We evaluated the association between visceral adiposity and left ventricular (LV) diastolic function in association with plasma adiponectin levels in 213 subjects without overt cardiac diseases. Abdominal visceral fat area was quantified by computed tomography. Excessive visceral fat was significantly associated with impaired diastolic parameters including E/A, E′ and E/E′. Although serum adiponectin levels decreased with increased visceral adiposity, there was no independent association between serum adiponectin levels and diastolic parameters, which suggest that the role of adiponectin in this association might be indirect. Previous studies have shown that the most common cause of HFpEF is left ventricular (LV) diastolic dysfunction3, and the progression of diastolic dysfunction is an independent predictor of HFpEF4. LV diastolic function slowly declines with aging6, and is accelerated by diabetes mellitus, hypertension, hyperlipidemia, obesity and other clinical factors7. To reduce the incidence of future HFpEF, it is essential to understand the pathophysiology of progression of LV dysfunction and to prevent its progression.The number of heart failure patients with preserved ejection fraction (HFpEF) is continuously increasing and now accounts for nearly half of all HF patients8, and is also an independent risk factor for LV diastolic dysfunction10. Although the mechanistic link between obesity and LV diastolic dysfunction is still debated, visceral adiposity has gained attention as one of the possible mechanisms for this link. A few studies reported that visceral adiposity assessed by computed tomography (CT) was associated with LV diastolic dysfunction in the general population12, patients with type 2 diabetic mellitus13, patients on peritoneal dialysis14 and patients with myocardial infarction15. In patients with type 2 diabetes mellitus, it was suggested that excessive visceral fat has a stronger association with the development of LV diastolic dysfunction than glycemic control13. However, the relationship between visceral adiposity and LV function has not been well defined in comparison with other clinical factors such as blood pressure, age or body weight in the general population.Obesity is a major risk factor for the development of heart failure16, was reported to have cardioprotective effects17. Thus, some investigators suggested that adiponectin might serve as a therapeutic target in LV diastolic dysfunction18. Indeed, it was reported that plasma adiponectin levels were decreased in the general population according to the severity of visceral adiposity quantified by CT19. However, none of the previous studies that reported an association between visceral fat and LV diastolic function15 examined plasma adiponectin levels. Furthermore, some previous studies reported an inconsistent association between plasma adiponectin levels and LV diastolic function in selected populations24. Thus, it is still unclear if adiponectin is involved in the relationship between visceral fat and LV diastolic function.In addition, the pathophysiological mechanism responsible for the relationship between visceral adiposity and LV diastolic function is not clear. Adiponectin, one of the adipocytokines produced by adipose tissueThe aim of our study was to elucidate the significance of the association between visceral adiposity and LV diastolic function in comparison with other clinical factors, and to determine if low plasma adiponectin levels or other metabolic parameters are involved in the association between visceral adiposity and LV diastolic function in the general population.A total of 213 participants  with preserved LV ejection fraction assessed by Teichholz formula were included in the study as shown in Table Multivariable linear regression analyses demonstrated that age, SBP, and VFA were independently associated with all diastolic parameters including E′, E/E′ and E/A, whereas plasma adiponectin levels were not associated with any of diastolic parameters Table .Table 3MICC of inter observer variability for each measurement was LV mass index , LA volume index (0.99 [0.95–0.997]), and E/E′ (0.91 [0.70–0.98]), respectively. ICC of intra-observer variability was LV mass index (0.84 [0.51–0.96]), LA volume index (0.99 [0.96–0.99]), and E/E′ (0.97 [0.90–0.99]), respectively.In this study, we found that visceral adiposity as well as hypertension and age were independent and important factors for LV diastolic function in the general population. Although plasma adiponectin levels significantly decreased with increased visceral adiposity, the association of adiponectin level and diastolic function was not independent. Decreased plasma adiponectin does not appear to play a central role in the association between visceral adiposity and LV diastolic dysfunction. To the best of our knowledge, this is the first study to evaluate the independent relationships among visceral adiposity, plasma adiponectin levels and LV diastolic function, by measuring all of these parameters in the same general population with preserved LV ejection fraction.2. Diastolic dysfunction is the most common cause of HFpEF3, and the progression of LV diastolic dysfunction is an independent predictor of HFpEF4. Given that the prognosis of patients with HFpEF has not improved in the past two decades26, prevention of the progression of LV diastolic function is the current best strategy to reduce the incidence of HFpEF. In this study, we found that visceral adiposity was an important and independent factor associated with LV diastolic dysfunction as well as SBP and age. Although some previous studies15 reported a significant relationship between visceral adiposity and LV diastolic function, the relationship between visceral adiposity and LV diastolic function may not be independent of other clinical factors. Our results suggest that controlling visceral adiposity as well as SBP might be important for preventing the progression of LV diastolic dysfunction with aging.Although the treatment of heart failure with reduced ejection fraction has improved drastically in the past two decades, no convincing treatment for HFpEF has been established16. Unlike other adipokines, adiponectin appears to be cardioprotective with both anti-inflammatory and anti-atherosclerogenic effects17; and decreased adiponectin levels are associated with increased cardiovascular risk factors such as low HDL-C, increased BMI, high fasting glucose and hypertension27. Low plasma adiponectin levels are known to be associated with insulin resistance and visceral rather than subcutaneous fat accumulation28. Some studies also demonstrated that low adiponectin levels may contribute to increased myocardial hypertrophy, cardiac fibrosis, nitrative and oxidative stress, angiogenesis, atherosclerosis and an inflammatory response through a number of adiponectin-mediated signaling pathways18. Furthermore, Ouchi et al.29 showed that low plasma adiponectin was associated with impaired endothelium-dependent vasorelaxation, which is closely associated with LV diastolic function7. Therefore, some investigators believe that adiponectin could be a therapeutic target in LV diastolic dysfunction18. However, there are only few clinical studies that examined the cardioprotective effect of adiponectin, which was reported to be decreased with increased visceral adiposity19, and the number of clinical evidences that prove the association between adiponectin and LV diastolic function is insufficient.The pathophysiological mechanism underling the relationship between visceral adiposity and diastolic function is still uncertain. Adipose tissue secretes a number of biologically active adipokines such as adiponectin, leptin, resistin, tumor necrosis factor-α and interleukin-624. A few studies showed a positive correlation between plasma adiponectin and LV diastolic dysfunction in conditions such as hypertension20, hypertrophic cardiomyopathy21 or early LV diastolic dysfunction22. However, some consideration should be given to interpretation of these results. Although Hong et al.20 found a significant relationship between plasma adiponectin and LV diastolic function assessed only by mitral inflow parameters in univariate analysis, they did not report if the association was independent of other clinical variables in multivariate analysis. Unno et al.21 investigated this relationship in 26 patients with hypertrophic cardiomyopathy, but statistical significance in such a small population might be weak and the pathological link between a genetic disease of the cardiac sarcomeres and plasma adiponectin levels is uncertain. Similarly, Negi et al. reported a significant relationship between low plasma adiponectin levels and diastolic dysfunction in hypertension22, but their study included only 25 cases with hypertension and 25 age-matched controls. In contrast, there are other studies which did not find a significant relationships between plasma adiponectin levels and diastolic function in type 2 diabetes mellitus23, or in the general population24. As for the effect of adiponectin on LV hypertrophy, we found a significant association in this study, and this confirms the results of a previous large-scale study30. However, visceral adipose tissue is a multifunctional organ, which secretes not only adiponectin, but also a number of biologically active adipokines16. We may conclude that adiponectin does not have a significant effect on the link between visceral adiposity and LV diastolic dysfunction. We need further studies to determine the precise mechanisms underlying this link. Interestingly, a recent study from Fontes-Carvalho et al.24 demonstrated that leptin rather than adiponectin was associated with LV diastolic dysfunction, although they did not assess visceral adiposity. Regrettably, we did not measure plasma leptin levels in the current study.Some previous investigations reported an inconsistent association between plasma adiponectin and LV diastolic function31. Experimental study demonstrated that apelin-knockout mice showed progressive and significant left ventricular dilatation and systolic dysfunction, which was attenuated by subcutaneous apelin infusion32. Zhang et al. showed that apelin is a negative regulator of angiotensin II-mediated adverse myocardial remodeling and dysfunction in a murine model33. Clinical studies also demonstrated decreased serum and myocardial apelin levels in patients with heart failure35. Furthermore, Boal F et al. demonstrated that obese heart failure patients have greater levels of plasma apelin than non-obese heart failure patients, which might provide the mechanism basis of “obesity paradox”36. Taken together, measurement of apelin level will provide valuable information to elucidate the underlying mechanism between obesity and diastolic dysfunction as well as to explore therapeutic strategies for diastolic dysfunction. Future study is warranted to investigate the association of serum apelin levels with LV diastolic dysfunction in larger number of general population.On the other hand, apelin is an endogenous peptide which belong to the family of adipocytokines. Apelin has an increasingly recognized role in cardiovascular regulation in both animals and humans37. In addition, the interpretation of E/E′ might be overestimates because there is a possible variability of E/E′ between the measure on the medial annulus and lateral wall. Unfortunately, our database did not contain the measurement of E/E′ on the lateral wall, although current guideline recommends the use of average of the two38. Third, the study population had normal or grade 1 diastolic function, and subjects with more than moderate LV diastolic dysfunction were not included. A larger-scale study including patients with moderate or severe LV diastolic dysfunction is needed to confirm our results. Forth, although apelin emerges as a novel biomarker against cardiovascular diseases which is a member of the adipose tissue-derived peptides, we did not measure them. Future studies is needed to evaluate the association between serum apelin levels and diastolic function to elucidate the underlying mechanism regarding obesity-related diastolic dysfunction. Finally, this was a cross-sectional observational study. Further longitudinal and interventional studies are required to verify if visceral adiposity could be a therapeutic target for preventing progression of LV diastolic dysfunction.Several limitations of present study should be considered. First, because the study sample was relatively young and few individuals were obese, the observed association might not allow generalization to populations with different demographic composition especially obese subjects. Second, we did not have LVEF measurement by Simpson’s methods. Although we exclude the participants with LV wall motion abnormalities, LVEF measurements by Simpson’s methods is more ideal than measurement by Teichholz formulaThis study had a cross-sectional design. Initially we enrolled 215 constructive subjects who underwent laboratory test, 2-dimensional echocardiography, and abdominal CT in the health check-up clinic at the University of Tokyo Hospital between April 2016 and June 2016. The exclusion criteria were: (1) LV ejection fraction <50%; (2) atrial fibrillation; (3) LV regional wall motion abnormalities; (4) significant valvular disease (more than mild grade), (5) cardiomyopathy (6) history of coronary artery disease and (7) congenital heart disease. Among all, 2 participants met exclusion criteria  and were excluded. Thus, the final population of this study comprised 213 participants . This observational study was approved by the institutional ethics committee of the University of Tokyo (#2650) and did not involve any of experiments. Written comprehensive informed consent that allows all de-identified data to be used for any study including our research protocol was obtained from all participants at the time of health check-up. We confirm that all methods were carried out in accordance with relevant guidelines and regulations.2).The medical health checkup included the following items: height, body weight, waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), blood-cell counts, blood chemistry, electrocardiography, chest radiography, transthoracic echocardiography and abdominal CT. Body mass index (BMI) was calculated as body weight (kg) divided by height-squared , dyslipidemia (triglyceride ≥150 mg/dl or/and HDL-C <40 mg/dl), raised blood pressure (SBP ≥130 mmHg or/and DBP ≥85 mmHg) or a disorder of glycometabolism (HbA1c ≥6.5% or previously diagnosed diabetes) based on the Japanese guideline40.Hypertension was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg at the time of visit or use of antihypertensive drugs. Diabetes was defined as glycosylated hemoglobin A1c (HbA1c) ≥6.5% or the use of antidiabetic drugs. Dyslipidemia was defined as low-density lipoprotein-cholesterol (LDL-C) ≥140 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 md/dl or triglyceride ≥150 mg/dl or the use of lipid lowering drugs. We defined obesity (BMI ≥30) according to the International Classification of adult using BMIVenous blood samples were collected between 8:00 and 10:00, after 12 hours overnight fast, with the participant in sitting position. Serum total cholesterol, LDL-C, HDL-C, triglyceride, hemoglobin, creatinine, and HbA1c by immunonephelometry. For insulin measurement, the blood was immediately centrifuged and the plasma stored at −20 °C for later analysis. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) score. The HOMA-IR score was calculated from the following formula:Serum total adiponectin levels were measured by an enzyme-linked immunosorbent assay using the Human Adiponectin Latex Kit , using an automatic clinical chemistry analyzer, Labospect008 Hitachi LABOSPECT 008 . When we investigated within-run precision of this method, measuring a pooled human serum sample for twenty times, we observed that the mean ± SD for the within-run study were 12.67 ± 0.08 g/mL and that the within-run CVs were 0.63%.41. Echocardiographic images were obtained using commercially available systems from the parasternal, apical and subcostal windows for the evaluation of right and left ventricular function. Two-dimensional and color Doppler imaging were performed to screen for valvular stenosis or regurgitation. LV and left atrial (LA) chamber quantifications were performed with 2-dimensional echocardiography, according to the guidelines of the American Society of Echocardiography37. LV ejection fraction was calculated using the Teichholz formula. LV mass was calculated by a validated Devereux’s formula42 using LV diastolic diameter and wall thickness on 2-dimensional echocardiography, and was indexed by body surface area. LA volume was measured using the biplane area-length method and was calculated as LA volume/body surface area. We evaluated diastolic dysfunction as previously described38. Briefly, peak velocities of the early (E-wave) and late (A-wave) phases of the mitral inflow pattern from Doppler recordings were measured in the apical four-chamber view, and their ratio (E/A) was calculated. The peak early diastolic (E′) velocities of the septal mitral annulus were measured by pulsed tissue Doppler imaging in the apical four-chamber view. The ratio between the E and the E′ wave (E/E′) was then calculated. To estimate inter- and intra-reader variability, two independent observers performed echocardiographic measurements of LV mass index, LA volume index and E/E in randomly selected 10 subjects and one observer repeated the measurements subsequently. The inter- and intra-observer variability was estimated using an intra-class correlation coefficients (ICC).Echocardiographic examination was performed using commercially available system . All images were acquired in the left lateral decubitus position according to a standardized protocol and interpreted by a trained imaging cardiologist who was blinded to all other clinical information. The echocardiographic equipment was maintained according to the guideline of the Japanese Society of Echocardiography43. The area of visceral fat was defined as the sum of the intraperitoneal fat area with CT density in the range of −150 to −50 Hounsfield units. Subcutaneous fat area was also measured in the same manner.Visceral adiposity was assessed as visceral fat area (VFA) quantitatively measured by CT taken at the level of the umbilicus as previously reportedThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.Statistical analyses were performed using JMP version Pro 11. Data are expressed as the mean ± standard deviation for quantitative variables with normal distribution. The relationships between variables were assessed using Pearson’s correlation coefficient. Univariable and multivariable linear regression analyses on diastolic parameters were performed to identify clinical and laboratory variables that were associated with diastolic parameters. The factors related at the p < 0.05 level were selected as independent variables for multivariable analysis. All tests of significance were 2-tailed, and P < 0.05 was considered statistically significant.


The current study was conducted on a sample of 91 patients diagnosed with diastolic dysfunction (DD) with preserved systolic function caused by a painful chronic ischaemic cardiopathy – angina pectoris stable at the effort. The diagnosis was established following anamnesis, electrocardiogram, and echocardiography. Myeloperoxidase (MPO) serum levels were assessed in all patients and then these values were correlated with some of the echocardiography parameters that proved the mentioned diagnosis.Stratifying the patients depending on the disease risk by early detecting of any possible DD with preserved systolic function.The use of the MPO increased circulating levels as a biomarker for diagnosis and risk due to the statistically significant correlation between those and the results of the other two aforementioned paraclinical investigation.In conclusion, the execution of this investigation triad  allows: Clinical studies on CI reveal that myocardial performance depends on the left ventricle (LV) diastolic function, which is primordially dependent on the relaxation ability of the heart muscleSince 1991, the medical practice has recognised a new clinical form of heart failure, diastolic dysfunction (DD),According to the incidence rates, the main pathogenic mechanism responsible for the onset of CI with normal LV ejection fraction is myocardial ischaemia that slows down the heart muscle relaxation, reduces the diastolic distension, and remodels the heart concentrically increasing the width/radius ratio. Under hypoxia/ischaemia conditions, the LV distension problems arise as an expression of healthy arias and ischaemic, even fibrous lesions coexisting in the heart muscle, which alter the relaxation process and generate a delay and inhomogeneity of relaxation – increasing the phenomena, especially during effort,Cellular oxidative stress is defined as the biological state characterised by an excess concentration of oxidative agents (reactive oxygen species (ROS) and reactive nitrogen species (RNS)), which results as a consequence of either intensified synthesis or decreased antioxidant systems activityLocal production of oxidant agents by implicating the cell structures of the particular organ or/and the cells migrated or infiltrated at that level.,,Systemic synthesis in other tissues and organsIn medical practice the pathogenesis induced by oxidative stress on the organic level is functionally evaluated to quantify the participation share, without regard of its primary source:,,Mobilisation of resident/responsive monocytes, from the central axis of laminar blood, flow into passing in the interstitial space by diapedesis.Initiating the stimulating process on the monocytes, which results in their partial activation.,,,Complete activation of monocytes, which allows them to metamorphose into macrophagesIn the case of ischaemic cardiomyopathy induced by coronary atherosclerosis in the first category, that of the local sources producing oxidant agents, there are the myocardial fibres, myocytes, endothelial cells from the regional vessels, whereas in the other class, the one of the migrated cells or the figurate elements implicated in inflammatory processes are placed neutrophils and especially monocytes turned into macrophages,,Through the production of chemoattractant factors, the activated monocytes have implications in the myocardial oxidative stress evolution, ensuring the persistence and expand of inflammation that generates other chemoattractant factors on its own. The structural–functional destructive processes in the ischaemic heart muscle are mediated by at least 24 such factors among which are tumour necrosis factor (TNF), interleukin-1 (IL-1), and stimulating factors such as granulocyte-monocyte colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and monocyte colony-stimulating factor (M-CSF),,–), which turns into hypochlorous acid (HClO) and gains lytic properties over the cells,Although the consulted medical literature recognises unanimously the myeloperoxidase (MPO) serum levels as a biomarker for oxidative stress and endothelial dysfunction in CI, there are limited studies available on the possible significance of MPO as an indicator of inflammation and heart muscle remodelling processesOn the basis of the overall acceptance of serum MPO among the markers used in endothelial dysfunction management, the present study is aiming to investigate the possible signification of serum MPO as a biomarker for CI with DD and preserved ejection fraction .The research sample consisted of 91 patients with a positive diagnosis of DD with preserved ejection fraction (PRESYF), having a unique aetiology caused by the only one aetiological factor, namely chronic ischaemic painful cardiopathy (CICD).The preservation of the systolic debit was an important condition imposed on the participants in the study to limit the sources of oxidant agents production, only to those on the myocardial level, in the case of mal-irrigation. Because of the fact that it is demonstrated and universally acknowledged that in chronic CI with reduction of the systolic flow there occurs a decrease in the organ debit, in these conditions all structures of the organism are forced to function under state of hypoxia. From pathogenic point of view, the consequence is the appearance of new sources of ROS and NOS production – a possibility that has been avoided through the selection of patients with ischaemic cardiopathy, but conserved systolic debitResting state electrocardiogram and supplementary effort test if the first could not demonstrate any ischaemic modifications.Echocardiography – bi-dimensional evaluation, M-mode, pulsed Doppler (PW), and tissue pulsed Doppler (TDI). Referring to the clinical utility of echocardiography, the specialized literature considers this to be the best non-invasive method for assessing DD and LV filling pressure. The M-mode used in the current study was limited because the DD is suggested indirectly. In comparison, the other echocardiographic techniques such as the transmitral blood flow Doppler and the tissue Doppler are more sensitive and more specific, which allows them to prove and stage the DDFor each one of the 91 patients (35 women and 56 men) in the study sample, the aetiological diagnosis of the myocardial contraction deficiency (ischaemic cardiopathy) is justified by the presence of stable angina pectoris at effort, reported during anamnesis, and the paraclinical exploration results. To evaluate the functional condition of the ventricular myocardium during diastole all participants underwent:Formula Devereux R.B. used to calculate the mass of LVIn order to include in the research sample only those patients with chronic ischaemic cardiopathy and preserved left ventricular ejection fraction (LVEF) (≥50%) (PRESYF), it was necessary to evaluate the global systolic function of LV. For this purpose the Simpson modified method was applied, with the use of the following formula:Signs and symptoms of CI:  • Symptoms: dyspnoea and/or arterial hypertension during effort states.  • Signs: gallop rhythm, respiratory sounds – pulmonary crepitation and even acute pulmonary oedema.Normal or slightly affected systolic function.,Abnormalities in diastolic relaxation, filling, distensibility, or stiffnessOn the next stage of positive diagnosis establishment, for the selection of the required study sample, in the conditions of confirmed normal ejection fraction values and absence of any associated diseases, excluding of course the ischaemic cardiopathy, the LV diastolic function was assessed, practically the existence of DD. The DD diagnosis was made on the base of the following 3 obligatory criteria given by the European Study Group on Diastolic Heart Failure:The successive executions of the aforementioned phases enabled the selection of sample patients with a positive diagnosis of DD with PRESYF, with the unique aetiology of chronic ischaemic painful cardiopathy (stable angina pectoris of effort).An essential criterion imposed for including patients in the study sample was their age. It was necessary because the medical literature unanimously acknowledges the interdependence between CI by DD and age, acquiring variable rates of this positive age-correlation . The research did not cover people older than 60 years, hence, the average age of the sample was 54.2 years old with subsamples according to ,The lack of voluntary participation of patients older than 60 years is based on the scientific demonstrated argument that although elderly people experience precocious alterations in the ventricular passive filling, the global filling is conserved due to the arterial systole contribution. It is universally accepted that after the age of 60, the participation share of the atrial systole in the ventricular diastolic filling reaches 30% of the cardiac debit2, which corresponds to a body mass value considered normal or with 10% ponderal excess and associated with a minimum riskThe body mass index (BMI) of the patients accepted in the current research presented variations within the margins of 26 ± 3 kg/mIn addition, for the purpose of the study, there were not accepted patients with arterial hypertension or with tachycardia/tachyarrhythmia, because these diseases, as well as the age, are predictors for some of the examined echocardiographic parameters – E/A ratio and TDEThe patients from the study sample underwent laboratory tests on venous blood, the outcome of which is shown in Whereas the main study objective was the MPO serum levels research, it was obligatory to include its determination among the conducted laboratory investigations. The reasoning of its establishment was that increased serum concentrations of this enzyme in patients with DD are an indicator for the existence of an inflammatory process that develops not only on the coronary level but also on myocardial one in the hypoxic/ ischaemic state.The analysis approach applied for quantifying MPO was the immunoenzymatic fluorescence method (FEIA) that uses as an antigen purified MPO enzyme acquired from human neutrophils. The method allows the anti-MPO antibodies detection, which according to the specialised literature data are implicated particularly in the vascular inflammatory pathogenesis, because of their role as co-participants responsible for the set of vascular dysfunction by atherosclerosis.t-Student’s test, with statistical signification being affirmed for values of p < .05.The data from the analysed parameters that will be further referred to in Discussion section were evaluated using From the symptomatological point of view, the diagnosis of DD among the patients in the research sample was based on the following :For the patients with chronic ischaemic cardiopathy but with no evident symptomatology , the DD diagnosis was established based on the data from the echo-Doppler test.LA volume indexLV mass indexRelative thickness SIV, respectively, PPVSE-wave speedTransmitral flux, calculated by the E/A ratioE-wave deceleration timeTDE,E/E′ ratio between the E-wave and E′-wave speedTo establish the diagnosis of DD according to the three recommendations of the European Study Group on Diastolic Heart Failure and to highlight abnormalities in relaxation, filling, distensibility, or stiffness of the LV the values of the echographical parameters from the list below were interpreted:With the use of “symptoms and signs of CI” criteria recommended by The European Study Group on Diastolic Heart Failure, the patients from the study sample were sorted in different classes of inotropic deficiency, after the classification of NYHA .The basic criterion of the NYHA classification is the symptomatology, which made it quite difficult to sort the participants in the research sample in the respective classes of the myocardial contractile deficit, considering that patients with DD and preserved systolic function present imprecise symptomatology – a particular aspect that is referred to in the specialised literature. In the same respect, it can be mentioned the existence of patients in the study that lacked symptoms of CI.,,In accordance with the NYHA classification aspects, the classes of the myocardial contractile deficit were as shown in As evaluating the signification of MPO serum values is the main objective of the study, it was necessary to establish the blood level of this enzyme. Serum concentrations above the negative result of 7 U/mL were detected in 67 patients (73.1%). The amount of cases is 2.7 times higher than the negative result, which corresponds to a positive correlation in 2 from 3 situations .Even if the number of cases in the current study is considered relatively small, the results in determining MPO serum levels represent a strong argument to support the fact that MPO can be used as a biomarker for diagnosis and risk estimation of DD, occurring as chronic ischaemic cardiopathy with conserved systolic debit volume.2 phospholipase (lp-PLA2), F2-isoprotan, and microalbuminuriaTo endorse the previous suggestion there is also the protocol recommended by Cleveland Heart Lab to use the multi-biomarker CVD Inflammatory profile test with the purpose of DD diagnosis. The latter includes two of the serum parameters measured in the present study, namely (MPO and hs-CRP), but also 4 additional ones: oxidised lipoproteins, AE-wave deceleration time, TDE, increased in 83 cases = 91.1%.Relative thickness SIV and PPVS, respectively, in 35 cases = 71.4%.LV mass – increased in 56 cases = 61.5%.LV index mass – increased in 59 cases = 64.8%.E/A ratio – abnormal in 78 cases = 85.7%.In comparison with the standard values the following echographic parameters showed pathological deviations in the patients of the research sample:The next stage of the study consisted of identifying possible correlations between MPO serum concentration and the determined values of some of these echocardiography parameters. Therefore, the serum MPO was compared with TDE, LV mass index, and E/A ratio. Therefore, the direction of level variation of the circulating MPO serum concentration variations was compared with that of the following echographic parameters’ variations: TDE, LV mass index, and E/A ratio.Referring to DD, the medical literature reports that the first echographic parameter to become abnormal by increasing its value is TDE. Incidence of values above 240 ms reaches 91.1% in the study sample, occupying the first place among the selected echographical parameters. The correlation between the TDE values and the MPO serum concentration showed a ratio of 83 cases/67 cases = 91.15/73.1%.Patients with DD and PRESYF MPO serum concentration above 7 U/mL is significantly correlated statistically with relaxation and even ventricular compliance modifications in the advanced stages of the disease. The thoroughgoing study based on the results from the present research, by conducting investigations on numerically significant samples of patients, possess high chances of proving and accepting the utility of serum MPO as a biomarker for DD with PRESYF.The fact that in 16 cases were reported prolonged TDE values while presenting normal MPO serum concentration (<7 U/mL), can be interpreted as caused by:the increased sensibility of the TDE parameter in identifying the existence of delayed relaxation in comparison with the circulating MPO levels that raise at a later phase during the disease evolution.The concordance in the proportion of ¾ of the analysed cases between these two parameters allows elaborating the following statements:The large accordance rate between these two parameters can also be used as an argument for supporting their association, as a complex biomarker, the information rendered by the two in medical practice being useful for the fact that they support each other, at the same time completing each other.,,In medical practice, the elevated SIV, PPVS, LV mass, and LV mass index values are considered an illustration of concentric cavity remodelling, but at the same time also an indication for myocardial hypertrophy, as a functional expression of modifications in the LV myocardial complianceIn the current research, the increased incidence of LV mass index (59 cases = 64.8%) was corroborated with that of LV walls relative thickness (SIV + PPVS) reported in 65 cases (71.4%), which had moderately higher values than those accepted as normal. Without taking into account the patients’ sex, the echographic existence of modifications in the aforementioned variables indicates that in at least 2/3 of the DD cases with PRESYF the ventricular concentric hypertrophy was present.In all 59 cases with increased LV mass index, there was also detected an increase in the serum MPO concentration ≥7 U/mL.The 100% accordance between the two parameters makes it possible to consider that the circulating MPO level can be recognised as an indicator for the onset of LV myocardial hypertrophy developing process and therefore can be accepted as a marker for DD.Despite DD being a relatively light medical condition, it possesses a prognostic importance, proving the existence of certain cardiovascular risk, with the possibility of installing a clinical syndrome of CI. Therefore, the interest in developing new laboratory and paraclinical non-invasive examinations for the detection of DD as early as possible is completely justified.The current study shares this aim and the obtained results allow the statement that MPO serum level, independently or in correlation with the echographic data, can become a useful investigation for the medical practice as a biomarker of DD with PRESYF.During the clinical track of DD with PRESYF evolution, between the two respective parameters, the informational value of the enzymatic serum concentration has a relatively delayed sensibility, whereas there are echographically evident signs of delayed or incomplete relaxation. Consequently, if it is not possible to perform the echocardiography, MPO serum concentration dosage is useful in diagnosing and evaluating the risk for DD with PRESYF.


Echocardiography (echo) is widely used to guide therapeutic decision-making for patients being considered for MitraClip. Relative utility of two- (2D) and three-dimensional (3D) echo predictors of MitraClip response, and impact of MitraClip on mitral annular geometry, are uncertain.The study population comprised patients with advanced (> moderate) MR undergoing MitraClip. Mitral annular geometry was quantified on pre-procedural 2D transthoracic echocardiography (TTE) and intra-procedural 3D transesophageal echocardiography (TEE); 3D TEE was used to measure MitraClip induced changes in annular geometry. Optimal MitraClip response was defined as ≤mild MR on follow-up (mean 2.7 ± 2.5 months) post-procedure TTE.p ≤ 0.01), paralleling smaller annular area and circumference on 3D TEE (both p = 0.001). Mitral annular size yielded good diagnostic performance for optimal MitraClip response . In multivariate analysis, sub-optimal MitraClip response was independently associated with larger pre-procedural mitral annular area on 3D TEE  and global LV end-diastolic volume on 2D TTE . Substitution of 2D TTE derived mitral annular diameter for 3D TEE data demonstrated a lesser association between pre-procedural annular size  and sub-optimal MitraClip response. Matched pre- and post-procedural TEE analyses demonstrated MitraClip to acutely decrease mitral annular area and circumference  as well as mitral tenting height, area, and volume : Magnitude of MitraClip induced reductions in mitral annular circumference on intra-procedural 3D TEE was greater among patients with, compared to those without, sub-optimal MitraClip response (>mild MR) on followup TTE (p = 0.017); greater magnitude of device-induced annular reduction remained associated with sub-optimal MitraClip response even when normalized for pre-procedure annular circumference (p = 0.028).Eighty patients with advanced MR underwent MitraClip; 41% had optimal response (≤mild MR). Responders had smaller pre-procedural global left ventricular (LV) end-diastolic size and mitral annular diameter on 2D TTE (both MitraClip alters mitral annular geometry as quantified by intra-procedural 3D TEE. Pre-procedural mitral annular dilation and magnitude of device-induced reduction in mitral annular size on 3D TEE are each associated with sub-optimal therapeutic response to MitraClip. Echocardiography (echo) is widely used to diagnose mitral regurgitation (MR) and assess its response to therapeutic interventions. MitraClip is the sole percutaneous device commercially approved in the United States to treat MR, and is increasingly utilized worldwide for this purpose – over 80,000 patients have undergone MitraClip in the last decade . RecurreOne reason for variable MR response to MitraClip stems from patient-specific differences in cardiac chamber remodeling. MitraClip is intended to reduce MR via focal leaflet coaptation. However, prior echo studies by our group and others have shown increased left ventricular (LV) size to augment risk for recurrent MR after MitraClip implantation , supportThis study tested impact of MitraClip on mitral annular remodeling. To do so, intra-procedural three-dimensional (3D) transesophageal echo (TEE) was used to quantify annular geometry prior to and immediately after MitraClip implantation. Transthoracic echo (TTE) was analyzed pre- and early (within 6 months) post-procedure to evaluate change in MR. Study goals were to test whether MitraClip acutely alters mitral annular geometry in a manner discernable via 3D TEE, and if magnitude of device-induced alterations in annular geometry stratifies MitraClip therapeutic response.The study population comprised consecutive patients with advanced (>moderate) MR who underwent MitraClip at Weill Cornell Medicine  in whom intraprocedural TEE was available to evaluate annular geometry, and TTE was performed pre- and post- (1–6 months [target 6 months]) procedure to assess change in MR: No otherwise eligible patients were excluded based on procedural outcomes, imaging findings, or clinical indices.Demographic data were collected in a standardized manner, including cardiac risk factors and medications. Procedural indices including number of MitraClip devices were also recorded. Ambulatory blood pressure, heart rate, and cardiac rhythm was measured at time of baseline and followup TTE. This analysis of pre-existing (retrospective) data for research purposes was approved by the Weill Cornell Institutional Review Board.TEEs were acquired intra-procedure in a mid-esophageal view using Philips iE33 or EPIQ7 systems equipped with matrix array transducers. 3D images of the mitral apparatus including the annulus were optimized for coverage and gain using single beat acquisition (Zoom 3D); datasets were selected for analysis based on optimal discernment of the mitral annulus.TTEs were obtained using commercial equipment. Images were acquired in parasternal long, parasternal short, and apical 2-, 3-, and 4- chamber orientations. Color and pulsed wave Doppler was used to assess MR; continuous wave Doppler included assessment of tricuspid regurgitant velocity (to quantify pulmonary artery [PA] systolic pressure).To evaluate mitral annular and cardiac chamber geometry in relation to MitraClip response, data were derived from TEE and TTE, both of which were acquired via a standardized protocol:3D TEE analysis was performed using a semi-automated program  tailored for 3D mitral annular modeling. All mesurements were performed blinded to MitraClip response. A late-systolic frame was selected for annular tracking defined as the last systolic frame before mitral valve opening. Landmarks denoting anterior and posterior mitral annulus were identified on long orthogonal views followed by identification of the coaptation points of the aortic and mitral valves and apical posterior aspect of the aortic annulus. Semi-automated contours of the mitral annulus and mitral valve leaflets were then generated throughout the cardiac cycle. Contours were were manually edited via rotation around the mitral annulus to ensure accurate border segmentation. Calculated indices included valvular tenting area and height, mitral annular linear  dimensions, as well as mitral annular area and circumference  for continuous variables, and chi-square test for categorical variables. Bivariate correlation coefficients were used to evaluate associations between continuous variables. Univariable and multivariate modeling was performed via binary logistic regression. Diagnostic utility of remodeling indices was evaluated in relation to MitraClip response using receiver operator characteristics curves, for which area under the curve (AUC) was used as an index of overall test performance. Statistical calculations were performed using SPSS 22.0 . Two-sided The study population comprised 80 patients with advanced (> moderate) MR who underwent MitraClip as well as pre- and post-procedure TTE to assess procedural durability, reflecting 78% of all patients who underwent this procedure at our site  during the study interval (2013–19). MitraClip implantation employed the NTr device type in over three-fourths of cases . In nearly all cases (76/80), MR was deemed primarily degenerative; leading pathologies were prolapse, annular calcification, and valve thickening. However, concommitant conditions predisposing to mixed MR  was common; 26% of patients had prior MI and 47% had systolic heart failure (LVEF< 50%). All patients underwent MitraClip without complications; a mean of 1.63 ± 0.58 devices were implanted per procedure (58% had multiple devices implanted during the index intervention).p = NS).Follow-up TTE (2.7 ± 2.5 months) was performed to assess short term procedural response based on MR: Whereas nearly all 91%) patients had some improvement in MR (≥1 grade MR reduction), less than half (41%) had optimal MitraClip response (≤mild MR). Regarding thereapeutic response, follow-up data demonstrated MR trace/absent in 10% (33% 1+ [mild] / 17% 2+ [moderate]/ 30% 3+ [moderately-severe] / 10% 4+ [severe]). Table % patientp < 0.01). Regarding LA remodeling, results similarly demonstrated sub-optimal MitraClip to be associated with chamber dilation: LA area was, on average, more than 25% larger among MitraClip non-responders – results were similar based on data acquired in 2- and 4-chamber orientation (both p < 0.05), as well as calculated LA volume (p = 0.01). LA dilation was accompanied by impaired LA function; LA circumferential and longitundinal strain were both lower among MitraClip non-responders (p < 0.05): circumferential (r = − 0.47) and longitudinal strain  were each negatively correlated with LA area.Table n = 66]). As shown, 3D TEE results paralleled those of 2D TTE with respect to associations between adverse remodeling and MitraClip response: Mitral annular area, circumference, and diameter were all equivalently larger among patients with suboptimal MitraClip response (p < 0.001), paralleling a trend towards increased tenting height (p = 0.08) in sub-optimal responders.Table 2/m2 [CI 1.22–3.06]), circumference (OR 1.96 per cm/m2 [CI 1.12–3.41]), or corresponding 2D area and linear based indices : Predictive utility of TEE indices of mitral annular size were similar, as evidenced by similar overall diagnostic performance (AUC 0.65–0.72). Table 2 [CI 1.04–1.50]) and LA (OR 1.22 per 10 ml/m2 [CI 1.03–1.44]) volume were each associated (p < 0.05) with greater residual MR (>mild) after MitraClip implantation. Similarly, increased mitral annular diameter as quantified on TTE was associated with MitraClip response (p = 0.02), as was the case for annular size on intra-oprocedural TEE imaging (p < 0.01).Regression analyses were used to test relative utility of remodeling indices for prediction of MitraClip response. As shown in Table 2/m2 [CI 1.19–3.13], p = 0.007) as well as global LV volume as quantified by 2D TTE . Substitution of 2D TTE derived mitral annular diameter (in place of corresponding 3D TEE area) weakened the predictive model (χ2 17.22 ➔ 10.87), and demonstrated a lesser association between pre-procedural annular diameter (p = 0.06) and greater residual MR (>mild) after MitraClip implantation.Multivariate analysis was used to further test the association of pre-procedural remodeling indices with MitraClip response. As shown in Table p < 0.001): Fig. n = 19) and prominent annular calcification (n = 25) – although device-induced reductions in tenting indices were non-significant in patients with prolapse.Given our observed association between pre-procedural mitral annular area and therapeutic response, 3D TEE data were further analyzed to test whether MitraClip acutely altered annular geometry, and whether such alterations predicted procedural success. Table p = 0.017); greater magnitude of MitraClip induced annular reduction remained significantly associated with MitraClip response even when normalized for pre-procedural circumference (p = 0.028). Similarly, 3D TEE analysis demonstrated intra-procedural device-induced reductions in mitral annular area to be greater among patients with sub-optimal MitraClip response  on follow-up TTE.As illustrated in Fig. p < 0.001) as quantified on intra-procedural 3D TEE. Consistent with the notion that remodeling factors beyond the device impact device efficacy, pre-procedural mitral annular and LV chamber size each independently predicted sub-optimal MitraClip response; substitution of 3D TEE derived mitral annular area for annular diameter on 2D TTE strengthened the predictive model. Magnitude of intra-procedural device-induced reduction in mitral annular size was greater among patients with sub-optimal MitraClip response (>mild MR) on followup, as evidenced by greater absolute and relative reductions in mitral annular circumference (both p < 0.05).This is the first study to examine the impact of MitraClip on mitral annular remodeling - findings provide new insights regarding mechanistic determinants of therapeutic response, as well as novel echo-based parameters to guide procedural decision-making. Results demonstrate that MitraClip alters annular geometry in regions beyond the device itself, as evidenced by acute device-induced reductions in annular circumference and area  of patients with degenerative MR have also shown increased LV end-diastolic diameter to predict decreased likelihood of procedural success as assessed at time of hospital discharge . Among pp = 0.09) than that of annular circumference or area (both p < 0.01). While reasons for this difference are uncertain, we speculate that it may stem from more advanced LV remodeling in our study population as evidenced by increased LV chamber size in our population (LV end diastolic diameter 6.0 ± 0.8 cm) compared to that studied by Oguz et al. (5.8 ± 0.7 cm): ), rather than a single quantitative measure. This approach is consistent with that employed in several prior studies in which greater severity of MR after MitraClip was shown to confer adverse prognosis , 4. DespThis study demonstrates that MitraClip alters mitral annular geometry, and that magnitude of intra-procedural reduction in annular size is associated with sub-optimal device response (> mild MR). Future larger scale studies are warranted to further discern mechanism by which device-induced annular remodeling drives recurrent MR after MitraClip, and test clinical utility of 3D echo guided MR therapeutic strategies paired to pattern and magnitude of mitral apparatus remodeling.


Clinical evaluation of pacing therapy in mitigating the aortic insufficiency after transchateter aortic valve implantation often gives contradictory outcomes. This study presents an in vitro investigation aimed at clarifying the effect of pacing on paravalvular leakage.A series of in vitro tests reproducing the heart operating changes clinically obtained by pacing was carried out in a 26 mm Edwards Sapien XT prosthesis with mild paravalvular leakage. The effect of pacing on the regurgitant volumes per cycle and per minute was quantified, and the energy and power consumed by the left ventricle were calculated.Results indicate that though pacing results in some reduction in the total regurgitation per cycle, the volume of fluid regurgitating per minute increases substantially, causing overload of left ventricle.Our tests indicate no effective haemodynamic benefit from pacing, suggesting a prudential clinical use of this therapy for the treatment of postoperative aortic regurgitation. Some in-vivo studies have debated the role of pacing to mitigate aortic regurgitation and its use as therapy to this aim.The discrepancies on the results are mainly due to some inaccuracies of in-vivo measurements and the improper use of aortic regurgitation index to assess the enhancement of the grade of insufficiency.The study indicates that pacing is ineffective as a treatment for postoperative aortic regurgitation, and may result detrimental both in term of regurgitation and heart power demand.The findings suggest a more widespread use of the left ventricular power as a heart performance parameter that allows an effective and consistent comparison between different heart beating conditions.Significant postoperative aortic regurgitation due to paravalvular leakage (PVL) is a common complication after transcatheter aortic valve implantation (TAVI), with incidence ranging from 5% to 25%, associated with an increase in early and late postoperative mortality.Pacing has been adopted as temporary or permanent therapy to mitigate PVL in patients affected by moderate/severe regurgitation after TAVI.The present study aims at assessing in vitro the effect of pacing on the cardiac load and its impact on the power consumption of the heart. In order to allow direct comparison between the different operating conditions, an in vitro approach was adopted. This enables full control of the working parameters, as well as an accurate measurement of the functional quantities. Tests mimicking mild PVL after TAVI and different pacing were carried out, and the efficacy of pacing was verified by investigating its effect on the ventricular overload per beat and per unit time . The distinction between these two time references becomes fundamental when adopting pacing, as quantities typically measured over a single heart cycle do not necessarily reflect the global benefit and may lead to erroneous interpretations of the results.orifice 12 mm2)   causing Following well-developed methodologies for evaluation of cardiovascular devices and in vitro haemodynamics features,Ao) were set to replicate conditions observed in vivo,Ao was maintained constant at 100 mm Hg. To better represent the changes in physiological contraction of the left ventricle with the increase of HR, the systolic percentage of the cycle was also extended, in agreement with the clinical evidence.Six tests were carried out at different hydrodynamic working conditions, as reported in For each testing condition, the instantaneous pressures in the aortic and ventricular chambers and the flow rate thorough the valve were measured during the entire cycle, collecting 256 samples per cycle.Data were averaged over 10 consecutive cycles and used to extract the following quantities:Stroke volume (SV (mL)).Closing regurgitant volume (CV (mL)), corresponding to the backflow as the valve leaflets move from the open to the closed configuration.Leakage volume (LV (mL)), corresponding to backflow occurring when the valve is fully closed.Total regurgitant volume (RV (mL)), equal to the sum of CV and LV.Regurgitant fraction (RF (%)), given by the ratio between RV and SV.Closing regurgitant mean flow rate (CFR (mL/min)), given by the product of CV and HR.Leakage mean flow rate (LFR (mL/min)), given by the product of LV and HR.Total regurgitant mean flow rate (RFR (mL/min)), given by the product of RV and HR.Energy per cycle (E (J)), calculated as ventricular pressure–volume integral .Power (P (W)), calculated as the ratio between the energy E and the heart beat duration:The values determined for the above parameters at the different testing conditions are summarised in The transaortic flow wave behaviour for the six study cases is depicted in a of The RV measured at the different testing configurations, with the contributions from both CV and LV, is summarised in the panel The RFR  and the two contributions due to CFR and LFR are reported in panel B of c of Left ventricle energy per stroke E and power P as a function of HR are shown in the panel et alet al,et alVarious studies performed in the 1960s with the dye dilution technique observed a reduction of RV in patients with increasedet al, which demonstrates the relatively low resolution of in vivo measurements through transoesophageal echo (the best cost–benefit ratio methodology for in vivo flow measurements) in quantifying the RV, and questions the reliability of ARI, especially when it is used to grade regurgitation as a function of HR.Some of the discrepancies in these studies may be justified by the use of different in vivo measurement techniques, as well as the limited accuracy of clinically available anemometric methodologies. This limitation is acknowledged in a topical work by Pibarot D)  that, due to the choice of setting a fixed value for the mean aortic pressure (100 mm Hg), is similar for all testing cases. This implies that, as the diastolic period reduces with pacing, LV over a single cardiac cycle decreases about proportionally, as reflected in the diagram in In the present study, for the first time, in vitro tests are carried out in order to verify and quantify the effect of pacing in presence of mild aortic regurgitation after TAVI. Flow measurement shows that the leakage rate determined in the diastolic period after full valve closure (LV per unit time) does not vary substantially for the tested conditions (between 15 mL/s and 20 mL/s), and it is consistent in value with the leakage rate expected from fluid dynamics theory , as well as the need for post implantation pacing to overcome the development of complete AV block as recently reported in multicentre studies, in which the permanent pacemaker was implanted up to 17.4% of the patients.Of course, the presented study is based on a number of necessary assumptions that may affect the relevance of the results, such as the adoption of idealised anatomical and operating conditions. In particular, the use of a rigid aortic root and a straight paravalvular orifice of constant semielliptical cross section is a generalisation, which suggests some caution when transposing the presented results to the clinical case. Also, the fluid behaviour is necessarily dependent on the dynamic of the selected valve, and on the features imposed to describe the contraction phase .Ao.The increment in mean aortic pressure typically observed with increased HRAnother approximation consists in the use of saline solution, which might result into different velocity profiles inside the paravalvular orifice, due to the reduced viscosity (this is about one fourth as the viscosity of blood at 37°C). However, theoretical considerations indicate that, for the used working conditions, the effect of viscosity is expected to be negligible.This study presents, for the first time, a systematic study of the efficacy of pacing as a treatment for PVL. The left ventricular operating conditions under pacing were simulated in vitro on a Sapien XT of size 26 mm, imposing mild paravalvular leakage.The RVs per cycle and per minute, the energy and power consumed by the ventricle in a single beat were estimated at different HRs.Although the shorter diastolic phase for high HRs causes a slight reduction of RF measured over the cardiac cycle, the volume of fluid regurgitating per minute increases substantially, causing overload of the left ventricle.The presented results indicate that pacing produces no effective haemodynamic benefits in patients with AR, in terms of regurgitation, and can result in significant increases in heart power demand. Moreover, collateral complications may arise due a persistent non-physiological shear stress, whose quantification has been demonstrated being rather complex.The study demonstrate that parameters typically adopted to evaluate and quantify aortic insufficiency , based on a single cardiac cycle, are not adequate to capture the effect of HR on the cardiac performance. This may result in erroneous interpretation and quantification of the clinical benefit deriving from pacing, leading to its improper adoption.To correctly evaluate the efficacy of this therapy, alternative parameters based on a fixed chronological period including several heart beats  should be used. In particular, we recommend the use of the left ventricular power as a heart performance parameter, as it allows an effective and consistent comparison between operating conditions characterised by different heart rhythms. In addition, other methodologies might be explored by considering coexisting features related to altered aortic valve haemodynamics, such as the sound of regurgitant jet.Finally, further specific studies would be appropriate to frame the role of the energy and power consumption in the perspective of optimisation of heart performance. This aspect may potentially enhance also the comprehension of the cardiac physiopathology characterised by ventricular remodelling.


Through this analysis, CPET provides a series of additional parameters  that characterize different patterns, helping in diagnosis process. Limitations to the routine use of CPET are mainly represented from the lack of measurement standardization and limited data from randomized multicentric studies. The integration of CPET with exercise stress echocardiography has been recently introduced in the clinical practice by integrating the diagnostic power offered by both the tools. This combined approach has been demonstrated to be valuable for diagnosing several cardiac diseases, including heart failure with preserved or reduced ejection fraction, cardiomyopathies, pulmonary arterial hypertension, valvular heart disease and coronary artery disease. Future investigations are needed to further promote this intriguing combination in the clinical and research setting.Cardiopulmonary exercise test (CPET) is a functional assessment that helps to detect disorders affecting the system involved in oxygen transport and utilization through the analysis of the gas exchange during exercise. The clinical application of CPET is various, it including training prescription, evaluation of treatment efficacy and outcome prediction in a broad spectrum of conditions. Furthermore, in patients with shortness of breath it provides pivotal information to bring out an accurate differential diagnosis between physical deconditioning, cardiopulmonary disease and muscular diseases. Modern software allows the breath-by-breath analysis of the volume of oxygen intake (VO This information has a critical practical relevance in different clinical settings since CPET provides data on functional capacity, training prescription . During ramp-like exercise VO2 increases exponentially up to a steady state corresponding to peak exercise. Three abnormal patterns of VO2 curve can be observed during ramp test. The first is the upward shift of the overall curve due to higher request of O2 consumption as it happens in obese patients. The second is a relatively shallow slope secondary to reduced oxidative enzyme activity in skeletal muscle due to chronic heart failure or deconditioning. The third pattern, known as “the hockey stick” pattern, i.e. ΔVO2/Δwork rate (WR) flattening, is represented by a sharp and sudden interruption of the slope anticipating the expected peak intensity. The sudden interruption of oxygen uptake during the exercise is due to the exhaustion of the patient’s energy reserve, which is typical of myocardial ischemia, diastolic or systolic dysfunction, valve regurgitation or of conditions in which the exercise related heart rate increase is blunted by beta-blockers . Th. Th2 res2 has an important prognostic value in patients with significant MR, although the mechanisms underlying this association are not well established. In this subset of patients, ESE can provide information about the hemodynamic response to effort by measuring mean pulmonary arterial pressure (PAPm), systolic pulmonary arterial pressure (PAPs), RV systolic function and cardiac output (CO). Recently, reduced values in pulmonary vascular reserve, measured by PAPm/CO slope, and in RV contractile reserve, expressed by tricuspid annulus plane systolic excursion (TAPSE)/PAPs changes between rest and peak effort, were found to predict a low peak VO2 response during effort. Accordingly, this association may explain the etiology of impaired exercise tolerance in patients affected by asymptomatic but significant MR. The combination of low pulmonary vascular reserve, impaired RV contractile reserve and low peak VO2 may also guide the optimal timing for mitral valve surgery [2, thus improving patient selection for targeted treatment. Of note, Laufer-Perl et al. demonstrated that in patients with moderate-to-severe MS, restrictive lung function, chronotropic incompetence and limited contractile reserve had a greater impact on symptoms compared to MS severity itself, as expressed by the transvalvular gradient and the mitral valve area [Given the complicated relationships existing between hemodynamic changes from resting condition to peak exercise in patients with valvular disease, new protocols combining ESE and CPET may give detailed information to better face the challenge in developing optimal individualized therapy . ESE ass surgery . Frequen surgery . It is clve area .2max resulted to be substantially reduced in athletes with HCM than in healthy athletes; in particular, a pVO2 > 50 ml/kg/min or >  20% above the predicted maximum VO2 differentiated athlete’s heart from HCM [Another possible combination of CPET and echocardiography involves cardiomyopathies and, in particular, the differential diagnosis with the athlete’s heart. Echocardiography is largely used for diagnosis of hypertrophic cardiomyopathy (HCM), it allowing to characterize a disproportionate increase of LV wall thickness and a reduction of LV end-diastolic diameter . Howeverfrom HCM . These r2 and CO2 [2/Δwork rate flattening, ie. the “hockey stick” pattern, demonstrated to reflect a significantly impaired functional phenotype whose major cardiac determinants are the excessive PAPs increase and the reduced TAPSE) [In chronic thromboembolic PAH, a fast and accurate diagnosis is pivotal for successful treatment. Clinical symptoms/signs may be nonspecific and risk factors not always detectable. Echocardiography is the recommended first-line diagnostic tool and guidelines recommend non invasively estimation of PAPs (by peak velocity of tricuspid regurgitation and atrio-ventricular pressure gradient) and detection of indirect signs of PAH  , 55. CPE and CO2 . In a re and CO2 . It is ad TAPSE) .2 slope to peak VO2 ratio was the best discriminator . These findings demonstrate that in patients with borderline results, a combined stress-echo with CPET, measuring stroke volume and A-VO2 difference throughout effort may be helpful for diagnosing significant coronary artery disease. Furthermore, stress echo derived wall motion abnormalities of isolated coronary lesions other than anterior descending artery, may require particular effort due to poor endocardial visualization, particularly when dealing with significant lesion of the right coronary artery. Blunted physiological VO2 increase and plateau in HR response during CPET has demonstrated to be indicative of myocardial ischemia of right coronary artery, anticipating ECG abnormalities [In the setting of coronary artery disease, the combination of ESE and CPET performed in 110 patients, allowed to discriminate between coronary circulatory disease and de-conditioning  . In factmalities . Hence, Table CPET is being increasingly applied together with echocardiography, in particular ESE, in order to combine functional and structural data. Its use may add crucial information to the echo exam, in particular during stress. The additional diagnostic value of this combined assessment has been demonstrated in multiple clinical settings, including heart failure, valvular heart disease, hypertrophic cardiomyopathy, chronic thromboembolic derived PAH and coronary artery disease. On the grounds of recognized evidences , 61, it


Objective: This longitudinal observational study investigated how neural stretch-resistance in wrist and finger flexors develops after stroke and relates to motor recovery, secondary complications, and lesion location.Methods: Sixty-one patients were assessed at 3 weeks (T1), three (T2), and 6 months (T3) after stroke using the NeuroFlexor method and clinical tests. Magnetic Resonance Imaging was used to calculate weighted corticospinal tract lesion load (wCST-LL) and to perform voxel-based lesion symptom mapping.Results: NeuroFlexor assessment demonstrated spasticity  in 33% of patients at T1 and in 51% at T3. Four subgroups were identified: early Severe spasticity (n = 10), early Moderate spasticity (n = 10), Late developing spasticity (n = 17) and No spasticity (n = 24). All except the Severe spasticity group improved significantly in Fugl-Meyer Assessment (FMA-HAND) to T3. The Severe and Late spasticity groups did not improve in Box and Blocks Test. The Severe spasticity group showed a 25° reduction in passive range of movement and more frequent arm pain at T3. wCST-LL correlated positively with NC at T1 and T3, even after controlling for FMA-HAND and lesion volume. Voxel-based lesion symptom mapping showed that lesioned white matter below cortical hand knob correlated positively with NC.Conclusion: Severe hand spasticity early after stroke is negatively associated with hand motor recovery and positively associated with the development of secondary complications. Corticospinal tract damage predicts development of spasticity. Early quantitative hand spasticity measurement may have potential to predict motor recovery and could guide targeted rehabilitation interventions after stroke. Spasticity of the muscles contributing to hand function (hereafter “hand spasticity”) is a common sensorimotor disorder after stroke , can be The use of a validated biomechanical assessment  could imClinicalTrials.gov Identifier: NCT02878304. Patients were recruited consecutively from a subacute inpatient rehabilitation unit in Stockholm, Sweden, admitting patients aged 18–67 years from March 2013 until September 2016. In Sweden, patients aged above 67 years are normally referred to geriatric rehabilitation clinics. The study comprised assessments at admission to a subacute in-patient rehabilitation at 2–6 weeks (T1), (on average 3), at 3 (T2) and 6 months (T3) after stroke   , taking cal.com) . The finwww.aggeromedtech.com) , EC > 6.0N, VC > 1.1N and resting tension ≥ 9.0N) (Force components of resistance to passive extension of wrist and finger flexor muscles were measured with the NeuroFlexor method (ech.com) . This inech.com) , thus acech.com) . A previech.com) . Furtherech.com) . NeuroFlech.com) , 34. Theech.com)  32). Th. Thwww.aech.com) , we used ≥ 9.0N) . Hence, www.usa.philips.com) with an 8HR head coil. High resolution T1-weighted anatomical images were acquired using TFE 3D (3D gradient echo based sequence): FOV 250 × 250 × 181 mm, matrix 228 × 227, slice thickness 1.2 mm and number of slices 301 . FLAIR images were acquired using FOV = 250 × 250 × 157 mm, matrix 224 × 224, slice thickness = 1.12 mm, number of slices 280, echo time = 289 ms, repetition time = 4,800 ms, inversion time = 1,650 ms, flip angle = 90.Imaging was performed with an Ingenia 3.0T MR-system (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). Cost function masking was used to avoid distortion of lesion by normalization procedure (http://people.cas.sc.edu/rorden/mricron/index.html).Before delineating lesion maps, the T1-weighted images were normalized to MNI template using SPM12 (rocedure . To rulerocedure  by researocedure . Lesion www.fmrib.ox.ac.uk/fsl) with regions of interest including precentral gyri, posterior limb of internal capsule, cerebral peduncles and anteromedial pons. Resulting CST tracts were normalized into MNI space , but patients who were treated with Botulinum toxin within the study period had a significantly higher level of NC at each time point .NeuroFlexor assessment showed varying individual levels of NC over time . Spasticn = 20 patients had hand spasticity (NC range 3.8–32.9N), which was Moderate for n = 10 and Severe for n = 10 (n = 14 developed Late spasticity and n = 27 did not (No spasticity group). Seven patients  received botulinum toxin injections on clinical indication in muscles contributing to hand function once during the study period (three patients at more than 10 weeks before the next assessment [T3] and four patients at 2–6 weeks before next assessment [T2 or T3]). Only one patient, who received botulinum toxin injection at 2 weeks before T2, shifted to a lower severity level at next assessment (from Severe to Moderate) while the other six remained in the same spasticity severity level or had shifted to a more severe spasticity level at further assessments.At T1, r n = 10 . The Modn = 9 (14%) at T1, in n = 7 (12%) at T2, and in n = 5 (9%) patients at T3. NC values correlated across hands .NeuroFlexor spasticity values and modified Ashworth Scale scores were discordant at T1 with only n = 11 (55%) patients with NC above cut-off showing modified Ashworth Scale ≥ 1 . Three pp ≤ 0.0036, Bonferroni corrected)  at T3  .F = 28.6, p < 0.0001] and group  but no significant group-by-time interaction   = 11.8, p < 0.0001; group: F = 5.0, p = 0.004; group-by-time: F = 0.77, p = 0.597]  = 8.0, p = 0.001] and subgroups differed  and there was no group-by-time interaction . Only the No spasticity and Moderate spasticity groups increased significantly over time  = 22.4, p < 0.0001] and group , and a significant group-by-time interaction   = 9.3, p < 0.001], with a group effect  and a significant group-by-time interaction   as well as botulinum toxin injection. The results also remained significant after excluding the four patient who received Botulinum toxin injections within 6 weeks before 3 or 6 months follow up assessments.p = 0.028, The Severe spasticity group had a larger proportion of patients reporting pain at T3 . wCST-LL correlated with NC at T1  and T3   = 18.7, p = 0.0001] but no statistically significant interaction. Multiple regression analysis including FMA-HAND, wCST-LL, and lesion volume showed that only wCST-LL predicted NC at T1, T2 and T3 Partial correlation at T1: R = 0.34, p = 0.022; T2: R = 0.32, p = 0.048 and T3: R = 0.43, p = 0.005, The wCST-LL varied widely between patients  . Mixed mp = 0.016), but not at T3  at T1, n = 5 (9%) at T2 and in n = 7 (13%) at T3. EC increased significantly over time in the Severe spasticity group only  (p = 0.027), T2  and T3 . Many patients also showed increased VC although this only contributed about 14% to the total average passive movement resistance at T1 and did not change over time (e-1).EC was above the 6.0N cut-off in = 0.028) . NC, EC This study provides longitudinal data on hand spasticity after stroke and its relation to hand sensorimotor recovery and development of secondary complications. A strong association between degree of hand spasticity and lesion of the CST was also demonstrated. These findings and their clinical implications are discussed below.Hand spasticity occurred in up to half of the patients studied, comparable to previous reports on upper limb spasticity , 42, 43,Spasticity subgroups showed different degrees of hand motor recovery, development of muscle contracture and pain over time. The Severe group, representing 16% of studied patients, showed negligible improvement in FMA-HAND (non-significant difference over time of two points) compared to the Moderate group (significant difference over time of 6 points), despite overlapping scores at T1 . Both thEarly Severe hand spasticity was also associated with development of contractures and pain as previously suggested , 4. HandThis study provides the first data showing that hand spasticity is related to lesion load of the CST, even when controlling for motor impairment and lesion volume. However, some patients with Severe and without hand spasticity (No spasticity) had similar CST lesion load , suggestThe NeuroFlexor assessments allowed detection of early hand spasticity in patients with a modified Ashworth , 57 scorNotably, although this study found a strong association between early spasticity and recovery of motor function, the study does not inform on how spasticity relates to active motor performance, which has long been a matter of debate . HoweverThe NeuroFlexor method enables standardized and clinically feasible quantification of force resistance of neural and non-neural origin. It should be pointed out that the NeuroFlexor method has some recognized limitations and does not include EMG recordings . Howevern = 10 in the Moderate and Severe spasticity groups). However, the significant results suggest an adequate sample size even though we cannot rule out that a larger sample could have changed results to some degree. Another issue is that we only included patients aged below 70 years, referred to subacute in-patient rehabilitation. We cannot rule out that patients with differing stroke severity and not represented in this sample, have different spasticity development. Finally, patients were followed until 6 months after stroke. Although motor recovery is most pronounced in the first months after stroke, spasticity, muscle contractures and pain may develop later.The number of patients within subgroups was relatively small (Finger and wrist flexor muscle spasticity was common with increasing occurrence and severity over time. Patients with early severe hand spasticity showed poorer hand motor recovery, decreased passive range of movement and reported arm pain more frequently over time. This contrasted with findings from the no and moderate hand spasticity groups who showed greater hand motor recovery. Hand spasticity was related to lesion of the CST, independently of total lesion volume and initial hand motor impairment. A lesion in the white matter below the hand knob was related to more severe hand spasticity at 6 months. This study advances our knowledge regarding the development of hand spasticity after stroke and findings are relevant for development of targeted treatment approaches and for the prediction of hand motor recovery post stroke.jeanette.plantin@ki.se.The datasets for this manuscript can be made available on reasonable request but are not made public since this study make part of a larger data collection that is under ongoing analysis. Requests to access the data should be directed to JP, EL, JB, and PL: study concept and design and study supervision was performed. JP, GP, and KW: acquisition of data was performed. JP, PR, J-CB, AG, and PL: analysis and interpretation of data was performed. JP, JB, GP, PR, J-CB, KW, AG, and PL: critical revision of manuscript for intellectual content was performed.The NeuroFlexor instrument described in this paper has been patented and the author PL is a shareholder in the manufacturing company Aggero MedTech AB. The remaining 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.