Patients with end-stage renal disease have higher cardiovascular morbidity and mortality compared with the general population. Preemptive kidney transplant (KTx) has been shown to be associated with improved survival, better quality of life, lower healthcare burden, and reduced cardiovascular risk. In this case–control study, we investigated the cardiovascular benefits of two approaches to KTx: with and without previous chronic hemodialysis. We enrolled 21 patients who underwent preemptive KTx and 21 matched controls who received chronic hemodialysis before KTx. Cardiac morphological and functional parameters were assessed by echocardiography. Overall, patients undergoing preemptive KTx showed less extensive cardiac damage compared with controls, as evidenced by higher global longitudinal strain, peak atrial and contractile strain, and early diastolic mitral annular velocity as well as a lower left ventricular mass, left atrial volume index, and the ratio of mitral inflow early diastolic velocity to the mitral annular early diastolic velocity. In the multivariable analysis, the presence of chronic hemodialysis prior to KTx was an independent determinant of post-transplant cardiac functional and structural remodeling. These findings may have important clinical implications, supporting the use of preemptive KTx as a preferred treatment strategy in patients with end-stage renal disease. Cardiovascular morbidity and mortality in patients with end-stage renal diseases is higher than in the general population ,2. PreemApart from vascular factors associated with accelerated atherosclerosis and arterial calcification, myocardial impairment has been postulated to deteriorate the clinical course in KTx recipients subjected to previous HD treatment ,8. EvideTherefore, in this study, we sought to investigate whether the treatment strategy based on preemptive KTx is associated with a better post-transplant cardiac functional and morphological profile than the approach including chronic dialysis before KTx.2.The databases of local transplant outpatient clinics as well as a registry of preemptive KTx were searched to identify patients who underwent preemptive KTx. Preemptive KTx was defined as a transplant before starting chronic hemodialysis. The inclusion criteria were first KTx, age above 18 years, and consent to participate in the study. The exclusion criteria were subsequent KTx, history of atrial fibrillation, moderate or severe valvular heart disease, ischemic heart disease, and poor-quality echocardiographic images. Finally, 21 patients were enrolled in the study group. These subjects were individually matched on the basis of sex, age (±6 years), and time after KTx (< ±30%) with 21 patients who had undergone at least a 12-month HD before KTx (a control group) and satisfied the inclusion and exclusion criteria. All enrollees from the study and control group had been placed on the transplant waiting list after achieving a steady eGFR of less than 15 mL/min/1.73 mEchocardiography was performed during the patient’s routine appointment at the transplant outpatient clinic. The time after KTx refers to the date of the echocardiographic examination. Likewise, on the day of echocardiography, routine laboratory assessments including of serum creatinine, eGFR, and hemoglobin were performed. Information on immunosuppressive and antihypertensive medications use and comorbidities such as hypertension, diabetes, and ischemic heart disease was also obtained. Ischemic heart disease was excluded during the process of pre-transplant evaluation on the basis of negative history and negative stress echocardiography. Coronary angiography was performed only in two patients from the control group, showing no significant atherosclerotic lesions. No participant reported symptoms of angina. The presence and localization of functional arteriovenous fistula (AVF) was verified in each patient.Investigations were in accordance with the Declaration of Helsinki and were approved by the Local Bioethical Committee (No 170/2021). Informed written consent was obtained from each study participant.Echocardiographic imaging was performed using standard equipment  with a M5S phased array multifrequency transducer. Imaging data were analyzed offline after being saved in the digital format on a secure server.The cardiac dimensions and wall thicknesses were measured according to recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging . The LV Left ventricular longitudinal deformation was evaluated by semi-automated two-dimensional speckle tracking  in the three apical views at a temporal resolution of 60–90 frames/s. The average negative value on the strain curve was presented as global longitudinal strain (GLS). The apical four- and two-chamber views were used to evaluate LA longitudinal strain, and the onset of QRS was accepted as the zero-reference point. The peak atrial longitudinal strain  was measured as the peak value of longitudinal strain during LV systole, and the peak atrial contractile strain  was assessed as the value of strain at the onset of the P wave on electrocardiography. The final LA strain values were calculated as the average of both apical views. Right ventricular (RV) GLS (RVGLS) was assessed from the RV-focused apical four-chamber view and calculated as the mean of the basal, mid, and apical segments of the RV free wall. All echocardiographic parameters were averaged over three consecutive cardiac cycles and were reported as absolute values.p-value of less than 0.05 was regarded as statistically significant.The continuous variables with normal distribution were presented as the mean and standard deviation (SD) and compared with an unpaired Student’s t-test. The not normally distributed variables were presented as median and interquartile ranges (IQRs) and compared with the Mann–Whitney test. The discrete variables were presented as numbers and percentages and compared with the chi-squared test with the Yeates correction when indicated. The homogeneity of variances was assessed by the Levene test. The Pearson correlation coefficient for parametric variables and Spearman correlation for non-parametric variables were used to analyze the relationships between echocardiographic parameters describing myocardial structure and function, and the clinical and laboratory parameters. A series of stepwise multiple linear regression models was developed to identify the independent determinants of cardiac function and morphology parameters in renal transplant recipients. The components of these models were selected on the basis of anticipated and univariate association. The following variables were tested: age, sex, BMI, eGFR, hypertension, diabetes mellitus, pre-transplant HD, and presence of AVF. The variables were placed in the models in the order of statistical significance in the univariate analyses. All calculations were performed using standard statistical software . A The study group included 21 patients who underwent preemptive KTx and 21 controls who received chronic HD before KTx. Kidney transplants in both groups were performed between 2005 and 2020. The median duration of HD in the control group was 29 months . In the study group, preemptive KTx was performed in nine patients as an elective procedure without vascular access for HD and with a family member as a living donor. The remaining 12 patients were put on the transplant waiting list and underwent preemptive KTx from a deceased donor while preparing for HD. Three of those patients were scheduled for regular HD with vascular access, and their AVFs remained functional throughout the study. The remaining nine patients underwent peritoneal dialysis for a maximum of three months before preemptive KTx without AVF. In the control group, 18 patients received a kidney graft from a deceased donor and three patients received a kidney graft from a living donor. A functioning AVF was found in 14 patients, while in the remaining seven participants, AVF closed spontaneously after KTx.The demographic, clinical, and laboratory characteristics of the subsets separated according to the approach to KTx are presented in In comparison with the preemptive KTx subset, patients with HD prior to KTx were characterized by a worse post-transplant cardiac morphological and functional profile, specifically larger LV mass and LA size and more impaired LV and RV longitudinal systolic function , LV diastolic function (lower e’ and higher E/e’), and LA function . This confirms the superiority of a myocardial deformation analysis over conventional echocardiographic indices  and provThe pathophysiology behind myocardial derangements in chronic kidney disease is complex; however, especially in the context of longitudinal systolic and diastolic abnormalities, the contribution of diffuse tissue processes including interstitial fluid retention and fibrosis should be emphasized .2, we cannot exclude that the possible shorter exposure to the impact of renal failure itself  might have contributed to less extensive cardiac damage in this subset. However, irrespective of the mechanisms of interaction with the cardiovascular system, the preemptive KTx strategy seems to cause less detriment to the myocardium than the HD-based approach. Unfortunately, because of the shortage of donors, the accessibility to this KTx modality is still limited. To better address cardiovascular problems in KTx recipients, the post-transplant reversibility of myocardial abnormalities should be more extensively explored, which might help define priorities on the KTx waiting list.Although all patients undergoing preemptive KTx were listed for a transplant at an eGFR of less than 15 mL/min/1.73 mLimitations. Several study limitations should be acknowledged. First, the number of patients in each group was small. Second, we did not have complete datasets for between-group comparisons of pre-transplant cardiac structure and function. However, we might presume that the matching process resulted in similar cardiac profiles in both study groups. Third, the case–control design might have provided a selection bias. Fourth, coronary angiography was performed only in the minority of cases and no noninvasive verification of coronary status was repeated at the time of inclusion to this study; therefore, we cannot definitely exclude the impact of ischemic heart disease on our results. Fifth, despite the absence of significant contribution from AVF in multivariable models, it is likely that the AVF-related volume overload, more frequent in the HD subset, might have contributed to the between-group differences in cardiac function and morphology [rphology .Preemptive KTx is associated with a better post-transplant cardiac functional and morphological status than the approach to kidney transplantation based on chronic dialysis. This finding may have important prognostic implications for KTx recipients, thus further supporting the choice of preemptive KTx as the preferred strategy.


Post myocardial infarction pericarditis is considered relatively rare in the current reperfusion era. The true incidence of pericardial involvement may be underestimated since the diagnosis is usually based on clinical and echocardiographic parameters.This study aims to document the incidence, extent, and prognostic implication of pericardial involvement in ST-segment elevation myocardial infarction (PISTEMI) using cardiac MRI (CMR).One hundred and eighty-seven consecutive ST-segment elevation myocardial infarction patients underwent CMR on day 5 ± 1 following admission, including steady-state free precession (SSFP) and late Gadolinium enhancement (LGE) sequences. Late Gadolinium enhancement and microvascular obstruction (MVO) were quantified as a percentage of left ventricular (LV) mass. Late Gadolinium enhancement was graded for transmurality according to the 17 AHA left ventricle (LV) segment model (LGE score). Late pericardial enhancement (LPE), the CMR evidence of pericardial involvement, was defined as enhanced pericardium in the LGE series and was retrospectively recorded as present or absent according to the 17 AHA segments. Late pericardial enhancement was evaluated adjacent to the LV, the right ventricle, and both atria. Clinical, laboratory, angiographic, and echocardiographic data were collected. Clinical follow-up for major adverse cardiac events (MACE) was documented and correlated with CMR indices, including LGE, MVO, and LPE.p = 0.002, and HR 0.48, 95% CI (0.26–0.9), p = 0.02, respectively.Late pericardial enhancement (LPE+) was documented in 77.5% of the study cohort. A strong association was found between LPE and the degree and extent of myocardial injury . Both LGE and MVO were significantly correlated with increased MACE on follow-up. On the contrary, LPE presence, either adjacent to the LV or the other cardiac chambers, was associated with a lower MACE rate in a median of 3 years of follow-up HR 0.39, 95% CI (0.21–0.7), Prognostic implication of pericardial involvement in ST-segment elevation myocardial infarction was documented by CMR in 77.5% of our STEMI cohort. Late pericardial enhancement presence correlated significantly with the extent and severity of the myocardial damage. Unexpectedly, it was associated with a considerably lower MACE rate in the follow-up period. Post-myocardial infarction pericarditis occurs within several days following ST-elevation myocardial infarction (STEMI) –4. Its rThe current practice of CMR performed early in the post-STEMI period suggested that pericardial involvement is more frequent than previously reported. This led us to conduct a dedicated, early post-STEMI CMR study to document the actual incidence and clinical significance of pericardial involvement. Cardiac MRI using the late Gadolinium enhancement (LGE) sequence is the modality of choice for assessing myocardial and pericardial pathologies , 8. The The current study documents the incidence, location, and extent of pericardial involvement using CMR in consecutive STEMI patients (PISTEMI). Clinical follow-up was conducted as well in order to evaluate the long-term clinical significance of PISTEMI.The study includes a single-center cohort of 187 consecutive patients who presented with a first STEMI. All study patients underwent primary percutaneous coronary intervention within 12 h of symptoms onset. Demographic characteristics, co-morbidities, pain-to-balloon time, ECG characteristics including MI location, and ΣST-segment elevation at presentation were documented. Laboratory results collected included serial troponin, creatine phosphokinase (CPK), and C-reactive protein (CRP) levels.Echocardiographic and angiographic parameters were recorded as well. The Institutional Ethics Review Board approved the study.N = 101/187 patients) and a 3-T magnet (Philips Ingenia 3T version 5.4.1.2) (N = 86/187 patients) according to scanner availability. Conventional CMR sequences included: balanced steady-state free precession (B-SSFP) cine imaging for cardiac function evaluation and LGE imaging for tissue characterization. Late Gadolinium enhancement was performed 8–12 min following the intravenous administration of Gadolinium-based contrast agent . A phase-sensitive inversion recovery technique was used. The in-plane resolution of the LGE images was 2 mm. Late Gadolinium enhancement sequences were performed with and without fat suppression to distinguish between pericardial fat and pericardial enhancement.All patients underwent cardiac MRI (CMR) on day 5 ± 1 following admission. Cardiac MRI was performed using a 1.5-T magnet  , LGE%, and microvascular obstruction (MVO) % of LV mass were calculated in the short axis plane using a dedicated platform . The LGE signal intensity threshold for scar quantification was set at five standard deviations (SD) above the reference ROI in the remote unaffected myocardium . This thLate Gadolinium enhancement series were obtained with and without fat suppression and were used to differentiate LPE from fat in the pericardium. Qualitative assessment of pericardial enhancement on the LGE images (LPE) was evaluated visually as present or absent in the left ventricular (LV), right ventricular (RV), right atrial (RA), and left atrial (LA) walls. For the LV, LPE was analyzed using the AHA 17 segment model, excluding the septal segments and apex segments 2, 3, 8, 9, 14, 17). The septal segments were excluded since anatomically, the pericardium does not cover the septum. The LPE adjacent to the RV, RA, or LA was considered a single segment for each chamber. Late pericardial enhancement score was calculated by summing all involved pericardial segments (LPE+) in the LV, RV RA, and LA. Late pericardial enhancement was evaluated in a control group of 34 consecutive patients referred for evaluation of non-acute pathologies, including . Late pericardial enhancement in this cohort was documented in only two patients  and only four pericardial segments .Late pericardial enhancement (LPE) was retrospectively evaluated and was defined as the presence or absence of enhanced pericardium on the LGE series , 2. LateThe correlation between LPE presence and different clinical, laboratory, and CMR parameters was examined. Late pericardial enhancement segmental location was correlated with segmental distribution and the extent of the myocardial damage (LGE and MVO scores).Pericardial effusion on CMR was determined using SSFP in the four-chamber plane and was defined as pericardial width ≥4 mm .The current study did not include T2 sequences in evaluating pericardial involvement, as LPE is better suited for evaluating the focal pericardial involvement in STEMI, as compared with T2 sequences. Post-processing for LGE, MVO, and LPE was performed by two experienced cardiovascular imagers (OG-16 years of experience and YB-9 years of experience).In order to establish the clinical significance of the CMR findings demonstrating pericardial involvement (PISTEMI), we set out to integrate it together with other findings related to diagnosis of pericarditis , 3, inclClinical follow-up for major adverse cardiac events (MACE) was performed. Major adverse cardiac event included recurrent MI, acute stroke, acute coronary syndrome necessitating urgent hospitalization and\ or percutaneous coronary intervention, hospitalization for heart failure, and cardiovascular death in a median of 3 years of follow-up.Kaplan-Meier survival analysis  was conducted to compare the incidence of MACE in patients with LPE vs. others. A similar analysis was conducted for patients with a left ventricle LPE (LV LPE) vs. others. A log-rank test was conducted to determine if there were differences in MACE incidence.p-value of <0.05 was considered significant. Categorical variables are reported in frequencies and percentages. The significance of categorical variables between groups was assessed using the chi-square test or Fisher's exact test.Statistical analysis was performed using the SPSS statistical software 25.0.0  and the R foundation statistical computing and graphics software (version 4.0.0). All statistical tests were two-sided, and a t-test. Continuous variables not normally distributed were reported as median and interquartile range  values, and significance was assessed using the Mann-Whitney-Wilcoxon or Kruskal-Wallis tests. Interobserver variability for the presence or absence of LGE, MVO, and LPE was assessed using blinded data from the study cohort. Inter-observer variability demonstrated a Cohen's κ weighted score of 0.76 [P < 0.001. 95% CI ], indicating a good inter-observer agreement.We tested all variables for normal distribution by the Kolmogorov-Smirnov test and visualized the QQ-plot, plotting the distribution and variance of the residuals. Normally distributed continuous variables were reported as mean and SD values, and differences between groups were assessed using the student's The study cohort was divided into two groups according to the presence or absence of LPE on CMR. A multivariable binary logistic regression model was constructed for the prediction of pericardial involvement. The model consisted of variables that were statistically significant in univariate tests and of clinically relevant indices. Notably, variables with missing values for more than 15% of the cohort (CRP) were excluded from the multivariate analysis. A K-M survival curve and Cox proportional hazard regression analysis examined the CMR indices and MACE association.Involvement of the pericardium (LPE+) overlying the ventricles and\or the atria was demonstrated in 145/187 patients (77.5 %). Among these 145 patients, spatial pericardial involvement was demonstrated as follows: LPE overlying the LV , RV , RA  and LA  .The study cohort was divided accordingly into LPE+ and LPE– subgroups. Baseline characteristics, laboratory and echocardiographic findings are presented in p = 0.03) and a lower LVEF on the first echocardiogram performed following primary PCI .LPE+ patients had higher peak CPK levels , typical ECG changes in 4/187 patients (2.1%), and pericardial effusion at trans-thoracic echocardiography in 6/187 patients (3.2%). Thus, a total of 13/187 patients demonstrated at least two clinical signs consistent with the diagnosis of pericarditis. Out of these patients, two patients only were treated with Colchicine .P < 0.01) .A robust association was found between the LGE score, expressing the degree and extent of the myocardial damage and the presence of LPE ( < 0.01) , 5. Furtp = 0.81) (p = 0.55).No statistically significant correlation was found between the location of the myocardial damage and LPE presence. The prevalence of pericardial effusion detected by CMR was similar in the presence and absence of LPE  . Moreovep = 0.002). The logistic regression model was statistically significant [p = 0.007], and the area under the ROC curve was 0.74   . No sign64–0.81) .Post-discharge clinical follow-up was available in 85% of patients (159/187) for a median period of 3 years. Overall, 46/159 patients (28.9%) sustained at least one MACE, including recurrent MI , acute stroke , acute coronary syndrome necessitating urgent hospitalization and\or percutaneous coronary intervention , hospitalization for heart failure , and cardiovascular death . The presence and extent of LGE, MVO, and LPE in the follow-up patients were not different from those lost to follow-up. A detailed comparison of MACE between subgroups of the cohort can be found in the p = 0.006 and 40 vs. 23%, p = 0.024, respectively). Patients with LPE+ involving more than one pericardial segment demonstrated a lower MACE incidence than patients without pericardial enhancement (LPE–) . Pericardial involvement adjacent to the LV (LV LPE) was also associated with a significantly lower MACE rate . A univariate log-rank survival analysis revealed a statistically significant difference in survival distributions between LV LPE (+) and LV LPE (–) patients (p = 0.04). However, significance was not maintained when comparing whole myocardium LPE (p = 0.12).Patients with a higher LGE score and MVO % of LV mass were more likely to sustain MACE during the follow-up period ,  = 0.02] . Pericar= 0.002] .The integrated approach for diagnosing post-MI pericarditis (PMIP), which combines the CMR findings of LPE together with either elevated CRP levels and/or the presence of pericardial effusion, demonstrates that 78 patients (41.7%) had PMIP. No significant differences in demographics, baseline characteristics and co-morbidities, were found between the two groups . PMIP+ pp = 0.02] ,  = 0.02] .The present CMR study demonstrated an unexpectedly high incidence of PISTEMI. Late pericardial enhancement (LPE+), the MRI manifestation of pericardial involvement, was documented in 77.5% of the patients on early post-STEMI. Cardiac MRI LPE was documented adjacent to the injured and non-injured LV myocardium, the RV, and both atria.Post-myocardial infarction pericarditis is traditionally classified as early and late (Dressler syndrome). Its reported incidence has markedly declined in the reperfusion era from 20% to <5% –6. DressIn the current study, clinical evidence of pericarditis was present in only 13/187 patients (6.9%), while PISTEMI CMR evidence was documented in 145/187 patients (77.5%).In addition, we documented a strong correlation between PISTEMI and infarct severity. A similar correlation was reported both in the pre and post-reperfusion era. However, the reported incidence of post-STEMI pericarditis was much lower in comparison . Lador eA single group of investigators reported the utilization of CMR in pericardial involvement diagnosis in two letters to the editor , 17. In Post-STEMI pericarditis in the pre-reperfusion era was associated with increased long-term mortality, although it was not found to be an independent prognostic factor in follow-up studies –4, 6. OuMoreover, our data introduces a novel idea suggesting that PISTEMI results from a physiologic rather than a pathologic mechanism triggered by the myocardial injury. Experimental animal studies focusing on myocardial damage in Zebrafish and low mammalians have recently suggested that cardiac injury may activate the epicardium as a source of a regenerative or/and reparative process –21. A siThus, our observation of frequent PISTEMI, together with those mentioned above in experimental and clinical studies, raises the challenging hypothesis that pericardial involvement is a part of a yet undefined residual myocardial repair process in the human heart. The current study did not measure specific biochemical factors and therefore cannot support this assumption with a defined physiological mechanism.The major clinical implication of our findings is the clear understanding that pericardial involvement detected by CMR is common, occurring in more than 3/4 of STEMI patients. Thus, it should not be regarded as a post STEMI complication.Moreover, this study documented that pericardial involvement was associated with pericardial effusion detected by echocardiography in only 3% of the cases. This is of high clinical importance since it challenges the traditional criteria of pericardial involvement diagnosis, which rely mainly on echocardiographic evidence of pericardial effusion. Cautioning that CMR detection of pericardial involvement should not be “automatically” considered as a clinical complication.This is a retrospective single-center study with the related inherent limitations. The study cohort included scans performed both on 1.5 and 3 T MR scanners. Still, there was no significant difference between scanner field strength and the documented LPE presence.Although CMR offers high spatial resolution on LGE images, there is an inability to separate the epicardial and parietal layers due to their anatomic proximity. Since the thickness of pericardium is usually <4 mm and the LPE signal is subtle, LPE quantification (similar to LGE quantification) cannot be performed. Compared to acute inflammatory pericarditis, pericardial involvement is local rather than global, rendering T2 sequences non-contributing to pericardial involvement diagnosis.Factors involved in myocardial repair described in the animal studies were not studied in the current study.The current CMR study demonstrated that early pericardial involvement detected by CMR is common, occurring in more than 3/4 of STEMI cases, involving the pericardium adjacent to all four cardiac chambers. PISTEMI is correlated with the extent and severity of the myocardial injury. PISTEMI is associated with a decrease in the major adverse events rate on follow-up.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Sheba IRB-Helsinki Committee  5897-19-SMC. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.EM and OG: conceptualization, data curation, project administration, analysis, supervision, visualization, validation, methodology, software, writing-original draft, review, and editing. YB and EK: conceptualization, supervision, CMR analysis, investigation, and validation. DO: methodology, software, writing-original draft, review, and editing. AF: methodology, software, analysis, supervision, and validation. SN, IM, AS, and RBein: conceptualization, investigation, supervision, and validation. RBeig: supervision, investigation, and validation. RG: CMR analysis, investigation, and validation. ES and SM: conceptualization, data curation, analysis, supervision, validation, writing-review, and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Systemic sclerosis (SSc) is a chronic autoimmune disorder with unknown triggering factors, and complex pathophysiologic links which lead to fibrosis of skin and internal organs, including the heart, lungs, and gut. However, more than 100 years after the first description of cardiac disease in SSc, sclerodermic cardiomyopathy (SScCmp) is an underrecognized, occult disease with important adverse long-term prognosis. Laboratory tests, electrocardiography (ECG) and cardiovascular multimodality imaging techniques , and novel imaging techniques, including myocardial deformation analysis) provide new insights into the cardiac abnormalities in patients with SSc. This state-of-the-art review aims to stratify all the cardiac investigations needed to diagnose and follow-up the SScCmp, and discusses the epidemiology, risk factors and pathophysiology of this important cause of morbidity of the SSc patient. Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by the following triad: microvascular damage, initial innate and adaptive immune response alterations, and further development of fibrosis in skin and several internal organs . SSc is The cutaneous involvement in SSc can be either limited (lcSSc) or diffuse (dcSSc), with major differences regarding skin changes, the extent and rate of disease progression, visceral lesions, immunologic profile, and prognosis. LcSSc patients are characterized by skin thickening limited to the face, neck, and extremities distal to knees and elbows . On the Even though certain systems are actively screened for the presence of the disease, including pulmonary fibrosis and pulmonary hypertension, SSc-related myocardial damage is an underrecognized entity with an incomplete understanding of the pathogenic mechanisms, long-term sequelae, and prognosis . What weThe complexity of SSc is reflected by its pathogeny. The current concept is that external factors, acting on a genetically susceptible host, trigger a chronic, multifocal, auto amplifying cascade with early vascular damage, inflammation, and autoimmunity, followed in more advanced stages by fibrosis—the trademark of SSc. Accumulation of collagen, elastin, glycosaminoglycans, and fibronectin leads to permanent tissular scarring generating compact and rigid connective tissue . AbnormaHistorically, in 1926 Heine performed the first description of cardiac disease in SSc using autopsy and describing abnormalities in the coronary arteries, myocardium, and pericardium ,8,9.Primary cardiac involvement directly involves the myocardium, pericardium, valvular structures, coronary arteries, and conduction system, and is determined by myocardial fibrosis, autonomic neuropathy, and small vessel disease ,11,12,13Primary ultrastructural alterations in the myocardium are most probably multifactorial: micro- and/or macrovascular changes are supposed to lead to irreversible damage through fibrosis . In 1976Cardiac RP is another possible explanation for the myocardial damage in SSc, as Alexander et al. identified cold, physical stress, and pharmacologic stress-induced myocardial perfusion defects by means of positron emission tomography (PET-CT), single-photon emission computed tomography (SPECT) and cardiac magnetic resonance (CMR) ,17. UsinLong-lasting vascular disease leads to generation of the other important, virtually irreversible aspect of the SSc-related cardiac disease: myocardial fibrosis, which is disposed in the interstitium, does not involve the immediate subendo/epicardial layer and is equally distributed among both ventricles, being linked with contractile band necrosis following repeated ischemia-reperfusion events ,13. The The multitude of potential tissular targets of the systemic disease may lead to polymorphic clinical expression: myocarditis, myocardial fibrosis, restrictive cardiomyopathy (RCM), systolic/diastolic ventricular dysfunction, heart failure (HF), valvular regurgitation, CAD, rhythm and conduction disturbances, pericardial disease  may all be seen ,22,23,24In patients with SSc, conventional cardiovascular risk factors (CVRF) and comorbidities like HTN, CAD, and dyslipidemia appear to have similar frequencies as in the general population . In an aData obtained by multiple regression analysis from the European Scleroderma Trials and Research Group (EUSTAR) Database have shown that the following are considered to be risk factors for primary myocardial involvement: advanced age, rapid progression of skin thickening, male gender, dcSSc, duration of disease, digital ulcers, simultaneous renal and muscular impairment, disease activity score, pulmonary fibrosis, pulmonary arterial hypertension (PAH) ,24,28. MUsing scintigraphy, Steen et al. showed that physical stress-induced perfusion defects predicted the occurrence of cardiac disease or death . CardiacDisease-specific autoantibodies offer important prognostic information in patients with SSc. The presence of anti-topoisomerase I (anti-Scl70), anti-Ku, anti-U3 RNP, anti-histone, and anti-ribonucleic acid (RNA) polymerase  antibodies are associated with a higher risk of SSc-related cardiac disease . In addip < 0.001) [Associated with more severe internal organ damage and an immunologic profile dominated by the presence of anti-Scl70 antibodies, dcSSc causes a higher rate of severe complications . However< 0.001) . An echo< 0.001) .Finally, more severe nailfold capillaroscopy findings have been demonstrated to associate with heart involvement in patients with SSc . A reducMyopericardial inflammation, perfusion defects, and fibrosis are the major underlying factors in the SScCmp . MyocardBy using CMR, Rodriguez-Reyna et al. identified myocardial fibrosis in 45% of 62 investigated SSc patients, and it was more prevalent in the dcSSc subtype . After aDespite having a high frequency of primary myocardial disease, SSc patients most frequently present with occult, asymptomatic initial disease ,15,21,44As mentioned earlier, being a systemic disease, SSc can generate signs and symptoms that can be falsely attributed to extracardiac pathology ,21. The The diagnosis of SSc-related myocardial involvement is not always straightforward, as it is intricated with other possible etiologies if concurrent CVRF are present. However, a multimodal diagnostic approach of myocardial alterations, not explained solely by CAD or significant valvular heart disease, will lead to a diagnosis of SScCmp.A summary of all cardiac investigations useful in assessing the cardiac injury in SSc is listed in p = 0.0003; 95% C.I.: 57–232) [An ideal biomarker should be defined by high sensitivity, specificity, and reproducibility. The N-terminal pro B-type natriuretic peptide (NTproBNP) fulfills these criteria, as it is cheap, reliable, and easy to detect through non-invasive procedures . Its ser 57–232) . Serum NCardiac troponins (cTn) are sarcomeric regulatory proteins with high specificity for myocardial tissue. According to Barsotti et al., high levels of high-sensitivity cTn (hs-cTn) are positively correlated with cardiac disease in SSc, but with low specificity and sensitivity  .Myocardial tissue anisotropy is defined by the increased spatial dispersion of ventricular repolarization and plays a role in arrhythmogenesis . The sevAn abnormal ECG tracing  is present in 25–75% of patients with SSc and it independently predicts mortality . In addiThe most relevant ECG change is represented by arrhythmias, as according to data from the 2010 European League Against Rheumatism (EULAR)/EUSTAR, 5–6% of total deaths in SSc population are attributable to arrhythmia ,59. In tEven though the highest clinical impact is generated by ventricular arrhythmias, data obtained by Ferri et al. through 24-h Holter ECG monitoring demonstrate that supraventricular arrhythmias are also frequent, detected in 66% of SSc patients . TransieThe presence and/or severity of arrhythmia does not appear to correlate with the skin subtype or the occurrence of signs/symptoms . MuresanDe Luca et al. demonstrated that ventricular arrhythmias aggravate the SSc patient’s prognosis, as more than 1190 PVB/24 h associate a sensitivity of 100% and specificity of 83% in predicting SCD or later necessity of implantable cardioverter defibrillator (ICD) implantation .To identify sensitive ECG markers for arrhythmic risk stratification, Ciftci et al. examined QT dynamicity (QTd) and heart rate variability in SSc patients . QTd is In the comprehensive process of imaging the SScCmp, echocardiography plays a key role. Reproducibility, large-scale availability, and high sensitivity are key attributes that propose this imaging method as a standard investigation for characterizing and following-up SSc heart disease .It is recommended that the patient with SSc should be actively screened by means of two-dimensional transthoracic echocardiography (2DTTE) annually in order to assess systolic and diastolic LV function and systolic pulmonary arterial pressure (sPAP) .In the SSc population, LV systolic dysfunction is well described from an epidemiologic viewpoint . Data frWhile the classical RP affects the extremities of almost all SSc patients, it is postulated by some investigators that a similar cold- or stress-induced excessive vasoconstriction may be an important cause of diffuse damage in internal organs ,68,69. AThe myocardium is composed of fibers with longitudinal, circumferential, and radial disposition and the subendocardial layer is the structure with maximum susceptibility to ischemia. Its fibers are mostly arranged in a longitudinal manner, so longitudinal contractile dysfunction is one of the earliest signs of myocardial damage . TherefoAssessing 113 SSc cases , Yiu et al. demonstrated that in this population, subtle LV contraction abnormalities are present before routinely used global echocardiographic parameters become abnormal  . In theiVan Wijngaarden et al. were the first authors to demonstrate many of the 234 SSc cases  that serial measurements with STE can detect progressive impairment of LV systolic function in a relative short time frame . During Another recent study from this group proved that from all echocardiographic parameters used, LV GLS was the only one independently associated with the combined endpoint  in an SSc population with a similar mortality rate (9%) and follow-up as the EUSTAR database . MoreoveIn order to better understand the early contraction abnormalities generated by the fibrotic process, D’Andrea et al. analyzed the association between LV function, coronary flow reserve (CFR) and endothelial function in 33 asymptomatic SSc patients (18 dcSSc and 15 lcSSc), compared with 30 healthy controls . StandarThe evaluation of myocardial electromechanical proprieties is a new approach for detecting latent heart disease and it is based on the existence of a heterogenous prolongation of the time from electrical impulse generation to mechanical contraction of the ventricle . In SSc,In contrast to systolic dysfunction, the incidence, risk factors, and effects of altered diastolic function in SSc patients are less studied .Even though heart failure with reduced ejection fraction (HFrEF) is a well-established clinical entity with adverse clinical outcomes, heart failure with preserved ejection fraction is less studied (HFpEF) but determines mortality and morbidity rates similar to the ones generated by HFrEF . DiastolTennoe et al. showed in a large and unselected SSc cohort (275 SSc cases) that baseline frequency of DD was 17% , and after a median follow-up of 3.4 years, it increased to 29% . Risk faHinchcliff et al. studied 153 patients with SSc , between 2005 and 2009, with a mean age of 51 ± 13 years, 60% lcSSc, and detected systolic dysfunction in 8/153 and diastolic dysfunction in 35/153 [Candell-Riera et al. published results of a comprehensive analysis based on non-invasive imaging techniques, conducted on 63 patients with lcSSc cases  and mean age of 53.8 ± 11.8 years . The mosLV myocardial early diastolic peak velocity presented low values at the basal segments of the interventricular septum, but also in the middle and basal segment of the LV lateral wall . Measurip = 0.07) [Even though the end-diastolic LV diameter, fractional shortening and LVEF are routinely used parameters for the 2D echocardiographic evaluation of SSc patients, they are load-dependent and do not systematically reflect the myocardial contractile status . VAC is  = 0.07) . Values  = 0.07) .Also, the authors document a possible intrinsic LV systolic dysfunction which is caused by the inability of the LV to compensate for the elevated afterload, which may be caused by the increased arterial stiffness because of collagen deposits; this, in turn, leads to high values of Ea and is associated with adverse outcomes . They coWith a thin free wall, three-dimensional complex geometry, and a continuous link with the pulmonary system, the RV poses certain challenges for the accurate evaluation of its internal chamber dimensions and changes during the cardiac cycle . In the In SSc, for direct echocardiographic evaluation of RV myocardial function, several parameters can be assessed: tricuspid annular plane systolic excursion (TAPSE), free wall tissue Doppler S’, RV fractional area change (RVFAC), RV ejection fraction (RVEF) using 3DTTE, sPAP, and mean pulmonary arterial pressure (mPAP) estimates. More recently a non-invasive marker of pulmonary vascular resistance—the ratio of tricuspid regurgitant velocity to pulmonary artery velocity–time integral—has been proposed .SSc determines early RV dysfunction, strongly associated with the degree of skin and pulmonary involvement, but also with the serology (anti-Scl70 antibodies correlate with early RV DD) ,54.In order to better characterize the primary myocardial damage of the RV, Kahan et al. conducted a study on 42 patients with SSc with normal sPAP and disease duration of less than 5 years, observing that RVEF correlated with LVEF and peak filling rate, while the alteration of pulmonary function or sPAP did not influence RV’s function, strongly implying the possibility of an intrinsic myocardial disease .Primary myocardial disease is directly caused by two factors: the fibrotic process and the coronary microvascular disease, with global diastolic function impairment alongside reduced CFR seen even in asymptomatic cases . ExperimDespite normal LVEF, TAPSE, and DMI systolic peak velocities, strain and SR were significantly low at the site of both free walls . SupplemEven though, in the recent years, many 2D and Doppler echocardiographic parameters have been proposed for the evaluation of RV contractile function, most of them are limited by the fact that they rely on geometrical assumptions, on load dependency and have suboptimal reproducibility in different clinical scenarios . STE is Mukherjee et al. demonstrated that even though conventional parameters routinely used to assess RV function  were similar between SSc patients and age- and sex-matched controls, RV free wall longitudinal strain (RVFWS) was significantly altered in the former, irrespective of the systemic disease subtype or sPAP . BesidesAs such, RVFWS may be able to help clinicians identify occult contractile dysfunction and as a consequence, intensify the screening frequency of the SSc patients .As the majority of patients with SSc suffer from DD of the LV, not systolic dysfunction, it is imperative to be able to early detect the abnormality in the pattern of relaxation of the ventricle. LV DD is an independent predictor of all-cause mortality in the general population, even in the preclinical stage . Unfortur), conduit (εCD), and booster pump (εCT) [From a general perspective, the LA has three basic functions, all of which have also been assessed in the systemic sclerosis population: reservoir (εmp (εCT) .R represents the LA function with the highest body of evidence from the literature regarding its usefulness in different clinical scenarios: in patients with atrial fibrillation, it correlates with age, LA size, and DD; it is a predictor of recovery of atrial contractility post-cardioversion and also a predictor of atrial fibrillation post transcatheter aortic valve replacement [Myocardial fibrosis characteristic of SSc will lead to altered relaxation of the LV, which in turn will increase the filling pressures that, in the end, will generate fibrosis of the atrial myocardium. Changes in LA strain are correlated with the presence of fibrosis and LGE on CMR . εR reprlacement ,85,86.r and εCD were significantly reduced in SSc [The first paper regarding changes in LA strain in patients with SSc was published in 2014 by Agoston et al., who compared 42 SSc patients with 42 healthy controls and observed that besides the fact that the first group had a higher E/e’ratio, εd in SSc . The autd in SSc .r reduction in SSc mirrors the one exhibited by LV GLS, even in a SSc population without DD [CD and εCT had reduced values in the SSc group with DD, but booster pump was reduced as well in patients with normal relaxation of the LV, with a mention that in grade 1 DD it increased as a consequence of the Frank-Starling mechanism [In 2018, Porpaczy et al. observed that εthout DD . The othechanism . One yeaechanism .Advanced assessment of LA function by multimodality imaging may provide further insight into the background of the sclerodermic process, but it also might be able to earlier detect subtle changes in myocardial function that should prompt the initiation of a more comprehensive cardiac screening program in certain SSc patients early.For a summary of different 2DTTE techniques employed for evaluating the SScCmp please see Because of its high capacity of tissular characterization, CMR is a very accurate method for the non-invasive, non-irradiating evaluation of inflammation, perfusion and myocardial fibrosis . DefininCMR sequences bring complementary information about LV function, regional perfusion, angiogenesis, myocardial viability, and spatial disposition of the cardiomyocytes . The supLarge areas of fibrosis represent the hallmark of SSc and LGE is considered to be the “gold standard” for detection and characterization of focal myocardial fibrosis . Unlike Supplementary, in the setting of suspected myocardial inflammation, Markousis-Mavrogenis et al. demonstrated that one-quarter of symptomatic SSc patients from their study did not show any significant signs of an active inflammatory response on T2-based analysis . In contUnlike subendocardial/transmural ischemic LGE, a patchy, mid-wall, linear pattern involving the basal and mid LV segments might be present in SSc . RodriguSubclinical perfusion defects detectable by CMR are considered to be, alongside fibrosis, the dominant mechanism of cardiac injury in SSc . The limAdenosine stress CMR is able to detect subendocardial perfusion defects in 79% of patients with SSc and cardiac disease .In order to better describe the pathophysiologic background of myocardial damage in SSc, Mavrogeni et al. conducted a study on 46 recently diagnosed asymptomatic patients with dcSSc , mean age of 41 ± 5 years, with normal clinical examination, ECG and 2DTTE by using detection of myocardial edema and stress CMR . Twenty Regarding systolic and diastolic function, CMR-derived markers for its evaluation are: peak systolic circumferential strain, peak diastolic strain rate and increased volume of LA, all of them being much more prevalent in the SSc population compared to controls .For the description of structural abnormalities involving the RV, CMR is considered to be the “gold standard”, allowing for accurate and reproducible measurements of ventricular dimensions, wall thickness and myocardial mass without relying on geometrical assumption . CompareThe comprehensive evaluation of the SScCmp using a multimodality approach can offer a complete description of the subtle changes undergone by the heart and is important at least in the research setting. Nuclear imaging-SPECT, PET-CT—is recommended for assessing myocardial perfusion dysfunction .Thallium-201 perfusion scintigraphy, together with SPECT, detects reversible myocardial perfusion defects induced by cold stimulus or physical stress, in almost all SSc cases . These aFollansbee et al. described a group of dcSSc cases without symptomatic heart disease that on post physical stress thallium scans presented a high rate of myocardial perfusion defects, in the absence of significant CAD .In SSc, one of the responsible mechanisms for myocardial injury and subsequent fibrosis is represented by the transitory coronary spasm induced by different stimuli. Moreover, even though CMR distinguishable fibrosis has large distribution, it seems that vascular spasm detectable by nuclear imaging leads to ischemia of large myocardial areas, since it is necessary for more than 5 g of hypoxic tissue/ventricular for thallium scintigraphy to detect it .Using thallium 210-SPECT, Kahan et al. reported that almost 20% of analyzed ventricular segments presented an uptake defect, detectable at rest and partly reversed after administration of dipyridamole, nicardipine or nifedipine ,94,95. AThe heart is one of the most important internal organs affected in SSc and is responsible for a large number of deaths in these patients 15%), while over the years, the rate of pulmonary and renal complications has declined gradually ,96. From%, while Overt cardiac disease is seen in 15–35% of cases, but in morpho-pathological studies it is identified in 21–100% of situations, and most patients suffer from subclinical disease ,58 Figu. Still, Although primary myocardial dysfunction is not seen as frequently as pericardial disease or arrhythmia, it is a major predictor of mortality, making early detection crucial ,23,97. HAfter a 10-year follow-up of 953 dcSSc cases, Medsger and Steen reported heart-related mortality of 20%, and in an Italian cohort of 1012 patients, heart disease solely accounted for up to 36% of deaths ,32,99. MOverall, cardiac comorbidity is responsible for 20% of total deaths in the SSc population and data from the Spanish Registry of Systemic Sclerosis demonstrates that the relative risk of mortality is superior to the one related to pulmonary or renal causes (2.8 vs 1.9 and 1.6) ,101. AftPresently, there is no specific treatment algorithm for SScCmp ,104. In Patients with SSc and HFrEF should benefit from initiation of guideline directed medical therapy consisting from beta-blockers (βb), angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA) . SufferiCCB lowers the risk of LV systolic dysfunction and also leads to improvement in cardiac function and perfusion detectable by SPECT, 2DTTE, and CMR ,105,106.If suspected, CAD should be detected and treated as in the general population .Medium dose oral corticotherapy improves LV function, but also, together with immunosuppressive agents, represents an option in SSc cases with myocardial fibrosis that exhibit progressive worsening of cardiac function, despite adequate therapy ,108. PulBecause myocarditis can complicate the clinical evolution of SScCmp, the clinician must be aware of the fact that immunosuppresive agents  used in these specific cases have led to clinical, cardiac biomarkers and CMR improvement ,108,110.In cases of advanced HF, cardiac transplantation, cardiac resynchronization therapy, and mechanical support devices should be used according to standard guidelines .Generated by a polymorphic systemic disease with very complex pathogenesis and intricated chronic mechanisms, SScCmp is an underrecognized and underdiagnosed clinical entity. However, the recent advancement of imaging techniques continues to pave the road started decades ago by nuclear radiology, in showing that the intricated interplay between microangiopathy and fibrosis continues to express itself at a myocardial level.The rate of adverse clinical outcomes, of systolic/diastolic dysfunction, conduction/arrhythmic disturbances, or even of SCD can be improved by a multimodality cardiovascular evaluation of the SSc patient for timely diagnosis of myocardial involvement.


Prospective regression analyzes were performed to identify the biomechanical determinants of postural instability unrelated to lower limb motor deficits from gait initiation factors. PIth was constructed using a logit function of biomechanical determinants. Discriminatory performance and performance differences were tested. Backward displacement of the pression center (APAamplitude) and active vertical braking of the mass center (Braking-index) were the biomechanical determinants of postural instability. PIth = − 0.13 × APAamplitude − 0.12 × Braking-index + 5.67, . OR (APAamplitude) and OR (Braking-index) were 0.878 and 0.887, respectively, i.e., for a decrease of 10 mm in APAamplitude or 10% in Braking-index, the postural instability risk was 11.391 or 11.274 times higher, respectively. PIth had the highest discriminatory performance (AUC 0.953) with a decision threshold value th, as objective clinical integrator of gait initiation biomechanical processes significantly involved in dynamic postural control, was a reliable and performing discrimination index of postural instability with a significant increased sensitivity, and may be useful for a personalized approach to postural instability in ALS.To assess the usefulness of a theoretical postural instability discrimination index (PI ALS may cause cognitive-behavioral, extrapyramidal and sensory disturbances by progressive extension of degeneration to the corresponding brain structures. There is accumulating clinical5, neuroimaging8 and postmortem neuro-pathological9 evidence of extrapyramidal involvement in patients with ALS10.Amyotrophic lateral sclerosis (ALS) is a progressive multisystem neurodegenerative disease that inexorably progresses and primarily affects the pyramidal motor system involving the motor cortex, cranial nerve motor nuclei and spinal cord motor neurons with additional evidence of non-motor functional involvements10. Postural instability can be an early functional sign preceding motor weakness, especially in patients with upper motor neuron predominance, as reported by our team11 and others13. Extrapyramidal stiffness is correlated with postural and balance disorders in ALS patients5. However, the conjunction of motor neuron features as well as potential extrapyramidal, cerebellar14 and vestibular15 disorders in ALS does not allow an accurate clinical evaluation of postural instability and gait impairment, which requires quantitative assessment approaches.In addition to motor weakness and spasticity, extrapyramidal involvement in ALS may contribute to postural system impairments with risks of falls and fractures affecting quality-of-life and mortality16, and is an essential component in assessing the effectiveness of interventions to improve balance18. Gait initiation is an interesting pattern to investigate dynamic postural instability related to different neurological disorders such as ALS. It is the motor transition from standing position to walking. It includes an anticipatory postural adjustment (APA) phase preceding the swing foot-off, followed by the step execution phase20. APAs result in a backward shift in the center of pressure (CoP)19 toward the swing leg side, which allows the propelling of the center of mass (CoM) toward the stance leg side prior to the swing heel-off22. APAs create the conditions which act to propel the CoM forward contributing to body forward progression to reach the intended gait speed at the first step end23, and the optimal conditions needed to maintain the stability of the whole body during step execution26.Postural stability is the dynamic postural response to applied or volitional perturbations27. However, the inter-examiner reliability of pull test may be considered suboptimal relying on some degree of subjective interpretation by examiners, which may provide an inadequate assessment of postural instability27.Postural instability is usually assessed clinically using the pull test, which is a common approach in Parkinson’s diseaseClustering is a multivariate technique of grouping individuals sharing similar values across several variables in which the data is usually not scattered evenly through n-dimensional space but instead forms clusters. Identifying these clusters may make sense of this clumped data and may provide a deeper understanding of data. Thus, cluster analysis of subjects across gait initiation and postural instability variables may be regarded as an alternative or complementary approach to the pull test, to the extent to which methods collecting data may assign the same score to the same postural instability variable.th) using multivariable regression models from the identified biomechanical determinants, evaluate its usefulness and added discriminatory performance value. Finally, to assess the inter-method reliability between the pull test and clustering of subjects, across the gait initiation and postural instability variables, in order to highlight clusters of data in relation to postural instability.The aim of the study was to identify the biomechanical determinants of postural instability unrelated to lower limb motor deficits from gait initiation factors in ALS. Then with a view to increase discriminatory performance, according to a personalized approach to postural instability, the purpose was to create a theoretical postural instability discrimination index : approval number RBM C12-13. All participants gave their informed written consent in conformity with the Declaration of Helsinki.The study was approved by the local ethics committee approval Ile-de-France CPI Paris VI, The pull test execution was standardized and performed by the same experienced neurologist (PFP). The patient was standing with eyes open and feet comfortably apart. The examiner stood behind the patient and applied a brisk and forceful pull on the patient's shoulders, while respecting the safety conditions for the patient, while the examiner stood ready to catch the patient to prevent its fall. The patient had to prevent himself from falling, if necessary, by taking a step backward after being pulled.The postural instability scores ranged from 0 to 4 , fall if not caught by the examiner; 3: very unstable, tendency to lose balance spontaneously; 4: unable to stand without assistance).Score of 1 or more was classified into the postural instability group, and 0, in the group without postural instability.11. From the biomechanical data records of gait initiation, accelerations, velocities, displacements of the CoM, and displacements of the foot CoP were computed during the first two steps19. By convention, accelerations, velocities, and displacements were considered positive when directed forward, upward, and toward the swing leg side.The gait initiation test was performed in natural gait conditions using a force plate . Twenty consecutive trials were recorded for each subjectduration (s) was the time between the backward movement start of the CoP and the swing foot-off. EPduration (s) was the time between the swing foot-off and the stance foot-off. APAamplitude (mm) was the maximal anteroposterior backward displacement of the CoP. L (mm) was the anteroposterior step length between the CoP position at the swing foot-off time and the stance foot-off time. Vm (m s−1) was the maximal anteroposterior progression velocity of the CoM at the end of the first step19, V1 (m s−1) and V2 (m s−1), the vertical downward V-shaped speed of the CoM with the minimal negative falling speed and the reduced falling speed at foot-contact time with the ground, respectively, during step execution. The Braking-index The gait initiation biomechanical variables in the APA and execution phases were analyzed. APAThe variables tested were the continuous biomechanical variables of gait initiation and the postural instability categorical variable dichotomized into with and without postural instability categories. Mean values and frequencies were expressed with their standard deviations (± SDs) and percentages (%), respectively.Differences in values of biomechanical parameters between the subject groups with and without postural instability were assessed using the non-parametric U Mann–Whitney test for quantitative variables.Univariate and multivariate multiple regression analyses were performed to evaluate the biomechanical parameters effects of APA phase on motor performances of step execution.Multivariate logistic regression analyses with mixed stepwise selection were performed to identify potential gait initiation factors that were independently associated with postural instability. The maximum threshold of the p value was 0.25 for an effect to be able to enter the model during a forward step, and the minimum threshold was 0.10 for an effect to be removed from the model during a backward step.J = maxc [Se(c) + Sp(c) − 1], was chosen to determine the optimal decision thresholds (c) for the discrimination.Receiver operating characteristic (ROC) analysis was performed for individual gait initiation classifiers regarding their discriminatory ability for postural instability. For each classifier, the ability of the logistic regression models to allow discrimination was quantified by the area under the ROC curve (AUC). The maximum Youden index, th was constructed using a multivariable logit function of the biomechanical classifiers of postural instability and modeled as follows:i were the gait initiation classifiers as effects of the model, i, the number of classifiers, bi, the parameters estimated using the maximum likelihood estimation, and PIth, the maximum likelihood estimate ranging from (−) infinite to (+) infinite.PIOdds ratios with confidence intervals were calculated for the postural instability responses.For given values of gait initiation parameters, the odds of postural instability were:i, the co-variables being determined, was therefore,The unit odds ratio for the classifier XLack-of-fit tests were performed to address whether there was enough information using the selected variables in the fitted model for postural instability discrimination. The significance of the model effects, as a whole, for the statistical adjustment of postural instability discrimination was assessed using the likelihood-ratio Chi-square tests (whole model tests). The usefulness of models was measured by RSquare for logistic regression. The significance of the contribution of each effect to the adjustment of the model for postural instability discrimination was assessed using the effect likelihood ratio tests.th classifier using the logistic regression multivariate effect likelihood ratio test29 to assess the discriminatory performance (AUC) for postural instability. Differences in discriminatory performance of classifiers were tested, for significance purposes, by comparing the AUC values using bivariable Chi2 tests.Next, ROC analysis was performed for the PIK-Means clustering was used to cluster the subjects together that share similar values across the gait initiation and postural instability variables. The number of clusters, K, was specified a priori. The optimal number of clusters providing the best fit was selected using the highest cubic classification criterion (CCC). The inter-method reliability between pull test and K-means clustering was assessed using the Kappa statistic.P value < 0.05).SAS 9.1  was used for statistical analysis  of biomechanical parameters are shown in Table amplitude, Vm, L, V1 and Braking-index were significantly lower , and APAduration, significantly higher (P = 0.0163), compared to subjects with no postural instability (Table amplitude was significantly associated with a decrease in step length (L) and CoM forward progression velocity (Vm) .Subjects with postural instability, the values of biomechanical parameters APAty Table . The decamplitude and Braking-index classifiers are shown in Table amplitude and Braking-index parameters . Their values significantly decreased by 46.06% and 83.67% (P = 0.0003 and 0.0001), respectively, in subjects with postural instability compared to those with no postural instability.The AUCs obtained from ROCs and optimal decision thresholds for APATheir accuracies were not significantly different  for postural instability discrimination. Their optimal decision threshold values for postural instability discrimination were th was modeled by the equation:P < 0.0001 and RSquare = 0.6119 for the whole-model effects, P = 0.9975 for the lack of fit Chi-square of the whole-model, and P = 0.0200, 0.0235 and 0.0156 for the parameter estimates and intercept, respectively.PIth value significantly increased by 128.76% (P < 0.0001) in subjects with postural instability compared to those with no postural instability . The unit odds ratios OR (APAamplitude) and OR (Braking-index) for postural instability were 0.8779  and 0.8870 , respectively.PIth for postural instability discrimination was P < 0.0001), with a sensitivity of 90.91%, and a specificity of 83.87%, calculated with the optimal decision threshold values of parameters APAamplitude and Braking-index , thus significantly increasing the sensitivity of discriminatory performance by 11.11%, i.e., from 81.82 to 90.91%  was designed as a theoretical integrator of the biomechanical determinants of postural instability, from gait initiation factors in the APA and execution phases, to increase discriminatory performance of postural instability. It was conceived on the basis of a nomogram of the postural instability established from the whole study population in the perspective of personalized approach of postural instability in ALS.Therefore, multi-fitted theoretical discrimination index of postural instability (PI(P < 0.0001) and useful (RSquare = 0.6119), which supported the conclusion that the model significantly reflected the gait initiation variables globally by fitting the variables APAamplitude and Braking-index. In addition, the test of lack-of-fit Chi-square for the whole model showed a large P value (P = 0.617) and did not conclude that there was a significant lack of fit for this model. This supported the conclusion that the selected terms from the mixed stepwise selection provided enough information to the fitted model, and there was little to be gained by introducing additional terms in the model, such as using polynomials or crossed terms. This was corroborated with the significant contribution of each of the effects of APAamplitude and Braking-index to the fit of the model . This shows that the biomechanical parameters APAamplitude and Braking-index each contributed significantly and usefully to the improvement of the model’s performance for postural instability discrimination.Statistical convergence for this model was achieved. The whole model effect was significant for postural instability discrimination amplitude and Braking-index were negative, indicating that as the APAamplitude or braking-index decreased, the probability of postural instability increased. Thus, for a 10 mm decrease in APAamplitude or a 10% decrease in Braking-index, the odds of postural instability were 11.4 and 11.3 times, respectively, higher than the odds of no postural instability.The regressors for APAamplitude, Braking-index and PIth can discriminate between the state of two patients, referred to as "postural instability" and "no postural instability". It was the probability that a subject with postural instability, randomly chosen, is ranked as more likely to have postural instability than a subject without postural instability randomly chosen, based on nonparametric Mann–Whitney U statistics used in calculating AUC.The area under ROC curve (AUC), referred to as an index of accuracy, is a measure of performance for a ROC curve. It was used to quantify how accurately the classifiers APAth) showed the highest discriminatory performance (AUC = 0.953). It significantly increased the sensitivity, that is the probability that the classifier correctly discriminates a postural instability condition that exists, while maintaining the specificity, which is the probability that the classifier correctly discriminates that a condition of postural instability does not exist. This was consistent with the aim of our study. Indeed, a false negative discrimination may have different consequences than false positive ones. Increasing sensitivity for postural instability discrimination has the advantage of initiating appropriate treatment and rehabilitation in a greater number of ALS patients who will have a condition of postural instability. This will also lower the possibility of falls and fractures with the acceptable risk of initiating treatment and rehabilitation in some patients who would not have needed it due to false positives. Moreover, maintaining specificity has the advantage of not increasing the unacceptable risk of not starting a rehabilitation program in some patients who will have a postural instability condition, due to false negatives. Not treating those patients who would have needed it would imply serious and costly consequences due to falls and fractures, impacting the quality of life.The theoretical discrimination index of postural instability (PIth) reliability depended on the reliability of the pull test and gait initiation biomechanical data. Variability in pull test performance can lead to inadequate evaluation of postural instability27. Indeed, a study27 on postural instability assessment in Parkinson's disease reported that specific aspects of pull test were incorrectly performed regarding the position in 27.3%, strength and briskness of the pull in 84.9%, examiner's response in 36.4%, and technique issues in 9.1%. This study reported27 that 77.3% of patients with early Parkinson's disease were pulled too lightly, underestimating the deficit with possible bias in the score, especially between 0 and 1. Furthermore, the number of steps backward to differenciate a normal recovery response from retropulsion was not being clearly defined, postural stability score was not easily interpreted, especially to differentiate the scores 1 and 227.Throughout our study, the theoretical discrimination index . For a successful execution of the pull test, the patients had sufficient space to move backward and assume an upright position that enabled a rapid corrective repositioning. Doing so, this avoided any attitude that could neutralize the pull before it was carried out, such as leaning forward or excessively widening the position of the feet. Consequently, the pulling force had not subjectively anticipated the postural instability degree. It was suitably adapted to the height and weight of the subjects to move the CoM to the point of compromising postural stability and requiring corrective trunk movements with a maximum of two steps backward for recovery31. The CoM forward movement is oriented in the direction of the stance leg32 to counterbalance prior to step execution34. Thus, the magnitude of imbalance plays an essential role in the regulation of global gait initiation kinematic31, as it creates the anticipatory conditions to propel the CoM forward23 while maintaining the stability during the step execution37. Our study showed that the CoP backward displacement, APAamplitude, was significantly associated with the motor performances in terms of step length and CoM forward progression velocity, and with the occurrence of postural instability in ALS patients. The shorter the magnitude of backward displacement of the CoP, the lower the step length and forward progression velocity, and the greater the risk of postural instability.During gait initiation, the anticipatory postural adjustments induce the CoP displacement backward relative to CoM, and toward the swing leg, which generates an imbalance which allows to initiate the CoM forward movement from the static posture38. The base of support is reduced by the act of lifting the swinging foot from the ground. The gap between the CoM and the CoP generates a disequilibrium which accelerates the CoM movement forward and downward39 in the direction of the swing leg. The CoM vertical downward velocity is actively braked before the foot contact with the ground40 by the increase in antigravity activity of the stance leg soleus muscle31. This reduces the bodily stress of the impact of the swing leg with the ground and maintains postural stability during the subsequent double stance phase41. Our study showed the CoM active vertical braking, or Braking-index, was significantly associated with the occurrence of postural instability in ALS patients. The greater the deterioration in active vertical braking, the greater the postural instability risk.During step execution, the CoM is propelled forward to step forward, and out of the base of supportth) combines the CoP backward displacement (APAamplitude) and CoM active vertical braking (Braking-index), which were independent underlying biomechanical mechanisms of gait initiation, significantly involved in dynamic postural control and the occurrence of postural instability in ALS patients.Thus, theoretical discrimination index (PI11. Some studies showed in patients with progressive supranuclear palsy41, or Parkinson disease42 that increased muscle tone with stance leg muscle stiffness can impairegait initiation, and be partly responsible of an unstable state.In our study, the gait initiation impairment in ALS patients did not stem from a decrease in muscle strength of the lower limbs, as the manual muscle tests revealed no significant differences between subjects with and without postural instability. However, patients with postural instability had increased muscle tone which can contribute to slow the CoM forward propulsion and deteriorate the dynamic postural stability during gait initiation10, cerebellar14, and vestibular15 origin. Consequently our model is applicable only in patients with a deficit limited in the upper limb and/or bulbar regions. Another limitation was that our model did not allow to discriminate between an extrapyramidal or pyramidal origin of the instability, and that we lack longitudinal data to validate whether our model can predict the occurrence and frequency of falls as well as the pull test.A limitation of this study was that we excluded patients with motor deficit in the lower limb that is a major cause of postural instability in ALS patients. We focused on other underlying mechanisms that are possibly of extrapyramidalThe theoretical postural instability discrimination index, designed as an integrator of the gait initiation biomechanical processes, significantly involved in dynamic postural control, was reliable and effective with a significant increased sensitivity in ALS patients. This, without reducing its specificity, which is key in view of the consequences of instability in terms of falls and fractures with repercussions on the quality of life. The importance of inter-method reliability between pull test and cluster analysis across the gait initiation and postural instability variables, represented the extent to which methods of data collecting in the study constituted correct representations of the variables measured.This work is of significant clinical interest by offering an objective and measurable clinical index of physical and pathophysiological processes of postural instability in ALS. This may also be a useful complementary expertise in these patients for a personalized approach to postural instability.


Background and Objectives: No data are available on whether the heritability of left ventricle (LV) systolic and diastolic parameters are independent of each other. Therefore, our aim was to assess the magnitude of common and independent genetic and environmental factors defining LV systolic and diastolic function. Materials and Methods: We analyzed 184 asymptomatic twins . Transthoracic echocardiography was performed to measure LV systolic  and diastolic  parameters using conventional and speckle-tracking echocardiography. Genetic structural equation models were evaluated to quantify the proportion of common and specific genetic  and environmental factors  contributing to the phenotypes. Results: LV systolic parameters had no common genetic or environmental heritability . Diastolic LV parameters were mainly determined by common genetic and environmental effects . Systolic parameters had no common genetic or environmental factors  with diastolic metrics. Conclusions: Systolic LV parameters have a strong genetic predisposition to any impact. They share no common genetic or environmental factors with each other or with diastolic parameters, indicating that they may deteriorate specifically to given effects. However, diastolic functional parameters are mainly affected by common environmental influences, suggesting that pathological conditions may deteriorate them equally. Estimation of the genetic and environmental influence and interdependence on systolic and diastolic LV function may help the understanding of the pathomechanism of different heart failure classification types. Heart failure (HF) is a highly prevalent, multi-factorial progressive disease associated with substantial morbidity and mortality, thus representing one of the main global health problems . The etiClassical twin studies use genetic structural equation models to quantify the proportion of genetic and environmental factors contributing to the given phenotype. This model is based on the fact that monozygotic (MZ) twins share 100% of their genes, while dizygotic (DZ) twins share only half. It is possible to decompose the variation of a measured parameter between the twin siblings into additive genetic factors (A), common environmental factors , and unique environmental factors . Additive genetic influence (A) describes the additive effect of multiple genes, while non-additive genetic factors (NA) represent interactive effects of different alleles and include genetic dominance within locus interaction (D). Shared environmental effects (C) and non-additive genetic effects are confounded (D), and the choice between them is based on the pattern of twin correlations. Previously, we have demonstrated that mathematical modelling of genetic influence shows high systolic myocardial deformation heritability in a Caucasian population without systolic dysfunction. However, environmental factors have a stronger influence on LV diastolic function . FurtherTherefore, the aim of our study was to assess whether there are common genetic or environmental factors that determine systolic functional parameters, diastolic functional parameters or both. Using accurate LV functional measurements and appropriate statistical methods might give a more precise estimation of the influence and interdependence of different genetic and environmental predisposing factors on systolic and diastolic LV function.The investigation was part of the BUDAPEST-GLOBAL (Burden of Atherosclerotic Plaques Study in Twins—Genetic Loci and the Burden of Atherosclerotic Lesions) clinical study, which is a prospective, single-center, classical twin cohort study established to assess the effects of genetic and environmental factors on different cardiovascular phenotypes . The twiBasic anthropometric parameters  of every person were measured. Past medical history and lifestyle habits were recorded. The physical examination included a blood pressure measurement, a 12-lead ECG, and an assessment of potential symptoms and physical signs of any cardiovascular disease.Transthoracic echocardiography  was performed. LV end-diastolic and end-systolic volumes and ejection fraction were calculated using the biplane Simpson method. The Devereux formula was used to quantify LV mass. Parameters of LV diastolic function  were determined according to current guidelines. Mitral inflow parameters included early diastolic inflow velocity (E wave), late diastolic inflow velocity (A wave), and deceleration time of E wave (DCT), even though tissue doppler examination measures lateral mitral annulus early diastolic tissue velocity (EeLat). Body surface area (BSA) was calculated by the Mosteller formula .Beyond conventional echocardiographic measurements, the protocol included the acquisition of high-quality images appropriate for two-dimensional speckle-tracking analysis. Parasternal short-axis views of the mitral valve, papillary muscle, and apical levels, as well as apical four-chamber, two-chamber, and long-axis views were acquired for speckle tracking. Raw data were exported to a standalone workstation for off-line analysis with commercially available software . After manual delineation of the endocardial surface, the software tracked the region of interest throughout three consecutive cardiac cycles. Peak systolic strains of the 16 LV segments averaged over three cardiac cycles were used to calculate the corresponding global values. GCS and GRS were quantified using the parasternal short-axis views. In addition, we determined the apical counterclockwise and basal clockwise rotations by averaging the four and six segmental values, respectively. Apical views were used to assess GLS and systolic strain rate, along with early diastolic strain rate values. Subjects with fewer than ten available segmental values were not included in the statistical analysis.Genetic structural equation models were evaluated to quantify the proportion of genetic and environmental factors contributing to the given phenotype. Based on the fact that MZ twins share 100% of their genes, while DZ twins only share half, it is possible to decompose the variation between the twin siblings into additive genetic factors (As), common environmental factors (Cs) that are similar between the twins and unique environmental factors (Es) that are specific to one of the siblings . SubmodeThree statistical models were considered. A Systolic Model, which assess the heritability and co-heritability of GLS, GCS, basal rotation, and apical rotation; a Diastolic Model using LSrE, EeLat, and DCT; and a Systolo-Diastolic Model considering GLS, Lsre, EeLat, and DCT were calculated. All calculations were adjusted for age and sex. All analyses were performed using R version 3.4.0 . Twin moIn the current study, we included 184 twin subjects . We excluded nine twin pairs from the original BUDAPEST-GLOBAL cohort because of inadequate echocardiographic image quality [Demographic characteristics and basic echocardiographic parameters of the study population were published previously by our workgroup . BrieflyLV systolic function, measured by both ejection fraction and GLS, was normal in every sibling . Early diastolic mitral inflow velocity (E wave) was higher in MZ twin pairs (E wave: 0.74 ± 0.16 m/s) compared with the DZ twin pairs (E wave: 0.70 ± 0.12 m/s). All other and echocardiographic parameters, including strain and strain rate measurements, were in normal range and comparable between the MZ and DZ pairs. Detailed comparisons were published earlier [When considering the Systolic Model on the common and specific genetic and environmental factors contributing to LV myocardial deformation, interestingly, we found strong genetic background of strain parameters. However, there were no common genetic or environmental determinations among GLS, GCS, and basal and apical rotation .The specific genetic contribution to the variance of strain parameters ranged between 61% and 75%, while the common genetic or environmental contribution accounted for 0%. We found some specific environmental effects for each LV systolic strain parameter, with relatively higher contribution to the variance in the case of basal and apical rotation (43% vs. 36%). GLS and GCS were only slightly affected by specific environment (23% vs. 24%).On the contrary, the investigated diastolic parameters in the Diastolic Model  were rather determined by environmental effects . The oveIn the third Systolo-Diastolic Model, investigating the major systolic and diastolic measures together, we found that GLS shares neither common genetic nor common environmental determination with diastolic parameters . AccordiSystolic, Diastolic, and Systolo-Diastolic Models.The detailed model fit results showing the model that fitted the best to our data is presented in We demonstrated mathematically that genetics have substantial impact on systolic LV function; however, none of the LV systolic parameters have any common genetic background, indicating that each systolic parameter has separate genetic determinants. Consequently, LV global longitudinal strain is independently inherited from circumferential strain, indicating that the strong inheritance (74%) of different myocardial layers is independent of each other. Diastolic function is defined mainly by environmental factors. Genetics have only modest influence on left ventricular diastolic function. The modest genetic influence (40%) on the accurate and sensitive LV early diastolic strain rate is mainly of common genetic background. However, the commonly used diastolic parameter of EeLat is affected 51% by genetics, which is equally shared between common and specific genetic determinants. Analyzing the co-heritability of LV systolic and diastolic parameters, we found that systolic and diastolic LV parameters have no common genetic or environmental determinants, suggesting that LV systolic and diastolic functional alterations may develop separately from each other.The LV myocardium is composed of a continuous sheet of myofibers that are arranged in a multi-layered, helical manner. The corresponding deformation directions measured by speckle-tracking echocardiography have a strong, independent genetic and environmental determination, indicated by the fact that we found no common genetic and environmental roots for strain parameters. Regardless of the inherited or acquired nature of the etiology, myocardial damage usually starts with the most sensitive inner LV subendocardial fibers affecting longitudinal shortening; however, impairment of mid-wall muscle fibers contraction occurs at a later stage, influencing circumferential shortening . CoronarWe have shown that myocardial deformation resulting from the contraction of each of the aforementioned three layers has a strong, independent genetic determination. The diagnostic and prognostic value of longitudinal and circumferential strain in different cardiac abnormalities varies. GLS is a sensitive parameter for assessing LV function in the subclinical state of cardiovascular diseases when the conventional LV EF is still in normal range . Our resThe genetic component of LV systolic function using strain parameters was assessed in the Hypertension Genetic Epidemiology Network (HyperGEN) Study. In this large population- and family-based epidemiologic study, they found that longitudinal myocardial function is heritable, even after adjusting for several clinical factors associated with these indices . CardiacSeveral limitations of classical twin studies must be considered. A number of assumptions are made in structural equation modelling. It is assumed that MZ and DZ twin pairs share their environments to the same extent. Furthermore, it is assumed that twins are not different from the general population in terms of the examined traits and that the gene–environment interactions are minimal for these traits. Our results are drawn based on middle aged, relatively healthy Caucasian twins at low–moderate cardiovascular risk. Further studies, including twins treated for heart failure with preserved or reduced EF, might give a better insight into the inheritance and co-heritability of different LV functional alterations and their development. Our sample size was relatively modest; studies with larger sample sizes, including representation of multiple ethnicities, are warranted. Furthermore, zygosity in our twin cohort was determined based on validated questionnaires .We demonstrated mathematically high heritability of LV systolic strain parameters with independent inheritance of each other. This substantial genetic determination of LV systolic biomechanics may help to preserve global LV systolic function for a longer period in the case of different environmental effects . The independent genetic determination of GLS, GCS, and basal and apical rotation might be one explanation of their separate deterioration in some diseases. However, LV diastolic function is much more sensitive to environmental changes, and diastolic dysfunction might be expressed independent of systolic dysfunction. Next-generation sequencing with whole exome and whole genome sequencing, as well as advances in epigenomics and analysis of gene–environment interactions will hopefully continue to improve our understanding of the genetics of cardiac structure and function.