacent myocytes, according to the Dallas criteria confirmed by immunohistochemistry. In particular, for the phenotypic characterization of inflammatory infiltrates, immunohistochemistry was performed for CD3, CD20, CD43, CD45RO, and CD68 .Patient sera were tested for the presence of circulating cardiac autoantibodies using a standard indirect immunofluorescence technique with a substrate of 4 μm thick unfixed cryostat sections of human atrium and intercostal skeletal muscle of blood group O patients. Briefly, patient sera were diluted 1/10 in pH 7.2 phosphate-buffered saline solution, and fluorescein-isothiocyanate-labeled rabbit antihuman immunoglobulin was used at 1:100 dilution. The intensity of immunofluorescence of the positive control (known positive serum) at 1/40 dilution was used as the cutoff point for positivity. Omission of the patient serum and known negative serum was included in every assay (negative controls).Patient sera were screened for the presence of Gb3 and myosin antibodies, detected by using a quantitative human MYO ELISA kit  and the semiquantitative ELISA for Anti-Gb3 ELISA. As controls, we used a pool of normal sera from participants matched with patients for age and sex.For antimyosin Ab detection, standards and undiluted samples were added to the micro-ELISA plate wells and combined with the specific antibody. The optical density proportional to the concentration of human myosin was measured spectrophotometrically at a wavelength of 450 nm. The detection range of the ELISA kit is 1.56 to 100 ng/mL. The concentration in the samples was calculated by comparing the optical density of the samples with the standard curve using the software interface GraphExpert Professional 1.4.0  and expressed as ng/mL. The positivity of serum abs for Gb3 was correlated with overimposition of myocarditis in our patient population of 85 patients with FDCM whose diagnosis was obtained with the assessment of pathogenic GLA gene mutations and detection of Gb3 accumulation at histology, immunohistochemistry, and ultrastructural examination of left ventricular endomyocardial biopsies.For the development of the in-house ELISA, the FSL-Gb3 construct , which is composed of Gb3 conjugated with the function–spacer–lipid (FSL) group, was employed. Different concentrations of FSL-Gb3 (ranging from 1 to 250 μM) were diluted in PBS pH 7.2 and used for the coating of Maxisorp microplates (NUNC). Coating was carried out for 3 h at 25 °C and at 4 °C for 12 h, and then, the plates were washed three times with PBS-T. The plate wells were then blocked with PBS-BSA at room temperature for 1 h. The commercially available anti-CD77 (globotriaosylceramide Gb3) monoclonal antibody produced in rat  was used as primary Ab in order to verify the coating efficiency. These preliminary results showed that coating overnight at 4 °C with 5 μM FSL-Gb3 was suitable for assay development. Further adjustments were made according to the results obtained by serial dilutions of the rat anti-Gb3 antibody. Dilutions ranging from 20 μg/mL to 0.6 ng/mL were employed in combination with different dilutions  of the secondary HRP-conjugated antibody specific for rat IgM . The assay was considered adequate when the 4PL curve generated plotting OD and antibody concentrations showed linearity (R2) > 0.95. The obtained results indicated with the positive control (rat anti-Gb3 antibody) that the dilution linearity was adequate for all tested conditions, so the coating with 5 μM FSL-Gb3 overnight at 4 °C was employed for assay development .Human serum from FDCM patients (n = 12) and two pools from healthy individuals (n = 40 pooled samples) were then employed to verify the suitability of the assay for the analysis of human anti-Gb3. After preliminary tests performed with serial dilutions of serum samples (from 1:10 to 800), the dilution 1/50 was selected. ®, Winooski, VT, USA). The resulting optical density (OD) measured in the FDCM serum samples was used to calculate the positive/negative (P/N) ratio  diluted 1:2000 in PBS-BSA 1% was added and the plates were incubated as indicated above, followed by three washes and the addition of OPD substrate . The plates were then incubated in the dark at RT for 10 min and the reaction was stopped by adding 3N HCl. The plates were read at 492 nm using a microplate reader (BioTekN) ratio .The cut-off point was set by analyzing n = 12 FDCM serum samples of FDCM patients with myocarditis and FDCM patients without myocarditis analyzed blindly. A common method to define a cut-off for discriminating positive samples from the negative ones is calculated by applying the following formula: cut-off = average value negative control (pool from 40) + 5 × negative control standard deviation.According to the analysis, the optimal cut-off value of circulating anti-Gb3 antibody in FDCM patients for predicting myocardial inflammation was P/N > 2.56 fold-change with respect to the reference (or control).Definition of virus-negative, immune-mediated, overlapping myocarditis followed the presence at histology of ≥7 CD3+ T lymphocytes per lo- power field associated with focal necrosis of the adjacent myocytes . Negative PCR on two frozen endomyocardial samples for the most common cardiotropic viral genomes including adenovirus, Epstein–Barr virus, herpes virus, parvovirus B19, cytomegalovirus, enterovirus, influenza, and A/B. Serological positivity for antiheart and antimyosin abs was analyzed.t-test, the χ2 test, and the Fisher exact test were used for comparisons; the difference between variables without normal distribution was tested with the Mann–Whitney U test. For all tests, a p value less than 0.05 was considered statistically significant. The receiver-operating characteristics (ROC) curve was used to describe the performance and predictive accuracy of circulating anti-GB3 antibody as a biomarker of myocardial inflammation in FDCM. The sensitivity, specificity, and area under the curve (AUC) were calculated, and the cut-off value was determined using the Youden index. All statistical analyses were performed using R statistical analysis software (R 4.3).The normal distribution of all continuous variables was checked with visual methods (Q-Q plot and histogram) and a significance test . For continuous variables, descriptive statistics were provided , while the median (interquartile range) was used for non-normal data. Categorical data were described as a number (percentage). Baseline demographic and clinical characteristics will be presented in table format. Student’s 2; p-value: 0.04) and reduction in LVEF  were documented. A more pronounced electrical instability and incidence of heart failure were reported in group A. Regarding systemic manifestations, in group A, an increased incidence of renal disease with lower eGFR and more noncardiac symptoms were revealed.From January 1996 to December 2021, we enrolled eighty-five patients with histological diagnosis of FDCM; forty-eight (56.5%) of them had an overlapping myocardial inflammation with negative PCR for the common cardiotropic viruses (group A). The remaining 37 FDCM patients had no overlapping inflammation at histology (group B). The demographic, clinical, and instrumental characteristics of the two groups are reported in The normalized values of the circulating anti-GB3 antibodies assays were performed twice on twelve controls; the values are summarized in The assay results showed that 42 out of 48 FDCM patients with myocarditis were positive for anti-GB3 antibodies, while 30 FDCM patients out of 37 without myocarditis had negative anti-GB3 antibodies see .Those patients with positive anti-Gb3 antibodies had, as previously described (7), serum positivity for antiheart and antimyosin antibodies.p-value: 0.001].As reported in According to the ROC analysis, the optimal cut-off value of circulating anti-GB3 antibodies in the FDCM patients for predicting myocardial inflammation was >7.5, with a sensitivity of 83.8% and a specificity of 87.5%  .All patients with overlapping myocarditis at histology were positive in the serologic assessment of antiheart abs see A–D.There is growing evidence that myocardial inflammation can be a cause of progression of Fabry disease cardiomyopathy as well as an unnoticed mechanism of disease resistance to ERT. Indeed, myocardial inflammation promotes cell dysfunction and death, causing the expansion of the interstitial space through oedema, inflammatory cell infiltration, and myocardial fibrosis, which result in both ventricular diastolic and systolic dysfunction.With regard to the origin of myocardial inflammation associated with Fabry disease cardiomyopathy, the absence of viral genomes in the myocardium and the strong positivity of antiheart and antimyosin antibodies described suggest myocardial inflammation to have an autoimmune/disreactive origin . In thisThe main objective of the present study was the identification of a reliable biomarker of myocardial inflammation overimposing in human FDCM. Indeed, comparing the serologic positivity of anti-GB3 abs with the presence at histology of left ventricular endomyocardial biopsies, the presence of inflammation was confirmed via serology with a sensitivity of 83.8% and a specificity of 87.5%. Remarkably, in our study, the presence of myocardial inflammation in patients with FDCM (group A) was associated with a mean increase in the left ventricular mass index, a lower LVEF, and an increased incidence of atrial fibrillation. Furthermore, in terms of systemic manifestations, a lower mean eGFR and increased noncardiac symptoms were evidenced in group A. These observations suggest myocardial inflammation in FDCM to have a clinical impact impairing cardiac function and increasing electrical instability. Additionally, a systemic compromise such as renal function can occur as well. We are, in fact, unable to attribute a specific pathogenic role to anti-GB3 abs, nor can we establish whether the myocardial damage associated with inflammation should be ascribed exclusively to T lymphocytes. The identification of a sensitive and specific circulating biomarker of cardiac inflammation in patients with FDCM resistant to ERT administration could allow the introduction of immunosuppressive therapy that may halt the progression of the cardiomyopathy and improve the efficacy of ERT. In this regard, the association of anti-GB3 with antiheart and antimyosin abs and negative PCR for the most common viral genomes suggests a strong activation of an immune autoreactive inflammatory process that may benefit from an immune-modulating treatment. A better understanding of the autoimmune/inflammatory activation in Fabry disease and its role in the disease morbidity and mortality will change the therapeutic approach to the disease, allowing the identification of patients with a high autoimmune/inflammatory burden who will benefit from an immunosuppressive treatment in addition to ERT. Positive results of a wider FDCM population are, however, necessary for the implementation of ERT with immunosuppressive therapy. The type of immunosuppressive regimen as well as its duration has yet to be established.In conclusion, serologic positivity of anti-GB3 abs represents a reliable biomarker of myocardial inflammation in FDCM. It may suggest ERT implementation with immune-suppressive therapy to enhance ERT impact and improve a patient’s outcome, particularly in those patients with a progressive impairment of cardiac function and/or the occurrence of complex/life-threatening cardiac arrhythmias. Further prospective, double-blind, clinical studies are, however, necessary for the inclusion of immune suppression in the therapeutic regimen of progressive FDCM with inflammation.


Left ventricular (LV) pressure-volume (PV) loops provide gold-standard physiological information but require invasive measurements of ventricular intracavity pressure, limiting clinical and research applications. A non-invasive method for the computation of PV loops from magnetic resonance imaging and brachial cuff blood pressure has recently been proposed. Here we evaluated the fidelity of the non-invasive PV algorithm against invasive LV pressures in humans.2 = 0.96, P < 0.0001, bias 4.6%), potential energy , end-systolic pressure-volume relationship , ventricular efficiency , arterial elastance , mean external power , and energy per ejected volume . Variations in estimated end-diastolic pressure did not significantly affect results . Intraobserver analysis after one year demonstrated 0.9–3.4% bias for LV volumetry and 0.2–5.4% for PV loop-derived parameters.Four heart failure patients with EF < 35% and LV dyssynchrony underwent cardiovascular magnetic resonance (CMR) imaging and subsequent LV catheterization with sequential administration of two different intravenous metabolic substrate infusions (insulin/dextrose and lipid emulsion), producing eight datasets at different haemodynamic states. Pressure-volume loops were computed from CMR volumes combined with (i) a time-varying elastance function scaled to brachial blood pressure and temporally stretched to match volume data, or (ii) invasive pressures averaged from 19 to 30 sampled beats. Method comparison was conducted using linear regression and Bland-Altman analysis. Non-invasively derived PV loop parameters demonstrated high correlation and low bias when compared to invasive data for stroke work (RPressure-volume loops can be precisely and accurately computed from CMR imaging and brachial cuff blood pressure in humans. Current guidelines for the management of suspected heart failure recommend CMR for assessment of myocardial structure and function2 but also acknowledge the need for improved assessment of patient-specific haemodynamic measures, including left heart catheterization.Left ventricular (LV) pressure-volume (PV) loops contain a wealth of information with the potential to improve assessment of cardiac health, providing decision-making support for clinicians and valuable data for researchers.Due to the invasive nature of conductance catheter experiments, PV loop analysis is not conducted routinely in clinical practice. Ethical considerations such as risk/benefit and procedural costs further limit PV loop applications. Furthermore, while LV catheterization is the only way to obtain absolute pressures, ventricular volumes are most accurately captured by short-axis CMR image acquisition. As such, whilst providing gold-standard haemodynamic assessment, PV loop interrogation does not provide the best quality volumetric assessment. Should non-invasive measures accurately predict invasive PV loops, the inherent risk and expense of invasive LV catheterization could then be avoided.3 combining LV volumes with a time-varying elastance function to compute time-resolved LV pressures.4 The advantage of this method is that it can be widely implemented using standard CMR images and provides measures of myocardial stroke work (SW), potential energy (PE), end-systolic pressure-volume relationship (ESPVR) (inotropic state), energy per ejected volume (EPEV), ventricular efficiency (VE), arterial elastance, and mean external power (MEP) . While the method has been validated using invasive data from a porcine model3 and sensitivity tested using a dobutamine infusion in healthy humans,5 it remains to be validated in patients using invasive LV pressure recordings from PV loops.Recent development has seen the introduction of non-invasively computed PV loops from CMR volumetry and a brachial blood pressure measurement,The aim of this project was therefore to provide the first validation of non-invasively computed PV loops against invasive measures in humans, testing the hypothesis that the methods are interchangeable.post hoc analysis of data from a study designed to investigate the effects of metabolic substrate switching on myocardial function in heart failure.6 Patients were originally recruited from the cardiology services of the Oxford University Hospitals NHS Foundation Trust. All participants gave written informed consent. The study was conducted in accordance with the Helsinki declaration and was approved by the National Research Ethics Service (REC reference 18/SC/0170). OJR had full access to all the data and took responsibility for its integrity and data analysis.This was a 7 All patients were scheduled for CRT implantation as part of routine clinical care, and all procedures were in accordance with institutional guidelines. After completing all study procedures, each dataset was assessed for technical quality and completeness. Only datasets where complete imaging and invasive data were available, and which were acquired during sinus rhythm, were considered for inclusion.Inclusion criteria were as follows: patients at least 18 years of age, willing and able to give informed consent, and diagnosed with non-ischaemic heart failure with reduced ejection fraction (HFrEF) meeting criteria for cardiac resynchronization therapy (CRT) as per the 2016 European Society of Cardiology guidelines.Exclusion criteria included inability to safely undergo study procedures, general MRI safety criteria  as well as disturbances of normal fat metabolism and allergies to soya or egg. Patients were also screened and excluded for severe liver damage, tuberculosis, pulmonary disease, anaemia, coagulation disorders, and recent fractures of pelvis or long bones.Figure 2. On the first visit, participants were randomized to receive either insulin/dextrose infusion or lipid emulsion  infusion after fasting overnight, with the other infusion given on the second visit at least seven days later, again after fasting overnight. The third visit consisted of the CRT implantation. Participants were fasted overnight as per clinical protocol and started on an insulin/dextrose infusion before the implant. During the implant, a pressure-conductance catheter was placed in the LV. Following the recording of pressure and conductance data, participants were switched onto an Intralipid™ infusion, with PV loops recorded again after 15 min of infusion.Study participants underwent three study visits, summarized in TM MR200 MRI safe monitoring system, MR Devices, UK), less than 1 h after acquiring short-axis images.A standard mid-physiological range euglycaemic hyperinsulaemic clamp was used, with participants clamped at their fasting blood glucose level, using a continuous infusion of insulin  at 0.8 mU/kg/min following a 10-minute loading regime and variable rates of dextrose infusion (200 mg/mL). Venous blood glucose measurements were performed every 5 min for the first hour to ensure a steady state had been reached. CMR was then performed , and brachial blood pressure was measured once near the end of the protocol  was also infused at 0.4 U/kg/min to further increase triglyceride breakdown. During invasive measurements, heparin was given as an intra-arterial bolus to keep activated clotting time ≥250 ms. CMR imaging was commenced at a steady state 60 min after starting Intralipid infusion, and brachial blood pressure was measured once near the end of the protocol, within one hour after short-axis imaging.An Inca™ conductance catheter  was passed via 8Fr femoral arterial access to the LV apex, following calibration to atmospheric pressure (‘zeroing’) prior to implant. PV loops were recorded for 1 min at a sampling frequency of 250 Hz. The largest measured volume was equalized to the end-diastolic volume measured from the preceding CMR. Conductance catheter data was analysed using commercial software provided by the manufacturer . A 10 Hz filter was applied to recordings. The pressure was adjusted to correct for any offset recorded at the time of catheter withdrawal from the femoral artery. Any catheter segments not in the LV were discarded from the final calculations and auto systolic and diastolic markers were manually checked for accuracy and adjusted if necessary. In the case of ectopy, the ectopic beat and the preceding and following beats were discarded from the recording. Frequent ectopy was grounds for exclusion.Study participants underwent CMR imaging in the supine position at 3T  using a cardiac coil. Balanced steady-state free precession (bSSFP) imaging was performed in the horizontal and vertical long-axis projections and a short-axis stack covering the entire left ventricle. Typical imaging parameters were: echo time (TE)/repetition time (TR) 1.45/46 ms, flip angle 50°, in-plane resolution 1.6 × 1.6 mm, slice thickness 8 mm, no slice gap. Images were acquired during end-expiratory breath holds. Retrospective ECG gating was employed and images were reconstructed to 25 frames per cardiac cycle.8 Image segmentation was repeated after one year to provide intraobserver data with the reader blinded to previous results. Interobserver analysis was similarly conducted for cardiac volumes.Image analysis was conducted using Segment 4.0 R11026 . LV volumes were computed over the cardiac cycle from time-resolved delineations of the LV endocardial boundaries in the short-axis stack, as previously described.5 trained on invasive data from porcine experiments. In short, the algorithm uses a digitized time-varying elastance curve4 to model dynamic LV pressures coupled to LV volumes measured in CMR images. The elastance model was scaled in time so that the minimal LV volume (end-systolic timeframe in CMR images) coincided with the middle of the elastance curve downslope. The elastance curve was scaled in amplitude to match LV peak pressure (LVPsystole) and LV end-diastolic pressure (EDP). An approximative LVPsystole was calculated from brachial pressure according to a previously proposed expression,9PV loops were computed using a previously published algorithm3 Data shown in this manuscript result from setting EDP to 7.5 mmHg for all patients. A sensitivity analysis for EDP estimates of 3–40 mmHg was also conducted, details are below.where SBP is systolic blood pressure and DBP is diastolic blood pressure. Since EDP is not possible to derive from a brachial blood pressure measurement, the user is prompted to estimate the EDP. A previous sensitivity analysis found varying user-input EDP in the 0–15 mmHg range had little effect on PV-loop-derived metrics in a porcine model.P(t) can be computed asVentricular pressure E(t) is the time-varying elastance and V0 is the intercept of the ESPVR and the volume axis, i.e. the volume where LV pressure would be 0 mmHg. Setting V0 to zero11 simplifies the expression to:where V(t) to visualize PV loops.which was computed and interpolated to 100 points per cardiac cycle, and subsequently plotted against P(t).Reference PV loops were computed using LV pressure curves averaged from 19 to 30 recorded cardiac cycles. Pressure curves from individual cycles were resampled to 250 points on a reference time axis using linear interpolation and subsequently averaged to produce a single pressure-time curve P(t) vs. V(t). This enables a direct validation of the pressure modelling employed in the non-invasive method and disregards the methodological differences between CMR and conductance catheter experiments for volumetry.Similar to the non-invasive approach, we used CMR LV volumes to plot Figure 1. Myocardial SW is a measure of the external work performed by the ventricle in ejecting blood and was defined as the area inscribed by the PV loop. The ESPVR was defined as the slope between V0, set to zero, and Emax, which is the point where the time-varying elastance function reaches its highest value  and hence a proxy measure of contractility.We studied seven PV loop-derived metrics, summarized in 1 It is optimally measured as the area inscribed by the (nonlinear) end-systolic and EDP-volume relationships below the end-systolic volume (ESV). Here we simplified PE and defined it as the area of a triangle with a base between V0 and ESV, and height equal to the ESPVR at ESV. The total mechanical energy of each cardiac cycle is defined as the entire pressure-volume area (PVA), equal to SW + PE, and is approximately proportional to myocardial oxygen consumption.12 VE was computed as SW/PVA.The mechanical PE is the internal energy to overcome in order to eject blood.a) was computed as the slope from Emax to the point of end-diastolic volume and zero pressure, equal to Emax/SV.The MEP delivered by the ventricle was calculated as SW*HR (Heart Rate)/60. EPEV is a measure of the energy spent ejecting a stroke volume (SV) and was computed as PVA/SV. Finally, the arterial elastance . Method agreement between invasive and CMR metrics as well as intraobserver and interobserver variability was assessed using linear regression and Bland-Altman analysis and presented as bias with limits of agreement (LoA).Figure 2). Of these, four patients were excluded due to high ectopic burden. A total of nine studies from five patients had LV pressure recordings of adequate quality for validation purposes. One patient (one dataset) was then excluded due to having been significantly hypotensive during the catheterization procedure, which resulted in a large difference between invasive and brachial blood pressures.Out of the 29 patients participating in the parent study, in addition to CMR, nine had undergone LV catheterization with attempted PV recording during metabolic substrate infusion (Table 1.Four patients (one woman) with average age of 63 (range 58–69) were included in the final analysis. All patients were in heart failure with left bundle branch block and echocardiographic EF <35% despite optimal medical therapy. Patient characteristics are summarized in Table 2. Heart rate was similar between catheter procedures and CMR examinations as well as between the two CMR examinations. Likewise, brachial blood pressure was similar between substrates for systolic and diastolic pressure. Brachial SBP measured at CMR correlated with invasive peak pressures  with an average positive bias of 11 mmHg, reflecting the narrowing of the pulse wave in the vasculature. Within each individual LV pressure recording, the peak systolic pressure varied on average by ±6.1 mmHg (1.96 SD).Haemodynamic and volumetric parameters are summarized in Figure 3. Loop-derived parameters  demonstrated high correlation and low bias when compared to invasive data for SW , PE , ESPVR , VE , arterial elastance , MEP , and EPEV .Non-invasively derived PV loops were computed for all datasets and are shown together with invasive loops in Figure S1). The intraobserver analysis for loop-derived parameters is summarized in Figure 5. The bias for SW was 5.2% (LoA −10.9–21.3), for PE 1.4% (LoA −4.6–7.3), for ESPVR −3.7 (LoA −10.2–2.8), for VE 2.3% (LoA −8.4–13.0), for arterial elastance −1.7% (LoA −14.1–10.6), for MEP 5.4% (LoA −10.6–21.5), and for EPEV −0.2% (LoA −8.4–8.0).Intraobserver variability was assessed by repeating LV delineations after one year with the observer blinded to previous results. The average volumetric bias was 2% (7 mL) for end-diastolic volume, 1% (2 mL) for ESV, and 5% (5 mL) for SV  for end-diastolic volume, 3% (4.5 mL) for ESV, and −4.5% (4 mL) for SV. The intraclass correlation coefficient was 0.94–0.99 (Excellent reliability).We similarly assessed interobserver variability for volumetry, shown in Figure 6). The effect of using true measures compared to a fixed EDP of 7.5 mmHg was not statistically significant on any of the studied parameters , although a trend was seen for EPEV.Varying EDP within a physiological range of values had minor effects on computed VE, EPEV, MEP, and SW , only four conductance datasets were deemed technically adequate (data not shown), and direct comparison between fully non-invasive and fully invasive PV loops was therefore not possible with preserved statistical power.Whilst dyssynchronous contraction is seen on CMR imaging, segmentation of short-axis cine images acquired using standard ECG gating produced PV loops with physiological shapes and good fidelity compared to invasive pressures. As such, we believe this algorithm is likely to perform at least as well in subjects with normal LV function and electromechanical synchrony. Furthermore, this study demonstrates that non-invasive PV loop analysis is feasible with good accuracy and precision even in patients where invasive experiments may not render data of sufficient quality. Indeed, the variability of the resulting PV loop parameters was similar in magnitude to the beat-to-beat variability seen in the invasive pressure recordings. The method thereby expands PV loop analysis to both low-risk patients and healthy controls, where the risk associated with invasive procedures may not be ethically justifiable, and to patients with severely impaired ventricular function, where accurate volumes may be difficult to obtain using conductance measurements. With the exception of significant valvular disease, the results from this study, therefore, support wide application of non-invasive PV loops.a, is a measure approximating the resistance in the peripheral vasculature. As such it is dependent on total peripheral resistance, which is unknown, and heart rate, which was similar between the catheterization and CMR experiments. It also depends on Emax, which is defined as the point along the PV loop of maximal ventricular stiffness. In the literature Emax is sometimes used interchangeably with end-systolic stiffness, Ees, although the two are not technically the same; maximal stiffness typically occurs sometime before cessation of ejection.14Arterial elastance, Emax will depend on the temporal scaling of the time-varying elastance function and is therefore subject to user-defined markers for end diastole and end systole. The presence of dyssynchrony complicates the determination of end systole and hence of Emax, as postsystolic contraction prolongs the isovolumic relaxation period, subsequently affecting the temporal scaling of the time-varying elastance function. From Figure 3, it is evident that the upper left corners of the loops differ slightly between the invasive and modelled loops. This likely explains both the slight overestimation of ESPVR and the slight underestimation of Ea in the model, as illustrated in Figure 8.The exact timing of the modelled Emax timing issue explains the errors in estimated Ea and ESPVR, in contrast to afterload conditions being truly different between CMR and cath procedures, remains to be investigated. To address this outstanding question would require CMR with simultaneous invasive and brachial pressure measurements, which was unfortunately not available at our centre.The precise degree to which the E15–18 and may be used to assess the effect of pharmaceutical, surgical, or device interventions.19 Sjöberg et al. studied the effect of dobutamine stress on LV PV relations in healthy controls and demonstrated the method’s sensitivity to changes associated with increased cardiac workload.5 Furthermore, we recently employed non-invasive PV loops to demonstrate that metabolic substrate switching in non-ischaemic cardiomyopathy elicits significant changes in SW and inotropic state, accompanying changes to ejection fraction, SV, and pressure change rates.6 Binka et al. used non-invasive PV loops to evaluate the haemodynamic effects of pulmonary valve replacement in tetralogy of Fallot and demonstrated a postoperative decrease in right ventricular SW and external power despite no improvements in LV function.20 And finally, Berg et al. found evidence of cardioprotective effects of hypothermia by studying ventricular-arterial coupling and VE in a porcine infarct-reperfusion model.21PV data can be used to derive valuable information about cardiac work,19 In contrast to invasive PV loops, which are often difficult to obtain with adequate quality in the setting of dyssynchrony,23 the method presented herein consistently performs well in the presence of significant regional wall motion abnormalities.Together, these findings indicate a potential for PV loop analysis for online evaluation and optimization of treatment strategies. For example, PV loops may be used to analyse cardiac workload immediately after initiation of resynchronization therapy to evaluate the acute effects of pacemaker programming and lead placement. The concept can be extended to the regional level using force-length loops.25 using automated LV segmentation and input from blood pressure monitoring equipment. As the PV area is an indicator of cardiac oxygen consumption,1 there is an opportunity to use PV loops as a window into ventricular energetics.26 As long as the elastance function is known, the method would also be applicable to the quantification of atrial function.Further, PV loops could be implemented as an in-line monitoring solution on the CMR system to provide immediate haemodynamic feedback during pharmacological or exercise studies,3 An EDP exceeding 16 mmHg at rest or stress is a commonly used criterion to diagnose heart failure with preserved ejection fraction.27 While the method is intrinsically insensitive to elevated EDP, these findings suggest it can be used to reliably quantify systolic and metabolic properties of the heart even in the presence of moderate relaxation abnormalities. Expanding the model to accurately estimate diastolic pressures would be of great clinical utility.29We found small effects of varying estimated end-diastolic pressures from 3 mmHg (very low) to 40 mmHg (severely elevated), which expands on the previous results reported by Seemann et al. who evaluated effects of estimating EDP between 0 and 15 mmHg.23 The situation is further compounded by the presence of postsystolic contractions and relaxation abnormalities. Conductance catheter estimations of LV volumes presuppose volumetric calibration against an external standard, either using a known volume of saline in a beaker or optimally LV volumes from CMR. Even when meticulously calibrated, conductance catheter volumetry is plagued by nonlinearity and bias.30–32 In our setup, conductance-based LV volumetry was unreliable in some participants due to profound dyssynchrony and mechanical interference between the septum and the catheter, and in datasets with acceptable data quality, the normalization to CMR volumes would render a direct comparison between fully invasive and fully non-invasive PV loops methodologically unsound. CMR imaging is widely considered the reference standard for quantification of cardiac volumes. We therefore focused on validating the non-invasive pressure estimation function.We studied heart failure patients with LV dyssynchrony, which introduces additional challenges for conventional conductance catheter measurements through the irregular, rocking motion of the LV.Measurement of brachial blood pressure is potentially sensitive to premature ectopic beats due to increased preload and SV in the succeeding beat, potentially leading to a slight overestimation of systolic blood pressure (BP) and hence average ESPVR. Ectopics are likely in distended and failing ventricles, and care should be taken to measure blood pressure sufficiently slowly so as to minimize the influence of breakthrough beats. As a result of the design of the parent study, in our protocol brachial BP measurement and short-axis imaging were separated by approximately 45 min. It is possible that greater accuracy could be attained through simultaneous BP and image acquisition.The pulse pressure may be overamplified in peripheral arterial disease, resulting in an overestimation of systolic LV pressures. Conversely, in the setting of severe aortic stenosis the ventriculo-aortic pressure gradient will not be accounted for, meaning PV loops will underestimate systolic LV pressures. Neither of these settings was studied in the present work, and careful consideration is advised before implementing non-invasive PV loop analysis in the presence of significant vascular or valvular abnormalities.PV loop analysis computed from standard cine CMR imaging and brachial cuff blood pressures is precise and accurate provides non-invasive access to unique physiological information and can be readily implemented in research applications to monitor outcome parameters or search for therapeutic targets.qyad035_Supplementary_DataClick here for additional data file.