EAT thickness showed a significant correlation with GWI and GCW , and also independently correlated with GWI and GCW in the multivariate regression analysis . EAT thickness is associated with left ventricular myocardial function in subjects with suspected metabolic syndrome, independently of other risk factors. Further studies are supposed to ensure the causal associations and related mechanisms.Given the inconsistent results on the prognostic significance of epicardial adipose tissue (EAT), the purpose of the present study was to investigate the association of EAT thickness and myocardial work by non-invasive left ventricular pressure-strain loop in people with suspected metabolic syndrome (MS). A total of 194 participants imaged with echocardiography were evaluated. In accordance with the median EAT thickness, MS patients fell into thin EAT group and thick EAT group. Conventional echocardiographic parameters, global longitudinal strain (GLS) and the global myocardial work parameters obtained by pressure-strain loop analysis, comprising the global work index (GWI), global work efficiency (GWE), global constructive work (GCW) and global wasted work (GWW) were compared between the two groups. In comparison with the thin EAT group, thick EAT group achieved significantly higher values in interventricular septal thickness, end-diastolic left ventricular posterior wall thickness, left ventricular mass index and GWW ( EAT is considered to be an independent predictor of visceral obesity and may be closely associated with the pathogenesis of metabolic syndrome (MS)4, adverse clinical outcomes of COVID-197, coronary artery disease, and diabetes8.Epicardial adipose tissue (EAT) refers to a type of visceral fat located between the myocardial surface and the visceral layer of the pericardium. EAT has been confirmed as an independent risk factor for accelerated progression of subclinical coronary atherosclerosis9. Several cardiovascular risk factors occur together and are interrelated, with common potential mediators, mechanisms, and pathways10. MS turns out to be a leading health problem for its correlation with cardiovascular disease. It was reported to be correlated with a twofold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality11. It is clear why MS is the focus of various studies. The prevalence of MS has increased significantly worldwide, making accurate assessment of changes in left ventricular (LV) systolic function particularly important at an early stage. Tadic et al.12 evaluated left ventricular mechanics in patients with metabolic syndrome through two-dimensional echocardiography speckle tracking analysis, but the impact of metabolic syndrome on left ventricular myocardial work has not yet been evaluated.MS represents a group of common cardiovascular risk factors, comprising insulin resistance, obesity, atherosclerotic dyslipidemia, as well as hypertension13. Based on the speckle tracking echocardiography, brachial artery cuff pressure has been employed to replace left ventricular pressure, such that the LV strain and pressure parameters are combined, which can reduce the influence of afterload on the myocardial strain. Currently, limited data are available regarding the changes in left ventricular myocardium work and the correlation between epicardial fat and left ventricular myocardium work in MS patients.Ejection fraction (EF) is the most commonly used index of LV systolic function examined by conventional echocardiography. However, the measurement of EF is a simplistic method, limited by the requirements of geometric assumptions. Thus, in high-risk subclinical patients with MS, subtle changes may be overlooked when myocardial systolic function is assessed using EF alone. The use of two-dimensional speckle tracking echocardiography for myocardial deformation imaging has made the progress of left ventricular quantification beyond EF and become an excellent prognostic marker of cardiac events. However, one of the main limitations of strain imaging is load dependence, which may affect the diagnostic accuracy of myocardial function assessment. LV pressure-strain loop (PSL) analysis refers to a novel echocardiographic method for noninvasive quantification of myocardial workBased on the above, we hypothesized that the accumulation of EAT in patients with metabolic syndrome is related to sub-clinical changes in left ventricular myocardial work. Therefore, in this study, we aimed to investigate left ventricular systolic function and myocardial work in patients with suspected metabolic syndrome using left ventricular pressure-strain loop technique. Furthermore, we assessed the correlation between EAT thickness and left ventricular myocardial work in patients with suspected metabolic syndrome.14: Elevated triglycerides > 1.7 mmol/L; reduced high‐density lipoprotein cholesterol (HDL-C) (< 1.3 mmol/L in women and < 1.03 mmol/L in men); hypertension (HTN) (≥ 130/85 mmHg); hyperglycaemia ≥ 100 mg/dL; abdominal obesity by waist circumference ≥ 80 cm in women and ≥ 90 cm in men15. Furthermore, the exclusion criteria included participants with a previous history of coronary artery disease, congenital heart disease, heart failure, atrial fibrillation, moderate or severe valvular heart disease, stroke, or any revascularization. This study protocol gained approval from the Ethics Committee of the First Hospital of Qinhuangdao (2021Q082). The median EAT thickness reached 3.82 (Inter- Quartile Range 2.28) mm. In accordance with the median EAT thickness, MS patients were divided into two groups: thin EAT group  and thick EAT group . The clinical data, laboratory examination, echocardiography and myocardial work were compared between the two groups.Among 213 suspected MS patients imaged with echocardiography from September 2020 to December 2021, 194 patients were recruited. The exclusion criteria for the 19 patients comprised poor image quality (n = 12), and arrhythmia (n = 7). The median patient age was 62 years, 95 patients (49%) were men. The MS was defined based on the presence of three or more components of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria (2005 Revision)Anthropometry  was performed for all participants in the study to calculate body mass index (BMI). Moreover, waist circumference, heart rate, systolic (SBP) and diastolic blood pressures (DBP) were examined. Fasting plasma glucose (FPG), uric acid, triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were examined less than two weeks prior to the echocardiographic evaluation using standard laboratory techniques.16. From the parasternal long axis view, we examined ascending aorta diameter (AAO), left atrial diameter (LAD), LV end-diastolic diameter (LVEDd), end-diastolic LV posterior wall (LVPWd) and interventricular septal (IVSd) thickness. LV ejection fraction (LVEF) was calculated using the modified Simpson's rule from apical 4- and 2-chamber views. LV mass (LVM) was determined using the Devereux formula17: LVM (g) = 0.8 × 1.04 × [(LVDd + IVS + LVPW)3 − LVDd3] + 0.6. The LV mass index (LVMI) was calculated by dividing the LVM by body surface area (BSA). BSA was calculated according to the Dubois formula18: BSA = 0.007184*Height0.725*Weight0.425. Pulse wave Doppler was adopted to measure the peak velocity of early and late mitral diastolic blood flow (E and A), tissue Doppler imaging was employed to measure the early diastolic motion velocity of mitral ring (e'), and E/e' were obtained.Echocardiographic examinations were performed using Vivid E95  ultrasound machine equipped with a M5S 3.5 MHz transducer (frame rate 50 ~ 80 frames/s). All records and measurements were taken according to American Association of Echocardiography guidelinesEAT refers to the fat pool between the outer wall of the myocardium and the visceral layer of the pericardium. The thickness of EAT was measured by echocardiography. Maximum EAT thickness was examined perpendicular to right ventricular free wall at the end of systole in a parasternal long-axis view. Three different measurements were recorded over three consecutive cardiac cycles, and the mean value of EAT was determined.GE EchoPAC version 203 software was employed for LV strain and myocardial work analysis. Three apical  views were captured and then stored for subsequent off-line analysis (average 3 consecutive cycles). Aortic valve closure was automatically recognized in apical long axis view. Click automated function imaging (AFI) button, the system automatically recognized the apical 4-chamber and 2-chamber view, and tracked the contour of the left ventricle endocardial and ventricular wall. The areas of interest were regulated by correcting endocardium boundaries or widths if required. The global longitudinal strain (GLS) was determined based on the weighted average of the peak systolic longitudinal strains at all 17 segments. After GLS was obtained, insertion brachial artery blood pressure, and timing of valve events, the software derived a non-invasive PSL. The global myocardial work parameters , global work efficiency (GWE), global constructive work (GCW), and global wasted work (GWW)) were obtained through the PSL analysis.p values ≤ 0.10 were included into the stepwise multiple regression analysis. A total of 20 patients were randomly selected and examined by two experienced cardiac sonographers. The consistency analysis of GWI, GCW, GWW and GWE was performed, and the same samples were analyzed again by one of the radiologists one week later. Intra-observer and inter-observer variables were calculated by intra-class correlation coefficient (ICC). A p value less than 0.05 was considered a difference that achieved statistical significance.The data were analyzed using SPSS software (version 27). Continuous variables are expressed as mean ± standard deviation if normally distributed or median with interquartile ranges if not normally distributed. Data are expressed as percentages in terms of categorical variables. Statistical comparisons comprised student t-test or Mann–Whitney U test. The correlation between different metabolic syndrome criteria and LV myocardial work parameters was determined using Pearson correlation coefficient. The variables with Informed consent was obtained from all subjects and/or their legal guardian(s). All methods were carried out in accordance with relevant guidelines and regulations. This study was approved by the Ethics Committee of the First Hospital of Qinhuangdao (2021Q082).p < 0.05; 138(10) vs. 140(20), p < 0.05; 80(12) vs. 85(12.25), p < 0.05; 93(12) vs. 97(15.75), p < 0.05; 2.01(1.08) vs. 2.59(2.74), p < 0.01). No significant differences were identified between the two groups in age, male proportion, heart rate, fasting blood glucose, uric acid, total cholesterol, LDL-C and HDL-C (p > 0.05).The baseline characteristics of MS patients are shown in Table p > 0.05). However, in comparison with the thin EAT group, thick EAT group showed significantly higher values in IVSd, LVPWd and LVMI (10(3) vs. 11(4), p < 0.05; 8(1) vs. 9(2), p < 0.001; 79.24(25.95) vs. 85.97(32.22), p < 0.05). The absolute value of GLS, E and e′ were significantly lower in the thick EAT group (17(2) vs.14(2.75), p < 0.001; 69.61(19.50) vs. 64(20.22), p < 0.05; 6.6(1.85) vs. 6(2.20), p < 0.01).Table p < 0.001). The GWI , GCW , and GWE (94(3) vs. 91(5); p < 0.001) were significantly decreased in the thick EAT group . Figure We further examined whether left ventricular myocardial work was affected by the change of EAT thickness. Detailed results on LV myocardial work are summarized in Table p = 0.001; r = − 0.253, p = 0.012) . Moreover, GCW showed a weak correlation with triglyceride . GWW and GWE had notable correlations with fasting blood glucose   Fig.  and SBP p = 0.001; β = − 0.199, p = 0.049) and SBP . GWW was independently correlated with fasting blood glucose   Compared with the thin EAT group, IVSd, LVPWd and LVMI in the thick EAT group were significantly increased, while the absolute values of GLS, E and e' were significantly decreased; (2) The thick EAT group achieved significantly higher value in GWW in comparison with the thin EAT group. Meanwhile, the GWI, GCW, and GWE were significantly decreased in the thick EAT group; and (3) EAT thickness was inversely correlated with GWI and GCW.19. In this study, conventional echocardiographic parameters were compared between the two groups. The results show that IVSd, LVPWd and LVMI in the thick EAT group were significantly increased compared with the thin EAT group, while the absolute values of GLS, E and e' were significantly decreased. In metabolic syndromes, left ventricular hypertrophy may occur with increased after-load20. It is the most prominent early cardiac manifestation in hypertensive patients, characterized by increased myocardial weight and ventricular remodeling. Diabetic myocardial microangiopathy can lead to chronic myocardial ischemia and hypoxia, cardiomyocyte necrosis, myocardial fibrocyte proliferation, and eventually left ventricular hypertrophy. Moreover, several inflammatory substances released from adipocytes, such as resistin have been suggested to contribute toward the adverse effects of obesity on the heart by promoting myocardial hypertrophy and dysfunction21. Extensive research has reported that the myocardial strain obtained by two-dimensional speckle tracking imaging can make left ventricular quantization beyond LVEF a better prognostic marker of cardiac events24. In this study, no significant difference in AAO, LAD, LVEDd, LVEF, A and E/e′ was reported between the thin and thick EAT groups. Compared with the traditional index of systolic function, GLS is more sensitive to indicate the degree of myocardial injury, and may decrease prior to the change of LVEF, consistent with previous literature reports. Among the measurements of myocardial function, GLS measured by echocardiography is the most widely studied marker, providing a simple, inexpensive, and quantitative way to assess global long-axis systolic function. However, one of the major limitations of strain imaging is after-load dependence. Moreover, it cannot reflect myocardial work or oxygen demand25. The noninvasive LV pressure-strain loop serves as a novel method of quantifying myocardial work in combination with myocardial strain and LV pressure measurements, and may provide incremental value for assessment of myocardial function26. The work contributed by the respective normal contracting component is positive and is called "constructive work". In the normal heart, very little work is wasted and thus there is a high work efficiency. Compared with the thin EAT group, GWW was significantly increased in thick EAT group, while GWI, GCW, and GWE notably declined. Prolonged systole and shortened myocardium after aortic valve closure will produce wasted work because it does not result in left ventricular ejection. In early untreated hypertension, diastolic dyssynchrony mainly affected constructive work, whereas post systolic shortening affected wasted work27.In general, the conventional clinical evaluation of left ventricular systolic function is performed through the measurement of myocardial fiber shortening indexes 28. However, excess body fat accumulation is correlated with metabolic abnormalities and myocardial dysfunction30. In this case, the protective properties of EAT may be destroyed and become harmful tissues that promote the development of cardiovascular diseases. Despite the unclear underlying mechanism, EAT has been confirmed as a potential source of inflammatory mediators, comprising interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Hirata et al. reported that the infiltration of inflammatory cells was enhanced in the epicardial adipose tissue of patients with coronary artery disease, instead of not in the subcutaneous fat31. Moreover, EAT has the potential to secrete adipotropic factors and free fatty acids, which may promote myocardial steatosis and induce cellular oxidative stress, as well as increased nitric oxide synthase activity and production of intracellular nitric oxide, and eventually lead to apoptosis of myofibrillar cells32. Recent research has placed a focus on myocardial fibrosis, a critical histological component of cardiac remodeling. Myocardial fibrosis scarring occurs most commonly after myocardial infarction, but can also occur in a variety of other diseases that promote myocardial fibrosis 33. As revealed by relevant data, EAT is capable of producing and secreting adipo-fibrokines , which may promote the formation of myocardial fibrosis34.To the best of our knowledge, this study has been the first to evaluate the role of MS on the correlation between EAT and myocardial work. The EAT is located outside the myocardial wall and maintains intimal contact with the epicardial vessels and myocardium, allowing for paracrine or vasocrine effects. Under health conditions, EAT has protective functions  while taking on critical significance in the energy supply of myocardium26. The left ventricular mechanics were significantly impaired by speckle tracking echocardiography in patients with metabolic syndrome. Previous studies have shown that epicardial fat volume is negatively correlated with left ventricular systolic dysfunction in patients with heart failure35. In this study, we found that EAT was negatively correlated with GWI and GCW in myocardial work parameters in patients with metabolic syndrome. In middle-aged male subjects with metabolic syndrome, EAT was correlated with inflammation represented by high‑sensitivity C‑reactive protein level, LV mass index, e′ and GLS, suggesting that the inflammatory activity of EAT induced myocardial remodeling and dysfunction29. Besides, this study further confirmed that EAT can have an adverse relationship with LV myocardial work at the early stage of LV remodeling.A significant correlation and agreement existed between the area of the non-invasive LV pressure-strain loop and glucose metabolism examined by positron emission tomography. Glucose metabolism is capable of indicating myocardial work. GCW refers to the work performed by the LV during contraction that contributes to LV ejection and is divided into shortening of cardiomyocytes during contraction and lengthening of cardiomyocytes during isovolumic relaxation. GWI is the total work in the LV pressure-strain loop area calculated from mitral valve closure to mitral valve opening36. Fibroblast growth factor-23 (FGF-23) is a biomarker of cardiovascular disease and may also be an early marker of cardiac injury in obese but otherwise healthy African American adolescents. Obesity may promote FGF-23 production in the absence of chronic kidney disease37. Previous studies have shown that blood pressure, waist circumference, and fasting glucose levels exert the most significant effect on left ventricular deformation of all metabolic syndrome components38. The findings in this study are similar to those of previous studies.Furthermore, LV myocardial work were also correlated with SBP, triglyceride, fasting blood glucose in metabolic syndrome. Men and women with impaired fasting glucose and impaired glucose tolerance have more severe alterations in cardiometabolic profiles and inflammatory markers than patients with impaired fasting glucose alone. Even in the absence of high blood pressure, these people were ten times more likely to develop preclinical cardiovascular diseaseSeveral limitations remained in this study. The correlation between increased EAT thickness and impaired LV myocardial work cannot prove that increased EAT inevitably leads to increased LV injury, and its pathophysiological mechanism needs to be further demonstrated. LV pressure-strain loop technology is based on two-dimensional speckle tracking echocardiography, which requires high-quality ultrasonic images. Brachial systolic pressure examined with a cuff and sphygmomanometer may be inaccurate because systolic pressure varies.Although no etiological relationships can be established from the current study, our intriguing finding of the independent relationship of EAT thickness and left ventricular myocardial function by LV pressure-strain loop in subjects with suspected metabolic syndrome may have important clinical implications. Moreover, EAT may serve as a useful marker for identifying metabolic syndrome patients at high risk of abnormal myocardial work. Nevertheless, there is no further mechanistic studies regarding associations between them. Further studies are supposed to ensure the causal associations and related mechanisms.


Purpose: Numerous electrocardiogram (ECG) abnormalities and late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (CMR) have been related to poor prognosis in acute myocarditis. We evaluated whether ECG parameters are associated with the distribution and dynamic of LGE along the course of myocarditis. Methods: Fifty-one patients with CMR confirmed acute myocarditis were included who underwent CMR with LGE and 12-lead ECG at baseline and 3-month follow-up at our institution. The association between the presence, regional distribution and change of ECG parameters and LGE was investigated using linear regression analysis. LGE was quantified as visual presence score (VPS) and visual transmurality score (VTS). Results: Among many ECG parameters only > 1 mm ST-elevation (STE) was associated with VPS and VTS at baseline . STE was most frequent in lateral and inferior ECG-leads (48% and 31%) and it was associated with VPS and VTS in these localizations , however no association between anterior-septal STE and LGE could be confirmed. At follow-up the regression of STE was associated with the regression of VPS and VTS in univariate analysis , which remained significant for VTS using a multivariate model . Conclusion: Although we demonstrated some promising associations between STE and LGE, the usability of ECG to estimate the territorial involvement and dynamical changes of LGE along the course of myocarditis is generally limited and cardiac magnetic resonance should be considered for this purpose. Acute myocarditis is an inflammatory disease of the myocardium with recent onset and variable presentation. While most patients only develop flu like symptoms and completely recover, some patients present with a fulminant course and up to 30% may develop left ventricle function impairment with dilatative cardiomyopathy . Early dConsecutive patients who underwent baseline and follow-up 12-lead ECG and CMR due to suspected acute myocarditis were retrospectively screened within a 4-year time period (January 2016 - December 2019) at our center. Only patients were included, in whom the diagnosis of acute myocarditis could be established in accordance with the respective guidelines . Our inc12-lead standard ECGs were recorded at 25 mm/s and 10 mm/V according to routine clinical protocol. ECGs at hospital admission (baseline) and at the time of the second CMR (follow-up) were analyzed. Additionally, the change between baseline and follow-up ECGs was evaluated, where “change” was defined the presence of a pathology at baseline and absence at follow-up or vice versa and “no change” was defined as the presence or absence of a pathology both on baseline and follow-up study. Two board certified cardiologists (I.M and M.K.) evaluated ECG recordings in consensus, blinded to clinical and CMR data.o), wide QRS complex (> 120 ms) and prolonged QT or QTc interval (> 420 ms) were evaluated. QRS-T angle was defined as the absolute difference between the frontal plane QRS and T axis values and it was adjusted for an angle > 180o (360o – angle) [Qualitative and quantitative ECG pathologies with an established association with acute myocarditis were analyzed . Among q– angle) .Studies were either performed on a 1.5 Tesla  or 3.0 Tesla  magnetic resonance scanner with dedicated setup for cardiac examinations. Cine sequences were acquired with retrospective ECG-triggering under expiration in standard orientations . Native T1 and T2 Mapping, as well as T2-weighted images sequences of the left ventricle (LV) were obtained in one to three short-axis slices  to assess myocardial edema. LGE images were acquired 10-minutes after gadolinium administration in standard orientations . The optimal inversion time was determined using an inversion time scout sequence.The CMR diagnosis of myocarditis was established if regional or global myocardial edema was present  and concomitant signs of a myocardial injury were existing  . LGE invhttps://www.r-project.org).We used the Shapiro-Wilk-test to assess the normality of continuous variables. Continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR). Categorical variables are expressed as numbers and percentages. Data analysis was performed on a patient and regional  level. According to the distribution of continuous variables, paired T-test and Wilcoxon signed rank test were used to compare patient characteristics, and the McNemar Test and Wilcoxon signed rank test were used to compare ECG and VPS/VTS between baseline and follow-up studies, respectively. The regional distribution of LGE was compared with Friedman’s ANOVA test. To assess the associations between ECG and LGE parameters, we used univariate linear and logistic regression analysis. In case any of the predictors was significant at a p < 0.05 level in univariate analysis, we included it into a multivariate model with all other significant predictors. A P-value < 0.05 was considered to indicate statistical significance. All analyses were performed using commercially available software . Patients’ baseline characteristics are summarized in Table 86% of the patients had an ECG abnormality at hospital admission, which decreased to 56% at follow-up (p < 0.001). Among qualitative ECG abnormalities, ST-T changes (> 1 mm STE or STD and T inversion) were most frequently documented at admission, overall, in 55% of the patients and persisted in 29% at follow-up (p = 0.007). Among quantitative ECG changes, pathological QTc interval was most frequently observed at baseline, overall, in 37% of the patients, which decreased to 8% at follow-up (p = 0.007). ECG findings at baseline and at follow-up are summarized in Table 96% of the patients showed LGE in a non-ischemic  localization in at least one myocardial segment. 19% of the patients had CMR findings comparable with associated pericarditis. LGE was most frequent in the lateral, and less common in inferior and anterior myocardial regions . 45% of the LGE positive patients at baseline showed a regression of VPS and 82% of the patients a regression of VTS at follow-up CMR. None of the patients showed an increase of VTS/VPS on follow-up CMR. LGE, as well as functional CMR data at baseline and at follow-up are reported in Table Among baseline qualitative ECG parameters > 1 mm STE showed an association with baseline VPS and VTS. The presence of > 1 mm STE at baseline ECG was associated with 3.1x increase of VPS  and 5.4x increase of VTS on baseline CMR  in multivariate models. No association between baseline quantitative ECG parameters and baseline LGE was found. The associations between baseline ECG parameters and LGE is summarized in Table When assessing the regional interrelationship between ECG parameters and LGE, > 1 mm STE at baseline showed a regional association with baseline VPS and VTS in the inferior and lateral localizations. No association in the anterior-septal localization between ECG and CMR pathologies could be revealed. The regional associations between baseline ECG parameters and LGE is summarized in Table Our study demonstrated that among several frequently seen ECG abnormalities in acute myocarditis, only > 1 mm ST-elevation correlates with the presence and extent of LGE on CMR. STE was most frequent in the lateral and inferior myocardial territories in our cohort and though we showed a regional interrelationship of STE with LGE in these regions, no association between STE and LGE in the anterior-septal territories could be demonstrated. Importantly, the regression of STE from baseline to follow-up ECG was associated with the decrease of LGE at 3-months’s follow-up CMR, while no other ECG parameters showed a distinct association with LGE.Acute myocarditis carries varying outcome and CMR deems extremely helpful in the prediction of a long-term prognosis. A meta-analysis found that positive LGE in myocarditis is a strong predictor of future adverse events  , and a rIf CMR is not available, estimation of prognosis, moreover, risk-monitoring with conventional diagnostic techniques only is challenging. ECG pathologies in the acute phase of myocarditis are frequent, yet, not specific. Still, certain baseline ECG abnormalities have been linked to the development of myocardial fibrosis and worse outcome in myocarditis . FurtherIn our study we found that ST-pathologies are the most common ECG findings related to acute myocarditis. >1 mm STE at baseline was associated with a 3.1-fold increase of VPS and 5.4-fold increase of VPS on baseline CMR. STE was most frequently related to lateral and inferior myocardial segments (48% and 31%). We could demonstrate a regional interrelationship between STE and LGE localized to lateral and inferior myocardial regions. While an earlier study could not demonstrate an association between STE and myocardial damage in CMR , similaro) was previously found to strongly correlate with the presence of LGE in CMR [Among quantitative ECG parameters, wide QRS-T angle (≥ 100E in CMR . AdditioE in CMR . ContrarOur study has more limitations. First, our study is limited by the retrospective analysis with the lack endomyocardial biopsy as reference standard and the lack of a long-term clinical follow-up. Nevertheless, large multi-center studies have already addressed the long-term predictive value of ECG and CMR parameters in myocarditis , 13, 17,In patients with suspected myocarditis among several qualitative and quantitative ECG parameters only ST elevation is associated with LGE on CMR, which may be used as a gatekeeper to identify individualist at risk of myocardial injury and future cardiac events. If CMR is not available, monitoring the resolution of ST elevation at follow-up seems to be valuable to estimate the dynamic of LGE, which is a well-known marker of fibrotic transformation of injured myocardium. While we showed some promising results regarding the territorial associations between STE and LGE in the inferior and lateral localizations as well, no association in the anterior-septal region could be revealed. This overall suggests, that the capability of ECG is limited to estimate the myocardial involvement along the course in myocarditis and CMR should be considered for this purpose.


Diabetes mellitus (DM) is the most common metabolic disease worldwide and a major risk factor for adverse cardiovascular events, while the additive effects of DM on left ventricular (LV) deformation in the restrictive cardiomyopathy (RCM) cohort remain unclear. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients with RCM.One hundred thirty-six RCM patients without DM [RCM(DM−)], 46 with DM [RCM (DM+)], and 66 age- and sex-matched control subjects who underwent cardiac magnetic resonance (CMR) scanning were included. LV function, late gadolinium enhancement (LGE) type, and LV global peak strains  were measured. The determinant of reduced LV global myocardial strain for all RCM patients was assessed using multivariable linear regression analyses. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between DM and decreased LV deformation.Compared with the control group, RCM (DM−) and RCM(DM+) patients presented increased LV end-diastolic index and end-systolic volume index and decreased LV ejection fraction. LV GPS in all three directions and longitudinal PDSR progressively declined from the control group to the RCM(DM−) group to the RCM(DM+) group . DM was an independent determinant of impaired LV GPS in the radial, circumferential, and longitudinal directions and longitudinal PDSR  in RCM patients. The multiparameter combination, including DM, showed an AUC of 0.81(95% CI 0.75–0.87) to predict decreased LV GLPS and an AUC of 0.69 (95% CI 0.62–0.76) to predict decreased LV longitudinal PDSR.DM may have an additive deleterious effect on LV dysfunction in patients with RCM, especially diastolic dysfunction in RCM patients, indicating the importance of early identification and initiation of treatment of DM in patients with RCM. Diabetes mellitus (DM) is considered a major risk factor for cardiovascular complications and is an independent risk factor for cardiovascular morbidity and mortality , 2. LeftPrevious studies have pointed out that RCM and DM can impair LV function and deformation, culminating in progressive deterioration and poor outcomes , 11. SimCardiac magnetic resonance (CMR) imaging provides comprehensive information on cardiac function, deformation, and myocardial tissue. The late gadolinium enhancement (LGE) can potentially enhance the diagnosis, management, and prognosis of RCM . The defThe study protocol was approved by the Biomedical Research Ethics Committee of our hospital. Informed consent was waived due to the retrospective nature of the research.Initially, we consecutively retrospectively enrolled 253 patients with RCM who had completed CMR examinations in our hospital between January 2010 and December 2022. The diagnostic criteria for RCM were invasive cardiomyopathy confirmed by biopsy or a combination of clinical symptoms and relevant cardiac examinations . The exc2 or 340 × 285mm2, and matrix 208 × 139 or 256 × 166. Gadolinium-based contrast agent  was intravenously injected at a dose of 0.2 mmol/kg body weight at an injection rate of 2.5–3.0 ml/s, followed by a 20 ml saline flush at a rate of 3.0 ml/s. LGE images were acquired in the corresponding slice position as the cine imaging 10–15 min after contrast injection. The images were obtained using a phase-sensitive inversion recovery sequence with the following parameters: temporal time 300 ms, TE 1.44 ms, flip angle 40°, slice thickness 8 mm, FOV 275 × 400 mm2, and matrix size = 256 × 184 mm2.All CMR examinations were performed in the supine position using a 3.0T whole body magnetic resonance scanner Trio Tim or MAGNETOM Skyra  equipped with 32-channel body phased array coils and a standard ECG trigger equipment. Balanced steady-state free precession (b-SSFP) cine images were acquired using a retrospective vector ECG gating technique at the end of inspiratory breath holding, and twenty-five frames were reconstructed per breath-hold acquisition. Standard short-axis, long-axis two- and four-chamber cine images were obtained. which covered the entire left ventricles. The following scanning parameters were used: repetition time (TR) 2.81 ms or 3.4 ms, echo time (TE) 1.22 ms, flip angle 40° or 50°, slice thickness 8 mm, field of view (FOV) 250 × 300 mmAll CMR data were uploaded to an offline workstation using a semi-automated software . The LV endocardial and epicardial traces were manually or semiautomatically delineated in the serial short-axis slices at the end-diastolic and end-systolic phases. Papillary muscles were considered as part of the ventricular cavity, and epicardial fat was excluded. LV functional parameters, including LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV stroke volume (LVSV), LVEF, and LV mass (LVM) were computed automatically. LVEDV, LVESV, LVSV and LVM were indexed to body surface area (BSA). The LV global function index (LVGFI) was calculated using the following formula :\documenFor LV global deformation analysis, LV long-axis cine images (2-chamber and 4-chamber) and short-axis cine (2-chamber) images were loaded into the feature tracking module by delineating LV endocardial and epicardial borders at the end-diastolic phases of all cine images. The LV global radial peak strain (GRPS), global circumferential peak strain (GCPS), and global longitudinal peak strain (GLPS) and their corresponding peak systolic strain rate (PSSR) and peak diastolic strain rate (PDSR) in the three directions were acquired automatically Fig. . LEG wasTo determine intra- and inter-observer variability, one observer (Y. G) measured LV global myocardial strain and strain rate in 60 random subjects (including 40 RCM patients and 20 controls) twice within one month. A second observer (R. S), who was blinded to the results of the first observer and clinical data, reperformed the measurements to assess the interobserver variability.Statistical analyses were performed with SPSS . Data are expressed as the means with standard deviations or medians with interquartile ranges (IQRs) for continuous variables. Categorical variables are presented as numbers (percentages) and compared using Fisher’s exact test or the chi-square test, as appropriate. Parameters among RCM(DM−), RCM(DM+), and control were compared by one-way analysis of variance (ANOVA) followed by Bonferroni’s post hoc test  or the Kruskal–Wallis rank test (nonparametric variables), as appropriate. Correlation analysis was conducted to identify the relationship between LV function, strain parameters, and clinical indexes. Pearson’s correlation was used between continuous variables, and Spearman’s correlation was used to analyze the rank correlation.Moreover, variables with a p-value of less than 0.1 in the univariable analyses and an absence of collinearity were included in a stepwise multivariable analysis to identify the independent determinants of LV strain parameters. The receiver operating characteristic curve (ROC) was performed to quantify the diagnostic efficiency of DM for LV impaired deformation. A p-value of < 0.05 was considered statistically significant.Overall, 182 RCM  patients and 66 controls were included in this study. The main clinical baseline characteristics of the study cohort are summarized in Table The CMR imaging results for LV function and global peak strain were summarized in Table Univariable and multivariable linear regression analyses were performed to evaluate the independent effect of DM on LV function and deformation in RCM patients. After multivariable adjustment for covariates among all RCM patients, DM was an independent determinant of impaired LVEF . Furthermore, NT-proBNP levels were independently associated with LVEF, LVMI, and LVMVR , LGE was independently associated with LVEF and LVMVR  type, gender were independently associated with LVMVR, LV global PSSR , and LV global PDSR  in all three directions.This study investigated the difference in LV function and deformation damage in RCM patients with or without DM and explored the independent predictors of LV dysfunction and deformation injury. The main findings of this study are as follows: (1) For RCM patients, DM further deteriorated LV function, LV GPS in all three directions and LV peak diastolic strain rate in the longitudinal direction; (2) For RCM patients, DM was an independent determinant of impaired LVEF and LV GPS in all three directions; (3) Patients with RCM comorbid with DM displayed a decreased LV peak diastolic strain rate in the longitudinal direction, in which DM plays the predominant role. Our study demonstrated that DM may aggravate LV dysfunction and deformation injury in RCM patients, especially exacerbating the LV diastolic deformation rate injury in RCM patients. Therefore, RCM patients with comorbid DM may have a hidden high risk that needs more advanced and personalized management.RCM is a heterogeneous group of heart muscle diseases characterized by restrictive ventricular physiology in the presence of normal or reduced diastolic volumes, with normal or near-normal LV systolic function and normal or near-normal wall thickness , 21. PatThe underlying cause of cardiac alterations in RCM patients with DM is a combination of multiple mechanisms. Myocardial metabolism disorder is the characteristic of patients with DM, and the underlying mechanisms of how DM affects LV function may be due to the synthesis effect of metabolic disorders, excitation–contraction coupling impairment, microvasculature dysfunction, and extracellular matrix fibrosis , 27. SevIn the early stages of RCM, LV diastolic dysfunction may occur due to increased myocardial stiffness, which causes a rapid rise in ventricular pressure at the beginning of the diastolic stage, while LV systolic function is typically preserved , 17. In Furthermore, our study showed that NT-proBNP levels were significantly higher in RCM(DM+) patients than in RCM(DM−) patients and were an independent determinant of LV global strains and longitudinal PDSR in RCM patients. LGE is associated with myocardial interstitial infiltration and is one of the most important CMR sign of RCM. Diffuse LGE independently predicted increased late mortality in RCM patients , 35. AltThe study had several limitations. First, this was a retrospective single-center study, so there may be some selection bias in the results. The information on the onset, duration, and treatment of DM was unavailable for some patients due to the nature of the retrospective study. Second, not all patients received biopsies to confirm the cause of their restrictive cardiomyopathy, so we based the inclusion criteria on the clinical biopsy results or combined clinical, ECG, and imaging findings, according to the ESC review . Third, This study demonstrated that DM is an important risk factor for LV dysfunction and deformation injury in patients with RCM; DM may have an additive deleterious effect on LV dysfunction in patients with RCM, especially diastolic dysfunction in RCM patients. Early identification and initiation of treatment of DM in patients with RCM may improve prognosis.


Changes of pressures, displacements, and velocity distributions, as well as pressure–volume (P-V) loops in the LV models of HCM and DCM patients were presented. Additionally, the results obtained from the SILICOFCM Risk Stratification Tool and PAK software for high-risk HCM patients closely followed the clinical observations. This approach can give much more information on risk prediction of cardiac disease to specific patients and better insight into estimated effects of drug therapy, leading to improved patient monitoring and treatment.Cardiomyopathy is associated with structural and functional abnormalities of the ventricular myocardium and can be classified in two major groups: hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Computational modeling and drug design approaches can speed up the drug discovery and significantly reduce expenses aiming to improve the treatment of cardiomyopathy. In the SILICOFCM project, a multiscale platform is developed using coupled macro- and microsimulation through finite element (FE) modeling of fluid–structure interactions (FSI) and molecular drug interactions with the cardiac cells. FSI was used for modeling the left ventricle (LV) with a nonlinear material model of the heart wall. Simulations of the drugs’ influence on the electro-mechanics LV coupling were separated in two scenarios, defined by the principal action of specific drugs. We examined the effects of Disopyramide and Dygoxin which modulate Ca Cardiomyopathies are defined as structural and functional abnormalities of the ventricular myocardium . When thHCM can cause outflow obstruction and abnormal movement of the mitral valve due to increased left ventricle (LV) wall thickness, which is called left ventricular outflow tract obstruction (LVOTO). It can be observed that approximately 70% of patients with HCM have LVOTO with severe basal septal hypertrophy and systolic anterior motion of the mitral valve .Understanding of cardiac muscle activity in HCM and DCM cardiomyopathies has been significantly improved with continuous development and integration of computational models . FurtherThe FE method can be applied standalone or coupled with different computational methods for modelling complex biological tissue behavior and treatments. In a recent study, the FE method  was succOn the micro level of cardiac tissue, micromechanics models based on the regulatory and contractile proteins in the sarcomeres analyzed the generation of force in the cardiac muscle tissue. They include the steady-state force–calcium, force–length, and force–velocity relationships and the length-dependent prolongation of twitches and increase in peak force .This study, as part of the SILICOFCM in silico clinical trial, brings novelty in multiscale examination of drug interactions applying coupled macro- and micro-simulation through FE modeling of FSI and molecular drug interactions with cardiac cells. With this approach, adverse drug effects can be avoided, sudden cardiac death can be prevented, and the time needed for the desired result of drug treatment can be shortened. The main motivation for such an approach relies on improvement of computational modeling in testing the effects of pharmacological treatment, aiming to reduce animal experiments and human clinical trials. Moreover, computer-aided drug design is a well-known approach in the production strategy of drugs . It can In this study, an FSI algorithm for FE simulation was firstly introduced, and then an algorithm of the FE model was integrated with stretches along muscle fibers. The principal actions of specific drugs were divided into two major groups. The first class of drugs modulates calcium transients (Disopyramide and Digoxin), while the second class changes the kinetics of contractile proteins ). We quantitatively assessed the effects of drugs Disopyramide, Digoxin, Mavacamten, and dATP on the pressure and volume changes in the LV models for relevant HCM or DCM patients. Results for pressure, displacement, and velocity distribution, as well as P-V loops for LV HCM and LV DCM patients for basic condition (without administered drugs) and with effects of using respective drugs are presented. Additionally, results from the Risk Stratification Tool and PAK software for high-risk HCM patients are presented and compared with available clinical observations.n’ and equilibrium iteration ‘i’ has the formn’ and ‘n + 1’ denote the start and end of the time step.The movement of fluid in the left ventricle can be considered as a laminar flow of the incompressible fluid, which is described using the continuity equation and Navier–Stokes equations:i is the iteration counter, and Using velocities as nodal variables, the incremental-iterative equations of the force-balance for a FE and per unit volume can be written in the usual form:The tangent constitutive matrix, There are two approaches for the FE modeling of FSI problems: (a) strong coupling method, and (b) loose coupling method. For the strong coupling, the solid and fluid domains are modeled as one mechanical system. In the loose coupling, solid and fluid domains are modeled separately with different FE solvers. Namely, the solid domain is modelled in a computational solid dynamics (CSD) solver and the fluid domain in a computational fluid dynamics (CFD) solver. Although the solutions are obtained with different FE solvers, the parameters from one solution which affect the solution for the other medium are transferred successively.E, which has nodes at the boundary, is calculated as in (6):There is no slip between the fluid and solid at the common boundary, which means that the nodes at the solid–fluid boundary have the same displacements and velocities for the solid and fluid domains. If the strong coupling approach is used, the terms of the FE matrices and forces corresponding to these common nodes are summed as is usual in the FE assembling procedure. In the loose coupling method, the systems of balance equations for the two domains are formed separately and there are no such computational difficulties. Both strong and loose coupling are available in our PAK FE software package . SimilarThis section explains how FE model was integrated with stretches along muscle fibers. A multi-scale model of muscle contraction together with graphical interpretation of the algorithm for the FSI problem is shown in i, the Mijailovich–Prodanovic (MP) surrogate model of sarcomere contractions  transients because it lowers peak and baseline levels of [Ca2+] [2+] transient during twitch contractions, but without influencing time to peak and relaxation times  . On otheon times .Furthermore, drugs such as Mavacamten and 2-deoxy adenosine triphosphate (dATP) change the kinetics of contractile proteins. Mavacamten has been used for treating HCM because it is associated with the regulation of transition rates between ordered parked (OFF) states and disordered myosin detached (ON) states . On the An example of a scenario of in silico testing of drugs that modulate calcium transients has been presented in DisopyramideOn a macro level, disopyramide reduces LVOT gradients, with a slight decrease in the resting ejection fraction. It has been observed that Disopyramide decreases early drag forces on the mitral valve. Additionally, Disopyramide results in a modest reduction of global systolic function—5% to 6%. 2+] peak and the level of basal calcium concentration  have been important in treating congestive heart failure for more than 200 years, in large part because of a positive inotropic effect. The effect of Digoxin results in higher diastolic [Ca tension .2+] peak during twitch contractions but keeping the time to peak and the relaxation time unchanged  and about 50% in twitch contractions. Furthermore, simulations also showed a significant decrease in resting tension, which is the expected outcome of Mavacamten treatment. These changes are similar to the tension responses predicted by Disopyramide, but the mechanisms of action of these two distinctive drugs are fundamentally different.The effects of Mavacamten on human trabeculae were preliminary assessed with MUSICO simulations by using the same calcium transient as observed in HCM. The simulations predicted a similar decrease in tension, ~30% for steady-state force development at high [CaIt has been observed that Mavacamten is related to a nearly complete resolution of mitral valve systolic anterior motion. This can be directly associated with a reduction in the LVOT gradient. Additionally, a decrease in left ventricle mass index, left atrial volume index, and lateral E/e’ have also been associated with the influence of Mavacamten. On the other hand, Mavacamten has not been associated with cardiac structural changes such as reductions in interventricular septum thickness or left ventricle end-diastolic diameter. However, there are observations for significant changes in inferolateral wall thickness and left ventricle end-systolic diameter .These data are suitable for FE analysis, i.e., for simulations of the heart using PAK solver , to quanb.2-Deoxy Adenosine Triphosphate (dATP)The molecule dATP can replace ATP as the energy source for the motor protein myosin contraction in striated muscle. dATP allosterically enhances myosin crossbridge binding to actin (and cycling kinetic) such that small amounts of dATP are potent ,43. IncrThe significant increase in cardiac muscle contractility could be beneficial for DCM cardiomyopathies. The effects of dATP on DCM mice trabeculae were preliminary assessed with MUSICO simulations at the level of muscle fiber .Five HCM patients who have not been used for training the machine learning model were randomly selected but in a such way that higher and lower risk are present in the population. The testing which was performed on the five selected patients provided the following results: two patients were at high risk (patients No. 3 and 5), whereas three patients were at low risk . The detailed reports from the Risk Stratification Tool are displayed in In addition to the Risk Stratification Tool, we employed PAK FE simulation for patients 3 and 5, who were at high risk of severe events. The LV geometries of the patients 3 and 5 are shown in It should be emphasized that our parametric geometrical models are simplified but reflect the features of patient-specific measurements, i.e., the geometrical parameters were obtained from the patient data . MeasureThe results obtained for patient 3 are shown in During diastole, the fluid is injected into the ventricle and its volume increases, and pressure is maximum at the mitral valve (t = 0.4 s) throughout the first part of the cycle. When the injection cycle is finished and the mitral valve is closed, the ventricle contracts and ejects fluid through the aortic valve, resulting in the highest pressure value in the model until the end of the cycle.Displacements, pressures, and velocity fields for patient 5 are presented in In addition, P-V diagrams obtained for patients 3 and 5 are shown in Left ventricle ejection fractions (LVEFs) in the initial (baseline) and posterior (follow-up) state for HCM patients 3 and 5 are shown in In clinical practice, the LVEF is useful for assessment of patient condition, but for a precise diagnosis cardiologists need additional medial information, knowing that the LVEF might be normal or even high but that this does not mean that much blood is being pumped out . For thaSimulations of the effect of drugs on improving the performance of HCM and DCM included the drugs that affect calcium transients (Disopyramide and Digoxin) and changes in kinetic parameters (Mavacamten and dATP). All simulations were performed using coupled PAK FSI, FE solver, and MP surrogate model. For this purpose, we created additional HCM and DCM parametric models of LVs using patient-specific measurements . The bouP-V diagrams for the HCM LV model at basic condition (without administered drug) and with using drugs Disopyramide and Mavacamten are presented in The predicted P-V diagram for HCM  at basicThe principal effects of drugs on HCM are a decrease in peak pressures and a shift of P-V loops toward higher volumes  and highIn addition, displacements, pressures, and velocity distribution for the HCM LV model at basic condition (without administered drug) and with using Disopyramide and Mavacamten are presented in The SILICOFCM platform as a whole enables in silico animal and clinical trials for testing the effectiveness of pharmacological treatment for LV heart performance. Such an approach can significantly reduce the time and cost of running real animal and clinical trials for drug development and optimal testing which is one of main motivations for this study. The presented study is performed using coupled macro- and microsimulation through FE modeling of FSI and molecular drug interactions with the cardiac cells, as part of the SILICOFCM project . The FSIThe study presents results of (i) SILICOFCM Risk Stratification Tool and PAK software for HCM patients at baseline and follow-up, as well as of (ii) simulated drug effects on the HCM LV model and the DCM LV model. The results closely follow the available clinical observations, which is a promising step for further improvement of computational methods also including a larger group of cardiomyopathy patients. 2+ transients, were included in the first scenario, while Mavacamten and dATP, which affect changes of kinetic parameters, were included in the second scenario. Changes of pressures, displacements, and velocity distributions, as well as P-V loops in the LV models of HCM and DCM patients, are presented. The results provide a quantitative assessment of the effects of different drugs  on cardiac output, including both systolic and diastolic LV pressures and volumes, as well as the LVEF.In the case of drug modeling, two major groups are described by the principal action of specific drugs on modulating calcium transients and changing the kinetics of contractile proteins. According to the principal actions of drugs on the electro-mechanics LV coupling, simulations were separated in two scenarios. The effects of Disopyramide and Dygoxin, which modulate CaIt should be emphasized that the performed simulations are based on simplified LV geometries. In the case of detailed and patient-specific models, FE analyses are very time-consuming, especially when muscle micromodels are included. In contrary, our models are patient-specific in terms of dimensions of specific LV components but are geometrically simplified in order to avoid manual construction of the FE meshes for a large number of patients. Since models are not anatomically precise, results may slightly differ from the real state of the patient’s cardiac health. Additional limitations of the study are the lack of details regarding fully physical and biological properties of the specific patient’s heart. Despite those limitations, the presented methods can be used together to obtain better insight into the cardiac health and optimal drug therapy for specific patients.In summary, this study was designed to propose that developed computational models can mimic, on a macroscopic level, the behavior of patients under different stages and types of cardiomyopathy disease. Moreover, this approach can give much more information for the risk prediction of cardiac disease in specific patients and better insight into the estimated effects of drug therapy, leading to improved patient monitoring and treatment.


Depressed cardiac systolic function in hemodialysis patients occurs for a variety of reasons and is a clinical problem. Beta-blockers are a key drug in the treatment of heart failure; however, hypotension may occur, particularly in dialysis patients, thereby complicating dialysis. Ivabradine has the unique property of a negative chronotropic effect only, without the negative inotropic effect. A 55-year-old woman who underwent dialysis presented with dyspnea and fatigue even at rest due to low cardiac systolic function. The left ventricular ejection fraction (LVEF) was 30%. Medications for heart failure, such as carvedilol and enalapril, were initiated; however, they were discontinued owing to intradialytic hypotension. Subsequently, her heart rate increased to over 100 beats per minute (bpm); therefore, we administered 2.5 mg of ivabradine before beta-blockers, which reduced her heart rate by approximately 30 bpm without a significant blood pressure decrease. Moreover, her blood pressure stabilized during dialysis. After two weeks, we added 1.25 mg of bisoprolol and adjusted the dose to 0.625 mg. After seven months of treatment with 2.5 mg ivabradine and 0.625 mg bisoprolol, systolic cardiac function significantly improved to 70% of LVEF. Prioritizing ivabradine over beta-blockers may not cause intradialytic hypotension; even low doses of ivabradine and bisoprolol were considered effective heart failure therapies. Ivabradine is a selective hyperpolarization-activated cyclic nucleotide-gated channel antagonist that reduces the heart rate in sinus rhythm without a negative inotropic effect . ClinicaImpaired cardiac systolic function is common in patients undergoing dialysis, which is multifactorial, including ischemic insults ,4. NeverA 55-year-old woman underwent dialysis three times a week for seven years because of non-diabetic renal disease. She visited our clinic because of shortness of breath and fatigue even while resting. Transthoracic echocardiography at dialysis initiation showed diffusely reduced left ventricular wall motion with a left ventricular ejection fraction (LVEF) of 44%. The LVEF was 44%, and the heart rate was sinus tachycardia (>100 beats per minute). Over the past six years, she developed heart failure. Recently, she gradually became concerned about breathlessness during exertion, such as walking stairs without chest pain. Finally, she felt fatigued even at rest. During scheduled dialysis, blood pressure often decreases. Nevertheless, a chest radiograph showed a large chest-thoracic ratio indicating over-volume Figure , and dryEventually, a reduced cardiac systolic function was discovered on routine transthoracic echocardiography. The LVEF dropped to 30% Figure , 2.She visited our clinic. We confirmed that there was no significant organic coronary artery stenosis on the coronary angiography. Carvedilol was started at 2.5 mg and titrated up to 8.75 mg over three months, and enalapril 2.5 mg was started simultaneously Figure .Carvedilol and enalapril were administered every morning before hemodialysis. Intradialytic hypotension developed after the initiation of these drugs. She experienced presyncope symptoms and collapsed several times because of orthostatic hypotension. Both carvedilol and enalapril were immediately discontinued to treat the low blood pressure (96/62 mmHg) with sinus rhythm at rest. Subsequently, her heart rate increased to >100 beats/minute. Ivabradine 2.5 mg/day was administered once daily under the electrocardiac monitor during hospitalization. The heart rate decreased by approximately 30 bpm within two weeks without a significant decrease in blood pressure. Figure Moreover, the blood pressure stabilized during dialysis. After two weeks, we added 1.25 mg of bisoprolol, and the dose was adjusted to 0.625 mg. Thereafter, these drugs were continued at the same dosage, and hypotension during dialysis was no longer observed.Heart rhythms were monitored during hemodialysis. The cardiac rhythm was preserved in sinus rhythm, and atrial fibrillation was not observed. The heart rate dropped to the 70s within two weeks of initiating ivabradine administration. Chest radiography showed chest-thoracic ratio reduction Figure . ThereafIvabradine, the so-called pure heart rate drug, decreases heart rate without adverse inotropic effects . TherapeReduction in heart rate with ivabradine can improve physiological myocardial performance and increase stroke volume . The SHIAggressive up-titration of beta-blockers for the treatment of heart failure in patients undergoing dialysis has been debated . In thisThe patient's cardiac function had been compromised since the initiation of dialysis; however, no organic stenosis was found on coronary angiography. The mechanisms underlying heart failure are not completely understood. In this case, the benefit of ivabradine may have been remarkable because the mechanism of heart failure was non-ischemic and the myocardium was viable.Considering blood pressure management in patients undergoing dialysis, ivabradine might be a first-line therapy prior to beta-blockers in patients undergoing dialysis with a very low ejection fraction. Prioritization of ivabradine can be a safe and feasible therapy in patients with low-systolic ejection fraction and low blood pressure.


Diabetes mellitus (DM) is considered a major risk factor for myocardial infarction (MI), and MI patients with DM have a poor prognosis. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients after acute MI.One hundred thirteen MI patients without DM [MI (DM−)], 95 with DM [MI (DM+)] and 71 control subjects who underwent CMRscanning were included. LV function, infarct size and LV global peak strains in the radial, circumferential and longitudinal directions were measured. MI (DM+) patients were divided into two subgroups based on the HbA1c level (< 7.0% and ≥ 7.0%). The determinants of reduced LV global myocardial strain for all MI patients and MI (DM+) patients were assessed using multivariable linear regression analyses.p < 0.05). Subgroup analysis showed that LV global radial PS and longitudinal PS were worse in MI(MD+) patients with poor glycemic control than in those with good glycemic control . DM was an independent determinant of impaired LV global peak strain in radial, circumferential and longitudinal directions in patients after acute MI . The HbA1c level was independently associated with a decreased LV global radial PS  and longitudinal PS  in MI (DM+) patients.Compared with control subjects, both MI (DM−) and MI (DM+) patients presented higher LV end-diastolic and end-systolic volume index and lower LV ejection fraction. LV global peak strains progressively declined from the control group to the MI(DM−) group to the MI(DM+) group (all DM has an additive deleterious effect on LV function and deformation in patients after acute MI, and HbA1c was independently associated with impaired LV myocardial strain. Coronary artery disease and myocardial infarction (MI) are major causes of global morbidity and mortality . AssessmPrevious studies have noted that both MI and DM can lead to LV dysfunction and impaired deformation, culminating in the progressive deterioration of HF and poor outcomes , 11. MeaCardiac magnetic resonance (CMR) imaging provides comprehensive information on cardiac function, deformation, and myocardial tissue. Deformation, especially impaired global longitudinal strain, has been proven to be associated with cardiovascular events and has better prognostic value than LVEF , 15. TheThe study protocol was approved by the Biomedical Research Ethics Committee of our hospital. Informed consent was waived due to the retrospective nature of the research.Initially, we consecutively retrospectively enrolled 648 patients with MI who had completed CMR examinations in our hospital between January 2010 and March 2022. MI was diagnosed in our hospital and meet the diagnostic criteria for the universal definition of MI , and have a history of MI by clinically diagnosed. The exclusion criteria were as follows: (1) cardiomyopathy, congenital heart disease, pericardial disease, severe arrhythmia, or valvular heart disease ; (2) acute or subacute MI patients ; (3) an 2 or 340 × 285mm2, and matrix 208 × 139 or 256 × 166. Gadolinium-based contrast agent was intravenously injected at a dose of 0.2 mmol/kg body weight at an injection rate of 2.5–3.0 mL/s, followed by a 20 mL saline flush at a rate of 3.0 mL/s. LGE images were acquired in the corresponding slice position as the cine imaging 10–15 min after contrast injection. The images were obtained using a phase-sensitive inversion recovery sequence with the following parameters: TR 750/512 ms, TE 1.18/1.24 ms, flip angle 40°, slice thickness 8 mm, FOV 240 × 300 mm2 or 288 × 360 mm2, and matrix 256 × 184 mm2 or 256 × 125 mm2.All CMR examinations were performed in the supine position using a 3.0 T whole body magnetic resonance scanner Trio Tim or MAGNETOM Skyra  equipped with 32-channel body phased array coils and standard ECG trigger equipment. Balanced steady-state free precession (b-SSFP) cine images were acquired using a retrospective vector ECG gating technique at the end of inspiratory breath holding, and twenty-five frames were reconstructed per breath-hold acquisition. Standard short-axis, long-axis two- and four-chamber cine images were obtained. that covered the entire left ventricles. The following scanning parameters were used: repetition time (TR) 2.8 ms or 3.4 ms, echo time (TE) 1.22 ms, flip angle 40° or 50°, slice thickness 8 mm, field of view (FOV) 250 × 300 mmAll CMR data were uploaded to an offline workstation using semiautomated software . The LV endocardial and epicardial traces were manually or semiautomatically delineated in serial short-axis slices at the end-diastolic and end-systolic phases. Papillary muscles were considered part of the ventricular cavity and LV mass, and epicardial fat was excluded. LV functional parameters, including LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV stroke volume (LVSV), LVEF and LV mass (LVM), were computed automatically. LVEDV, LVESV, LVSV and LVM were indexed to body surface area (BSA). The LV global function index (LVGFI) was calculated using the following formula:For LV myocardial deformation analysis, LV long-axis cine images (2-chamber and 4-chamber) and short-axis cine images were loaded into the feature tracking module. LV endocardial and epicardial borders were delineated at the end-diastolic phases of all cine images. The LV global LV global radial peak strain (GRPS), global circumferential peak strain (GCPS), and global longitudinal peak strain (GLPS) were acquired automatically  were measured twice within 1 month by one observer . A second observer , who was blinded to the results of the first observer and clinical data, reperformed the measurements to assess the interobserver variability.p value of less than 0.1 in the univariable correlation analyses and an absence of collinearity were then included in a stepwise multivariable analysis to identify the independent determinants of LV global peak strain parameters. A p value of < 0.05 was considered statistically significant.Statistical analyses were performed with SPSS  and GraphPad Prism . Data were expressed as the mean ± standard deviation (SD) or median interquartile range (IQR) for continuous variables and frequencies for categorical variables. Categorical variables are presented as numbers (percentages) and were compared using Fisher’s exact test or the chi-square test, as appropriate. Parameters among MI(DM−), MI(DM+) and control groups were compared by one-way analysis of variance (one-way ANOVA) followed by Bonferroni’s post hoc test  or the Kruskal–Wallis rank test (nonparametric variables), as appropriate. Spearman’s and Pearson’s correlation analyses were conducted to identify the relationship between LV myocardial strain and clinical indices. Pearson’s correlation was used between continuous variables, and Spearman’s correlation was used to analyses the rank correlation. Moreover, variables with a p > 0.05). The NYHA functional class in the MI(DM+) group was decreased compared with that in the MI(DM−) group (p < 0.05). The left anterior descending artery was the most common culprit vessel in both the MI(DM−) group and MI(DM+) group . There was a higher number of diseased vessels in the MI(DM+) group than in the MI(DM−) group (p < 0.05). Additionally, the NT-proBNP value was significantly higher in the MI (DM+) group than in the MI (DM−) group (p < 0.05), and there was no difference in troponin value between the MI groups.Overall, 208 MI patients and 71 controls were included in this study. Of the 208 patients after acute MI, 95 patients were identified as having DM, and 113 patients were classified as non-DM patients. The main clinical baseline characteristics of the study cohort are summarized in Table p < 0.05). The MI (DM+) group exhibited a higher LVMI and lower LVGFI than the MI (DM−) group , whereas the LVEF showed no difference between these two groups (p > 0.05). Regarding LV deformation parameters, all LV GRPS, GCPS and GLPS were decreased from in the controls to the MI (DM−) group to the MI (DM+) group . There was no significant difference in MI territory in MI patients with or without DM (p > 0.05).The CMR results for LV function and global peak strain are summarized in Table p = 0.004) and increased LVMI  (Table p < 0.05). Age, hyperlipidemia and hypertension were independently associated with LVMI   Table . Furtherp = 0.007), GCPS  and GLPS  (Table p < 0.05), GCPS , and GLPS  . There was no significant difference between MI(DM−) patients and patients with good glycemic control (HbA1c < 7.0%). LV GCPS was significantly decreased in poor glycemic control patients compared with good glycemic control patients , whereas LV GRPS and GLPS showed a decreasing tendency. Moreover, there were increased LVESVi values and decreased LVSVi and LVGFI values in MI(DM+) patients with poor glycemic control compared with good glycemic control patients .According to the status of glycemic control, MI (DM+) patients were divided into two subgroups: good glycemic control  and poor glycemic control . The LV global peak strain among MI (DM−) patients and MI (DM+) patients with good or poor glycemic control were shown in Fig. p = 0.026) and positively associated with GCPS  and GLPS   and GLPS . Moreover, the log-transformed NT-proBNP level and infarct size were found to be independent determinants of global peak strain in all three directions   patients showed that HbA1c was negatively associated with GRPS  and infract size of LV .This study investigated the combined effects of DM on LV function and deformation in patients after acute MI. The main findings of this study are as follows: (1) MI patients presented impaired LV function and deformation, whereas DM further deteriorated LV function and global peak strain in all three directions ; (2) For MI patients, DM was found to be an independent determinant of impaired LVGFI and LV global peak strain in all three directions; and (3) LV global peak strains declined progressively with the increase in HbA1c in MI patients with DM, and HbA1c was an independent determinant of decreased LV GRPS and GLPS. Our study indicated the deleterious effect of DM on LV deformation in patients with MI, and poor glycemic control may further aggravate the impairment.DM, as the most common chronic metabolic disease, is the major risk factor for cardiovascular complications and adverse cardiovascular events. There is a high diagnosis rate of DM among patients with MI, and previous studies have reported a similar twofold increase in the risk for major adverse cardiovascular events in patients with DM after AMI , 20. ForIn this study, we conducted multivariable linear regression analysis and found that comorbid DM augmented the impairment of LV global peak strain in all three directions by CMR-FT in MI patients, and DM was an independent determinant of LV global peak strain in patients after MI. The underlying cause for cardiac alterations in patients after MI with DM is complex. Myocardial metabolism disorder is characteristic of patients with DM, and microvascular endothelial damage is aggravated in this microenvironment, leading to an increased incidence and severity of coronary atherosclerosis , 24. In Blood glucose control is an important indicator to prevent adverse cardiovascular events in diabetic patients –27. HbA1Additionally, our study showed that NT-proBNP levels and infarct size were significantly higher in MI patients with DM than in those without DM, and these indices were independent determinants of LV global strains in MI patients with DM. Several clinical trials have demonstrated that NT-proBNP and infarct size are associated with reversed cardiac remodeling and dysfunction, which means that MI patients with DM have a more pronounced cardiac load and LV stiffness –32.The study had several limitations. First, this was a retrospective single-center study, so there may be some selection bias in the results. Second, some MI patients underwent PCI and other operations, so the long-term effects of treatment on MI cannot be completely ruled out. However, there was no difference in the proportion of MI patients who received treatment between the two groups, and the possible deviation was reduced as much as possible. Third, we did not assess the type of MI in each patient, and future studies could be investigated with a larger cohort to evaluate the effects of different MI types on LV.In patients after MI, DM had an additive deleterious effect on LV myocardial strain. In addition, LV function and myocardial strain deteriorated with increasing HbA1c in these patients, which emphasizes the importance of glycemic control in MI patients.


Background: Cardiovascular diseases (CVDs) are frequent in patients having chronic obstructive pulmonary disease (COPD). Despite that, comorbid CVDs receive less guideline-recommended screening in this population compared to others. We aimed to evaluate the cardiac function using echocardiography and to assess spirometry, arterial blood gas (ABG) as well as brain natriuretic peptide (BNP) as prognostic indicators of cardiovascular dysfunction in COPD patients.Methods: One hundred moderate to very severe COPD patients according to GOLD guidelines with no history of cardiac diseases were recruited from two hospitals in Saudi Arabia and evaluated using electrocardiography (ECG), chest X-ray, BNP, pulmonary functions, ABG analysis, and transthoracic echocardiography. Multiple linear regression analysis was used to determine the predictors of right ventricular (RV) and left ventricular (LV) dysfunction.Results: Pulmonary hypertension (PH) was detected in 28% of the patients, while 25% had abnormal tricuspid annular plane systolic excursion (TAPSE). Low left ventricular ejection fraction (LVEF) and abnormal LV strain were present in 20%, abnormal right ventricular strain was present in 17%, and abnormal fractional area change (FAC) was detected in 9% of patients. Multiple linear regression analysis was used to explore possible determinants of cardiac function. Age, gender, and the presence of diabetes and hyperlipidemia were significant predictors of cardiac dysfunction in COPD patients. Forced vital capacity (FVC) was an independent predictor of LVEF  and FAC . Hypoxemia and hypercapnia significantly predict both RV and LV dysfunctions. BNP was an independent predictor of FAC .Conclusion: Cardiac abnormalities are common in moderate to very severe COPD patients. Echocardiography could be considered for the assessment of these patients even in the absence of a history of cardiac disease. Pulmonary functions, ABG, and BNP may offer additional predictive information on cardiac functions in COPD patients. Chronic obstructive pulmonary disease (COPD) is currently considered as a pulmonary component of systemic endothelial disease in which many cellular and humoral inflammatory processes simultaneously affect multiple organs leading to a state of multi-morbidity . CardiovSmoking, age, hypoxemia, systemic inflammation, oxidative stress, and increased pulmonary vascular resistance all play a role in this intimate association . From an1- To evaluate cardiac functions in COPD patients who had no previous history of cardiac disease using echocardiography. 2- To assess respiratory functions and brain natriuretic peptide (BNP) as predictors of cardiac abnormalities. Study designWe conducted this cross-sectional study from January 2022 to January 2023 at two hospitals in Saudi Arabia: Ibn Sina College Hospital in Jeddah and King Khalid Hospital in Hail. The study was performed in compliance with the Helsinki Declaration and in accordance with the regulations approved by the local committee for bioethics research in Hail health affairs via review according to King Abdulaziz City for Science and Technology Good Clinical Practice (KACST GCP) regulations (IRB registration number: H-08-L-074) and (IRB log number: 2021-26). The proposal has undergone a full review by the above-mentioned committee which implements regulations of the law of ethics of research on living creatures in the Kingdom of Saudi Arabia and other applicable national and international regulations.Study populationA sample size of at least 74 patients was calculated using G*Power 3.1.9.4 with an effect size of 0.15, alpha error probability of 0.05, power of 0.95, degree of freedom (DF) of 57, and the number of predictors set of 16. Therefore, a total of 100 patients were recruited consecutively from inpatient wards of both hospitals who met the criterion for diagnosis of COPD that is based on history, previous physician diagnosis, and presence of irreversible airway obstruction on spirometry in compliance with the latest guidelines for diagnosis and management of COPD [AssessmentsAll patients were subjected to full medical history, clinical examination, plain chest X-ray, electrocardiography (ECG), and spirometry with the following indices recorded; forced expiratory volume in the 1st second (FEV1%), forced vital capacity (FVC%), and FEV1/FVC ratio. Resting ABG analysis on air was done and the following values were recorded: oxygen saturation (SaO2%), partial pressure of oxygen (PaO2 mmHg), partial pressure of carbon dioxide (PaCO2 mmHg), bicarbonate (HCO3 mEq/L), and potential of hydrogen (pH).Cardiac functions were assessed by resting transthoracic Doppler echocardiography in accordance with the guidelines of the American Society of Echocardiography  using ViRight ventricular (RV) parameters included: RV dimensions, tricuspid annular plane systolic excursion (TAPSE), and percentage of FAC. Measures of RV diastolic function by pulsed Doppler through tricuspid flow including tricuspid early and late diastolic filling velocities and tricuspid flow early deceleration time. RVSP was estimated from the tricuspid regurgitant velocity, inferior vena cava diameter, and its collapsibility. The tissue Doppler velocities of the tricuspid valve annulus at the RV free wall are determined. Measured velocities include peak systolic tricuspid annular velocity, early diastolic tricuspid annular velocity, and late diastolic tricuspid annular velocity and RV global longitudinal strain (GLS) by 2D speckle tracking. Left ventricular (LV) parameters included: LV internal dimensions and M-mode/2D echo ejection fraction (EF). Doppler Echocardiography was used to measure mitral inflow velocity including early, late diastolic velocities and deceleration time. Tissue Doppler velocities were obtained by calculating the average of early and late diastolic velocities from four mitral annuli. LV systolic function was measured by 2D speckled tracking echo.Diagnosis of abnormalityAn elevated RV/pulmonary artery systolic pressure (PASP) >35 mmHg indicated PH. TAPSE is known as a noninvasive surrogate for RVEF. It is considered as an accurate measure of RV function in PH patients, a TAPSE value < 17 mm indicates RV systolic dysfunction. FAC provides an estimate of the global RV systolic function, values <35% indicate systolic dysfunction. Right ventricular (RV)-global longitudinal strain (RV-GLS) is a well-established tool to detect early RV dysfunction, a value of <20% suggested RV dysfunction. LV-global longitudinal strain (LV-GLS) is a well-established tool to detect early LV dysfunction, a value of <17%, indicated LV systolic dysfunction. Left ventricular ejection fraction (LVEF) is the central measure of LV systolic function, a value of <50% indicates LV systolic dysfunction .Statistical analysisData were analyzed using the SPSS software package, version 20.0 . The normality was tested using the Shapiro-Wilk test. Normally distributed data are presented as mean ± standard deviation (SD). Non-normally distributed variables are expressed as the median and interquartile range (25th-75th percentile). Categorical variables are presented as numbers and percentages. Multiple linear regression analysis was used to determine factors related to cardiac dysfunction and to assess the effect of selected variables on ventricular systolic and diastolic function. Standardized coefficient beta (odd ratio) was interpreted as the absolute change in dependent variables per change in cardiac function. A p-value <0.05 was considered statistically significant. Baseline characteristicsThe study included 86 males and 14 females. Their mean age was 67.09 ± 6.38 years, ranging from 54 to 79 years. Most patients (52%) had moderate airflow limitation (GOLD 2); 42% had severe airflow limitation (GOLD 3), and only 6% of them had very severe airflow limitation (GOLD 4)  followed by dyslipidemia (34%) and diabetes (25%). Atrial fibrillation (AF) was detected in 14% of patients. All the pulmonary function parameters were below normal limits , and 20% had low LVEF. Abnormal LV global strain was detected in 20% and RV global strain was detected in 17%. Abnormal TAPSE was detected in 25% of patients while 9% had low FAC , BNP , and FVC  were the significant predictors of FAC     and EF   Table . SignifiIn this study, the most common echocardiographic abnormalities were PH (28%) followed by TAPSE (25%). Many studies demonstrated a reasonable correlation between pulmonary arterial pressure measured by echocardiography and pressure measured by right heart catheterization . The EurFor a long time, the evaluation of RVSP in COPD patients was the main interest of both pulmonologists and cardiologists . In thisEven though cardiac abnormalities in COPD have often been mainly assessed with respect to the right ventricle -15, the In this study, we used a multivariate model to investigate possible predictors of cardiac function in COPD patients. The results revealed that age, male gender, and the presence of diabetes and hyperlipidemia were predictors of cardiac dysfunction in our patients. These findings are in line with studies conducted by Feary et al.  in the UPulmonary function indices were tested as a possible determinant of cardiac function among our patients. Our results revealed that FVC was the only independent predictor of cardiac function and according to our findings, FVC was associated with FAC and LVEF. In a study done on 57 Duchene muscular dystrophy patients, right ventricular ejection fraction (RVEF) and right ventricular end diastolic volume (RVEDVI) were related to FVC% which suggests that worsening respiratory function may have a negative impact on the heart and can be used to monitor the cardiac function in these patients . Das et In our study, hypoxemia was the persistent significant predictor of many cardiac parameters including RVSP, RVGLS, and LVGS. Hypoxia is associated with increased systemic inflammation, oxidative stress, and endothelial dysfunction which may all contribute to cardiovascular disease . Wells eGiven the recognized cardiovascular phenotypes within COPD, the use of validated cardiovascular biomarkers is warranted . NatriurThe present study had some limitations: as it was a cross-sectional study, the absolute causal relationship between COPD and cardiac dysfunction cannot be confirmed. Baseline comorbidities were reported by patients themselves and not verified by detailed laboratory tests, which may lead to recall bias. The PASP was estimated by echocardiographic Doppler study only and not confirmed by RHC, which is the gold standard method to assess PH. Although we excluded patients with a history of CAD, the presence of CAD among included patients was not excluded by interventional angiography. Additionally, the absence of data about COPD treatment and its effect on echocardiographic parameters is another limitation of this study.Cardiovascular diseases are common among patients with moderate-to-very-severe COPD. Worsening respiratory functions may have a negative impact on the heart and can be used to monitor the cardiac function in these patients. In addition to the standard cardiac risk factors, FVC, hypoxia, and BNP may add predictive information about cardiac functions in COPD patients. Echocardiography screening and evaluation of both RV and LV functions in COPD patients can identify patients who need close monitoring and intense treatment, thus improving their prognosis.


One third of human life is spent sleeping, thus the importance of sleep in the maintenance of correct homeostatic balance is well established. During the night, restoring changes go on and psychophysical capacities are reduced. One hundred years have passed since the first article linking heart activity and sleep  and currSleep-related breathing disorders are frequently present in patients with hypertension, ischemic heart disease, heart failure and arrhythmias. Perhaps in the setting of cardiopulmonary relationship, hypertension was one of the first aspects detected when it was found that nocturnal hypoxaemia played a key-role in the aetiology of systemic hypertension in patients with sleep-related breathing disorders . InsteadIn recent years, a contribution of the autonomic nervous system (ANS) is highlighted for a better comprehension of several mechanisms involved in the heart–sleep–breath interaction. Alterations in sympathetic tone during apnoeic events stimulate sympathetic activation such as severe intermittent hypoxemia, acidosis, and hypercapnia can result in sympathetic activation leading to heart rate elevation. Thus, the link between obstructive sleep apnoea and arrhythmias, above all AF, may be a combination of sympathetic and parasympathetic drivers and electrophysiologic substrate modification. At the same time initiation and maintenance of AF may be partially influenced by intrinsic cardiac ANS.In the ANS, fibres travel from the central nervous system to the ganglia of visceral effectors organs. Ganglia of the parasympathetic division of the heart are distributed in mostly in epicardial regions, identified in humans in the posterior-superior surface of the right atrium adjacent to the superior vena cava, junction and right atrium; the posterior-superior surface of the left atrium; the interatrial groove; the posterior-medial surface of the left atrium; the posterolateral surface of the left atrium; and the ligament of Marshall densely innervated by the left vagus nerve .Most of the mentioned localizations are the potential triggers during catheter ablation of AF and subsequent potential applications for neuromodulation in appropriately selected patients is the present and the future in the electrophysiologic study of the atrial activity and AF. Following the discovery that ganglia stimulation may result in triggered activity in PVs and fractionated EGMs sites thought to maintain AF, modulating or eliminating key neural connections to the heart by using endocardial ablation could be a target that is reflected also in global circadian activity, not only about the heart. A stable heart rhythm could have a positive influence on nightly desaturation and sleep patterns . Heart rIf there are nightly respiratory disorders, the cardiac work is energy-consuming; but probably at the same time a heart that beats as a metronome gives the pace for a regular and restoring nightly breathing. It is clear that disturbed sleep, due to disturbed nightly breath, is not healthy for the heart.