In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups—overt, either genotype-positive (G+LVH+) or genotype-negative (G−LVH+), and subclinical (G+LVH−) HCM—exploring relationships with electrical changes and genetic substrate.This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G−LVH+), 77 patients with G+LVH−, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging , and cardiac diffusion tensor imaging measuring fractional anisotropy , mean diffusivity , and second eigenvector angle (measuring sheetlet orientation).P<0.001) and MVD . Patients with G−LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G− patients . Patients with G+LVH− compared with healthy volunteers similarly had altered microstructure, although to a lesser extent , and MVD . Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy .Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all Microstructural alteration and MVD occur in overt HCM and are different in G+ and G− patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy. With the use of diffusion tensor imaging in hypertrophic cardiomyopathy, evidence of myocardial disarray is detectable in pathogenic sarcomere mutation carriers even in the absence of hypertrophy.Diffusion tensor imaging parameters suggestive of myocardial disarray are related to electrocardiographic abnormalities in subclinical and overt hypertrophic cardiomyopathy.In overt disease, the presence versus absence of sarcomeric mutation has differing effects on microstructure and microvasculature.Diffusion tensor imaging may discriminate pathogenic sarcomere mutations from health and mutation status in overt disease.Disarray and ischemia are associated with stage of phenotype evolution.819Editorial, see p 1 Characterized clinically by hypertrophy, HCM has considerable heterogeneity of presentation and outcomes.3 Cardiac function, extreme hypertrophy, and extent of fibrosis are known to be adverse markers, but these may be late in phenotype development and may only modestly predict adverse events.5 Histologically, HCM is characterized by myocyte hypertrophy and fibrosis but also by 2 other features: small-vessel disease and disarray.6 It is thought that these may be important in both phenotype development, from subclinical (in the absence of hypertrophy) to overt disease, and risk; but until recently, these have been hard to measure clinically, and no study has measured them concurrently.9 Novel advances permit quantification of microstructural indices indicative of disarray and microvascular disease (MVD), bypassing the need for tissue specimens or ionizing radiation.11Hypertrophic cardiomyopathy (HCM) is a leading cause of heart failure and sudden death.15  measures the diffusion of water within an imaging voxel, thereby characterizing the myocardial microstructural environment. HCM is characterized by: 1) low fractional anisotropy (FA), a measure of the directional variability of water diffusion, with low values suggestive of myocyte disarray and collagen deposition; (2) high mean diffusivity (MD), measuring the magnitude of diffusion, thought to reflect myocyte packing, with high values reflecting increased interstitial fibrosis and changes in intracellular and extracellular volume; and (3) elevated absolute second eigenvector angle (|E2A|), reflecting sheetlet orientation . Sheetlets conform to hypercontracted states (elevated |E2A|) in systole with failure to reorientate in diastole, implying roles in diastolic failure in HCM and increased cardiomyocyte tension low frac17 Individuals with pathogenic sarcomeric variants without hypertrophy (G+LVH−) identified on cascade genetic screening have architectural and functional abnormalities . Furthermore, G+LVH- with abnormal electrocardiographic findings have a 4-fold increased risk of progression to overt disease.20Patients with overt HCM without a detectable sarcomeric mutation, called genotype-negative (G−LVH+), represent approximately half of patients and are characterized by fewer events (heart failure or ventricular arrhythmia), less fibrosis (lower extracellular volume [ECV] or less scar), and differing morphology .21 Analyzing the effect of sarcomeric mutation on phenotype development will enhance precision medicine in the future.22 We aimed to investigate the prevalence, extent, and interrelationships of microstructural alteration and MVD in both overt and subclinical HCM. We then studied the associations between these biomarkers and pathological electrocardiographic findings, nonsustained ventricular tachycardia (NSVT), and genetic substrate (genotype positive [G+LVH+] and genotype negative [G−LVH+]).As novel sarcomere modulators provide promise for disease modification, early markers of disease are a rapidly emerging research priority.23 Inclusion criteria were as follows: (1) Overt HCM (G+LVH+ and G−LVH+) was diagnosed according to American Heart Association and European Society of Cardiology guidelines .3 (2) Patients with subclinical HCM (G+LVH−) had pathogenic/likely pathogenic variants confirmed on cascade screening but without hypertrophy . (3) Healthy volunteers (HVs) with no relevant medical history or risk factors for coronary disease were prospectively matched for age, sex, and ethnicity to the subclinical HCM (G+LVH−) cohort under the same ethics protocol. A separate age-, sex-, and ethnicity-matched cohort of HVs was compared with the overt HCM group to assess whether any diffusion tensor imaging (DTI) changes were attributable to demographics variables . HVs were not genotyped and were not relatives of those with HCM. To optimize conditions for cDTI and to reduce the risk of confounding, those with known obesity (body mass index ≥30 kg/m2) and poorly controlled hypertension (poor blood pressure control despite 2 antihypertensives) were excluded. Presence of LV outflow obstruction and gradients was collected from clinical echocardiographic data at the time of recruitment.The data that support the findings of this study are available from the corresponding author on reasonable request. We formed an academic collaboration consisting of 3 recruiting tertiary referral centers  and a technological collaboration of 2 US sites and 2 UK sites to deploy advanced cardiac magnetic resonance imaging (CMR) techniques: cDTI: Cleveland Clinic  and Leeds Institute of Cardiovascular and Metabolic Medicine ; and quantitative perfusion mapping: National Institutes of Health  and Barts Heart Centre. Participants with subclinical or overt HCM who were 18 to 76 years of age were prospectively and consecutively recruited from databases of genotyped patients. Ethics approval for the study was given by the research ethics committee (IRAS 227168). All subjects gave informed consent for all study procedures. Pathogenicity for detected variants was assessed with American College of Medical Genetics criteria.Other exclusion criteria were as follows: claustrophobia, unwillingness to consent, known coronary disease or significant pretest probability for coronary disease without previous coronary imaging, contraindications to adenosine, pulmonary hypertension, previous alcohol septal ablation or myectomy, previous cardiovascular surgery, congenital disease, and implantable cardiac devices.25 T1 mapping before and after contrast was performed with Modified Look-Locker Inversion Recovery (MOLLI 5s[3s]3s) with automated contouring using Circle CVI42 software (version 5.14.1) and manual adjustment when required for septal ECV (using same-day hematocrit) in line with recommendations.26 Fully quantitative vasodilator stress perfusion was performed with a validated dual sequence approach as previously described.10 In brief, adenosine was given intravenously at 140 to 210 µg·kg−1·min−1 for a minimum of 4 minutes, until a minimum heart rate increase of 15 bpm and symptoms suggestive of an adequate physiological stress response. Gadolinium-based contrast  was then administered intravenously at 0.05 mmol/kg. The same was repeated for rest imaging, which was acquired at a minimum of 7 minutes after adenosine. Automated in-line adenosine stress perfusion maps were acquired to obtain stress and rest myocardial blood flow , myocardial perfusion reserve , and visual perfusion defects  assessed separately by 2 experienced operators (G.J. and J.C.M.) from conventional images and perfusion maps.28All scans were acquired on a single 3-T Prisma . Standard long- and short-axis cine imaging was performed, with segmentation for ventricular dimensions and function performed with fully automated algorithms that exceed human precision.13 This was free breathing without respiratory navigation, has been validated both ex vivo and in vivo, and has been demonstrated to detect microstructural changes in HCM.29 cDTI analysis was performed according to previously described protocols; in brief, data processing was performed with custom-built Matlab software (MathWorks), with each image quality-controlled for misregistration or artifacts. Average magnitude images were generated from registered data by averaging cross-repetitions, and diffusion tensors were calculated. Contouring was performed on cDTI maps, with tensor eigenvalues, MD, FA, and absolute |E2A| obtained globally and segmentally. Segments containing artifacts were omitted from analysis.13 Late gadolinium enhancement (LGE) imaging was performed 5 minutes after administration of gadolinium-based contrast agent for pixelwise quantification of focal fibrosis . Circle CVI 42 (version 5.14.1) was used for LGE map analysis with automated contouring of endocardial and epicardial borders and manual adjustment when required.A second-order motion–compensated single-shot spin-echo echo-planar imaging DTI sequence was performed for 3 short-axis slices at peak systole following previously described protocols.30 For overt HCM, Holter recordings were available in 99% of patients (101/102) within 6 months of the CMR, with NSVT defined as 3 beats ≥120 bpm occurring on Holter monitoring.A same-day standard resting digital 12-lead ECG was performed with a Mindray Beneheart R3 electrocardiograph , and automated analysis was performed by a core laboratory to identify abnormalities associated with disease progression: abnormal Q waves , Sokolow-Lyon index (SV1+RV5/6>3.5 mV) or Cornell criteria (RaVL+SV3>2.8 mV in men and >2.0 mV in women), and repolarization abnormalities (defined as T-wave inversion in ≥0.1 mV in ≥2 contiguous leads or ST-segment depression ≥0.1 mV in ≥2 contiguous leads).t test. For nonnormally distributed variables (tested with the Shapiro-Wilk test), median and interquartile range with equivalent comparison tests were used. Categorical/binomial variables were expressed as absolute values and percentages and compared with χ2 or Fisher exact test as appropriate. Univariable and multivariable linear regression models were used to determine associations of diffusion tensor, perfusion, fibrosis, and hypertrophy parameters. Between-group comparisons involving DTI were adjusted for age (see later discussion), fibrosis, and hypertrophy  and expressed as standardized β coefficients and 95% CIs. A variance inflation factor <3 excluded multicollinearity. Logistic regression models with inclusion of fibrosis (ECV and LGE) and hypertrophy (MWT) variables as covariates were used to test for odds ratios (ORs) for independent risk of electrocardiographic abnormalities and NSVT. Continuous predictors were normalized before entering the logistic regression, and ORs are expressed per 1-SD increase in MD and |E2A| and 1-SD decrease for FA, stress MBF, and MPR. A 2-sided value of P<0.05 was considered significant. Multiple testing correction with Bonferroni was done for the primary end points (perfusion and DTI in patients with G+LVH− versus HVs and G+LVH+ versus G−LVH+) in a table-by-table basis . Age, sex, ethnicity, and body mass index were tested for associations with DTI parameters  in pooled HVs (n=41), subclinical HCM, and overt HCM. MD was found to be associated with age in overt HCM; therefore, age was included in all between-group regression analyses involving DTI. An exploratory analysis was performed to determine whether any gene-specific differences could be detected .Statistical analysis was performed with SPSS . Continuous variables were described as mean±SD for normally distributed variables and compared with independent-samples MYBPC3, 23% (18) MYH7, 6% (5) TNNI3, 6% (5) TNNT2, 1% (1) MYL2, 1% (1) TPM1, and 1% (1) CSRP3. Of 51 with G+LVH+, pathogenic/likely pathogenic variants were 55% (28) MYBPC3, 25% (13) MYH7, 8% (4) TNNI3, 8% (4) TNNT2, 2% (1) CSRP3, and 2% (1) TNNC1 (Table S3). Demographics and conventional CMR parameters are summarized in Table Table S1. To examine the effect of LVH on parameters in those with pathogenic/likely pathogenic sarcomere variants, comparisons between G+LVH− and G+LVH+ are included in Table S2. Of the overt HCM cohort, 23% (23) had a peak LV outflow tract gradient ≥30 mm Hg; these patients’ average gradient at rest was 27 mm Hg (18–60 mm Hg) and on provocation was 56 mm Hg (38–85 mm Hg).Overall, 206 participants were studied: 101 with overt disease (51 G+LVH+ and 50 G−LVH+), 77 with subclinical HCM (G+LVH−), and 28 HVs. Of 77 with G+LVH−, pathogenic/likely pathogenic variants were 60% (46) Table S1).Overt HCM was characterized by higher ejection fraction and more severe markers of hypertrophy (higher MWT and higher LV mass) and fibrosis .There were no differences in ejection fraction and MWT. Patients with G−LVH+ had higher LV mass. G−LVH+ had similar LGE burden and lower ECV .Compared with HVs, patients with G+LVH− had a lower indexed end-diastolic volume, higher ejection fraction, but no difference in markers of hypertrophy (MWT or LV mass) and no difference in markers of fibrosis .Patients with HCM had evidence of MVD (lower stress MBF and MPR) with a higher prevalence of perfusion defects , but all 51 G+LVH+ patients had perfusion defects compared with 82% (41/50) G−LVH+ patients (P=0.002) but no difference in MPR .Patients with G+LVH− had reduced stress MBF but not after correction for multiple comparisons Table B. PatienSupplemental Results.Associations of DTI parameters, fibrosis, and MWT are presented in Table S1). Differences remained after adjustment for fibrosis and hypertrophy . Results relating to DTI were similar compared with age-, sex-, and ethnicity-matched HVs .Compared with HVs, patients with overt HCM had evidence of microstructural alteration: lower FA, suggestive of disarray and higher MD, and higher |E2A| suggestive of a more hypercontracted sheetlet configuration (P=0.011 before correction for multiple comparisons). Differences remained after adjustment for fibrosis and hypertrophy .Compared with HVs, patients with G+LVH− had evidence of microstructural alteration , although this was less severe compared with patients with overt HCM (Table P<0.02), but when fibrosis and hypertrophy were accounted for, only |E2A| was independently associated , sex (P=0.46), MWT (P=0.43), and ECV (P=0.85) but had a higher prevalence of LGE , similar global stress MBF (P=0.053), lower global MPR , and no difference in electrocardiographic abnormalities  compared with those without (n=54) focal perfusion defects were similar in age .Patients with G+LVH− with defects had evidence of more severe microstructural alteration .MPR but not stress MBF was associated with FA and |E2A|, and relationships remained after adjustment for fibrosis and hypertrophy , stress MBF, and MPR (both P<0.016). When accounting for fibrosis, hypertrophy, and stress MBF, independent predictors of abnormal ECG were FA  and |E2A| . Stress MBF was also an independent predictor .Of patients with overt HCM, 84% (85/101) had an abnormal ECG. Abnormal ECG was associated with all 3 DTI parameters  had abnormal Q waves; 71% (72) had T-wave inversion; 49% (49) had ST-segment depression; and 50% (50) met LVH voltage criteria. Logistic regression analyses of DTI/perfusion parameters and individual ECG abnormalities are included in P=0.026), higher MWT (P=0.002), higher LGE mass (P<0.001), and higher ECV (P=0.023). No DTI parameter was associated with NSVT (FA: P=0.08). No DTI or quantitative perfusion parameter was independently predictive of NSVT.Thirteen percent (13) of patients had NSVT. NSVT was associated with lower stress MBF (P<0.001) and MPR (P<0.003). When adjusted for MPR, fibrosis, and hypertrophy, all 3 DTI parameters remained independently predictive of abnormal ECG .Of patients with subclinical HCM, 34% (26) had an abnormal ECG. An abnormal ECG was associated with all 3 DTI parameters . There were no independent predictors of T-wave inversion, ST-segment depression, or LVH criteria.Regarding individual electrocardiographic abnormalities, 21% (16) had abnormal Q waves; 9% (7) had T-wave inversion; 12% (9) met voltage criteria for LVH; and no participant had ST-segment depression. When we considered associations with individual electrocardiographic abnormalities in isolation, only FA and MD were predictive of abnormal Q waves after adjustment for MPR, fibrosis, and hypertrophy . This suggests that changes in DTI and quantitative perfusion are sensitive to mutation status.Recent evidence suggests that genotype-positive HCM and genotype-negative HCM are different in LV morphology and clinical outcomes.This study is both the largest in vivo cDTI study performed to date and the largest prospective study of subclinical HCM. The study used a validated DTI sequence and consecutive recruitment from genetics databases of 3 referral cardiomyopathy centers where phenocopies are routinely screened. The exact mechanisms behind how disarray and MVD are present, even without hypertrophy, in those with pathogenic sarcomeric mutations are still elusive.31 In line with other studies, overt disease was characterized by low FA and high MD.22 Although others found an independent association of FA and MD with fibrosis, our study findings also demonstrate an independent relationship with hypertrophy, mirroring previous histological work.32 Our study is the first to systematically examine the presence of microstructural abnormalities, including disarray, in patients with G+LVH+ and those with G−LVH+. Genotype-negative HCM has been hypothesized to result in part from polygenic inheritance.17 |E2A| elevation reflects a hypercontracted microstructural state in systole with failure to reorientate in diastole.15 Although G−LVH+ has been associated with less severe outcomes and fibrosis, here, it unexpectedly is related to elevated |E2A|, suggesting a more severe microstructural phenotype. Conversely, although both patients with G−LVH+ and those with G+LVH+ displayed considerable MVD compared with HVs, all G+LVH+ patients had visual perfusion defects compared with 82% of G−LVH+ patients. In overt disease, perfusion defects are associated with abnormal blood pressure response to exercise and, in apical HCM, aneurysm formation.34 In a previous positron emission tomography study, global MBF was more impaired in patients with G+LVH+ compared with those with G−LVH+, and although this was not found here, our study also supports the hypothesis of a more direct deleterious impact of sarcomeric mutation on microvascular function.35According to several preclinical models, DTI abnormalities are likely related to microstructural alteration , although further human histological validation is needed.8 Recent 3-dimensional histological analysis uncovered that disarray is detected ex vivo in fetal murine models without hypertrophy.9 Our previous work and other investigations have modeled early disease by examining DTI parameters of nonhypertrophied myocardium in overt disease; however, this has limitations, as remote remodeling (in nonhypertrophied segments) occurs by the time LVH is detected.36 Elevated |E2A| in patients with G+LVH− suggests that the hypercontracted microstructural state demonstrated in overt disease is also present before hypertrophy.14 Elevated |E2A| may have a role in the hyperdynamic function, diastolic dysfunction, and impaired myocardial mechanics found in this cohort.37 Overall, our findings support the hypothesis that altered myocardial microstructure is an early phenomenon in the disease pathophysiology, in keeping with animal model work.9Subclinical HCM was characterized by LVH and fibrosis parameters similar to health, and despite this, DTI demonstrated lower FA, suggestive of more myocyte disarray. Although historically, disarray has been described in HCM for several decades, its presence in phenotype evolution was less understood.38 In overt HCM, compressive forces of hypertrophied myocardium and LV outflow tract obstruction also worsen ischemia.39 An interrelationship of perfusion, disarray, and myocardial mechanics could explain the compounding of perfusion and microstructural changes with LVH and their continued association in overt disease.Twenty-eight percent of patients with subclinical HCM had perfusion defects, and these had evidence of low FA, suggestive of more disarray, and more elevated |E2A| than those without perfusion defects. This relationship also persisted into overt disease, with markers of MVD being independently associated with markers of microstructural integrity. A unifying explanation for the findings of abnormal microstructure, fibrosis, and abnormal microvasculature is the capillary:myocyte coupling hypothesis, whereby microvasculature and the matrix meshwork are abnormal even during organogenesis.40 The study shows for the first time that microstructural alteration  is independently associated with electrocardiographic abnormalities in subclinical disease. Prognostically, pathological electrocardiographic findings in subclinical HCM are associated with a 4-fold increased risk of progression to overt disease.20 Mechanisms linking disarray to arrhythmia susceptibility include disruption of gap junctions, alteration of longitudinal to transverse conduction velocity ratios, and provision of different pathways for conduction.8 A pioneering DTI study elicited FA of the thickest LV segment associated with NSVT; however, histological studies demonstrate large variations in disarray from segment to segment.32 This relationship was not replicated here when global FA was used, accounting for the low number of individuals with NSVT in this relatively low-risk cohort (implantable devices excluded).22 Others have hypothesized that ischemia results in scar, which, in turn, leads to reentry circuits.6 We found an independent association of MVD parameters with abnormal ECG, with MPR associating with electrocardiographic abnormalities in subclinical HCM, suggesting that the arrhythmogenic potential of MVD could be more complex than scar formation itself.20In line with other studies in subclinical HCM, pathological electrocardiographic findings occurred in 34% and were more common in overt disease at 84%.DTI parameters are variably influenced by the presence of fibrosis and other factors and therefore are not direct measures of disarray. However, the best available techniques were used for measurement of the important confounders: fibrosis, perfusion, and hypertrophy. MBF using adenosine stress is also an indirect measure of MVD and does not physiologically represent exercise. We are unable to fully exclude coronary disease, as systematic invasive coronary imaging was not performed. HVs did not undergo genotyping or Holter monitoring. Subclinical genotype-negative disease was not assessed. As with all contemporaneous cDTI sequences, susceptibility artifact, particularly in the inferolateral wall, was commonly found, and patients with devices were excluded.Microstructural alteration and MVD occur in overt HCM and are different in G+ and G− patients; both occur even in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Microstructural alteration and MVD are associated in both subclinical and overt disease, suggesting relationships in phenotype development. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.The authors acknowledge Dr Sam Coveney’s contribution to the DTI data analysis. The authors also thank Sandy Gardner, Peter Sutton, Joel Isaacs, Kim Le, Carol McGann, Kirsty-Ann Bladen, Gemma James, Debbie Lewis, Sarah Hudson, Aysha McCall, Jodee Cooper, Dan Roberts, Carl Roberts, Shane Palmer, Ryan Evans, Katia Menacho, Justine Greenhorn, Simin Varghese, Muddassar Rashid, Saira Joy, Catherine Mammen, Gizem Pasa, Vera Mitchell, Salma Mohammed, Russell Hall, Hibba Kurdi, George Thornton, Ben Dowsing, Aderonke Abiodun, Christian Nitsche, Jonathan Bennett, Jessica Artico, Hunain Shiwani, João Augusto, Kristopher D. Knott, Andreas Seraphim, Andrew Lin, Clement Lau, Robert Adam, Konstantinos Moschonas, Petros Syrris, and Alessandra M. Ardissino.Dr Joy is funded by a British Heart Foundation clinical research training fellowship (FS/CRTF/21/2469) and has received funding from a Barts Charity project grant (MRC0281). Dr Das has received funding from Heart Research UK (RG2668/18/20). Dr Lorenzini has received consultancy fees from Pfizer, UK. Dr Manisty receives funding directly and indirectly from the National Institute for Health and Care Research Biomedical Research Centres at University College London Hospitals and Barts Health NHS trusts. Dr Lambiase is funded from University College London/University College London Hospitals National Institutes of Health and Care Research Biomedical Research Centre and Barts Biomedical Research Centre and by educational grants from Abbott and Boston Scientific. Dr Teh acknowledges funding from the British Heart Foundation (PG/19/1/34076). Dr Schneider acknowledges grant funding from a Wellcome Trust investigator award (219536/Z/19/Z). Dr Dall’Armellina has received funding from a British Heart Foundation intermediate clinical research fellowship (FS/13/71/30378). Dr Moon receives funding directly and indirectly from the National Institutes of Health and Care Research Biomedical Research Centres at University College London Hospitals and Barts Health NHS trusts, is the chief executive officer of MyCardium AI Ltd, and has served on advisory boards for Sanofi and Genzyme. Dr Lopes is supported by a Medical Research Council UK Research and Innovation Clinical Academic Research Partnership award (MR/T005181/1).None.Supplemental MethodsSupplemental ResultsFigure S1Tables S1–S3


Heart failure (HF) is a complex syndrome characterized by impaired cardiac function. Two common subtypes of HF include heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). In this study, we aimed to evaluate and compare the plasma levels of 3-nitrotyrosine (3-NT)—as a marker of nitrosative/oxidative stress and myeloperoxidase (MPO)—as an indicator of inflammation between HFpEF and HFrEF. Twenty-seven patients diagnosed with HFpEF and twenty-two with HFrEF were enrolled in this study. Additionally, forty-one patients were recruited for the control group. An echocardiographic assessment was conducted, followed by the collection of blood samples from all participants. Subsequently, the levels of 3-NT and MPO were quantified using the ELISA method. Comprehensive clinical characteristics and medical histories were obtained. Circulating levels of 3-NT were significantly higher in the HFpEF patients than in the control and the HFrEF groups. Nitrosative/oxidative stress is significantly intensified in HFpEF but not in HFrEF. Heart failure (HF) remains a severe problem for individual patients and public health. Approximately 1–20 new cases are diagnosed per 1000 persons every year . About h2O2, the uncoupling of endothelial nitric oxide synthase (eNOS), and the decreased production of nitric oxide (NO). In cardiomyocytes, diminished NO bioavailability leads to the lower stimulation of soluble guanylate cyclase (sGC), reduced formation of cyclic guanosine monophosphate (cGMP), and reduced protein kinase G (PKG) activity. The latter is associated with decreased titin phosphorylation and increased passive stiffness of cardiomyocytes  and the Myeloperoxidase ELISA Kit (Colorimetric) , strictly according to instructions provided by the manufacturer. MPO antibody was used to quantitatively determine autoimmune response to the target antigen. The eGFR was calculated utilizing the CKD-EPI equation based on plasma creatinine levels. Renal dysfunction was characterized by an eGFR of less than 60 mL/min/1.73 m². Anemia was identified by Hgb concentrations below 12 g/dL in females and below 13 g/dL in males.TTE was performed by experienced cardiac sonographers using a Philips Affinity 70 Ultrasound machine. All procedures were conducted in accordance with European Society of Cardiology (ESC) guidelines. LV diameters and wall thickness were measured using a parasternal long-axis view. LVEF was determined using Simpson’s method by measuring LV volume in systole and diastole obtained from apical four- and two-chamber views. LV mass index (LVMI) was calculated using the formula for estimation of LV mass from LV linear dimensions and indexed to body surface area (BSA). LV geometry was classified based on relative wall thickness (RWT). LA volume was assessed using the biplane area–length method from apical 2- and 4-chamber views at end-diastole from the frame preceding mitral valve opening and was indexed to BSA . The early diastolic peak flow velocity (E velocity) and late diastolic peak flow velocity (A velocity) were assessed through pulsed wave Doppler from the apical 4-chamber view by positioning the sample volume at the tip of the mitral leaflets. Peak early diastolic tissue velocity (e’) and peak systolic tissue velocity (s’) were measured from the septal and lateral aspects of the mitral annulus. The E/e’ ratio was calculated as E velocity divided by mean e’ velocity . The inferior vena cava (IVC) diameter was measured using M-mode echocardiography in subcostal view at end-expiration (IVCmax) and at inspiration (IVCmin). The IVC collapsibility (IVCC) was calculated as (IVCmax − IVCmin)/IVCmax and was expressed as a ratio. Sample echocardiographic measurements from selected patients are presented in 2 test. Quantitative variables are presented as means (standard deviation [SD]) or medians (interquartile range [IQR]). The ANOVA test  and the Kruskal–Wallis H test  were performed to compare variables between the three groups. Appropriate post hoc tests were performed (Dunn and Tukey tests). The Shapiro–Wilk test was used to assess the normality of data. The equality of variances was assessed using the Levene test. Statistical data were considered significant with a p-value < 0.05. All statistical analyses were performed using RStudio software . Depending on whether the distribution of the quantitative data was normal or not, either the Pearson correlation method or the Spearman analysis was employed to assess linear correlation.Categorical variables are expressed as numbers and percentages and compared using the χNitrosative/oxidative stress measured via circulating levels of 3-NT is significantly intensified in HFpEF but not in HFrEF. The extent of inflammation assessed by MPO concentration is comparable between patients with two types of HF and the healthy population. These findings provide input to the current discussion about the pathogenesis of HF, diagnostic markers, and new therapeutic targets.


Patients with mitral valve prolapse (MVP) may develop ventricular arrhythmias, ranging from premature ventricular contractions through more complex non-sustained ventricular tachycardia to sustained life-threatening ventricular arrhythmias. The prevalence of MVP in autopsy series of young adults who died suddenly has been estimated to be between 4% and 7%. Thus, “arrhythmic MVP” has been reported as an underappreciated cause of sudden cardiac death, leading to a renewed interest in the study of this association. The term “arrhythmic MVP” refers to a small subset of patients who have, in the absence of any other arrhythmic substrate, MVP, with or without mitral annular disjunction, and frequent or complex ventricular arrhythmias. Our understanding of their coexistence in terms of contemporary management and prognosis is still incomplete. While literature regarding the arrhythmic MVP may be contrasting despite recent consensus document, the present review summarizes the relevant evidence concerning the diagnostic approach, prognostic implications, and targeted therapies for MVP-related ventricular arrhythmias. We also summarize recent data supporting left ventricular remodeling, which complicates the coexistence of MVP with ventricular arrhythmias. As the evidence for a putative link between MVP-associated ventricular arrhythmias and sudden cardiac death is scarce and based on scant and retrospective data, risk prediction remains a challenge. Thus, we aimed at listing potential risk factors from available seminal reports for further use in a more reliable prediction model that requires additional prospective data. Finally, we summarize evidence and guidelines on targeted therapies of ventricular arrhythmias in the setting of MVP, including implantable cardioverter defibrillators and catheter ablation. Our review highlights current knowledge gaps and provides an action plan for structured research on the pathophysiological genesis, diagnosis, prognostic impact, and optimal management of patients with arrhythmic MVP. The association of mitral valve prolapse (MVP) with life-threatening ventricular arrhythmias (VA) has baffled cardiologists since the early 1980 s. There is currently a renewed interest in the study of this association, which has led to the development of new concepts. Mitral valve prolapse often presents with premature ventricular contractions (PVCs) –4. The rClinical presentation of the arrhythmic MVP may vary in severity, ranging from asymptomatic patients, through palpitations to presyncope/syncope . SyncopeEarly data showed a high prevalence of PVCs in MVP patients, ranging from 58% to 89% . A more Cardiac MRI may help in the diagnosis of MAD as a part of the arrhythmic MVP complex as well as phenotypic markers of higher risk as fibrosis , 18. IndContrast-enhanced cardiac magnetic resonance data of a large cohort of patients with primary MR showed that replacement fibrosis affected 36% of patients with MVP specifically in the basal segments, as well as extending to the mid inferolateral LV wall . In thisThe outcome in MVP is determined by both MR severity and its left-atrial and left-ventricular consequences , 23. DisIn previous studies, severe VAs were rarely documented before SCD , possiblThe yearly incidence of SCD in patients with MVP has been estimated to be 0.2%–0.4% and up to 1.8% per year for those with severe MR due to leaflet flail , 26, 27.per se, lead to risky electrophysiological interventions  should prompt Holter monitoring to identify VA , 17. In Specific data on ICD therapy for VAs in patients with MVP are lacking. Accordingly, ICD therapy is recommended following general principles of current recommendations for non-ischemic cardiomyopathy , 38. PlaThere are no specific data on the efficacy of beta-blockers for the prevention of SCD in the setting of organic MVP, but they are widely used as first-line medical therapy for suppressing frequent symptomatic or complex PVCs and VT. Other anti-arrhythmic agents may also be effective in the management of MVP-associated VAs but must be used with caution, given their potential to cause adverse events. Reduction of VA burden using flecainide combined with beta-blockers after excluding structural heart disease has been recently reported in patients with MVP .Class I In the event of non-responsiveness or contraindication to antiarrhythmic agents, catheter ablation (CA) of symptomatic VAs originating from the PPM in the presence MVP has been reported to be effective –44. AblaA recent study demonstrated the efficacy of CA to reduce the VA burden for patients with MVP and MAD . In the Current ESC and AHA/ACC/HRS guidelines for the management of patients with VAs and the prevention of SCD indicate CA for PVCs that trigger recurrent VF as a class I indication , 38. CA Seminal data suggest that VA are common in patients with MVP but rarely severe and that severe VA is linked to excess mortality. While literature remains sparse and contrasted, recent prospective data provided a definition of the arrhythmic MVP complex, ascertained in an expert consensus to guide future research and clinical trials in order to define the appropriate diagnosis and therapeutic approach.Holter monitoring is not systematically recommended and the diagnosis of VAs in MVP is still at the discretion of the cardiologist. Arrhythmic MVP is a particular phenotype of MVP that should be part of all MVP comprehensive assessment and trigger episodic or frequent Holter monitoring during follow-up. Little is known about the prevalence and patterns of VAs, in particular transient and subclinical VAs, in mild MVP. Thus, the results and indications of cardiac monitoring by 12-lead Holter monitoring and more recent diagnostic tools, such as sensitive loop recorders, should be prospectively determined in this setting. Establishing the burden, type, sites of origin, and severity of VAs using these methods and exploiting large registries is a starting point for further appropriate prospective research that warrants careful planning. Our understanding of LV remodeling in the setting of MVP at early stages is still insufficient and additional research is needed to elucidate the potential link between VA burden and LV dysfunction.The severity and prognostic implications of VAs for patients with MVP will require large registries providing sufficient power to define the clinical determinants of outcome. The role of electrophysiological testing and imaging techniques, including cardiac MRI for the detection of ventricular fibrosis and the definition of patterns of the arrhythmogenic substrate, needs to be determined. Further quantification of the identified abnormalities will serve as the basis for establishing data-driven thresholds of clinical severity of arrhythmic MVP.Pilot data suggest that targeted therapies for MVP-related VAs may be effective, but larger clinical trials will be required to define the indications and optimal timing of CA and its impact on the quality of life and survival. While the risk of life-threatening VA appears to be attenuated after mitral valve surgery, the benefits and indications for ICDs for primary prevention are still poorly defined. More data is needed to identify the burden and character of VAs following valvular surgery using loop recorders and 12-lead Holter monitors.Despite current knowledge and undeniable recent progress in our understanding of the underlying mechanisms, the association of MVP with VAs is still underestimated. Recent contributions to the arrhythmic MVP complex will set the basis for large and well-defined trials to gather more evidence on genetic, phenotypic, and therapeutic aspects.


Ischemic heart disease (IHD) continues to be a significant global public health concern and ranks among the leading causes of mortality worldwide. However, the identification of myocardial ischemia in patients suspected of having coronary artery disease (CAD) remains a challenging issue. Functional or stress testing is widely recognized as the gold standard method for diagnosing myocardial ischemia, but it is hindered by low diagnostic accuracy and limitations such as radiation exposure. Magnetocardiography (MCG) is a non-contact, non-invasive method that records magnetic fields produced by the electrical activity of the heart. Unlike electrocardiography (EKG) and other functional or stress testing, MCG offers numerous advantages. It is highly sensitive and can detect early signs of myocardial ischemia that may be missed by other diagnostic tools. This review aims to provide an extensive overview of the available evidence that establishes the utility of MCG as a valuable diagnostic tool for identifying myocardial ischemia, accompanied by a discussion of potential future research directions in this domain. Ischemic heart disease (IHD) remains a significant global public health issue, and its prevalence has been increasing over the years. According to the 2023 report from the National Center for Biotechnology Information (NCBI), IHD is responsible for 17.8 million deaths annually, positioning it as the third most common cause of mortality worldwide . This isMagnetocardiography (MCG) is a non-contact, non-invasive, radiation and contrast-free method that enables the recording of magnetic fields generated by the electrical activity of the heart –9. AlthoThis review will provide an overview of the evidence supporting the utility of MCG, a valuable tool for diagnosing myocardial ischemia that is currently available, and discuss the potential impact of these findings on the future integration of MCG into clinical practice.Previous studies have explored the application of MCG for the diagnosis or ruling out of stable CAD in Numerous studies have provided evidence that MCG, whether conducted in a shielded or unshielded environment, at rest, or under conditions of exercise or pharmacologic stress, can effectively differentiate between patients with angiographically confirmed stable CAD and healthy individuals , 40, 41.n = 101) and a control group of healthy subjects (n = 59)  orientation between patients with CAD (n = 59) . They yi9 . They (n = 59) , 35, 36,(n = 59) , 50–52, (n = 59) , spatial(n = 59) , and the(n = 59) –27. In a(n = 59) . The incn = 27), whereas T wave MCG parameters were most sensitive to changes in patients with prior MI (n = 17)  . For the(n = 17) . MCG demSeveral studies have directly compared the diagnostic efficacy of MCG with other tests. In a study by Park et al., MCG exhibited superior sensitivity compared to 12-lead EKG in detecting CAD using a conventional dobutamine stress protocol . Anothern = 83) and age-matched individuals presenting with chest pain but without clinical indications of CAD  do not have an acute cardiac cause for their pain. Current diagnosis of ACS in patients with acute undifferentiated chest pain involves a resting 12-lead EKG, multiple measurements of cardiac troponin levels over several hours, and clinical judgment. Integrating MCG into the diagnostic pathway could help reduce the time to diagnosis and the costs associated with serial troponin testing. Another challenge in emergency medicine is the risk of missed diagnoses of patients with NSTEMI or unstable angina, which can lead to adverse outcomes after discharge. MCG has the potential to decrease the likelihood of missed diagnoses and improve clinical outcomes. The benefits of early identification of patients with non-cardiac chest pain have been demonstrated through accelerated risk algorithms that incorporate high-sensitivity cardiac troponin assays, resulting in significant improvements in time to discharge, cardiac outcomes, and hospital resource utilization. Further evaluation through prospective observational studies involving unselected cohorts of patients presenting to the emergency department with acute chest pain will provide insights into whether MCG could be used prior to cardiac troponin testing to expedite patient assessment. Most of the original multichannel MCG devices have specific operational requirements and high running costs, primarily due to the need for external electromagnetic shielding (EMS) or liquid helium cooling. However, the recent development of portable MCG devices holds the potential for bedside assessment of patients with acute chest pain upon their initial presentation to the emergency department , 58. EnhFinally, validation studies are necessary to determine the diagnostic accuracy of MCG parameters compared to current diagnostic pathways in undifferentiated patient populations. Validated MCG diagnostic criteria should be evaluated in well-defined cohorts including patients with stable CAD, ACS, inducible ischemia, and non-ischemic chest pain. Furthermore, there are indications in the literature that MCG may have broader clinical applications in CAD beyond diagnosis. For instance, its use in stress testing to detect functional ischemia could provide valuable prognostic information for risk stratification. Future clinical studies should explore other endpoints such as infarction location and severity, as well as the prediction of major adverse cardiac events and post-MI arrhythmias.MCG presents a non-invasive and non-contact imaging modality that is free from emissions, offering potential improvements in the management of patients with CAD. It has demonstrated the ability to detect myocardial ischemia in patients with stable CAD and ACS. However, further clinical studies are necessary to evaluate the use of MCG in undifferentiated patient cohorts. It is also important to validate and standardize MCG analytical techniques and parameters. Prospective, multicenter observational studies are currently needed to investigate the effectiveness of MCG in ruling out ACS in emergency settings. These studies will help determine the utility of newer MCG devices and their potential integration into routine clinical practice as complementary diagnostic tools.


Looking back, the historical evolution of the heart team is somewhat unclear. The referral of patients from internists (cardiologists) to surgeons (cardiac surgeons) has always existed. Inherent in this interaction was the assumption that both had considered and agreed about the best management for a patient. However, this collaboration became much more interactive and important as cardiologists began applying percutaneous interventions to treat conditions for which surgery had been the only alternative. Coronary artery disease was, of course, the major stimulus for direct communication and interaction between physicians in selecting treatment and primarily involved interventional cardiologists and surgeons. The concept of a heart team, that is, a collaboration of a group of physicians and health care professionals involved in selecting the optimal care of a patient, was first formalized in 2010 by the European Society of Cardiology specifically for myocardial revascularization.A number of procedures have been applied for the electrophysiological abnormalities associated with heart failure. Cardiac resynchronization therapy has proven beneficial to patients with abnormal conduction associated with failure. In addition, intracardiac defibrillation devices have been effectively employed for ventricular arrhythmias. These procedures have resulted in a collaboration between electrophysiologists and heart failure specialists but usually in a referral for a procedure that was deemed indicated and directed primarily to the electrical abnormality. Such patients have not usually come to the attention of the heart team.A variety of interventional procedures for heart failure due to a structural disease have existed for some time. Cardiac surgery has been the traditional therapy for patients with heart failure due to a disease of any of the heart valves since the 1970s. Transcatheter aortic valve replacement for aortic stenosis was the first transcatheter therapy for heart failure due to valvular heart disease. Similarly, coronary bypass surgery and coronary angioplasty and stenting have been applied for heart failure due to a coronary disease. However, in both cases, surgical and percutaneous approaches were directed toward the pathology of the valves and/or coronaries causing the heart failure. Although surgical valve replacement and repair has been applied for functional mitral regurgitation due to left ventricular dysfunction, the benefit has been equivocal. Surgical edge-to-edge mitral plication for regurgitation has been applied in the past with some success by Alfieri et al.A variety of devices have been and continue to be developed that are suitable for surgical or transcatheter implantation for different grades of heart failure. For patients with advanced heart failure or shock, several mechanical cardiac support devices exist or are being investigated. A spectrum of techniques from simple aortic balloon counter pulsation to external membrane oxygenation are being used to support patients with severe levels of failure. More such devices are being developed for these critically ill patients. These technologies lend themselves to percutaneous application and, therefore, often involve the heart team.A greater number of patients exist with lesser degrees of heart failure. Traditional medical therapy for these patients has reached a plateau of benefit and stimulated the development of interventional approaches. Perhaps the best example of such approaches is the creation of an interatrial communication to reduce left atrial pressure, especially in patients with heart failure and preserved ejection fraction. In terms of systolic dysfunction, cardiac contractility modulation by electrical intervention and autonomic interventions involving the vagus and baroreceptors are actively being pursued to alleviate heart failure. Again, these interventions are all notable in patients in whom the major mechanism of failure is left ventricular dysfunction. This is a patient population that has not usually come under consideration by the heart team.Structural Heart. The net result is an increase in the size, scope, vitality, and importance of the heart team, all to the benefit of our patients.The common theme of the foregoing is the increasing number of interventional procedures for heart failure that are directed primarily to benefit ventricular function rather than structural pathology. This has brought an increasing number of heart failure patients and their physicians to the attention of the heart team. In fact, heart failure specialists who had previously only interacted sporadically with the heart team are progressively becoming regular members of the group. Their presence has clearly enriched the heart team and expanded its role. A recent meeting entitled “THT” for Technology and Heart Failure Therapeutics was recently held entirely on the topic of interventions in heart failure and highlighted in The author has no funding to report.The author reports no conflict of interest.


Indeed, there is a large amount of clinical studies dedicated to a link between key pathogenetic mechanisms in any phenotypes of chronic HF, a risk of HF decompensation and cardiac/non-cardiac comorbidities (Acute heart failure (AHF) remains one of the leading cause of hospital admission among patients with known cardiovascular diseases (CVD) . The levnagement . Meanwhibidities .Keir et al. focused on the prognostic value of an augmented peripheral chemo-reflex hypoxic ventilatory response as measured from brief hypoxic exposures in HF patients with preserved (HFpEF) and reduced (HFrEF) ejection fraction. They found that transient hypoxic ventilatory response tests exerted high capability of identifying differences in peripheral chemo-reflex sensitivity among HFpEF patients. The authors proposed that this methods may be addressed to further longitudinal studies to identify HFrEF patients with plausible benefit from carotid body intervention.In the four papers of this Research Topic various aspects of heart failure are discussed. In the first paper, Agra-Bermejo et al. yielded that the combination of adipocytokine omentin with anti-inflammatory properties and the acute-phase inflammatory protein orosomucoid known as α-1-acid–glycoprotein exhibited higher discriminative value than NT-proBNP, omentin and orosomucoid alone for re-admission and/or death in patients with de novo AHF. This study illustrates not only It suggests an independent predictive value for omentin and orosomucoid for AHF, and maybe but also plausible role of help in improving AHF outcomes during management with sodium-glucose co-transporter 2 inhibitors, which present anti-inflammatory properties. In the second study Li et al. investigated the association between acute kidney injury and adverse cardiac remodeling in a large patient population (n = 11573 patients with CVD, diabetes mellitus, chronic HF and chronic kidney disease, who were treated with undergone coronary angiography. The authors established that patients with acute kidney injury had a significantly higher risk of adverse cardiac remodeling when compared with those without acute kidney injury. Thus, the authors linked a the risk of HF due to left ventricular dysfunction with to kidney dysfunction after conventional coronary angiography. Taking into consideration a large amount of these procedures, a significance of the findings appears to be extremely important. In the third study, Budde et al. performed a narrative review which they thoroughly elucidated innate molecular mechanisms associated with systemic inflammation and oxidative stress regarding the nature of with a focus on the contribution of abundant cellular responses to HFpEF development. The authors discussed a role of age, gender, cardiac and non-cardiac comorbidities including diabetes mellitus, obesity along with adipose tissue dysfunction in the development of HFpEF. The authors emphasized that clustering of risk factors for HFpEF has hitherto not drawn much attention in clinical trials.The results of the prospective observational study provided by


Background: CRT improves systolic and diastolic function, increasing cardiac output. Aim of the study: to assess the outcome of LV diastolic dyssynchrony in a population of fusion pacing CRT. Methods: Diastolic dyssynchrony was measured by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral walls. New parameters introduced: E″ and, respectively, A″ time (E″T/A″T) as the time difference between E″  peak septal and lateral wall. Patients were divided into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline characteristics: 62 pts (62 ± 11 y.o.) with idiopathic DCM, EF 27 ± 5.2%; 29% type III diastolic dysfunction (DD), 63% type II, 8% type I. Average follow-up 45 ± 19 months: LVEF 37 ± 7.9%, 34%SR, 61%R, 5%NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling  and lower LV filling pressures . DD profile improved in 65% of R with a reduction in E/E′ ratio . Significant cut-off value calculated by ROC curve for LV diastolic dyssynchrony is E″T > 80 ms and A″T > 30 msec. Conclusions: The study identifies the cut-off values of diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up. Cardiac resynchronization therapy via biventricular (BiV) pacing is the standard of electrical care therapy that reduces ventricular dyssynchrony in advanced heart failure patients with complete left bundle branch block (LBBB) .The presence of LV dyssynchrony contributes to aggravating LV hemodynamics, increases the risk of adverse cardiac events, and worsens the patient’s prognosis. In the case of BiV pacing, RV stimulation causes interventricular and intraventricular delays and therefore creates asynchrony . The stuThe aim of our study was to assess the outcome of LV diastolic asynchrony in a population of fusion pacing CRT without right ventricular (RV) lead. This article offers valuable data in a grey area of CRT and highlights the importance of LV dyssynchrony occurring in the diastolic phase.Prospective data were collected from a cohort of patients with idiopathic dilated cardiomyopathy and CRT-P indication. Briefly, inclusion criteria were heart failure New York Heart Association (NYHA) class III–IV despite optimal pharmacological treatment during the 3 months prior to CRT, QRS complex greater than 130 ms, typical LBBB pattern, preserved atrioventricular conduction. The exclusion criteria were represented by acute coronary syndrome or history of coronary artery disease, primary cardiomyopathy such as hypertrophic cardiomyopathy or stress cardiomyopathy (Takotsubo), secondary cardiomyopathies , permanent atrial fibrillation, severe comorbidities  or noncardiac health conditions that limit physical activity . Patients with CRT-D indication in primary or secondary prevention were also excluded.Systematic 6-month full follow-ups , including exercise tests were recorded in all patients. Device and medication optimization were performed at each follow-up, when needed, in order to maximize CRT response ,9.Permanent transvenous cardiac pacing was achieved using direct percutaneous subclavian vein puncture. The first pacing lead was positioned in the right atrium and the left ventricular lead was placed in different branches of the coronary sinus: anterolateral lateral, lateral, posterior, or posterolateral. In the case of atrioventricular block occurrence during implantation, a triple chamber CRT-P with right ventricular lead placement was available.Standard transthoracic echocardiography, including Doppler studies, was performed before and the day after device implant and at 6-month intervals using a Vivid E9 system  and a 2.5 or 3.5 MHz phase array transducer. For each patient, ECG was simultaneously recorded. The following parameters were evaluated: left ventricular end-diastolic and end-systolic diameters , left-ventricular end-diastolic and end-systolic volumes , left-ventricular ejection fraction (LVEF) assessed by Simpson’s equation using the apical four-chamber view, the ratio of peak flow velocity in early diastole and peak flow velocity in late diastole during atrial contraction (E/A), deceleration time of E-wave (DTE), E/E’ ratio, LA diameter, area and volume , aortic root motion using M-mode. Myocardial PW Doppler velocity signals were reconstituted from TDI colour images, providing regional myocardial velocity curves.Evaluation of diastolic dyssynchrony was performed in the diastolic phase by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral wall in a 4-chamber view. In addition, we defined the following new parameters: E″ and A″ time (E″T/A″T) as the time difference between the septal and lateral wall E″ and A″ peaks . We measExercise tests, medication optimization, and device management were systematically performed to maintain constant fusion and improve CRT response. The following device check-up included 12-lead ECG pacing on/off, spontaneous AV interval, LV threshold, and response of pacemaker functioning during exercise. CRT assessment during ET analyzed maximum heart rate, 12-lead beat-to-beat ECG analysis of LV fusion pacing, occurrence of LV capture loss and improvement in exercise capacity. Based on the large clinical trials proving the clinical benefit of CRT, such as MIRACLE  or CARE-The CRT response was evaluated by means of 3 important criteria : 1. clinThree groups of patients were identified during the study: responders (R), super-responders (SR), and non-responders (NR). SR pts were defined as those with LVESV/LVEDV improvement ≥30% with an increase in diastolic filling time >50% and shorter E″T/A″T, while the responders were those with >5% increase in LVEF and 15% decrease in LVES/DV. Non-responder group was characterized by a reduction in LVESV/DV < 15% and larger E″T/A″T ,12.p-value < 0.05 were considered to indicate statistical significance. All statistical analyses were performed with SPSS software version 23 and GraphPad software, version 9.5, Boston, MA, USA.Continuous data that approximate a normal distribution are presented as mean values ± standard deviation and as proportions for categorical variables. The T-test (or ANOVA if it was the case) was used for normally distributed continuous variables, and a chi-square test was used for categorical data. The optimal cut-off value of E″T and A″T was determined by receiver operating curve (ROC) analysis. Only variables with a The analytic group included 69 patients with idiopathic dilated cardiomyopathy implanted with a RA/LV DDD pacing system. During implantation, two patients developed acute AV block due to sheath manipulation, and they received a triple chamber CRT-P. Of all 69 initially assessed pts, 5 had poor echocardiographic images , and strain rate analysis was not possible with a final feasibility of 85%. The final true RA/LV CRT-P group consists of 62 patients.The baseline demographic data are presented in The average follow-up was 45 ± 19 months. Among the 62 patients, 29% had type III diastolic dysfunction (DD), 63% type II DD, and 8% type I DD.p < 0.0028) and lower LV filling pressures . A comparison between the baseline and the follow-up data is presented in After 6 months of RA/LV fusion CRT, among the 62 patients, there were 21 super-responders (34%), 38 responders (61%), and 3 non-responders (5%).The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling  significantly improved in all patients. A reverse remodeling of the left atrium, correlated with its volume and surface, was noticed in both super-responders and responders. However, the responder patients had the maximum benefits in term of LA reverse remodeling. At baseline, severe mitral regurgitation (MR) was found in 12% of patients, 32% of patients had moderate MR, and 56% had mild MR. At the last follow-up, only the non-responders still had severe mitral regurgitation, and 20% of patients had moderate MR (8% SR and 12% R).During follow-up, death occurred in 3 pts (2%) with type III DD, severe LA volume, and larger E″T/A″T (E″T > 85 msec A″T > 30 msec) due to refractory HF associated with pulmonary sepsis. At the end of the follow-up, NYHA class improvement was noted in 87% of patients: 89% in NYHA II (versus 10% at baseline) and 8% in NYHA III (versus 76% at baseline). Readmissions due to decompensated HF were noted in all NR patients (median readmission rate 3/year), while in R and SR groups only 6 patients (10%) needed hospitalization. The main causes for HF decompensation were diet and medication non-compliance, supraventricular tachyarrhythmias, and pulmonary infections.Among the baseline echocardiographic parameters in responders when compared with non-responders, DD profile improved in 65% of patients, reaching a significant statistical importance in E/E′ ratio both in super-responders and in responders. Both E″T and A″T were significantly decreased in responders when compared with baseline (76 ± 13 vs. 51 ± 11 and 26 ± 8 vs. 7 ± 5), and the non-responders group was associated with larger baseline E″T and A″T and no statistically significant difference was noted in these patients after CRT. .p = 0.0914) was recorded; for A wave, an AUC of 0.6968  was recorded; and for the E/A ratio, an AUC of 0.7523  was recorded. Compared to these parameters, a value of E″T > 80 ms  and a value of a A″T > 30 ms  were shown to be stronger predictors for the response to CRT. These comparisons are highlighted in We assessed the most important parameters of diastolic asynchrony that predict the response to CRT using ROC (receiver operating characteristic) analysis. Thus, for E wave an area under the ROC curve (AUC) of 0.5890  as the time difference between the septal and lateral wall E″ and A″ peaks, respectively. We measured these parameters before and after resynchronization therapy. In the majority of SR and R patients we observed a substantial reduction of E″T and A″T after implantation, which indicates that a quantitative measurement in the time domain could predict LV functional recovery. Therefore, they are indirect markers of systolic asynchrony.As is well known, poor reprogramming of AV delays contributes to the reduction of the effectiveness of CRT ,25,26. TTo maintain constant fusion in our population, we have performed AV optimization using PW Doppler echocardiography with assessment of the mitral inflow pattern, drug optimization, and CRT reprogramming during follow-ups with exercise tests. Hereby, we noticed that a prolonged diastolic filling time was associated with better diastolic synchronization and therefore a reduction in E″T and A″T. In addition, it must be emphasized that in our study we have provided exclusive fusion pacing CRT using RA/LV dual chamber devices, without the potential of additional desynchronization through right ventricular pacing. Our analysis was limited by collecting data from only one image plane, with the apical view providing in all our patients reliable information on radial and longitudinal deformation in two opposite walls. Although we included in the study only patients with non-ischemic cardiomyopathy, typical LBBB, and QRS > 130 ms (well-known predictors of favorable CRT response), the patients are different in terms of comorbidities and HF treatment, and this reflects a real-life population of patients.The low number of non-responders is a significant limitation of the study that can reduce the impact of the statistical test. However, the small number of non-responders is due to a highly selective population included in the study and a close and tailored follow-up for each patient in order to maximize the CRT response. To the best of our knowledge, there is no validated data regarding this subject, and we hope that the new introduced parameters will be analyzed in larger, randomized trials with higher statistical power.Demonstrated in several studies, approximately 30% of patients will be CRT non-responders ,30. AmonAlthough the end point of the study was not a clinical one in terms of mortality or HF hospitalizations, we succeeded in demonstrating that E″T and A″T have powerful implications for predicting CRT response.In conclusion, this study identifies the cut-off values of new defined diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up. Larger randomized trials are needed to define the role of diastolic asynchronism in cardiac resynchronization therapy.


Shor women have the lowest values Et/At ratios (p = 0.05). RV diastolic dysfunction was detected mainly in women compared with men , somewhat more often in Shors. Ethnicity was one of the factors associated with the right ventricular diastolic dysfunction presence (p = 0.002). Among the factors associated with the RV diastolic dysfunction were risk factors , blood pressure, gender, ethnicity, and left ventricular parameters . Thus, our study established the influence of ethnic differences on the right heart echocardiographic parameters in Shors and Caucasians with arterial hypertension. The effect of sex on RV diastolic dysfunction was a lot bigger compared to the effect of ethnicity. The revealed differences should improve the assessment of the right heart structure and function in patients with arterial hypertension from small ethnic groups, which will help to improve the diagnosis and treatment of such patients.Aim of this study was to compare right ventricular echocardiography parameters in urbanized hypertensive patients of the Shor and non-indigenous ethnic groups in the Mountain Shoria region. The study included patients with arterial hypertension: 58 Shors and 50 non-indigenous urbanized residents, comparable in age, and divided by ethnicity and gender into 4 groups: Shors men (n = 20), Shors women (n = 38) , non-indigenous men (n = 15) and non-indigenous women (n = 35). All underwent echocardiographic examination, and the right heart parameters were studied. Shor men with arterial hypertension had the lowest values of the pulmonary artery index ( A similar situation is observed when examining ethnic minority populations in other regions, for example, in Russian Siberia4. To improve treatment and control rates and reduce differences between populations, it is necessary to identify the determinants of these rates across ethnic groups, and to develop and implement ethnicity-specific intervention strategies, which ultimately help reduce ethnic disparities in hypertension-related complications2.Recent studies have pointed out an unfavorable course of arterial hypertension in European ethnic minority populations compared to host populations7. However, this information mainly relates to chronic heart failure, coronary artery disease or valvular diseases10. Assessment of right ventricular (RV) function is still insufficiently studied in patients with arterial hypertension, despite the first information about its dysfunction in hypertension being obtained over 30 years ago11. Researchers are currently studying the factors associated with RV remodeling in hypertension12 and have already shown an independent effect of RV parameters on the prognosis in these patients13. Distinguishing between normal and abnormal right heart dimensions and functions is therefore clinically relevant. However, a routine assessment of RV function in hypertensive patients ) has not yet been widely used in clinical practice. Limited normative data is one of the possible barriers: developing normative indicators for right heart echocardiographic assessment used the results of studies carried out mainly in Caucasians in Europe and North America15, which cannot be extended to other racial and ethnic groups. Several recent multicenter studies have been aimed primarily at obtaining information about the ethnic characteristics of the left heart structural and functional indicators18. For the right heart, such studies are extremely scant20, therefore, the study of right heart ethnic characteristics in normal and pathological conditions remains an important scientific direction.There are more and more data on importance of the right heart’s clinical and prognostic significance in cardiac diseases4 and in the city21, . While the ethnic differences in left ventricular echocardiographic parameters were studied both for healthy urban residents of these groups21 and for patients with arterial hypertension , the indicators of the right ventricle were only compared in healthy individuals21. Accordingly, the aim of this study was to compare right ventricular echocardiography parameters in urbanized hypertensive patients of the Shor and non-indigenous ethnic groups.However, there is another aspect of the problem. Changes in the structure and function of the heart may not only be caused by genetic characteristics of a particular ethnic group, but also by peculiarities of the lifestyle , living conditions , as well as influence of pathological conditions. Previous studies have studied the features of echocardiography in representatives of two ethnic groups of the Gornaya Shoria region—the indigenous population (Shors) and the non-indigenous population (Caucasians) living both in rural areas3; in small rural communities in the middle mountains, their lifestyle is focused on hunting, fishing, subsidiary animal husbandry, primitive manual farming and gathering. Following intensive urbanization, the Shors are resettling from the countryside to the cities, which changes the usual way of life. The present study included Shors living in urban conditions. Recruitment of the studied indigenous nationalities and comparison groups was carried out by a continuous method according to the lists provided by the Myski city administration  and non-indigenous (Caucasians) population living in Gornaya Shoria in the south of Western Siberia was carried out during 2017 and 2018. The Shors belong to the South Siberian segment of the Asian race15. Reported values of all echocardiographic parameters were obtained as the average value of 3 consecutive cardiac cycles. Structural parameters of the left and right heart were assessed using M-modal and B-modal scanning in standard positions. All structural indicators were indexed to the BSA. The following left heart indicators were used: end-diastolic and end-sistolic diameters (EDD and ESD), posterior wall thickness (TPWLV) and its index (TPWLVi), interventricular septum thickness (TIVS) and its index (TIVSi), end-diastolic and end-systolic volumes (EDV and ESV) of the LV, index of the end-diastolic volume of the LV (LVEDVi). LV mass was calculated in B-mode at the end of diastole, and LV myocardial mass index (LVMi) was also calculated. The LV ejection fraction (LVEF) was determined by the Simpson method. In the section of 4 chambers at the end of diastole, the maximum transverse diameter of the left atrium (LA), its volume (LAV) and index (LAVi) were measured. In the pulse-wave Doppler mode, the velocity of early diastolic atrioventricular flows (E), the flow rate of atrial systole (A). Using spectral tissue Doppler, the parameters of the regional function of the mitral valve annulus, related to the diastolic  and systolic parts of the spectrum (s'), were measured.All subjects underwent echocardiography on a Vivid S5 ultrasound system  using a phased array sector probe. All echocardiographic examinations were performed by the same examiner (OA), measurements were carried out according to the current guidelinesFrom the data of the right heart, the diameter of the pulmonary artery (PA), its index (PAi), the end-diastolic anteroposterior size of the right ventricle (RV), its index (RVi) were assessed; the size of the right atrium (RA), its area (RAS) and the area index (RASi). In the M-mode, the longitudinal systolic function of the RV was assessed by measuring the systolic excursion of the tricuspid annulus (TAPSE).14.In the pulse-wave Doppler mode, the velocities of early diastolic atrioventricular flows (Et), the time of their deceleration (DTt), the flow rates of atrial systole (At), the ratio Et / At were assessed. We assessed the parameters of the regional function of the tricuspid valve annulus, related to the diastolic , and the systolic part of the spectrum (s't). The index of the overall performance of the RV were calculated as the ratio of the sums of the isovolumic relaxation time and the isometric filling time to the expulsion time (Tei index). Using color M-modal scanning, we measured the propagation velocities of the early tricuspidal flow (Vft) according to the slope of the brightest part of the spectrum. RV diastolic dysfunction was considered with the ratio Et/At < 0.8 or > 2.1 and/or the ratio Et/e’t > 610.Since the assessment of the RV has not been well established, we used a sufficient number of right heart measurements to detect possible ethnic differences. In assessing the systolic function of the right ventricle, we focused primarily on the indicators of s't and TAPSE. Right ventricular diastolic function was assessed using the ratio Et/At, the ratio Et/et’, Vft, and the ratio e’t/a’t based on our previous studiesp < 0.05. Performance of RV values for diagnosing the RV diastolic dysfunction presence was assessed through receiver operating characteristic curve analysis. For intra-observer variability, the analysis was repeated 1 week after the first measurement in 20 random patients. Reproducibility was expressed using the coefficient of variation and interclass correlation coefficients.Statistical processing was performed using the standard Statistica 10.0 and SPSS 17.0 software packages. Qualitative values were presented in absolute numbers (n) and percentage (%), comparisons between the groups were performed using χ2 tests. The normality of the distribution was verified using the Kolmogorov–Smirnov test. For a distribution other than normal, all quantitative variables were presented as the median, low and upper quartiles . Comparison of quantitative data was carried out using the Kruskal—Wallis test. Qualitative and binary characteristics were compared using the χ2 (chi-square) test with Yates' correction for small samples. Intergroup differences were assessed using the Mann—Whitney test with Bonferroni's correction. Using binary logistic regression analysis (enter method), we studied the relationship of possible factors with RV diastolic dysfunction. The level of statistical significance was taken as p = 0.069). Smoking was more common among the Shors (p = 0.012). Obesity, and office diastolic blood pressure levels were higher among the non-indigenous population . The Shors had significantly lower triglyceride, LDL and urea levels and higher HDL levels than the non-indigenous population. A more detailed description of these groups, depending not only on ethnicity, but also on gender, was presented by us earlier .General characteristics of the Shor and Caucasian groups are presented in Table p = 0.016 and p = 0.034, respectively).The main structural indicators of the left ventricle, stratified by sex, had no ethnic differences Table . Only thp = 0.05), right atrium sizes (p = 0.04), and the highest values of the propagation velocity of the RV filling flow (p = 0.01), velocity of early diastolic (p = 0.05) and systolic (p = 0.05) tricuspid annulus movement were identified. Shor women showed the smallest values of the Et / At ratio (p = 0.05).Right ventricle parameters had more noticeable ethnic differences Table . In Shorp = 0.406). However, stratification by sex  primarily due to the more frequent detection RVDD in women compared with men . At the same time, ethnic differences in RVDD between women and men wasn’t revealed.The right ventricle diastolic dysfunction was detected in the Shors as often as in the non-indigenous population : ethnicity, sex, smoking, body mass index, obesity, systolic blood pressure, urea, LVMM index, diastolic LV function . The model explained 67.8% (Nagelkerke R2) of the variance in RVDD and correctly classified 90.1% of cases. In multiple binary logistic regression model (forward LR method), sex was the only significant factor included in the model , but this model explained only 16.2% (Nagelkerke R2) of the variance in RVDD and correctly classified 74.3% of cases. Nevertheless, despite the reliable statistical significance of the latter model, its low quality (judging by the Nagelkerke R2 indicator) does not allow us to reject univariate analysis with other indicators associated with RVDD in , in particular, the ethnicity of the patients.In a univariate binary logistic regression including of all variables Table , the folROC-curves of the studied left ventricular variables  association with RVDD are presented in Fig. When assessing the right ventricle parameters in hypertensive patients we revealed lower values of the pulmonary artery index, the size and area of the right atrium, as well as the highest values of the RV velocity flow propagation, the rate of the tricuspid annulus early diastolic and systolic movement in Shor men compared with Caucasians. Shor women had the lowest values of early transtricuspid blood flow and the Et / At ratio. RV diastolic dysfunction was detected mainly in women, somewhat more often in Shor women. Accordingly, ethnicity was one of the factors associated with the RV diastolic dysfunction presence. Risk factors , blood pressure, gender, ethnicity, as well as LV parameters  were also associated with detection of RVDD.21. In that study, an increase in the dimensions of the pulmonary artery and right ventricle was found in Shor men and women compared to Caucasians. The indicators of the RV diastolic filling in the Shors were moderately better, which was manifested, in particular, by higher RV filling velocity in them. Participants of the present study were older and, therefore, both arterial hypertension and age influenced the state of the right heart, leveling out the initial ethnic differences in the LV structural parameters observed when comparing healthy individuals, and the right heart indicators in Shor women. It is possible that genetic factors influenced this dynamic of indicators during hypertension development. It was previously shown that different ethnic groups of rural Gornaya Shoriya residents had different genetic associations with LV hypertrophy. At the same time, LV hypertrophy among hypertensive patients was more prevalent in the Shor group than in the non-indigenous (Caucasian) group4. In the previous study, no genetic associations with the state of the right ventricle were studied, however, in our study, there were no ethnic differences in the severity of LV hypertrophy. A possible reason for this is the influence of environmental factors: the shift from the traditional way of life of the Shors in rural areas to life in the city, greater availability of medical care, and an increase in the educational level. Examining healthy individuals in the MESA-Right Ventricle Study has shown that age, sex, and race are associated with significant differences in RV mass and volumes19. The authors suggested that these differences could potentially explain distinct RV responses to cardiopulmonary disease19; however, in our study, on the contrary, we noted the leveling of the initial ethnic differences in RV parameters during the development of arterial hypertension.Our previous study assessed the state of the right heart in healthy individuals of the Shor nationality22, smoking23 and the left ventricular hypertrophy24 affect the right ventricle. It was previously shown that healthy residents of highlands have small left heart and large right ventricle due to exposure to hypoxemia at high altitudes, and these changes did not depend on ethnicity25. In the present study the RV dimensions are higher in Shor men than in non-indigenous men, which can be explained by a combination of several factors .Previous studies have shown that the level of physical activity27 and during the disease’s development28, adversely affecting the prognosis at the same time29. Our study confirmed the influence of the above factors on the presence of RVDD. The detection rate of RVDD was significantly lower than in a number of previous studies, where it was up to 45–60%. However, these studies examined patients with stable coronary artery disease before surgery10 or with uncompensated hypertension24. The more frequent RVDD detection in women turned out to be unexpected for us. In previous studies, on the contrary, there was a greater resistance of women to the RV dysfunction development compared to men30. Perhaps this is characteristic of RV systolic dysfunction, but not of diastolic dysfunction. It also cannot be ruled out that the existing criteria for RV diastolic dysfunction may inaccurately reflect its presence in women, which apparently requires further research in this area.We focused on the RV diastolic function since its development precedes systolic dysfunction both in experiment31. It is proposed to continue the study of the 4D-MRI technique in assessing the RV diastole32, but, apparently, it is impossible to leave out the echocardiographic assessment of the RV filling flows due to the greater availability of this examination technique. Furthermore, this is consistent with the notion that, due to its high availability, echocardiography is the first choice of imaging modalities for assessing the right ventricle. In turn, MRI should be performed as a second-line imaging modality in cases where surgery is planned for congenital heart disease or when differential diagnosis is needed33.Among the RVDD echocardiographic indicators, the velocity of RV filling to the greatest extent reflected its presence. This is probably a natural result. First, this indicator changes linearly with the increasing severity of RVDD, in contrast to the ratio of transtricuspid flow velocities. Secondly, assessing the filling flows of the right ventricle using 4D-MRI turned out to be the most informative in identifying initial changes in the right heartWe see the clinical significance of the study in the fact that, firstly, the leveling of most ethnic echocardiographic differences between Shors and Caucasians in the development of arterial hypertension shows that the clinical assessment may not take the influence of the patient's ethnicity into account. Secondly, the obtained data emphasize the complex interactions of genetic factors, environmental conditions, development of diseases, as well as a change in the traditional lifestyle of the Shors , increasing the availability and quality of medical care for them for changes in the right heart. Revealing the diastolic function of the right ventricle predominantly in women among hypertensive patients requires additional study.Besides, the Shors are a small people, the total number is about 14 thousand people. However, they are close to other Turkic-speaking peoples living in Siberia . Therefore, the results obtained by us can be useful for examining representatives of other small peoples of Siberia, as well as other representatives of the Mongoloid race in Asia.30. However, an international study has shown that new technologies such as global longitudinal strain and 3D echocardiography are rarely used to quantify right ventricular function in clinical setting 34. Therefore, the use of traditional RV indicators, in our opinion, at present can be justified, especially in an essentially screening study similar to ours. However, in the future, it is rational to conduct research using new technologies for assessing ethnic differences in RV function.Several limitations should be mentioned. Subclinical coronary artery disease cannot be excluded in this study because coronary angiography was not performed. However, invasive diagnostics had not been indicated since this study included asymptomatic participants with no evidence of atherosclerotic lesions in other arterial regions. Another limitation is the relatively small number of included patients. This was due to the relatively small number of Shors living in urban settings. Nevertheless, we managed to obtain statistically significant results, which are desirable to confirm in larger studies. Finally, the assessment of right ventricular function was based on standard indicators of right ventricular systolic and diastolic function without the use of second-level methods , which have been used in recent years, including in patients with arterial hypertensionOur study established the influence of ethnic differences on the right heart echocardiographic parameters in Shors and Caucasians with arterial hypertension. We revealed in Shor men the lowest values of the pulmonary artery index, the size and area of the right atrium, as well as the highest values of the RV velocity flow propagation, the rate of the tricuspid annulus early diastolic and systolic movement in comparison with Caucasians. Shor women had the lowest values of early transtricuspid blood flow and the Et / At ratio. RV diastolic dysfunction was detected mainly in women, somewhat more often in Shor women. Accordingly, ethnicity (Shors) was one of the factors associated with the RV diastolic dysfunction presence. The revealed differences should improve the assessment of the structure and function of the right heart in patients with arterial hypertension of minor ethnic groups, which help to improve the diagnosis and management of such patients.