Myocardial strain can early detect the myocardial damage and may be an appropriate target for preventive strategies before abnormalities of EF.The aims of the study were to identify subclinical global systolic function abnormalities and evaluate influencing factors associated with left ventricular (LV) strain parameters in hypertensive subjects using cardiovascular magnetic resonance imaging feature tracking (CMR-FT). The study enrolled 57 patients with essential hypertension  and 26 healthy volunteers  who underwent clinical evaluation and CMR examination. Compared with controls, hypertensive patients had significantly impaired myocardial strain values while ejection fraction (EF) did not differ. After multivariate regression analyses adjustment for confounders, the global radial strains (GRS) was independently associated with the mean arterial pressure (MAP) and left ventricular mass index (LVMI) ( Hypertension remains deserving for more attention since it is a potent risk factor for cardiovascular diseases and it may brings considerable morbidity and mortality4. Given the prevalence of hypertension in the population, early identifying subclinical left ventricular (LV) systolic dysfunction among hypertensive subjects might have an important role in assessing the prognosis and choosing treatment strategies.Strain imaging has emerged as a sensitive and powerful tool to detect early and subtle myocardial dysfunction in various cardiac diseases, and may provide a novel method for LV risk assessment in hypertensive patients7.Essential hypertension is defined as a rise in blood pressure which can increase risks for cerebral, cardiac, and renal events with unknown reason8. CMR tagging has been the most available and reproducible method to quantify the myocardial deformation and remains the reference standard for evaluating myocardial strain10. However, CMR tagging needs to acquire additional sequences and its post processing is time-consuming. The spatial resolution of tagging is quite low, which is another limitation of tagging. Therefore, CMR tagging has not yet been widely applied in clinical circumstances. Speckle tracking echocardiography (STE) has solved these issues to a large extent, but it is still limited by the observer dependency, signal noise, angle dependency, inadequate acoustic windows and poor image quality13. Cardiovascular magnetic resonance imaging feature tracking (CMR-FT), which derives from cine balanced steady-state free precession (bSSFP) sequence, has the advantages of measuring myocardial strain with no need for contrast agents or additional sequence acquisition, a wide field of view, no anatomic plane restriction, semi-automatic and time-saving post-processing procedure16. Hence, CMR-FT has been increasingly used as a novel non-invasive technique for the quantitative evaluation of myocardial function17.Myocardial strain was first used by cardiovascular magnetic resonance (CMR) tagging in 1988The aims of the study were to identify subclinical global systolic function abnormalities in hypertensive subjects using CMR-FT, and evaluate influencing factors associated with left ventricular strain parameters for hypertensive patients.The study has comprised of 57 hypertensive patients  and 26 healthy volunteers . The distributions of clinical and demographic parameters of the two groups showed in Table Mann-Whitney U test for triglycerides, the Chi square test for sex, and the independent-sample Student’s t test for other variables. BMI, body mass index; BSA, body surface area; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure, LDL cholesterol, low density lipoprotein cholesterol; HDL cholesterol, high density lipoprotein cholesterol.Comparison of variables between the two groups was performed by using the There were no significant differences in LV end-diastolic volume indexed (EDVI), LV end systolic volume indexed (ESVI) and LVEF between the two groups, except for LV mass indexed (LVMI) Table .Table 2Cβ = −0.331, 0.121, and 0.09, respectively) and LVMI (LVM/BSA)  , global circumferential strains (GCS) and global longitudinal strains (GLS) Table , Fig. 1.After multivariable regression analyses adjustment for confounders including age, sex, BSA, high density lipoprotein cholesterol (HDLC) and LVMI, the associations with MAP remained significant for GRS, GCS and GLS Table . In multICC of ≥0.85, the reproducibility of the circumferential and longitudinal strain was better than that of the radial strain. The Bland-Altman plots of intra- and inter-observer agreement were displayed in Fig. In our study, all segments were available to be tracked. Intra- and inter-observer variabilities were showed in Table The main findings of the study were that (1) The hypertensive patients were inclined to have higher weight, BMI, BSA, serum lipids and LV mass. (2) The myocardial strain valueshad already significantly impaired before EF, EDVI and ESVI appeared abnormal in hypertensive patients. (3) There were a negative association between MAP and reduction of GRS, GCS and GLSwhen adjusting for key confounders of LV myocardial dysfunction, including age, sex, BSA, HDLC and LVMI in hypertensive patients. (4) All the strain parameters above had good reproducibility.18, which indicates EF may be inaccessible to identify subtle and mild degrees of LV systolic abnormalities23. Maciver et al. reported that although longitudinal systolic strain had been reduced, EF may be normal by compensated with the increased radial wall thickness in LV hypertrophy24. Our results showed that hypertensive patients had significantly reduced myocardial strains in early normal EF stage compared with control subjects, which confirmed the value of the strain in detection of early and subtle myocardial impairment with previous studies29.LVEF has been recognized as the routine prognostic parameter and reference standard of LV global systolic function. However, LVEF is only a representative of LV geometric change other than the function change31. Saeed et al.27 reported reduced GLS was particularly associated with hypertension and Navarini et al.25 reported 3D strains had the similar results. Our results indicated GRS and GCS both had a negative association with LVMI (LVM/BSA). Higher BP could result in LV hypertrophy (LVH) which had increased LVMI32. LV hypertrophy secondary to pressure overload is a compensation for high intracavitary pressures for maintaining normal wall stress and cardiac output35. According to our results, the process of myocardial hypertrophy may have been accompanied by the decrease of radial and circumferential strains. In addition, our results showed that GLS may decrease with age. Kaku et al. also found that GLS have significant age dependency, with the highest value in infancy and a gradual reduction with age36. The age-related association with GLS may reveal the process of myocardial maturation and aging. Recently, the association of reduced strain with poor prognosis in hypertension was reported by Lee et al.37. Despite the established role of LVEF and increased LV mass for higher incidence of cardiovascular risk38, more and more studies showed strain  was superior and incremental for assessing the relation with major adverse cardiac events (MACE)41.The reason that reduced GRS, GCS and GLS were all independently associated with MAP may be that long-standing hypertension cause microscopic changes such as increased collagen turnover, myocardial fibrosis and subendocardial ischemia which lead to impaired strain, as other study explained44. For example, for healthy adults, Hwang et al. reported left ventricular GCS value was comparable to our result, but the values of left ventricular GRS and GLS were higher than that in our study45. Thus, the normalization and standardization of strain parameters are required. In recent years, the reproducibility of LV strains by using CMR-FT had been proved48. Our results showed good reproducibility for all global strain parameters with intra- and inter-observer ICC of ≥0.85, the reproducibility of the circumferential and longitudinal strains was better than that of the radial strain. Our outcomes were consistent with the previous studies50. The good reproducibility of the strain may owe to the advantages of superior image quality and accurate definition of the endocardial border, as well as the algorithm by using automated process and background smoothing46. For the comparatively lower reproducibility of radial strain, the likely reason is that radial strain is derived from both endocardial and epicardial motion which is different with circumferential strain and longitudinal strain, and that the contrast of the epicardial signal intensity is less clear than that of the endocardial signal intensity46. In addition, the accuracy of the strain parameters by using CMR-FT could be validated by comparing with CMR tagging. Good agreement with CMR tagging had been proved51.The normal reference values of strain parameters by using CMR-FT varied in different study. The discrepancies among different studies may attribute to different applied vendor or software version, as well as different patient characteristics such as age, sex, BMI, BP and HRThe main limitations of this study were that: First, our study was limited by the relatively small number of subjects, which made it impossible for subgroup analysis with and without LV hypertrophy. Second, although several factors were incorporated toevaluate the associations with strains, there are other possible important confounders such as the application of antihypertensive drugs that have not yet been assessed. Thus, our results should be interpreted in the circumstances of the limitations, and it may be difficult to generalize our results. Of course, larger patient populations and more confounders should be performed to confirm our initial results.Myocardial strain can early detect the myocardial damage and may be an appropriate target for preventive strategies because it occurs before abnormalities of EF. Among essential hypertensive patients, increased MAP may have an adverse effect on LV myocardial strains. CMR-FT may have potential to quantitatively analyze cardiac motion and apply in routine clinical practice in the future.52. The patients had BP measurements using an automated electronic sphygmomanometer . According to the 2017 guideline52, after a minimum 5-min rest without caffeine, exercise, or smoking for at least 30 min in sitting position, blood pressure measurements were performed three times consecutively at 1–2 min intervals. Then, the individual’s level of BP was calculated by the average of three measurements. Clinical and laboratory data were also obtained. The exclusion criteria includedsymptoms of chest pain or a history of coronary heart disease, myocardial infarction, cardiomyopathy, severe valvular disease, arhythmia, heart failure, severe obstructive lung disease, stroke, diabetes, kidney disease, thyroid disease and hypohemia. The patients who had contraindications for CMR such as claustrophobia, implantable not CMR safe materials, severe mental disorder were also excluded. In addition, we recruited 26 healthy volunteers as a control group for matching age and sex with case group. Volunteers with any of the symptoms and signs or a history of cardiovascular diseases, cerebrovascular diseases or relevant noncardiac diseases were excluded. All of the volunteers had normal blood test results.Written informed consent was obtained from all study participants. The study was approved by the ethics committee of central China Fuwai hospital. All methods were performed in accordance with the guidelines and regulations of the Declaration of Helsinki.The prospective study enrolled 57 participants with a diagnosis of essential hypertension from our hospital between October 2017 and October 2018. The patients had normal EF (≥50%) and no history or clinical evidence of cardiovascular disease. Hypertension was defined as a history of hypertension, use of antihypertensive medicines, or the values ≥130 mmHg SBP and/or ≥80 mmHg DBP according to the 2017 guidelineAll imaging was performed on a 3.0 Tesla MRI scanner  using an 18-channel cardiac phased-array receiver coil with patients in the supine position. Cine images were acquired using a standard balanced steady state free precession (bSSFP) sequence with retrospective electrocardiogram-gating in short axis (SAX) views from base to apex of the LV and long axis 2-, 3- and 4-chamber views. To cover the entire LV, 8 to 12 short-axis slices were performed with 4 to 6 breath-holds. All cine images were acquired with 25 phases per cardiac cycle. The scan parameters were: repetition time (TR) 3.2 ms, echo time (TE)1.40 ms, temporal resolution 44.66 ms, spatial resolution 1.8 × 1.8 mm, field of View (FOV) 369 × 369 mm, matrix 208 × 146, flip angle 49°, slice thickness 8 mm, slice gap 2 mm, acceleration factor 3.42 version 5.9.1, Circle Cardiovascular Imaging, Calgary, Canada). The endo- and epicardial border lines were marked automatically and trimmed manually in the end-diastolic phase (reference phase) on SAX slices. By using a maximum likelihood method, the software algorithm automatically drew the borders and traced the myocardium voxel points throughout the other cardiac phases during a cardiac cycle based on the endo- and epicardial contours of reference phase. The borders could be manually adjusted if inadequate tracking. Finally, the 2D strain values were calculated with the movement of the features relative to the reference phase53  were evaluated by two independent blinded observers. For intra-observer variability, the interval time between the two measurements is one month. For inter-observer variability, the two separate observers were blind to each other’s measurements.Shapiro-Wilk W test. Continuous variables with normal distribution were presented as mean ± standard deviations, continuous variables with nonnormal distribution were presented as median with interquartile range (IQR). Categorical variables were presented as percentages. Comparisons of variables between the hypertensive patients and the controls were performed by using the independent-sample Student’s t-test for normally distributed continuous variables, the Mann-Whitney U test for non-normally distributed continuous variables and the Chi square test for categorical variables. Univariable and multivariable linear regression analyses were used to evaluate the associations between LV strain parameters and the influencing factors. Covariates for multivariate models were selected based on the significant variables in the univariable analysis (p < 0.20) and clinically relevant parameters. For reproducibility evaluation, intraclass correlation coefficient (ICC) and Bland-Altman plots were calculated. A P value of <0.05 was considered statistically significant.Statistical analyses were performed with SPSS statistics 22  and MedCalc15.2.2 . Normal distribution of variables was assessed by


We examined patients who showed laboratory and histological evidence of primary biliary cirrhosis (PBC) in the absence of antimitochondrial antibody (AMA) to elucidate the characteristics of AMA negative PBC.From a total of 5,805 patients with symptomatic PBC, 2,419 cases (41.7%) were selected in the present study, who were diagnosed using the following criterion; chronic non-suppurative destructive cholangitis was histologically observed and laboratory data did not contradict PBC. The information collected from records included sex, age, symptoms, physical findings, and complicated autoimmune diseases. We then evaluated these data according to the positivity of AMA.γ-glutamyl transpeptidase, and IgM were significantly lower among patients with AMA negative PBC than among those with AMA positive PBC. Complications such as Sjögren’s syndrome, rheumatoid arthritis, and scleroderma, including CREST syndrome, were found with significantly higher frequency among patients with AMA negative PBC than among those with AMA positive PBC.Of the total subjects, 470 cases (19.4%) were found to be negative for AMA. The proportion of female patients was higher among the AMA negative group than among the AMA positive one. Pruritus was found less frequently among patients with AMA negative PBC than among those with AMA positive PBC. Levels of alkaline phosphatase, Considering serum level of IgM and frequencies of complicated autoimmune diseases, it is possible that Japanese patients with AMA negative PBC are consistent with the disease entity of autoimmune cholangitis reported in western countries. The presence of antimitochondrial antibody (AMA) in the sera is a very important finding for the diagnosis of PBC. However, it has been reported that some patients with laboratory and histological findings compatible with PBC do not have detectable AMA,3 whose conditions met one of the three criteria outlined by the previous reports in Japan;4-6 (1) chronic non-suppurative destructive cholangitis is histologically observed and laboratory data do not contradict PBC; (2) AMA is positive, and chronic non-suppurative destructive cholangitis is not histologically observed but histological findings are compatible with PBC; and (3) histological examination is not performed, but AMA is positive and clinical findings and course indicate PBC.In Japan, symptomatic PBC was specified as one of “the intractable diseases” from 1990. Patients with symptomatic PBC who want to receive public financial aid from the Ministry of Health, Labour and Welfare have to sign agreements and write applications. They are then registered and can receive public financial aid. In 1999, the Ministry permitted the use of clinical data from the patients diagnosed with symptomatic PBC. Therefore, the data was available to the research committee of intractable hepatic diseases and the research committee on the epidemiology of intractable diseases. Using these data, we have already shown the clinical features of 5,805 prevalent cases of symptomatic PBC,In the present study, we tried to elucidate the characteristics of AMA negative PBC in Japan using the clinical data when they applied to receive the public financial aid.7 We used the clinical data of 6,305 patients being that not all prefectures provided the data, and chose the cases of 5,805 patients whose clinical data were written and collected between 1999 and 2000; the data from residual cases were not written during this time, for example written in 1998 or before. From these 5,805 patients, 2,419 cases (41.7%) who were diagnosed according to the above-mentioned criterion,1 i.e. chronic non-suppurative destructive cholangitis was histologically observed and laboratory data did not contradict PBC, were selected in the present study. After then the following information of each patient was collected from the records; sex, age, symptoms and physical findings, complicated autoimmune diseases, laboratory data including serum levels of bilirubin, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GTP), total cholesterol, IgM, and frequencies of positivity of AMA. We evaluated symptoms and physical findings, laboratory data, and complicated autoimmune diseases according to the positivity of AMA. In the present study, the frequencies of items in the clinical data were analyzed, excluding “unclear” or blank spaces.In the fiscal year 1999, 9,761 prevalent cases with symptomatic PBC were registered; they were about 81% of 12,000 patients estimated in Japan.® version 10.0 (SPSS Inc.). The chi-square test was used for comparing the proportions of two groups, and the Mann-Whitney test was used to evaluate differences in clinical variables. P < 0.05 was considered significant.Statistical analysis was performed using SPSSOf the total subjects, 470 of the 2,419 cases (19.4%) were found to be negative for AMA. Pruritus was found significantly less frequent in patients with AMA negative PBC than among those with AMA positive PBC (P=0.03) . Splenomγ-GTP, and IgM were significantly lower among patients with AMA negative PBC than among those with AMA positive PBC.Key laboratory data are summarized in Complications such as Sjögren’s syndrome, rheumatoid arthritis, chronic thyroiditis, and scleroderma, including CREST syndrome  were found in 20.5%, 9.7%, 6.0%, and 4.0% of the patients with AMA negative PBC, respectively . These c8 In the present study, therefore, cases that had been diagnosed by histological confirmation were selected.AMA is the serologic hallmark of PBC. However, a small number of patients with PBC lack AMA, as such these patients are often referred as AMA negative PBC. When patients who have cholestatic disorders are found, it is necessary to differentiate PBC from other diseases causing cholestasis, such as primary sclerosing cholangitis.γ-GTP, and IgM were lower among patients with AMA negative PBC. And (4) Complicated autoimmune diseases were found more frequently among patients with AMA negative PBC. It may be one explanation to the frequencies of pruritus and complicated autoimmune diseases in two groups that the AMA negative group included more women than the AMA positive one. It could be that hormonal differences between the sexes may exert modulating factors that predispose each sex toward a particular immune response.9,10 However, we cannot immediately conclude that these statistical differences are truly meaningful, because we dealt a large number of cases with PBC in the present study. Fore example, difference in percentage of pruritus was 6% and not so large. Further studies of the pathophysiological mechanism of PBS will need to be conducted in order to explain these differences comprehensively.Our patients with AMA negative PBC presented some revealing features; (1) The proportion of female cases was higher among the AMA negative group than among the AMA positive one. (2) Pruritus was found less frequently among patients with AMA negative PBC than among those with AMA positive PBC. (3) Levels of ALP, 11 and Lacerda et al.12 reported that the AMA negative group had significantly lower serum IgM than the AMA positive controls, but the level of ALP showed no significant difference between the AMA negative and positive groups. Regarding the level of IgM, our result was consistent with these two reports, but our AMA negative group had significantly lower levels of ALP, and γ-GTP compared with the AMA positive group. One possible explanation may be the number of cases examined; In the previous studies, 17 and 35 cases with AMA negative PBC were examined respectively, whereas we examined 470 AMA negative PBC cases. Although Michieletti et al.11 and Lacerda et al.12 showed that the AMA negative group had lower levels of ALP compared with the AMA positive group, these were not statistically significant. Sánchez-Pobre et al. also reported lower serum levels of ALP and IgM among AMA negative PBC patients.13Michieletti et al.14 and it was considered that such a subgroup might be termed autoimmune cholangiopathy;15 sometimes AMA tests by immunofluorescence technique (IFT) were negative but other autoantibodies such as antinuclear antibody were positive.16,17 In addition, ‘autoimmune cholangitis’ was proposed in some reports.11,12,18-21 Michieletti et al. believed that AMA negative patients have a form of autoimmune cholangitis distinct from that seen in AMA positive PBC and other autoimmune liver diseases.11 Lacerda et al. presented AMA negative PBC cases having other atutoantibodies, such as antinuclear antibody and antismooth muscle antibody, despite the chronic non-suppurative destructive cholangitis in liver biopsy specimens.12 On the other hand, the belief that PBC and autoimmune cholangitis are part of the same spectrum of immunologically mediated disease has risen recently.22 This spectrum would include classic AMA positive PBC as well as the syndrome with the absence of AMA in the serum. Perhaps a similar pathogenetic mechanism may underlie these diseases.22-24 It was also suggested that a part of AMA negative PBC might rapidly progress to liver cirrhosis within a short time.13 Future research is required to clarify the relationship between AMA positive and negative PBC.Ben-Ari et al. described four AMA negative patients with overlapping features of PBC and autoimmune chronic active hepatitis,11,21,22,25 Moreover, the prevalence of positivity of AMA by ELISA method is reported to be 92-93% among patients with PBC.16 It has been suggested that patients with AMA negative results may be shown to have AMA by more sophisticated detection techniques.25,26 For detecting AMA, more sensitive assays, such as immunoblotting, have been developed, and this method is expected to prove AMA positivity for most patients with AMA negative PBC by IFT or ELISA.26Serum from patients suspected of having PBC is usually tested by IFT or enzyme linked immunosorbent assay (ELISA) for the detection of AMA. Most patients with PBC have AMA when serum samples are tested by IFT, but it was suggested that 1-16% of PBC patients do not have AMA when tested by IFT.The present study has several limitations. Firstly, we cannot completely deny that our AMA negative cases obtained by IFT or ELISA turn into AMA positive ones by other AMA detection methods such as immunoblotting. This is a critical problem that needs to be resolved, but it may be difficult to generalize immunoblotting methods for detecting AMA because of the complex nature of their techniques and expenditure. Secondly, other clinical findings including level of IgG, autoimmune antibodies such antinuclear antibody and antismooth muscle antibody were not available, because our patients’ protocols had only the information essential for their receiving public financial aid. Additionally, we could not get adequate information about treatment and use of drugs, such as ursodeoxycholic acid. Nevertheless, to our knowledge, the present study has reported the largest number of AMA negative PBC in Japan, and we consider that we could present an outline on AMA negative PBC.In conclusion, considering serum level of IgM and frequencies of complicated autoimmune diseases, it is possible that Japanese patients with AMA negative PBC are consistent with the disease entity of autoimmune cholangitis reported in western countries.


MYBPC3, TNNI3, MYH7, and MYL7. Variants of uncertain significance were identified in 28 patients. There were significant differences in the presence of non-sustained ventricular tachycardia (p = 0.030) and myocardial fibrosis on CMR (p = 0.029) in the detected compared to the not-detected groups. Event-free survival was superior in the not-detected group (p = 0.006). Conclusion: Genetic variants in patients with HCM are relatively common and are associated with adverse clinical events and myocardial fibrosis on CMR. Genotypic analysis may add important information to clinical variables in the assessment of long-term risk for HCM patients.Background: The spectrum of genetic variants and their clinical significance of Hypertrophic cardiomyopathy (HCM) have been poorly studied in Asian patients. The objectives of this study were to assess the spectrum of genetic variants and genotype–phenotype relationships within a Korean HCM population. Methods: Eighty-nine consecutive unrelated HCM patients were included. All patients underwent genotypic analysis for 23 HCM-associated genes. Clinical parameters including echocardiographic and cardiac magnetic resonance (CMR) parameters were evaluated. A composite of major adverse cardiac and cerebrovascular events was assessed. Results: Genetic variants were detected in 55 of 89 subjects. Pathogenic variants or likely pathogenic variants were identified in 27 of HCM patients in  Hypertrophic cardiomyopathy (HCM) is a genetic heart disease with an estimated prevalence of 0.2% of the global population . The cliIdentification of disease-causing variants and their particular phenotypic expression and natural history has been attempted in many molecular and clinical genetic studies yet much remains unclear. To date, more than 1500 different variants in at least 14 genes have been reported in patents with HCM ,3. HowevThe aims of this study were to understand the distribution of genetic variants among Korean HCM patients and to link their clinical and imaging phenotypic characteristics by genotype status.This study is based on subjects with HCM from the prospective HCM registry of the Samsung Heart Vascular Stroke Institute, Seoul, Korea. Patients with diagnosis of HCM based on echocardiography were consecutively enrolled. Inclusion criteria were (i) end-diastolic LV wall thickness of ≥15 mm in any site or LV septal thickness:posterior wall thickness ≥ 1.3 with the absence of any underlying condition that may be associated with LV hypertrophy ; (ii) end-diastolic LV septal thickness:posterior wall thickness ≥1.5 in patients with systemic hypertension; or (iii) LV hypertrophy confined to the LV apex  with maximal apical wall thickness of ≥15 mm or a ratio of maximal apical to posterior wall thickness of ≥1.3 at end-diastole, regardless of the presence of systemic hypertension ,12,13.We excluded subjects with poorly controlled hypertension, uncontrolled ventricular arrhythmias, severe valvular diseases, and other concomitant systemic diseases including malignancy and those who were contraindicated for cardiovascular magnetic resonance imaging (CMR) or had poor echocardiographic windows for analysis. We also excluded those who were diagnosed on echocardiography as having non-compaction cardiomyopathy, defined as the presence of prominent trabeculation with an increased ratio of non-compacted to compacted LV segments.All patients provided written informed consent, and Institutional Review Board approval was obtained by the institutional review board of Samsung Medical Center, Sungkyunkwan University School of Medicine (IRB No. 2015-06-076-001).Genomic DNA was extracted from peripheral blood leukocytes of each patient using MagNA Pure 96 instrument  with MagNA Pure 96 DNA and Viral NA Large Volume Kit  following the manufacturer’s instructions. Of the 89 total patients, samples from 77 were enriched using the TruSeq Custom Enrichment Kit and sequenced with a MiSeq , and the other 12 were enriched using the AmpliSeq custom panel (Thermo Fisher Scientific) and sequenced with an Ion Torrent S5 XL . Sequence reads were aligned to the Human Reference Genome (NCBI build GRCh37) using Burrows-Wheeler Aligner (BWA) 0.7.12; duplicated reads were marked using by Picard Tools v1.130; local-realignment, base quality recalibration, and variant calling were performed using the Genome Analysis ToolKit  v3.4.0; and variant annotation and effect predictions were performed using SnpEff v4.1g.The number of candidate variants was filtered and prioritized using a four-step strategy. Initially, we included variants over 10× depth of coverage. Based on HCM prevalence, the minor allele frequency (MAF) below 5% in the Genome Aggregation Database (gnomAD) or Korean Reference Genome Database (KRGDB) were included ,15. The Candidate variants were interpreted using the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) . These gBaseline demographic and clinical data included age, sex, cardiovascular risk factors such as presence of hypertension, diabetes mellitus or smoking history, and clinical presentations. Patients were evaluated for first-degree familial history of HCM or SCD. Dyspnea was categorized with New York Heart Association (NYHA) functional classification. Additionally, 24-h Electrocardiography (ECG) monitoring and a symptom-limited treadmill test were performed to identify the risk of SCD. Abnormal exercise blood pressure (BP) responses were defined as follows: (i) increase in systolic BP (sBP) < 20 mmHg during or after exercise; (ii) decrease in sBP < 20 mmHg during or after exercise, without an initial increase in sBP; (iii) decrease in sBP ≥ 20 mmHg during exercise after initial rise; or (iv) an initial increase in sBP with a subsequent fall of sBP > 20 mm Hg compared with peak sBP ,24,25,26Standard two dimensional (2D) echocardiographic images were acquired with standard methods using a commercially available system . LV chamber size and wall thickness were measured by M-mode echocardiography using the 2005 American Society of Echocardiography (ASE) guideline and standards . LV ejecHCM were classified into four types according to the pattern and degree of LV hypertrophy under the following criteria: (i) septal hypertrophy alone; (ii) septal and apical hypertrophy; (iii) concentric hypertrophy involving the entire LV myocardium; and (iv) apical hypertrophy alone .®; Bayer Healthcare, Berlin, Germany) using a multi-shot, turbo field echo, breath-hold sequence with a phase-sensitive inversion recovery method. The inversion time (TI) was adjusted using a Look-Locker-based TI scout sequence to determine the proper TI to null normal myocardium.All study patients underwent CMR using an identical protocol on a 1.5T MR scanner  . After lAll imaging analysis was performed at the Samsung Medical Center CMR core laboratory with a dedicated workstation . The images were analyzed by two experienced CMR imaging specialists who were blinded to other data, and discrepancies in interpretation were reconciled during consensus reading. Endocardial and epicardial borders were traced manually on short-axis images at end-diastolic and end-systolic phases, respectively. Papillary muscles and LV trabeculae were excluded from the endocardium and included in the LV cavity volume. For quantification of fibrosis, LGE was defined as areas with a signal intensity > 6 standard deviations (SD) above the mean signal intensity of remote normal myocardium.LGE volume was calculated by summing areas with hyper-enhancement of all short-axis slices and expressed as a volumetric proportion of LGE to the total LV myocardium (% LV).Clinical outcomes were investigated by medical record review. Major adverse cardiac and cerebrovascular events (MACCE) were defined as all-cause death, sudden cardiac death, sustained ventricular tachycardia/ventricular fibrillation (VT/VF) with or without implantable cardioverter defibrillator (ICD) implantation, hospitalization due to worsening of heart failure (HF) at NYHA class III or IV, hospitalization due to new onset atrial fibrillation (AF), stroke, syncope, and acute myocardial infarction (AMI).t-test or Mann–Whitney test was performed to test for differences in continuous variables. All tests were 2-tailed, and a p value of less than 0.05 was considered significant. Pearson’s and Spearman’s correlation coefficients were calculated to determine the relationship between two variables. The probability of freedom-from-MACCE was estimated according to the Kaplan–Meier method and compared using the log-rank test. Data were analyzed using SPSS statistical software .Categorical variables are presented as frequencies and percentages. The Chi-square test or Fisher’s exact test was performed appropriately to compare categorical variables. Continuous variables are presented as mean ± SD to analyze the difference between numeric variables. The Student’s Patients were categorized into two groups according to identification of their involved variants: the detected group and the not-detected group. “Detected” was defined as the presence of at least one variant classified as PV, LPV, or VUS.n = 76) were male. Median follow-up duration was 47.3 months (range 2 to 106.3 months). Demographic and clinical characteristics of the study population are summarized in Between March 2013 and February 2017, a total of 100 unrelated consecutive subjects with HCM were included in this study. Among them, eight patients with absent or poor CMR image quality and three patients with non-compaction were excluded. A total of 89 patients were finally analyzed. Their mean age at diagnosis was 48.5 ± 10.5 years, and 85.4% (n = 51), including alterations of MYBPC3 (MIM: 160781) (43.6%), MYH7 (MIM: 160760) (18.2%), TNNI3 (MIM: 191044) (10.9%), MYH6 (MIM: 160710) (7.3%), and TNNT2 (MIM: 191045) (3.6%), in order of decreasing frequency. Thick filament genes were found to be 18.0%, intermediate filament genes were 27.0%, thin filament genes were 10.1%, and non-sarcomeric genes were 4.5%. The distribution of identified variants for each analyzed gene is shown in in MYBPC3, MYH7, TNNI3, and TPM1 genes  were found to carry at least one rare variant. PV or LPV were identified in 27 (30.3%) patients, and 28 VUSs were identified in 28 (31.5%) patients. Within the detected group, most of the changes mapped to sarcomeric loci .p = 0.040) and non-sustained ventricular tachycardia (NSVT) was more commonly present on 24-h ECG monitoring .In the detected group, palpitation was more frequent, . LV geometry such as LV wall hypertrophy, LV volumes, LV mass, and LV ejection fraction as assessed by both echocardiography and CMR were similar between the two groups. Echocardiographic and CMR findings are summarized in The average maximal LV wall thickness was 17.14 ± 4.0 mm, and mean LV mass index (LVMI) was 123.0 ± 37.8  was the most common morphological subtype, followed by septal and apical (34.8%), apical (16.9%), and concentric (5.6%) subtypes, and no statistical difference was detected in the distribution of morphological subtypes between the groups. p = 0.008, and 62.5%, p = 0.083, respectively). However, no differences were demonstrated in the presence of LV cavity obstruction or SAM between the detected and not-detected groups.LV cavity obstruction was found in 27 patients (30.3%), with LVOT obstruction in 16 patients, MV obstruction in 13 patients, and systolic anterior motion of mitral valve (SAM) in 16 patients (18.0%). In particular, LVOT obstruction and SAM were most commonly found in the septal type of HCM  and LVMI (p < 0.001) on 2D echocardiography.LGE on CMR was detected in 86.5% of patients with HCM, and the amount of LGE showed significant correlation with maximal wall thickness (p = 0.029). Accordingly, the volume percent of LGE was greater in the detected group .LGE was present more frequently in the detected group than in the not-detected group . Interventions such as ICD implantation, septal myectomy, and heart transplantation were more frequently performed in patients in the detected group, but the difference was not statistically significant . Distribution of MACCE and interventions are summarized in The incidence of composite events was higher in the detected group than in the not-detected group . Kaplan–Meier event-free survival curves for MACCE are shown in Overall event-free survivals were 94.4%, 88.6%, 78.1%, and 67.7% at 1, 3, 5, and 10 years, respectively. Notably, the not-detected group had better event-free survival than the detected group  and MYH7 (19.2%), followed by other variants of TNNI3 (10.9%), MYH6 (7.3%), and MYL3 (MIM: 160790) (3.6%). This distribution of variants according to gene location was similar to previous studies on sarcomeric variants, in which the prevalence of variants in MYBPC3 and MYH7 account for 75–80% of the genetic basis of HCM [Since the first genetic variant in HCM was documented, many additional variants have been identified over the last 30 years ,29,30. IYBPC3 43.% and MYHACTN2 (MIM: 102573), ANKRD1 (MIM: 609599), CALR3 (MIM: 611414), CAV3 (MIM: 601253), CRYAB (MIM: 123590), CSRP3 (MIM: 600824), DES (MIM: 125660), JPH2 (MIM: 605267), LDB3 (MIM: 605906), MYLK2 (MIM: 606566), MYOZ2 (MIM: 605602), MYPN (MIM: 608517), NEXN (MIM: 613121), PLN (MIM: 172405), TCAP (MIM: 604488), and VCL (MIM: 193065) [loci: ACTN2, ANKRD1, CAV3, CRYAB, CSRP3, JPH2, LDB3, MYLK2, MYOZ2, NEXN, PLN, TCAP, and VCL. Non-sarcomeric variants accounted for only 7.2% of the total detected variants, making it difficult to interpret their influence on disease phenotype. The low prevalence of non-sarcomeric variants in the current study is similar to a recent meta-analysis by Walsh et al. [Non-sarcomeric variants might be causal variants, but data confirming pathogenicity are lacking. There are few studies concerning non-sarcomeric variants, and reported locations include N MIM: 6121, PLN ( 193065) . In our N MIM: 6121, PLN (MYH7 variant compared to the variant negative group [Current risk estimation for sudden cardiac death for HCM is based on clinical features, including age, familial history of SCD, maximal wall thickness, left atrial diameter, maximal LVOT gradient, NSVT on 24-h ECG, and unexplained syncope . In the ve group .In our study, LV myocardial fibrosis on CMR was significantly more severe and prevalent in patients with detected variants. CMR has been reported to be superior to standard echocardiography in the detection of subtle evidence of disease and early information of myocardial deformation in patients with sarcomeric variants . MeanwhiIn the current study, patients with detected variants were at increased risk of occurrence of MACCE, and event-free survival was higher in the not-detected group compared to the detected group, accordingly. There have been varying reports on the prognostic significance of genotypic analysis in HCM, with some studies showing poor prognosis in sarcomeric variant-positive patients, including increased risk for cardiac death and progression to NYHA class III or IV HF and stroke ,38, whilIt is also interesting to note that, among the events on follow-up, hospitalization associated with new-onset atrial fibrillation was especially more frequent in the detected group. As atrial fibrillation is gaining more attention as a problem of morbidity and an initiating cause of heart failure and stroke in HCM ,46, moreThere are several limitations in this study. First, a relatively small number of patients were included and the frequency of adverse events was low, resulting in limited statistical power. In addition, the properties of the non-sarcomeric variants that we included in this study may have affected the clinical phenotype of the detected group along with the sarcomeric variants, complicating the interpretation of how genetic status influences clinical prognosis. Control studies are needed for a more rigorous evaluation of the genotype–phenotype association in HCM. Lastly, there were only 23 genes included in the gene panel, which suggests that selection bias could exist in the not-detected population.Nonetheless, our findings suggest that clinical presentation and prognosis are significantly worse in patients with HCM who possess pathogenic sarcomeric variants. As the risk stratification in HCM is highly problematic due to the genetic and clinical heterogeneity of the disease, incorporating both genotype and clinical phenotype analysis in assessment may be crucial in future studies of HCM and its consequences.


P‐wave dispersion (PWD) is believed to be caused by inhomogeneous atrial conduction. This statement, however, is based on limited little solid evidence. The aim of this study was to determine the relationship between atrial conduction and PWD by means of invasive electrophysiological studies.Cross‐sectional study in 153 patients with accessory pathways and atrioventricular node reentry tachycardia (AVNRT) undergoing an electrophysiological study. Different atrial conduction times were measured and correlated with PWD.P = .008) and ΔDCS‐PCS  are independent predictors of PWD. Performing the multivariate analysis for arrhythmic substrates, it is observed that only ΔDCS‐PCS continued to be an independent predictor of PWD. Analysis of the receiver operating characteristic curves showed that regardless of the types of arrhythmic substrates, PWD discriminates significantly, but moderately, to patients with P‐DCS and ΔDCS‐PCS ≥75 percentile.Only the interatrial (P‐DCS) and left intra‐atrial conduction times (ΔDCS‐PCS) showed a significant correlation with PWD, but this correlation was weak. Multivariate linear regression analysis determined that both P‐DCS  is considered by many to be an electrocardiographic parameter originating from regional differences in atrial conduction. The aim of this study was to determine the relationship between atrial conduction and PWD by means of invasive electrophysiological studies. Interatrial and intra left atrial conduction times were directly and significantly correlated with PWD, but weakly, and were independent predictors of PWD.  The cases were randomly selected from a study population of 286 patients with a clinical history of palpitations and a confirmed diagnosis of atrioventricular node reentry tachycardia (AVNRT) or accessory pathways, who underwent electrophysiological study and endocardial ablation at the service of Cardiac Electrophysiology of the Cardiovascular Hospital "Ernesto Guevara" from Santa Clara city, Cuba, between June 2017 and February 2020. The electrophysiological study was performed after at least 6‐8 hours fasting and without antiarrhythmic medication, at least for 5 or more half‐lives of the drug. All subjects were assessed by transthoracic echocardiography for exclusion of cardiac anomaly.Exclusion criteria were: (a) Had >2 electrocardiographic leads that did not allow measurement of the P wave and/or any channel of the atrial intracavity records with poor signal quality. (b) Permanent ventricular preexcitation (excluded because of the difficulty of measuring the P‐wave offset).2.1The following general variables were taken into account: age, sex, comorbidities, body weight, and occurrence of atrial fibrillation during the electrophysiological study. Atrial fibrillation was considered to be present if paroxysms lasting >10 seconds were documented.The electrocardiographic parameters studied included:Heart rate: measured from R‐R interval, at time of the P wave and electrophysiological measurements.Maximum P‐wave duration (PMax): P wave of greater duration in any of the 12 leads of the electrocardiogram.Minimum P‐wave duration: P wave of shortest duration in any of the 12 leads of the electrocardiogram.P‐wave dispersion (PWD): determined by subtracting the minimum P‐wave duration from the maximum P‐wave duration in any of the 12 standard leads of the electrocardiogram Figure .Up to three consecutive P waves were measured in each of 12 leads and averaged. Electrocardiographic records were obtained at a calibration of 20 mm/mV and a sweep speed of 50 mm/s. The onset of the P wave is defined as the point of first detectable upward or downward slope from the isoelectric line for positive or negative waveforms, respectively. Return to the isoelectric line is considered as the end of the P wave. If the start or end of the P wave was not clearly defined, that lead was excluded. All electrocardiographic measurements were expressed in milliseconds.The electrophysiological parameters studied included:P‐high right atrium (HRA) interval: Measured from the onset of the P wave to the onset of the earliest reproducible rapid deflection of the atrial electrogram in the high right atrium, recorded with the distal pair of a BIOTRONIK quadripolar catheter . This parameter was accepted as a measure of the intraright atrial conduction time from the sinus node to the respective recording area Figure .P‐HIS interval: Measured from the onset of the P wave to the onset of the earliest reproducible rapid deflection of the atrial electrogram in the His bundle recording. The local bipolar electrogram was obtained with the distal poles of a quadripolar BIOTRONIK catheter . This parameter was accepted as a measure of the intraright atrial conduction time from the sinus node to the respective recording area Figure .P‐proximal coronary sinus (P‐PCS) interval: Measured from the onset of the P wave to the onset of the earliest reproducible rapid deflection of the atrial electrogram recorded from the proximal poles  of a decapolar catheter (BIOTRONIK) positioned into the coronary sinus to the left lateral portion of the mitral ring . This parameter was accepted as a measure of the intraright atrial conduction time from the sinus node to the respective recording area Figure .P‐distal coronary sinus (P‐DCS) interval: Measured from the onset of the P wave to the onset of earliest reproducible rapid deflection of the atrial electrogram recorded from the distal poles of a decapolar catheter (BIOTRONIK) positioned into the coronary sinus around the left lateral portion of the mitral ring . This parameter was accepted as a measure of interatrial conduction time Figure .ΔHIS‐HRA: calculated as the difference of P‐HIS − P‐HRA. It was a way of quantifying the activation difference between two regions within the right atrium.ΔPCS‐HRA: calculated as the difference of P‐PCS − P‐HRA. It was a way of quantifying the activation difference between two regions within the right atrium.ΔPCS‐HIS: calculated as the difference of P‐PCS − P‐HIS. It was a way of quantifying the activation difference between two regions within the right atrium.ΔDCS‐PCS: calculated as the difference of P‐DCS − P‐PCS. It was considered a measure of intraleft atrial conduction time.Morphology of the electrograms: refers to whether these were biphasic, triphasic, quadriphasic, pentaphasic, or hexaphasic. Morphology was determined for each local electrogram .Electrogram duration: refers to the duration of each local electrogram  measured from onset to offset.The measurements were performed in sinus rhythm by an experienced electrophysiologist, avoiding interobserver error, blinded from the data of each case and with the patient awake, without the effect of anesthetics or isoprenaline, and before the application of radiofrequency, on an EP TRACER (CardioTek) multichannel polygraph. Electrophysiological measurements were made manually using electronic calipers at sweep speed of 300 mm/s, and expressed in milliseconds. The catheter positions were monitored using biplane fluoroscopy with standard right anterior oblique and left anterior oblique views.The diagnosis of atrioventricular node reentry tachycardia (AVNRT) was confirmed by inducing tachycardia in all cases. The presence of accessory pathways was demonstrated by revealing abnormal retrograde conduction through the pathway through stimulation from the right apex ventricle, and in most cases, orthodromic tachycardia could be induced.The echocardiographics parameters studied were: interventricular septal thickness in diastole; left atrium size (anteroposterior); left ventricular internal diameter in diastole; left ventricular posterior wall thickness in diastole; right atrium size (minor axis), measured according to current recommendations from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.2.2t test was used, for variables with nonparametric distribution the Mann‐Whitney U test was used. The verification of the normal distribution of the data or its absence was determined by the Kolmogorov‐Smirnov test. The comparison of categorical variables was carried out using the chi square test. For the correlations, the Pearson's correlation coefficient was determined, except when the morphology of the electrograms  was included, estimating in this case the Spearman correlation coefficient. Multivariate analysis was performed using multiple linear regression. The discriminant capacity of the PWD to find cases with values ≥75 percentile in electrophysiological parameters was determined using ROC (Receiver Operating Characteristic) curves. Values of P < .05 were set as the minimum level of statistical significance throughout the study.For all analyses, commercially available computer software  was used. For the comparison of variables with parametric distribution the Student's 2.3All patients included in the study gave their informed consent to carry out the electrophysiological study and radiofrequency endocavity ablation. The local ethics committee approved this study.3General data shows that patients with AVNRT were older than those with accessory pathways. The prevalence of male sex and atrial fibrillation was higher in cases with accessory pathways. High blood pressure was more prevalent in the AVNRT group. No significant differences were found in diabetes mellitus, heart rate, body weight or echocardiographic parameters Table .The Pmax and PWD showed average values that are higher than the normal cutoff points for these variables but with no significant differences between patients with AVNRT and accessory pathways Table .R2 = 0.071; 7.1%) and ΔDCS‐PCS  weakly explain PWD.Of the 16 variables used to assess atrial conduction only P‐DCS and ΔDCS‐PCS showed a significant correlation with PWD. This correlation was direct and weak Figure . The lowIn the multivariable linear regression analysis, ΔDCS‐PCS and P‐DCS were independent predictors of PWD controlling for potential confounders such as age, arterial hypertension, atrial fibrillation during the electrophysiological study, the types of arrhythmic substrates (AVNRT and accessory pathways) and the atrial size Table . PerformThe ROC analysis showed that regardless of the types of arrhythmic substrates, PWD discriminates patients with P‐DCS  and ΔDCS‐PCS  ≥75 percentile Figure .When the analysis by arrhythmic substrates was performed, it was found that in the cases with AVNRT, the PWD had discriminant power to find cases with ΔDCS‐PCS ≥75 percentile , but not with P‐DCS intervals ≥75 percentile Figure . In the 4The mean values of PWD and Pmax are increased in our series with respect to the reported upper cutoff points for these parameters. Analyzing 295 patients randomly selected from the original cohort of the Framingham study with a wide age range and without cardiovascular disease or hypertension, diabetes mellitus or obesity, Magnani et alPWD is considered by many to be an electrocardiographic parameter originating from regional differences in atrial conduction, but the evidence supporting such an assertion derives primarily from echocardiographic techniques  that are approximations of true electrophysiological measurements, although such techniques have been validated.r = .429; P < .001) with the interatrial electromechanical delay estimated by tissue Doppler. In hypertensive patients with no history of atrial fibrillation, PWD was found to be an independent predictor of intraleft atrial conduction time  and interatrial conduction time  measured by tissue Doppler, in addition to showing direct and significant correlations with interatrial (r = .722), intraright (r = .643) and intraleft (r = .722) atrial conduction times.r = .653; P = .001),r = .72; P < .001).r = .46; P < .001) and intra‐atrial  electromechanical delay have been shown to correlate directly and significantly.r = .54; P < .01) in patients with polycystic ovary syndrome.Demir et alr = .45, P < .00001) with the quantification of the electromechanical delay of the left atrium, but this finding was not found in the control group. In addition, higher values of PWD and of the interatrial, right atrial and left atrial electromechanical delay times measured by 2D strain rate have been found in nondipper hypertensive patients compared to dipper.Badran et alThe previous studies show that there is a relationship between PWD and atrial conduction, which coincides with our results that also demonstrate this relationship, which occurs mainly with electrophysiological parameters that involve the left atrium. Although we analyzed 16 variables that evaluate atrial conduction, only P‐DCS and ΔDCS‐PCS are related to PWD, and predict it. These data suggest that PWD may be preferentially explained by changes in left atrial conduction and/or interatrial conduction. PWD was better related to ΔDCS‐PCS than P‐DCS, a parameter that constitutes a measure of left intraatrial conduction time. No conduction parameters confined to the right atrium had any effect on PWD.Previous research has found moderate to strong relationships between atrial conduction and PWD.5Interatrial and intraleft atrial conduction times were directly and significantly correlated with PWD, but weakly, and were independent predictors of PWD. In general, PWD correctly discriminates patients with high values in interatrial and intraleft atrial conduction times, but moderately. This is maintained in cases with accessory pathways, but in patients with AVNRT it only does so for intraleft atrial conduction times. Interatrial and intraleft atrial conduction times weakly explains PWD.The authors declare no conflict of interest for this article.


Permanent His-bundle pacing (HBP) is a true physiological form of ventricular pacing that has been shown in recent years to be both safe and feasible in clinical practice. However, there are limited data about its long-term performance, especially when compared with both right ventricular and biventricular pacing. In this article, we present a thought-provoking case study that illustrates the usefulness of permanent HBP in a patient with long-standing complete infranodal heart block and progressive heart failure, and discuss the current literature highlighting the evidence behind this form of permanent pacing. Here, we present a case study to illustrate the usefulness of HBP from a clinical perspective, followed by a review of the current literature discussing this form of permanent pacing.Right ventricular pacing (RVP) has been the standard of care in cardiac pacing for decades. However, a growing body of evidence has shown that RVP leads to dyssyn-chronous activation of the ventricles, resulting in adverse clinical outcomes such as increased incidence of heart failure (HF), atrial fibrillation (AF), mitral regurgitation, and mortality.. She had a right bundle branch block (RBBB) pattern escape rhythm, and was monitored for 48 hours on telemetry prior to revising her lead as she was hemo-dynamically stable. Also, she had been developing progressive HF symptoms over the past three years, along with a cardiomyopathy. She was diagnosed with right breast cancer in 2012 and was treated with doxorubicin. An echocardiogram in early 2015 demonstrated that her LV ejection fraction had decreased to 35%. It was unclear if her cardiomyopathy may have been related to chemotherapy, or was due to pacing-induced cardiomyopathy.Our patient is a 76-year-old woman with a past medical history of complete infranodal heart block diagnosed in the year 2000 with an electrophysiology study. She underwent the implantation of a dual-chamber pacemaker, and in 2003 she presented with sudden cardiac arrest (in the setting of preserved left ventricular (LV) systolic function) that was attributed to long QT syndrome. She was upgraded to a dual-chamber implantable cardioverter-defibrillator (ICD) at that time. She did well for 12 years, until she presented in late September 2015 with RV lead fracture and total failure to capture. She was lightheaded with activity, and her electrocardiogram (ECG) demonstrated marked bradycardia and complete heart block . During the proce-coil was in the middle cardiac vein. Additionally, she had dure, a temporary pacing wire was initially placed from suboptimal coronary venous branches and LV pacing the right femoral vein. It was discovered that her old RV requiring very high outputs (4.5 V at 1 ms), resulting in left phrenic nerve capture. Her options included surgical placement of an epicardial LV lead or attempts at HBP. However, it was unclear whether HBP would help recruit conduction in a patient who had had long-standing infranodal block with no atrioventricular (AV) conduction for the past 15 years.Given this patient’s complete heart block and worsening HF symptoms in the setting of a wide QRS RVP morphology, it was elected to upgrade her pacing system to a biventricular (BiV) ICD 5 Primary outcome  occurred in 45.8% of CRT patients and 55.6% of RV-paced subjects. Although better outcomes were demonstrated with BiVP than with RVP, it should be noted that patients with BiVP did not fare well either with regards to high event rates. Also, the primary end-point was driven by a change in LV end-systolic volume index. LV stimulation can be achieved in patients with left bundle branch block (LBBB) and complete heart block by recruiting the native conduction system with HBP. Barba-Pinchardo et al. attempted HBP in candidates for CRT in whom LV stimulation via the coronary sinus was not achievable, and found that direct His-bundle pacing (DHBP) corrected conduction in 13 of the 16 patients (81%) selected.6 In nine patients, DHBP successfully resulted in definitive resynchronization with improvement in functional class and parameters of LV function. Similarly, Lustgarten et al. assessed DHBP in patients with standard indications for biventricular pacing, and noted that it resulted in a significantly narrower QRS as compared with native conduction and biventricular pacing .7 This finding of electrical resynchronization was revisited by the same group of researchers again in a crossover comparison study assessing the feasibility of, and the clinical response to, permanent HBP as an alternative to BiVP in CRT-indicated patients. It was found that HBP can elicit 6-month CRT clinical responses similar to those of BiVP.8 Therefore, HBP can be considered an alternative to CRT if the traditional method of LV resynchronization via the coronary sinus fails. Vijayaraman et al. demonstrated in a large series of patients that HBP can be successfully achieved in both nodal block and infranodal block contexts. The investigators were able to demonstrate chronic stable pacing thresholds with both selective and non-selective HBP  in both AV nodal block and infranodal block patients, with minimal use of a backup RV pacing lead.9 Two types of responses can be seen with permanent HBP. SHBP occurs when the pacing stimulus to QRS onset is equal to the intrinsic HV interval with no fusion with local myocardium at the pacing output selected . NSHBP is defined as His-bundle capture with local myocardial fusion at the pacing output selected, and with the pacing stimulus to QRS onset being shorter than the intrinsic HV interval.The BLOCK HF trial, reported by Curtis and colleagues, examined the efficacy of CRT in HF patients with high-grade AV block over RVP..10 In this case, NSHBP was achieved via reducing pacing output from 5 V at 1 ms to 1 V at 1 ms . The His-bundle lead was connected into the LV port, and the RV lead  was connected into the RV port . LV to RV offset was programmed to 80 ms to promote HBP while minimizing the possible effects of fusion . Her old RV ICD lead was capped. The patient reported significant improvement in her symptoms (from NYHA class II to class I), and a repeat cardiac electrocardiogram 3 months later demonstrated normalization of her LV systolic function. Owing to the rapid reversal of LV systolic function, it was felt that her cardiomyopathy was primarily related to pacing-induced cardiomyopathy.11 Seventeen months later, she remains symptom-free, with no functional limitations. Pacing thresholds remain at 0.5 V at 1 ms with SHBP and no fusion, and NSHBP at outputs > 1 Vat 1 ms.It was elected to try HBP in this patient and, if it failed, the decision was made that she would be referred for surgical LV lead placement instead. His-bundle mapping was performed using a C315 His sheath and a 3830 pacing lead . In a unipolar configuration, clear His-bundle electrograms were recorded, demonstrating complete infranodal block and, once the lead was screwed into place, His-bundle current of injury 12 Scherlag and colleagues published their technique for recording His-bundle activity in humans in 1969.13 Functional longitudinal dissociation of the His-bundle was first proposed by Kaufman and Rothberger in 1919.14 Predestined fibers within the His bundle selectively conducted to the individual bundle branches, and these fibers originated within the proximal portions of the common bundle. This concept was demonstrated in humans by Narula in 1977.15 Patients with LBBB and baseline prolonged HV intervals were paced slightly distal to the proximal His-bundle, resulting in a narrowing of the QRS.The bundle of His is an important part of the conduction system that transmits impulses from the AV node to the ventricles. The AV node and the bundle of His constitute the AV junction. The bundle of His then branches into the right and left bundle branches, which divide into fascicles, giving rise to the Purkinje fibers. These specialized cardiac myocytes are named after the Swiss anatomist and cardiologist Wilhem His, Jr., who first discovered them in 1893.16 Following AV nodal ablation, HBP was successful in 12 of these patients, and resulted in an improvement in LV function in almost all of the studied patients. Since then, several investigators around the world have published their own experiences with permanent HBP, and the field has gradually progressed since then.In 2000, Deshmukh et al. demonstrated the first clinical trial with permanent HBP in a group of 18 patients with a history of chronic AF, dilated cardiomyopathy and normal ventricular activation.17 HBP has been shown to correct bundle branch blocks in the presence of complete AV block (considered to be infra-Hisian heart block), resulting in a normal QRS complex. In addition to normalizing bundle branch blocks, several other studies considered the hemodynamic and clinical benefits of HBP over right ventricular apical pacing (RVAP). Kronborg et al. showed that stable direct HBP or para-Hisian pacing is feasible in 85% of patients with narrow QRS and high-grade AV block, and leads to normalization of the ventricular activation pattern with statistically significantly less LV dyssynchrony as compared with RVP.18 Catanzariti et al. also examined HBP effects acutely and found that it prevents inter- and intraventricular asynchrony either on the same day as the procedure, or on the following day.19 These beneficial effects of improved ventricular contractile performance persisted after 2 years of follow-up. This reduced asynchronous pacing induced LV ejection fraction depression and mitral regurgitation in comparison with RVAP.20Barba-Pichardo et al. attempted HBP in selected patients referred for pacemaker implantation, and found that HBP corrected conduction abnormalities in 73% of patients .21 In a study by Pastore et al., 37 patients with normal cardiac function had permanent HBP with an apical RV backup lead, and underwent 3 months of HBP followed by 3 months of RVAP.22 Switching from HBP to RVAP resulted in a significant increase in systolic and diastolic electromechanical delays and consequent inter- and intraventricular dyssynchrony. Finally, one of the largest studies on HBP was published by Sharma et al., and its findings supported the clinical benefits of HBP previously examined in smaller studies; namely, HF hospitalization was reduced in the HBP group compared with the RVP group, with no difference in mortality noted between the two groups.23 However, it should be noted that this study was not powered to detect mortality benefit. Selective studies comparing HBP and RV pacing are summarized in Table 1.Similarly, Zanon et al. conducted a crossover mid-term study in which patients underwent 3 months of DHBP, and then three months of RVAP. Myocardial perfusion was found to be significantly better during DHBP than during RVAP.24 Furthermore, Sharma et al. found that permanent HBP without a mapping catheter or a backup RV lead was successfully achieved in 80% of patients.25 Pacing thresholds were higher and fluoroscopy times were similar in these individuals to those of the RVP group. Furthermore, no increased risks were noted when the procedure was performed by experienced operators. The higher pacing threshold is relatively problematic depending on the type of HBP that is pursued. As described earlier, SHBP and SHHBP can be encountered. Given that NSHBP is capturing myocardium in addition to the His-bundle, it may be preferred in patients with complete heart block, where a backup RV lead is not utilized. NSHBP has also been associated with lower pacing thresholds than SHBP. No statistically significant differences in clinical outcomes were noted between the two types of pacing in the study conducted by Catanzariti et al., but there still needs to be further investigation completed via larger randomized controlled trials prior to drawing any final conclusions.19When it comes to the safety of HBP, Vijayaraman et al. noted that catheter manipulation during HBP caused injury to the His-bundle in 7.8% of patients undergoing permanent HBP with resultant RBBB, in most cases. However, complete spontaneous resolution of the RBBB occurred in most cases, and RBBB itself persisted in 2.5% of the cases .Several issues unique to HBP also need to be considered carefully. These include both undersensing and over-sensing issues, local atrial capture from HBP, elevated pacing thresholds, and increased battery drain because of inherently higher pacing thresholds than RVP. With improvements in lead design and pacemaker technology relating to permanent HBP, it is likely that we will soon have better device systems that successfully address all of these issues.Although the observations initially made by Deshmukh et al. represent an important step towards achieving true physiological pacing, the adoption of HBP has been slow due to perceptions that permanent HBP is technically challenging, and may not be possible in heart block and bundle branch block patients. However, in recent years, these myths have been broken, and the electrophysiology community has begun to realize the true potential of this form of pacing. With continued technological advances and the demonstration of clinical benefits through large-scale randomized trials, permanent HBP is likely to find an important role in permanent cardiac pacing.


The mechanism of low back and leg pain involves mixed neuropathic and nociceptive components. Spinal neuropathic pain is related to increased levels of inflammatory cytokines and disrupted and increased permeability of the blood–spinal cord barrier, originally composed of tight junctions of capillary endothelial cells surrounded by lamina. The phase angle (PA) estimates cell membrane integrity using bioelectrical impedance analysis. We evaluated the predictive value of the PA for analgesic efficacy in lumbosacral transforaminal block. We retrospectively collected data from 120 patients receiving transforaminal blocks for lumbosacral radicular pain and assessed the PA before and 5 min following the block. Responders (group R) and non-responders (group N) were defined by ≥50% and <50% pain reduction, respectively, on a numerical rating scale, 30 min following the block; clinical data and the PA were compared. Among the 109 included patients, 50 (45.9%) and 59 (54.1%) had ≥50% and <50% pain reduction, respectively. In group N, the PA change ratio showed 88.1% specificity, 32.0% sensitivity, and 62.4% accuracy; a ratio of <0.087 at 5 min following the block predicted non-response. A PA change ratio of <0.087 at 5 min following lumbar transforaminal blocks predicted non-responders with high specificity. Lumbar epidural injection of local anesthetics and steroids is one of the methods of managing low back and radicular pain . As one http://cris.nih.go.kr/cris/index.jsp, KCT0005642). The need for individual consent was waived by the institutional review board, as this was a retrospective study involving medical record review. Among the 120 patients assessed for eligibility, 11 were excluded due to zero PA values at T0 or T5, which led to zero PA change ratios on calculation; thus, the data of 109 patients were analyzed. We defined responders, or group R, as patients who showed a reduction of ≥50% on a numerical rating scale  for pain at T30, and non-responders, or group N, as those who showed a reduction of less than 50% at T30  a primary diagnosis of lower back pain radiating to the lower limbs, (b) availability of a cross-sectional imaging study (either CT (computed tomography) or MRI (magnetic resonance imaging)) of the lumbosacral spine in patients diagnosed with spinal stenosis or herniated nucleus pulposus. This study was approved by our departmental ethics committee (SMC 2020-09-170) and registered with CRIS  was injected to confirm that the point was well placed in the epidural space. After confirming that the contrast had spread throughout the epidural space, a total volume of 5 mL  was infused. Following the procedure, patients were observed for any adverse effects. Whole-body BIA measurement was assessed using the Inbody S10 . Following the standardized protocol, electrodes were placed on the bilateral hands and bare feet for 2 min [All procedures were performed under fluoroscopic guidance and were standardized. The lesion level for transforaminal injections was selected based on clinical manifestations, physical examination, and review of imaging studies. Lesion severity was categorized at any of three different levels  by reviewing the imaging data. Exclusion criteria included any history of lumbosacral surgery, lumbosacral neuroplasty, neoplastic disease, or peripheral vascular disease. Patients were placed in the prone position, and anteroposterior and lateral view images were obtained using a C-arm  to ensure proper site of entry. Following aseptic preparation and application of 1% lidocaine, a 23-gauge Tuohy needle  was inserted into the skin surface over the upper quadrant of the target foramen. Aspirations were routinely performed for assessing the presence of blood or cerebrospinal fluid. When negative for aspirate, 0.5–2 mL of contrast medium  or numbers (proportion), as appropriate. Demographic data for the two groups were compared using a Chi-square test, t-test, or Fisher’s exact test. To minimize individual variance in PA absolute values, we calculated the PA change ratio (PA at T5 − PA at T0/PA at T0). Temperature change (temperature at T5 − temperature at T0) was calculated. The PA change ratio was compared using the Wilcoxon rank sum test. The cut-off value of the PA change ratio was analyzed using Youden’s index. A p-value less than 0.05 was considered statistically significant.All data were analyzed using SAS 9.4 . Data are expressed as the mean ± standard deviation  (p < 0.001)  . The PA ctively) . PA chanctively) . In grouctively) . Pain se< 0.001) . Cold se< 0.001) . None ofIn the present study, we found that a PA change ratio of <0.087 showed high specificity for identifying non-responders following transforaminal block. We speculate that low PA change ratios are attributable to lesser relief of inflammation and/or swelling of the affected nerve roots and are related to non-improvement of cellularity and non-response after epidural injections. Excessive nerve root swelling is a known risk factor for persistent or recurrent radiating pain after lumbar surgery . It leadLumbosacral radicular pain is caused by irritation or compression of the affected nerve root . It is cIn this study, we aimed to evaluate whether the PA has predictive value for analgesic efficacy after lumbosacral transforaminal blocks. There was no significant difference in the PA values between the groups. However, the PA change ratio showed 88.1% specificity in non-responders. The cut-off value of the PA change ratio was <0.087 at 5 min following the block. We followed up the PA at 5 min after the block because the perfusion index change ratio was significant at that time point, and it correlated with pain relief . We suspWe observed that the PA change ratio has high specificity in identifying non-responders after lumbar transforaminal blocks. Further prospective controlled studies are needed to determine whether the PA provides superior diagnostic value in other forms of acute and chronic pain treatment.


Max), integral of kinetic energy (iK), and maximal power (PMax) can be computed as scalar parameters, both in linear and rotational dimensions. Standard echocardiography and 2-dimensional speckle tracking imaging echocardiography were performed on 34 healthy volunteers who were infused with increasing doses of dobutamine (5–10–20 μg/kg/min). Linear VMax of BCG predicts the rates of left ventricular (LV) twisting and untwisting (both p < 0.0001). The linear PMax of both SCG and BCG and the linear iK of BCG are the best predictors of the LV ejection fraction (LVEF) (p < 0.0001). This result is further confirmed by mathematical models combining the metrics from SCG and BCG signals with heart rate, in which both linear PMax and iK strongly correlate with LVEF . In this setting of enhanced inotropism, the linear VMax of BCG, rather than the VMax of SCG, is the metric which best explains the LV twist mechanics, in particular the rates of twisting and untwisting. PMax and iK metrics are strongly associated with the LVEF and account for 50% of the variance of the LVEF.Ballistocardiography (BCG) and Seismocardiography (SCG) assess the vibrations produced by cardiac contraction and blood flow, respectively, by means of micro-accelerometers and micro-gyroscopes. From the BCG and SCG signals, maximal velocities (V Modern BCG and SCG can measure linear and rotational velocities and accelerations of blood stream and cardiac mass using linear and rotational channels, respectively, and in three cardinal axes using three-axial sensors 6. In such a way, a multi-dimensional assessment of blood flow and cardiac function can be obtained with 12 degrees-of-freedom (DOF). Additionally, from the BCG and SCG waveforms, linear and rotational kinetic energy (K), its temporal integral (iK), maximal power (PMax), displacements (D) and maximal velocities (VMax) can be computed for each contractile cycle using specific algorithms based on Newtonian equation2.Under the assumption that the cardiovascular system equates a Newtonian system, the propulsion of blood mass into the main vessels at each cardiac contraction makes the body’s center of mass move rhythmically at each heartbeat, with a strength equal in magnitude but opposite in direction to the one of the ejected blood. Contraction of myocardial muscle, opening and closure of heart valves, blood flowing into cardiac chambers generate micro movements that are transmitted to the chest surface as low-frequency vibratory phenomena. Seismocardiography (SCG) and ballistocardiography (BCG) record the micro-vibrations generated rhythmically as a consequence of the movements of cardiac mass and blood in the major vessels, respectively, with micro-accelerometers and gyroscopes placed on the body surfaceiK and PMax secured from BCG and SCG signals are well correlated to stroke volume (SV) and cardiac output (CO)2; the peak of maximum energy well represents myocardial contractility expressed as dP/dtmax in animal models7; BCG and SCG signals provide information on myocardial dysfunction after an acute coronary syndrome9 and can assess the clinical status of patients with heart failure10.A growing number of evidences provide the signals recorded with BCG and SCG as good indicators of myocardial function and dysfunction. Metrics of 13. LV twist can robustly estimate myocardial function, expressed as LVEF16 in some studies or dP/dtmax in others20. LV untwisting rate provides the atrio-ventricular pressure gradients which assist cardiac chambers to fill during the early phase of relaxation22.Left ventricular (LV) twist is the rotational movement of the LV along its longitudinal axis and results from the net difference between the torsional angles of the apical and basal rotations23.Recently, cardiac rotations have been evaluated using gyroscopes in animal models and results seem promising on the feasibility of measuring LV twist with this techniqueWhether velocity and acceleration signals recorded with modern BCG and SCG can reliably estimate cardiac rotations in humans is not known.iK and PMax obtained from the BCG and SCG signals.The aims of the present study were: (1) to examine the relationships between LV twist mechanics with displacements and velocities metrics computed from the BCG and SCG signals; (2) to estimate myocardial function expressed as LVEF through the metrics of NCT03107352 on ClinicalTrials.gov). The protocol has been approved by the local Ethics Committee and subjects gave written informed consent before being enrolled. Each subject received increasing doses of dobutamine (5–10–20 µg/kg/min) or normal saline as placebo (5–10–20 µg/kg/min). Allocation to the group receiving dobutamine first (group 1) or placebo first (group 2) was randomly determined. For each session, echocardiographic study was performed before any drug infusion (referred to as baseline) and during infusion of 5–10–20 µg/kg/min of dobutamine and placebo. According to the aims previously listed, only the dobutamine arm was considered in the present study for analysis and interpretation of results. Because of obvious changes in cardiac echocardiography following dobutamine infusion, investigators were not blinded for data analysis. Details about the protocol can be found in our previous work2.The present study is based on a previous randomized, double-blind, placebo-control, cross-over study in 34 healthy volunteers aged between 18 and 50 years  and its temporal integral (LVOT VTI) were measured25.Standard echocardiography was performed with the GE VIVID E95 by an expert cardiologist in non-invasive imaging. Two dimensional images of the LV were obtained from the apical 2-, 3- and 4- chamber views along the parasternal long-axis. LV volumes and LVEF were calculated by Simpson biplane methods. Stroke volume (SV), cardiac output (CO), left ventricle ejection fraction (LVEF), LV outflow tract velocity . The LV endocardial border was manually traced at the basal and apical levels and the speckle tracking thickness of LV wall was automatically selected, as previously described15. The width of the selected region was accommodated to the LV wall as needed.For the 2D-STI speckle tracking study, parasternal basal and apical short axis views were obtained for the measurement of basal and apical rotations. The basal level was defined from the tip of mitral valve, while the apical level was defined as the level of LV cavity without papillary muscles13.By convention, counterclockwise rotations are expressed with positive values and clockwise rotations with negative values, looking from the apex13.LV twist is defined as the net difference of angular displacements between the basal and apical rotations along the LV longitudinal axisFor the analysis of apical and basal rotation/rotational rates, LV twist and LV twisting/untwisting rates, short-axis views were considered. Data plots were then exported to Excel version 16 (Microsoft) and the peak of LV twist as well as angular rates were calculated.The highest positive peak of the LV strain curve has been considered as the maximal angular displacement occurring during systole and is expressed in °. Rotational rates have been obtained as the temporal derivation of LV twist according to the following equation:Rates are expressed in °/s. The positive peak of the rate of LV twist is termed “LV twisting rate”, the negative peak “LV untwisting rate”.Figure A wearable device with two modules, one for the BCG acquisition and one for the SCG acquisition, was used. Each module contains a microelectromechanical systems (MEMS) accelerometer and gyroscope sensor  and is attached to the body with standard sticky gel electrodes. The acceleration and angular rates of the sensor were set to ± 2 g and ± 250 dps, respectively with a resolution of 0.061 mg/LSB and 4.375 mdps/LSB and an RMS noise of 80 μg/√Hz and 4 mdps/√Hz with an output bandwidth of 416 Hz. The device is controlled with a smartphone or a tablet connected via Bluetooth and collects a one-lead ECG at 200 Hz  together with 3-DOF linear (LIN) accelerations and 3-DOF rotational (ROT) angular velocities from both the BCG module and the SCG module. In brief, a total of 12-DOF linear acceleration and angular velocity signals are recorded at 50 Hz. A 25 Hz hardware low-pass filter is applied.x is the lateral (left-to-right) axis, y is the longitudinal  axis and z is the anteroposterior  axis; for SCG signals, the z-axis points in the opposite direction  and the x-axis right-to-left.The standard nomenclature was used: for BCG signals, The BCG module was placed in the lumbar lordosis curve, between the second and the third lumbar vertebrae, close to the subject’s center of mass. The SCG module was placed on the manubrium of the sternum below the clavicle where the great vessels emerge from the heart.28. Linear kinetic energy (KLin) and rotational kinetic energy (KRot) of BCG and SCG are shown on Fig. A 90-s record was acquired after each echocardiographic study using a tablet remotely connected to the device via Bluetooth and data were sent to the main server for further processing. Data were subsequently exported and processed offline using a specific toolbox written in MATLAB . Further details describing this methodology can be found in previous publicationsiK) and the maximal power (PMax) for both linear and rotational channels  f f\documeRot is the rotational kinetic energy, Rot is the rotational power.For the rotational components, the scalar metrics are calculated according to Eqs.  to 6).4.46).4\doLin and KRot over the cardiac cycle (CC) was computed for both SCG and BCG as in Eqs. ..Lin and Max for both SCG and BCG according to Eqs. Max for bThe metrics of interest described so far are computed using a specific toolbox written in MATLAB .x, y, z). From these, the maximum of velocity (VMax) and the maximum of displacement (DMax) were computed  of the subject.From the BCG and SCG accelerations signals, linear and angular velocities, as well as linear and angular displacements were computed by integration and twofold integration, respectively. Velocities and displacements signals were therefore obtained for each degree of freedom in the orthogonal axis  on Windows. GRAPHPAD PRISM version 5.01 and MATLAB (MATHWORKS INC) were used for graphing figures on Windows.Normality of data distribution was assessed using the Kolmogorov–Smirnov test.One-way parametric or non-parametric ANOVA were applied according to data distribution.The Spearman’s rank correlation was used to assess association between variables. Correlation coefficients range from − 1 to + 1 where 0 indicates no monotonic association and a value of 1 a perfect monotonically decreasing (− 1) or increasing (+ 1) relationship.Max and iK.Generalized linear model was used to predict LV twisting and untwisting rates from velocity metrics and to predict the LVEF from metrics of PP-values < 0.05 were considered statistically significant.Intra-observer variability was examined in 35 randomly selected echocardiographic images and expressed as the intraclass correlation coefficient (ICC) between the measurements of the two readings as well as their mean (± SD) difference.Max, VMax, iK and PMax. 47.1% of the participants were men, the mean age was 25 years (± 1.72), the mean BMI was 22.48 kg/m2 (± 2.07), while the mean SV, CO, and LVEF at baseline were respectively 62.78 ml (± 13.79), 4.32 l/min (± 0.1) and 63.3% (± 4.5).Baseline characteristics, echocardiographic parameters and SCG/BCG parameters of the entire study population are presented in Table Maximum of linear displacements and angular displacements computed with SCG and BCG have been associated with the LV twist. Results are shown in Table Max from BCG signal both in the linear and in the rotational dimension  and with DMax from the SCG signal in the rotational dimension only , but the strength of association is very week.LV twist poorly correlated with displacements obtained from SCG and BCG signals. Specifically, it correlates with DMaximum of velocities computed with SCG and BCG have been associated with rates of LV twisting and untwisting. Results are shown in Table Max of the SCG  and to VMax of the BCG . LV untwisting rate correlates as well with VMax of the SCG  and with VMax of the BCG .LV twisting rate is related to VMax of the BCG is the best predictor of the LV twisting and untwisting rates, rather than the VMax of the SCG , iK is considered as the comparative factor, the strength of association is lost to some extent, both for the SCG and the BCG .LVEF is associated with all the parameters derived from the BCG and SCG. The strongest association is observed with the metrics derived from the SCG, specifically iKRot; R = 0.46 for The association is slightly weaker when the same metrics are computed from the rotational channel of the BCG , by 1.3% for one unit increase of the linear PMax of the SCG (J/s/m2), by 4.35% for one unit increase of the linear iK of the BCG (µJ s/m2).The linear PMax and iK are the metric which strongest correlates with LVEF , in line with the results from the generalized linear model , thus accounting for 49% of the variance of the LVEF. While this model is of interest, it was empirically constructed and its main contribution is not to be used as it is but rather to highlight that more advanced statistical techniques, such as machine learning algorithms, could allow to build a function explaining LVEF changes on the basis of BCG and SCG linear and rotational channels.In our previous work, we introduced max is the maximal velocity of blood flow across the left ventricle outflow tract, and the temporal integral of LVOT V is the integrated velocity throughout a cardiac cycle (LVOT VTI)37; both are important echocardiographic parameters of cardiac systolic function and cardiac output46. We found that all the metrics computed from the SCG and the BCG are correlated with LVOT Vmax and LVOT VTI, but metrics of the BCG are better associated than the same metrics of the SCG. This difference between metrics of SCG and metrics of BCG can be explained through the different genesis of the signals. As explained above, while the SCG signal is the resultant of several combined cardiac phenomena, BCG signals are generated mainly by blood acceleration and deceleration into the aorta and its main branches47.LVOT V49, scalar parameters secured from BCG signals may prove useful in the detection of LV dysfunction in patients with cardiac diseases. Scalar metrics secured from SCG and BCG signals can also estimate the LVEF. This information complements the current knowledge on the SCG and BCG, by adding that metrics of iK can estimate not only the CO and SV2, thus providing information on the hemodynamic aspect of cardiovascular system, but can estimate as well the LVEF, thus providing information on the contractility status of the heart.The results of this investigation are of main importance since they shed further light on the physiological genesis of the SCG and BCG signals, enriching the current knowledges on the SCG and BCG. Indeed, we demonstrated that the twisting motion of the heart play a fundamental role in the genesis of the BCG signal but no in the one of the SCG. The BCG signal, specifically the linear velocity, can estimate rates of LV twisting and untwisting, thus providing significant information on the twisting motion of the heart. Since the LV twist is impaired early in a variety of cardiomyopathiesiK as a new parameter for myocardial contractility.Acknowledged that metrics of kinetic energy and velocities secured by the SCG and BCG signals seem promising in the monitoring of hemodynamic profile and cardiac contractility in healthy subjects, this technique may be extended to patients suffering from cardiovascular diseases, with the promise to remotely monitor their cardiovascular conditions. Thanks to the easy-to-use properties of the device, cardiac patients might be empowered to follow their own medical conditions in a near future. Additionally, to our knowledge, markers of myocardial contractility are not provided by the smartwatches currently in use and this device may complement the existing ones by adding the cardiac NCT03107352 on ClinicalTrials.gov), enrolling exclusively healthy subjects with a small final sample size (N = 34)2. Additionally, results should not be applied to cardiovascular patients. In this previous study, the sample size was calculated and accounted for 32 included subjects. The sample size was estimated by assuming that cardiac contractility measured by the SCG/BCG device would increase by over 10% for the smallest dose of dobutamine, similar to its effect on SV50. Power analysis demonstrated that to achieve 80% power at α = 0.05, at least 32 subjects were needed. Therefore, 36 subjects were recruited to account for possible dropouts and/or technical failures. For the final analysis, 34 participants completed all the echocardiographic, ECG, and SCG/BCG acquisitions (there were 2 dropouts)2.Several possible limitations need consideration. Firstly, this is a retrospective data analysis based on a previous randomized double-blind investigation  was calculated in 35 random 2D STI echocardiographs using a two-way mixed model. The ICC was 0.94  for the LV twist, 0.90  for the LV twisting rate and 0.92  for the LV untwisting rate. Means (± SEM) of the difference between the measurements of first and the second readings were: 0.02° ± 0.61° for the LV twist (p = 0.97); 1.44 ± 6.51°/s for the LV twisting rate (p = 0.83); 6.88 ± 7.32°/s for the LV untwisting rate (p = 0.35).Statements about the physiological relationship between the velocity parameters of SCG and BCG and LV twisting/untwisting rates are speculative and have been postulated on the basis of the current knowledge of blood fluid dynamics. Thus, our results do not enable us to confirm such a hypothesis, which remain conjectural. Indeed, a quantification of blood flow by mean of particle image velocimetry is needed to confirm this hypothesis and may be the object of further researches.Despite what was highlighted up to this point, authors believe that these limitations do not preclude our conclusions.Max and iK secured from the SCG and BCG waveforms provide reliable information on the contractile status of the heart and account for 49% of the variance of the LVEF.We conclude the follow: (1) in a context of pharmacologically induced incremental rise of myocardial inotropism in healthy subjects, rates of LV twisting and untwisting play a central role in the physiological genesis of the BCG signal but not of the SCG signal; (2) the linear velocity of BCG, rather than the one of the SCG, predicts the behavior of LV twisting and untwisting rates and this estimation of LV twist mechanic by the BCG signals may reflect indirectly the blood stream and relocation within cardiac chambers driven by LV twist mechanic according to the phase of a contractile cycle; (3) metrics of P