Among patients with angina and nonobstructive coronary artery disease, those with coronary microvascular dysfunction have a poor outcome. Coronary microvascular dysfunction is usually diagnosed by assessing flow reserve with an endothelium-independent vasodilator like adenosine, but the optimal diagnostic threshold is unclear. Furthermore, the incremental value of testing endothelial function has never been assessed before. We sought to determine what pharmacological thresholds correspond to exercise pathophysiology and myocardial ischemia in patients with coronary microvascular dysfunction.Patients with angina and nonobstructive coronary artery disease underwent simultaneous acquisition of coronary pressure and flow during rest, supine bicycle exercise, and pharmacological vasodilatation with adenosine and acetylcholine. Adenosine and acetylcholine coronary flow reserve were calculated as vasodilator/resting coronary blood flow . Coronary wave intensity analysis was used to quantify the proportion of accelerating wave energy; a normal exercise response was defined as an increase in accelerating wave energy from rest to peak exercise. Ischemia was assessed by quantitative 3-Tesla stress perfusion cardiac magnetic resonance imaging and dichotomously defined by a hyperemic endo-epicardial gradient <1.0.Ninety patients were enrolled . Area under the curve using receiver-operating characteristic analysis demonstrated optimal CFR and AchFR thresholds for identifying exercise pathophysiology and ischemia as 2.6 and 1.5, with positive and negative predictive values of 91% and 86%, respectively. Fifty-eight percent had an abnormal CFR . Of those with a normal CFR, 53% had an abnormal AchFR, and 47% had a normal AchFR; ischemia rates were 83%, 63%, and 14%, respectively.The optimal CFR and AchFR diagnostic thresholds are 2.6 and 1.5, with high-positive and negative predictive values, respectively. A normal CFR value should prompt the measurement of AchFR. A stepwise algorithm incorporating both vasodilators can accurately identify an ischemic cause in patients with nonobstructive coronary artery disease. Nearly half of all patients with angina are found to have unobstructed coronary arteries.Those with coronary microvascular dysfunction have poorer clinical outcomes; however, it is unclear how to accurately diagnose this condition in routine clinical practice.Our study has revealed that contemporary diagnostic algorithms for angina may fail to identify patients with symptoms due to coronary microvascular dysfunction.We propose a stepwise algorithm, with clear diagnostic thresholds incorporating tiered use of adenosine and acetylcholine pharmacological vasodilatation, validated using novel physiological tools.Future therapeutic studies should enroll characterized cohorts of patients with demonstrable vasodilator flow impairment assigned to medical and placebo therapies, to demonstrate the prognostic utility of these mechanistically determined thresholds.2 The most studied of these, CMD, is usually diagnosed by demonstrating impaired augmentation of coronary blood flow (CBF), or reduced coronary flow reserve (CFR), in response to adenosine. Like all biological measurements, CFR is a continuous variable but, for practical reasons, clinical algorithms and trial protocols dichotomously classify physiological indices. The COVADIS  group acknowledges a gray-zone, stating that CMD can be diagnosed at a CFR of below 2.0 or 2.5, a view shared by experts within the field.4 Indeed, many clinicians will only diagnose CMD and initiate therapy if the CFR is below 2.0, this dichotomy being centered around the reported incidence of death and major adverse cardiovascular events.8 Additionally, CFR only interrogates the endothelial-independent component of the coronary vasculature, as adenosine acts largely independently of endothelium. Acetylcholine interrogates the health of the endothelium, which acts as a transducer of mechanical forces (or shear-stress) and has a paracrine effect on the smooth muscle layer in the healthy heart. Acetylcholine testing in catheter laboratories is mainly confined to the diagnosis of epicardial artery vasospasm; however, graded infusion with flow assessment can characterize microvascular endothelial function and prognosticate patients with NOCAD.9 Coronary vasodilator testing in the catheter laboratory acts as a surrogate for abnormal coronary perfusion during physical exercise and global myocardial ischemia, but the optimal threshold of adenosine and acetylcholine-mediated flow reserve for detecting each pathophysiological state is still to be defined.11 Recent European Society of Cardiology guidelines on the management of Chronic Coronary Syndrome have strengthened the indication for coronary reactivity testing in NOCAD from IIb to IIa, and thus CMD diagnostic thresholds warrant reappraisal.12 The primary aim of this study was to determine the optimal CMD diagnostic threshold using adenosine-mediated CFR in patients with NOCAD, and the secondary aim was to assess the incremental value of measuring acetylcholine-mediated flow reserve (AchFR) in this cohort.Approximately half of all patients with angina have nonobstructive coronary artery disease (NOCAD), the majority will have occult coronary abnormalities, including coronary microvascular dysfunction (CMD), endothelial dysfunction, or coronary spasm with pharmacological vasodilators used to diagnose these entities in clinical practice.The data that support the findings of this study are available from the corresponding author on reasonable request.2), concomitant valve disease (greater than mild on echocardiography), recent acute coronary syndrome or cardiomyopathy. Antianginal medications were stopped, and patients abstained from caffeine 24 hours before all study visits. The study protocol was approved by the UK National Research Ethics Service (17/LO/0203), and all participants gave written informed consent. The study was registered with the National Institute for Health Research UK Clinical Research Network portfolio database .Consecutive patients undergoing diagnostic angiography for investigation of exertional chest pain were screened from elective waiting lists. All patients underwent adenosine based CFR assessment and a subset of patients also underwent testing with a graded intracoronary acetylcholine infusion at the discretion of the catheter laboratory operator. High-resolution perfusion cardiac magnetic resonance (CMR) was performed within 6 weeks of the index angiography procedure. Inclusion criteria were preserved left ventricular (LV) systolic function (ejection fraction >50%) and unobstructed coronary arteries . Exclusion criteria were intolerance to adenosine, chronic kidney disease (estimated glomerular filtration rate <30 mL/min per m10 Hemodynamic measurements were recorded under resting conditions and following intravenous adenosine-mediated hyperemia (140 μg/kg per minute) and continuously during bicycle exercise, using a specially adapted supine ergometer  attached to the catheter laboratory table. Exercise began at a workload of 30 W and increased every 2 minutes by 20 W and continued until exhaustion.11 After full recovery from exercise, resting hemodynamic data was acquired before graded intracoronary acetylcholine administration for the acetylcholine study. Graded intracoronary acetylcholine concentrations of 0.182 and 18.2 µg/mL were infused (2 mL over 3 minutes) through the coronary guide catheter with cine images obtained before and after for quantitative coronary angiography.13 Severe coronary artery vasospasm was prespecified as >90% diameter reduction in target vessel caliber, and these patients would be excluded from subsequent analysis of coronary physiology.14Catheterization was performed via the right radial artery using standard coronary catheters. All patients received 1 mg intravenous midazolam, 1 mg isosorbide dinitrate via the radial sheath and intraarterial unfractionated heparin (70 U/kg) before intracoronary physiological measurements. A dual pressure and Doppler sensor-tipped 0.014-inch intracoronary wire  were used to measure coronary pressure and flow velocity in the left anterior descending artery, as previously described.10 CFR was calculated as average peak velocity during adenosine-mediated hyperemia divided by average peak velocity during rest.Signals were sampled at 200 Hz, with data exported into a custom-made study manager program . Pan-cardiac cycle analysis and wave intensity analysis were performed on custom-made software, Cardiac Waves  as previously described.For measurement of AchFR, cross-sectional area was calculated from the coronary diameter measured 5 mm distal to the tip of the guidewire. CBF was calculated using the equation CBF = cross-sectional area × average peak velocity × 0.5 at rest (CBFrest) and following 18.2 µg/mL intracoronary acetylcholine administration (CBFach) and AchFR was calculated as (CBFach/CBFrest). We did not proceed to higher doses of provocation testing for coronary spasm in this protocol.10 Perfusion efficiency is a simplified metric to indicate energy expenditure in augmentation of CBF during different physiological states and is calculated as the percentage of accelerating wave intensity in relation total wave intensity, using areas under the respective curves. In this study, change in perfusion efficiency was measured from resting condition to peak exercise; in the healthy heart perfusion efficiency has been shown to increase from rest to peak exercise, therefore, a reduction signified exercise pathophysiology.11Wave intensity analysis is a technique that provides directional, quantitative, and temporal information on the waves that govern coronary flow, as previously described.k-t sensitivity encoding accelerated gradient-echo method, followed by rest perfusion 15 minutes later, using a dual-bolus gadobutrol  contrast agent scheme to correct for signal saturation of the arterial input function as previously described.11 Quantitative analysis was performed as previously described by Fermi-constrained deconvolution.15 Myocardial blood flow estimates were quantified in mL/min per gram during rest and hyperemic stress; myocardial perfusion reserve was defined as the ratio between stress and rest perfusion. A myocardial perfusion reserve <2.0 is widely accepted to signify global myocardial ischemia following vasodilator stress and was a parameter used to identify to optimal coronary vasodilator thresholds in this study.16 Endocardial-to-epicardial perfusion (endo/epi) ratios were calculated during hyperemic stress and rest, by comparing the inner and outer layers of myocardium averaged across the basal, mid-, and apical LV segments. The reversal of subendocardial hyperperfusion during vasodilator hyperemia is considered a marker of ischemia in patients with NOCAD.17 A hyperemic endo/epi ratio <1.0, signified the presence of inducible ischemia during stress and indeed forms the basis upon which visual appraisal for the presence of ischemic heart disease is performed.18 CMR analysis was performed by observers blinded to the catheter laboratory results.All scans were performed on a dedicated 3-Tesla CMR scanner . Contiguous short-axis slices were acquired from the base to the apex for calculation of LV function and mass . Following 3 minutes of intravenous adenosine (140 µg/kg per minute) stress perfusion data were acquired in 3 short-axis slices with a saturation-recovery 20 To allow for potentially unequal distribution between groups and data censoring due to quality issues and incomplete data sets, we sought to enroll 90 patients. Continuous normally distributed data are expressed as mean±SD and compared using unpaired Student t tests or ANOVA testing as appropriate, while categorical variables were compared with χ2 tests. Receiver-operating characteristic analysis was used to determine the optimal adenosine (CFR) and acetylcholine (AchFR) threshold for detecting ischemia and exercise maladaptation and likelihood ratios were used to determine optimal cutoff values. In the acetylcholine group, patients were subsequently classified based on these optimal dichotomous thresholds as concordant abnormal CFR (CFR−/AchFR−), discordant normal CFR (CFR+/AchFR−), and concordant normal CFR (CFR+/AchFR+). Correlations were assessed using the Pearson correlation coefficient with correlation coefficients displayed as ρ values. Baseline variables found to correlate with exercise perfusion efficiency or inducible ischemia on univariate analysis (P<0.05) were assessed by a multiple linear regression model. For all analyses, a P value of 0.05 was considered significant, and all P values were 2-sided. Statistical analyses were performed using Prism GraphPad 8.0 and SPSS version 24 .The primary aim of this study was to determine the optimal CFR threshold for identifying myocardial ischemia and abnormal exercise physiology. We have adopted stress perfusion CMR as this is considered one of the most sensitive tests of ischemia that assesses the early part of the ischemic cascade and powered the study accordingly. Assuming a 50% prevalence of inducible ischemia among NOCAD patients, a sample of 75 patients gives 95% CIs of 70% to 95% for sensitivity and 63% to 92% for specificity using a CFR measurement.As the 2 most widely used CFR thresholds in clinical practice are 2.0 and 2.5, an exploratory analysis was also planned to compare patients with definite CMD (CFR<2.0), gray-zone , or normal CFR (CFR>2.5) in relation to their invasive exercise physiology and CMR perfusion characteristics.2, and none of the subjects had scar or fibrosis identified during late gadolinium enhancement imaging. Univariate regression analysis demonstrated no effect of risk factors upon primary outcome measures of exercise coronary physiology and myocardial perfusion.Ninety patients were enrolled into the study, 74 underwent catheter laboratory exercise, and 77 completed the CMR protocol while 40 patients additionally completed the acetylcholine study protocol. Patient characteristics are shown in Table P<0.001) and for predicting subendocardial hypoperfusion (endo/epi<1.0) the optimal CFR value was 2.6 . The optimum dichotomous CFR threshold for predicting an improvement in exercise perfusion efficiency was 2.6 . A dichotomous CFR threshold of 2.6 had a positive predictive value of 91%, a negative predictive value of 68%, and 95% CI of 83% to 98%.The optimum dichotomous CFR threshold for predicting global myocardial ischemia was 2.5  and for predicting an improvement in perfusion efficiency was also 1.5 . A dichotomous AchFR threshold of 1.5 had a positive predictive value of 81% and negative predictive value of 86% and 95% CI of 59% to 96%.No patients had severe coronary artery vasospasm during graded infusion of acetylcholine, and thus all were included in the subsequent analysis. The optimum dichotomous AchFR value for predicting inducible ischemia was 1.5 .Applying the optimal vasodilator thresholds above, 24 patients were classified as concordant abnormal (CFR−/AchFR−), 8 as discordant normal CFR (CFR+/AchFR−) and 7 as concordant normal  compared with a CFR <2.5 threshold, which was 78% accurate (sensitivity 80% and specificity 76%). For predicting an improvement in perfusion efficiency on exercise, the accuracy of a CFR <2.0 threshold was 67% (sensitivity 50% and specificity 100%) compared with an accuracy of 87% for a CFR <2.5 threshold (sensitivity 81% and specificity 100%).P=0.98) and 27% in the normal CFR group (P<0.001). With adenosine-mediated hyperemia, myocardial perfusion reserve was 2.66±0.42 in the normal CFR group compared with 2.00±0.36 in gray-zone and 2.01±0.48 in patients with CMD (P<0.001 and P=0.92), while the endo/epi ratio was 1.04±12 in the normal CFR group compared with 0.93±0.08 in gray-zone and 0.95±0.09 in CMD (P<0.001 and P=0.65). With exercise, coronary flow increased by 1.90±0.62 in the normal CFR group compared with 1.43±0.21 in gray-zone and 1.43±0.32 in patients with CMD . Perfusion efficiency during exercise was 65±14% in the normal CFR group compared with 45±8% in gray-zone and 43±12% in CMD .Myocardial perfusion and exercise physiology parameters of gray-zone patients resembled those with CMD Table . The likCombined use of vasodilator testing to stratify a NOCAD diagnosis offers the optimal accuracy for identifying abnormal exercise physiology or global myocardial ischemia and hence an ischemic substrate for chest pain. An adenosine CFR threshold of 2.6 offers excellent specificity with a high positive predictive value for ruling in ischemic chest pain while an AChFR of 1.5 has excellent sensitivity with a high negative predictive value for ruling this out. NOCAD should, therefore, first be investigated by measuring adenosine-mediated vasodilatation and if normal, acetylcholine-mediated vasodilatation; wider access to coronary flow assessment and pharmacological testing would allow improved risk stratification among this common group of patients.24 Indeed, there is a known continuous risk associated with worsening CFR and likelihood of major adverse cardiovascular events and when harder end points such as cardiovascular death are monitored, the best discriminatory CFR threshold is lower compared to prediction of angina recurrence.25 The continuum of risk predicted by CFR demonstrates that ischemia detection occurs before the onset of cardiovascular events, the latter perhaps too crude an end point for determining whether a patient with NOCAD has symptoms due to CMD , had a greater incidence of major adverse cardiovascular events.9 Our study demonstrates that an increment in CBF of >50% in response to acetylcholine rules out the presence of inducible ischemia and also predicts normal exercise coronary physiology. Despite the prognostic utility of this index, acetylcholine flow reserve does not feature within international guideline criteria for the diagnosis of microvascular angina, which largely center around adenosine flow reserve measurements.3 Combining the high sensitivity of intracoronary acetylcholine vasodilator testing with the high specificity of adenosine testing would serve an accurate method for directly ruling out ischemic chest pain upon discovering NOCAD.As diminished endothelium-independent function is almost invariably associated with endothelial dysfunction, there would be little added benefit in measuring acetylcholine response within this group in routine clinical practice. Conversely, approximately half of all patients with normal endothelial-independent function have endothelial dysfunction, associated with a higher burden of inducible ischemia and exercise pathophysiology. Currently, the main use of acetylcholine in the catheter laboratory is for the diagnosis of coronary vasospasm. In high bolus doses, acetylcholine acts directly on muscarinic receptors in smooth muscle, producing vasoconstriction, an effect that occurs at lower doses in patients with pathological vasospastic angina.28 The prevalence of microvascular dysfunction is recognized to be high among patients with NOCAD.29 With an increasing recommendation to treat CMD now supported by randomized-trial data, defining this condition has become increasingly paramount; while comprehensive, the COVADIS guidelines do not specify a diagnostic CFR threshold nor the role of acetylcholine vasodilator testing.30 Future placebo-drug trials should consider enrolling patients based upon a CFR<2.6, followed by those with AchFR<1.5, rather than adopting the historical, undifferentiated Cardiac Syndrome X definition. Use of disease-modifying therapies, such as statins and ACE (angiotensin-converting enzyme) inhibitors. may have greater benefit if initiated earlier in the disease course and should be studied in adequately powered trials enrolling well-characterized patients.31Undifferentiated NOCAD yields poor outcomes with patients often undergoing repeat invasive testing, while less sensitive noninvasive tests may fail to identify diminished CFR.The current study would promote the assessment of acetylcholine flow reserve, following the discovery of normal adenosine flow reserve to increase the diagnostic accuracy for ruling out an ischemic source of chest pain symptoms Figure . Subsequ18 Additionally, we aimed to use an invasive exercise end point in addition to help corroborate the presence of ischemia during noninvasive testing. These are surrogate markers and therapy stratified according to the onset of these changes, may not necessarily reduce the risk of major adverse cardiovascular events, and would need to be validated in adequately powered prospective studies. Our control group was not healthy volunteers but had symptoms that had led to angiography and indeed patients within this group may have abnormalities, such as coronary vasospasm, that could be unmasked during provocation testing. Our primary aim was to define the exercise physiology and myocardial perfusion of adenosine-mediated hyperemia (CFR assessment) as this is the most widely used method of characterizing CMD. Due to the demanding nature of the protocol, a smaller subgroup completed the acetylcholine study; however, this remains the largest invasive protocol with paired high-resolution perfusion imaging to date. Premedication using radial nitrates was necessary to enable bike exercise via this protocol and while the same dose was administered to each study participant, this may have attenuated the response to intracoronary acetylcholine. However, with angiography being increasingly performed via the transradial approach, this method is more representative of contemporary practice.This was a mechanistic single-center study with relatively small numbers of patients, although this is the largest invasive exercise data set in a cohort of patients with angina and no obstructive coronary artery disease. Subendocardial hypoperfusion during hyperemia represents a very early stage of the ischemic cascade, and so its presence may not correlate perfectly with later stages such as wall motion abnormalities. Although this is a widely adopted index for identifying the presence of inducible ischemia in several clinical trials, we have also used the increasingly recognized index of myocardial perfusion reserve.CFR is a readily available metric following the discovery of NOCAD, capable of characterizing pathology during physical exercise and global myocardial ischemia in addition to predicting major adverse cardiovascular events. A dichotomous CFR threshold of 2.6 has an excellent positive predictive value for ruling-in the presence of ischemia; however, a normal CFR does not rule out ischemia. Subsequent measurement of AchFR using acetylcholine will have an excellent negative predictive value for ruling-out the presence of ischemia; normal response to both vasodilators would suggest a nonischemic cause of chest pain. As better characterized cohorts are enrolled into therapeutic studies, stratified management can be further refined to improve personalization of healthcare and better resource utilization.This work was supported by the British Heart Foundation (FS/16/49/32320 and RE/18/2/34213) and by the National Institute for Health Research via the Biomedical Research Centre award to King’s College London.None.


Using mortality as an endpoint in studies comparing different reperfusion strategies in STEMI requires increasingly large sample sizes to test advances with existing therapy. Thus, there is rising interest in surrogate endpoints allowing a reduction in sample size. One of those measures is myocardial salvage which can be assessed retrospectively by T2-weighted and delayed enhancement images as shown in animal studies . CurrentTo assess the reproducibility of myocardial salvage measurements in a group of patients with acute myocardial infarction scanned at two subsequent days with a second contrast agent injection.In 20 patients with acute STEMI transverse electrocardiographically gated T2-weighted triple-inversion-recovery images were acquired to assess the area at risk and delayed enhancement (DE) images using a 3D inversion recovery gradient echo sequence assessed the infarct size. All patients underwent a repeated measurement the subsequent day starting with new scout images and using the same dose of the contrast agent. Area at risk and infarct size were determined as the percentage of left ventricular mass (%LV) by two independent observers and subsequently the myocardial salvage index was calculated as area at risk-infarct size/area at risk. In addition extent of microvascular obstruction was assessed. Inter-, intraobserver variabilities and reproducibility data were calculated according to standard definitions and compared by the method of Bland and Altman. Image quality was assessed by a score ranging from 0–4 .The mean difference between percutaneous coronary intervention and MR imaging was 2.8 ± 1.3 days. All images were suitable for analyses with a mean image quality of 3.2 ± 0.6 for DE-images and 2.5 ± 0.6 for T2-weighted-images. The area at risk was as high as 47.4 ± 11.7%LV and the infarct size 20.2 ± 9.6%LV. The corresponding myocardial salvage index was 57.7 ± 14.9 (range 23.4–75.8). In 17 (85%) patients there was evidence of microvascular obstruction. Area at risk difference (bias) between scan I and scan II was 1.2%LV and limits of agreement were ± 7.5%LV. The results for infarct size were 0.5%LV ± 2.6%LV limits of agreement. The resulting bias for myocardial salvage index was -0.3 with limits of agreement of ± 5.0. Intra- and interobserver variability was low with a mean bias of -0.7 (limits of agreement ± 4.6) and -0.0 (limits of agreement ± 4.7), respectively.The multimodal MRI approach is an excellent tool for myocardial salvage assessment with excellent reproducibility in acute STEMI. It has therefore the potential to serve as a surrogate endpoint to uncover advantages of new reperfusion strategies and allows a further reduction in the sample size of clinical trials. The previously shown excellent reproducibility for infarct size measurement could be confirmed in this trial.


Adults with obesity and type 2 diabetes mellitus (T2DM) related to obesity are at increased risk of heart failure with preserved ejection fraction (HFpEF). Whether left ventricular (LV) diastolic function abnormalities related to obesity and T2DM start in adolescence and early adulthood is unknown. We non-invasively evaluated the differences seen in LV diastolic and left atrial (LA) function in adolescents and young adults with obesity and T2DM.We analyzed echocardiographic measures of LV diastolic function in patients with structurally normal hearts which were divided into 3 groups . Spectral and tissue Doppler and 2-D speckle tracking measurements of diastolic function were obtained. Logistic regression was performed to compare the prevalence of abnormalities in diastolic function based on the worst 25th percentile for each measure to determine the prevalence of diastolic and LA function abnormalities in obese and T2DM patients.331 teenagers and young adults (median age 22.1 years) were analyzed . Obese and T2DM group had lower E/A and higher E/e′. Obese and T2DM patients had significantly lower atrial reservoir, conduit, and booster strain and worse reservoir and conduit strain rate compared to normal patients . All patients had normal LA volumes. On multivariable analysis, conduit strain and reservoir and conduit strain rate were independently associated with having below the 25th percentile e′. Conduit strain rate was independently associated with having below the 25th percentile for mitral E/A ratio on multivariable analysis.Abnormal indices of LV diastolic function are detected in adolescents and young adults with obesity and T2DM. LA function and strain analysis were able to detect evidence of decreased reservoir, conduit, and booster strain in these patients although LA volume was normal. The use of LA function strain may increase our ability to detect early diastolic function abnormalities in this population. Adults with obesity and type 2 diabetes mellitus (T2DM) related to obesity are at increased risk of heart failure with preserved ejection fraction (HFpEF). Obesity and type 2 diabetes (T2DM) represents an epidemic in the United States and western countries. The prevalence of obesity in adults is 38% and up to 30% in children . RecentlIn our study we compared diastolic function and LA strain measures of adolescents and young adults who were either normal weight, obese, or diagnosed with T2DM. We hypothesized that diastolic function and LA strain function measures are impaired in patients with obesity and further impaired in T2DM as compared to the normal controls and that there are associations between LA function measures and measures of diastolic dysfunction in adolescents and young adults.This was a single center, retrospective review of echocardiographic measures of LV diastolic function and LA strain. The patient population used was from a previous prospective research study that examined the effects of obesity and T2DM on cardiovascular structure and function . WrittenAll echocardiograms were performed using the same research standardized protocol and using either a GE or Philips Sonos 5500  system with the patient in the left decubitus position. We analyzed traditional markers of diastolic dysfunction such as LA volumes and mitral inflow Doppler patterns as well as deformation analysis. Diastolic function was assessed based on the 2016 American Society of Echocardiography (ASE) guidelines  with theThe LA functions to permit appropriate filling of the LV. There are three main functions of the LA. First, it serves as a reservoir for pulmonary venous return during ventricular systole. Second, it acts as a conduit for passive ventricular filling in early ventricular diastole, and finally as a booster pump for atrial kick at end ventricular diastole Fig.  15, 16], 1615, 1Distributions of the data were examined for shape, and possible outliers. Bivariate scatterplots with smoothed regression lines were constructed to look for bivariate outliers, as well as for a visual representation of relationships between variables. Summary data for demographics, anthropometrics, and medication use and cardiac data were compared by study group , using Fisher’s exact tests for categorical data, and Kruskal–Wallis tests for continuous data, owing to the non-parametric distribution. Bivariate correlation analyses were performed to assess association between the strain data, and the other echocardiographic data. This was done for the cohort overall, and by study group.Differences in diastolic function between the groups were categorized as being normal or abnormal based on the 75th percentile measure of the normal group  across multiple parameters. Proportions of subjects in the obese and T2DM category with abnormal diastolic function were compared using Fisher’s exact tests. Stepwise logistic regression was performed to determine independent predictors of abnormal diastolic function as defined by the normal derived cut-points. The initial parsimonious model included demographic data and established markers of diastolic function. Logistic regression was repeated to evaluate predictors of abnormal LV function. The model included LA strain and LA size to assess the strength of contribution of these variables to LV diastolic dysfunction.The study included 331 subjects  with adequate echocardiographic images to determine LA function (each group started with 250 patients). Demographic data are shown in Table There were significant differences between the groups in several markers of LV diastolic function. Obese and T2DM patients had significantly higher average E/e′ (p < 0.0001) and lower septal (p < 0.0001) and lateral (p < 0.0001) e′ compared to the normal group. Additionally, there were significant differences in mitral inflow E/A ratios (p < 0.0001) with T2DM patients having the lowest ratio , conduit (p = 0.007) and booster strain (p = 0.0002) compared to normal subjects . The conduit strain rate was also significantly worse (less negative) in obese and T2DM subjects (p = 0.001). There were no significant differences among the groups in booster strain rate.There were no differences among the groups in left atrial dimension indexed to body surface area (p = 0.2). However, indexed left atrial volume to body surface area was significantly lower in the obese and T2DM groups compared to the normal group (p < 0.0001) due to the larger body surface area in obese and T2DM groups. There was no significant difference among the groups in atrial emptying fraction (p = 0.3).Correlation analysis showed that higher LV mass was associated with lower reservoir and conduit strain p < 0.0001), reservoir strain rate (p = 0.003), and worse conduit strain rate (p = 0.002). A higher indexed LA volume was associated with lower conduit strain and worse reservoir strain rate  correlated to a lower e′ and thus a higher E/e′ ratio  was a significant predictor of being in the worst 25th percentile of mitral E/A (odds ratio (OR), 2.18; confidence interval (CI) 1.57–3.03 per unit increase in strain rate, p < 0.0001). Additionally, a lower reservoir strain rate was a significant predictor of being in the worst 25th percentile for septal e′ . Importantly, indexed LA volume and LA dimension were not predictors of diastolic dysfunction . Multiple studies have shown improvement in LV diastolic function within 3 months of therapy , 35. TheA major concern for using LA function as a reliable assessment of diastolic function is the inter and intra observer variability. It is important to note, that echocardiography is a reliable method to assess LA functional parameters . In our These aforementioned studies are important for children and young adults such as those in our study population, who currently are asymptomatic but considered at higher risk for development of atrial fibrillation and diastolic heart failure. Clinically, the implications of our study are relevant, even in the absence of longitudinal follow up data due to the noted literature of the negative effects of obesity and T2DM on diastolic function in adults , 32, 33.There were several limitations to our study. Firstly, this was a single center retrospective study. Secondly, there is a lack of outcome data owing to the grant for the initial study ending. The majority of the patients in this study had normal diastolic function, despite differences between the groups and this may be perceived as a limitation of clinical impact, however, given the young age of the patients in this study, the trend towards abnormality is concerning that many of these patients will progress to abnormal diastolic function at a young age. We also could not include tricuspid regurgitation velocity, a known important marker of diastolic function in our assessment as most of our subjects had trivial tricuspid regurgitation insufficient to assess right ventricular pressure. An important question we could not answer from this data, is whether the LA function and strain became abnormal prior to the mitral and tissue Doppler markers, as that would support our theory that LA strain may be the first marker of diastolic dysfunction in this patient population. Additionally, the causes of HFpEF are multifactorial including age and additional comorbidities which limits our abilities to make definitive conclusions. Finally, although the initial studies were evaluated by two pediatric cardiologists, we did not perform a formal statistical analysis for reproducibility in our study as measuring atrial strain has been validated by previous studies .Abnormal diastolic function measures were detected in adolescents and young adults with obesity and T2DM. LA function and strain analysis were able to detect evidence of decreased reservoir, conduit, and booster atrial function in these subjects although LA volume was normal. LA function measures were associated with diastolic function measures and predicted subjects in the worst 25th percentile of diastolic function measures. The use of LA function strain may provide early detection of diastolic function abnormalities.Additional file 1: Table S1. Correlations between traditional diastolic function measurements and left atrial strain measurements of the entire cohort. Table S2. Correlations between traditional diastolic function measurements and left atrial strain measurements of the normal weight patients (n = 101). Table S3. Correlations between traditional diastolic function measurements and left atrial strain measurements of the obese patients (n = 114). Table S4. Correlations between traditional diastolic function measurements and left atrial strain measurements of T2DM patients (n = 116).


A large percentage of thalassemia major (TM) patients shows a significant heterogeneity of segmental distribution of T2* values in myocardium, measured by multislice multiecho T2* cardiac magnetic resonance (CMR). This finding is in agreement with previous histological studies that have detected heterogeneous iron deposition in hemochromatotic hearts. However, it is not yet clear if that represented true heterogeneous iron density or if it could have been generated by geometric and susceptibility artefacts.The purpose of this study is to investigate myocardial T2* heterogeneity in TM patients by CMR, and to determine if it is related to inhomogeneous iron overload distribution.230 TM patients consecutively affered to our laboratory were retrospectively studied. Three short-axis views  of the left ventricle (LV) were obtained by multislice multiecho T2* CMR. T2* segmental distribution was mapped on a 16-segment LV model. The level of heterogeneity of the T2* segmental distribution on each patient was evaluated by the coefficient of variation. Measured heterogeneity was compared with that of a surrogate data set obtained from measurements of subjects without iron overload, to determine whether the inhomogeneous segmental distribution of T2* could be generated only by susceptibility artefacts.In 45 (20%) TM patients, segmental T2* values were all below the lower limit of normal (20 ms). In 104 (45%) patients, T2* values were heterogeneous with respect to the normal threshold. Of these patients, 74% showed a normal T2* global value. Eighty-one (35%) patients had all normal segments (A). T2* value heterogeneity assessed by the CoV in TM patients and in the surrogate data is shown in Figure A true heterogeneity in iron overload distribution may be present in TM patients. Heterogeneity seemingly appears in the borderline myocardial iron and stabilizes for moderate to severe iron burden.


The health of athletes has been recognized as a worldwide public concern with more reported sudden cardiac deaths (SCD). Therefore, early detection of abnormal heart function in athletes can help reduce the risk of exercise. A novel valid non-invasive method to evaluate left ventricular (LV) myocardial work (MW) using LV pressure-strain loop (PSL), was used in this paper to explore LV systolic function in young male strength athletes.Thirty-six professional young male strength athletes (the athlete group) and 32 healthy, age-matched young men (the control group) were involved in the study. The LVMW parameters were calculated as the area of PSL by two-dimensional speckle tracking echocardiography (2D-STE) and peak systolic LV pressure. The differences between two groups of data and the predictive efficacy of MW parameters for LV systolic function were analyzed.P<0.05). Global myocardial work index (GWI), global constructive myocardial work (GCW) and global longitudinal strain (GLS) were lower in the athlete group than that in the control group, although statistical significance was not reached (P>0.05). Due to the proportion of GWW and GCW, statistically significant reduction was found in global myocardial work efficiency (GWE) in the athlete group. Conventional echocardiography parameters were well correlated with GWW and GWE (P<0.05). The best predictor of LV myocardial contractile performance in the athletes using receiver operating characteristic curve (ROC) was GWE, with the area under ROC (AUC) of 0.733, sensitivity of 83.3% and specificity of 59.4%.The athlete group had significantly higher values of global wasted myocardial work (GWW) and peak strain dispersion (PSD) than did the control group (Subclinical changes have appeared in the hearts of young male strength athletes after long-term intensive exercise and LVMW parameters by PSL play an important role in the evaluation of athlete’s LV contractile performance. The concept of “athlete’s heart”, including physiological adaptation and pathological changes both in cardiac morphology and function after prolonged and intensive exercise, was firstly raised by the end of nineteenth century –3. To daAs a new parameter taking both deformation and afterload of left ventricular (LV) into account, myocardial work (MW) potentially could provide more reliable value to myocardial function assessment than that of strain only . RussellThe purpose of this study aimed to: (i) describe the basic echocardiography characteristics of LV in the hearts of the athletes and (ii) explore the possibility of LVMW parameters to evaluate myocardial function among the athletes.The study was performed in 36 male athletes engaged in wresting (average age 19.50 ± 1.38 years) and 32 control individuals (average age 20.03 ± 1.06 years). The inclusion criteria of the athlete group were training years≥5, training time ≥ 30 h per week, never stop training and never use doping substances. The healthy controls with no records of participation in long-term intensive training were collected from the physical examination center of the First Affiliated Hospital of Zhengzhou University. Meanwhile, the participants having good image quality for myocardial speckle tracing analysis and without cardiovascular disease such as arrhythmia, valvular stenosis or regurgitation were necessary. Subjects that did not fulfill all the inclusion criteria were excluded. The study was authorized by the local ethics committee, and written informed consent was obtained.Transthoracic echocardiography was performed to obtain images for analysis, employing a Vivid E95 ultrasound system equipped with a M5S 3.5mHz transducer . The participants maintained a left lateral decubitus position when scanning under peaceful breath and connecting the electrocardiogram synchronously. Collect standard 2D gray-scale dynamic images consisting of three consecutive cardiac cycles in long-axis, apical two-chamber and four-chamber views, then put in a certain workstation for offline analysis. Ultrasonic recordings and measurements were processed in line with the recommendation of the American Society of Echocardiography and European Association of Cardiovascular Imaging .Left ventricular end-diastolic diameter (LVDd), diastolic interventricular septal thickness (IVSTd), and diastolic posterior wall thickness (PWTd) were obtained in the parasternal long-axis section of LV, and relative wall thickness (RWT) was computed using the ratio: (IVSTd+PWTd)/LVDd. Left ventricular mass (LVM) was obtained by the standard cube formula and normalized to body surface area (BSA). LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and cardiac output (CO) were measured and indexed to BSA using biplane Simpson’s method as recommended , and LV 2D gray-scale images were obtained from the apical two-chamber, four-chamber and long-axis views at frame rates ≥60 frames/sec. By manually clicking on the mitral annulus and apex of three sections at the end-systolic frame, the region of interest between the endocardium and epicardium was automatically defined using 2D-STE and manually adjusted if necessary . Then, tLVMW parameters were calculated from non-invasive pressure-strain loop (PSL) area as previously described Fig. . BrachiaGlobal myocardial work index (GWI) was the total work derived from the area of LV PSL Fig. . Global t-test for normal distribution and Mann-Whitney U test for non-normal distribution. Pearson correlation analysis was performed between conventional echocardiography and MW parameters. Receiver operating characteristic curve (ROC) was applied to find optimal parameters to predict LV systolic function in athletes with values of sensitivity, specificity and the area under ROC (AUC). Intra-observer and inter-observer variability were assessed in 10 randomly selected subjects. P-value<0.05 were considered as statistically significance.All statistical data was processed using standard statistical software SPSS . Continuous variables were confirmed for normal distribution by the Kolmogorov-Smirnov test and expressed as mean values±standard deviation (SD). Differences between the two groups in continuous variables were analyzed using independent P<0.05). However, there were no statistical differences in age, systolic blood pressure (SBP) and diastolic blood pressure (DBP) between the two groups (P>0.05). Compared with the control group, the LVDd, IVSTd, PWTd, RWT, LVM index (LVMI), end-diastolic volume index (EDVI), end-systolic volume index (ESVI), stroke volume index (SVI) and cardiac index (CI) of the athlete group were significantly greater (P<0.05), but LVEF was excepted (P>0.05).Demographic data and conventional echocardiographic parameters of the athletes and controls were shown in Table P<0.05). Although the level of GWI, GCW and GLS in the athlete group were lower than that of the control group, there were no statistical differences (P>0.05). In correlation analysis (Table P<0.05). ROC was used to determine whether MW parameters in athletes were able to forecast the changes of LV systolic function. According to the results of ROC analysis  exceeding the reference value (RWT >0.42) and LVMI  remaining within standard range. All of these suggested that concentric remodeling of LV in athletes was displayed after recurrent exercise, which was well consistent with previous researches [As is known to all that moderate exercise not only benefits to reduce the risk of developing cardiovascular disease but also promotes physical and mental health . Neverthsearches .After prolonged exercise, the augment of RWT and the dropping of capillary density in strength athletes would lead to increased regional myocardial oxygen consumption and insufficient blood supply to myocardium , 21. MorPrevious studies have demonstrated that the reduction of GLS in athletes was an early sign of LV dysfunction . HoweverSeveral limitations to this study need to be acknowledged as follows: (i) The sample scale was small. The research had only considered the context of young male strength athletes, regardless of the female and endurance ones. (ii) The use of brachial cuff pressure to evaluate LVMW might not be applicable to all the situations such as aortic stenosis, which was likely to impact the accuracy of LVMW parameters evaluation , 9. HoweIn summary, this study revealed that the athletes after long-term intensive training not only generated LV concentric remodeling, but also developed subtle subclinical changes in LV contractility performed by increased GWW and decreased GWE. Compared with the conventional echocardiographic indicators, the MW derived from novel non-invasive PSL was a promising tool to evaluate progressive changes of LV performance and produce incremental practical significance to detect myocardial function abnormalities of LV in order to prevent athletes from being SCD in the early stage.


Ventricular ectopic beats (VEBs) are very common and often occur in hypertensive or obese individuals, as well as in patients presenting with either sleep apnea or structural cardiac disease. Sympathetic overactivity plays a crucial role in the development, continuation, and exacerbation of ventricular arrhythmias. Recent studies have reported the relevance of sympathetic activation in patients with ventricular arrhythmias and suggested a potential role for catheter-based renal denervation (RDN) in reducing the arrhythmic burden.We describe a 38-year-old female symptomatic patient that at the time of presentation was complaining of fatigue in response to minor and medium efforts and not tolerating any physical activity, and episodes of tachycardia associated with dyspnoea, pre-syncope, and syncope.She had a high incidence of polymorphic VEBs on 24-hour-Holter monitoring who also presented with left ventricular (LV) hypertrophy for which she was treated with bisoprolol 10 mg/d. The 24-hour-Holter on bisoprolol at baseline showed sinus rhythm with an average heart rate of 92 bpm. There were 44,743 isolated VEBs. A total of 2538 nonsustained ventricular tachycardia events were registered. Her cardiac magnetic resonance imaging showed an increase in LV diastolic diameter and impairment of the right ventricle.The patient underwent endocardial ablation of the right ventricular outflow tract and the LV free lateral wall, and concomitantly underwent bilateral RDN.Three months post-procedure, her 24-hour-Holter off medication demonstrated an average heart rate 72 bpm and a substantially reduced number of 2823 isolated monomorphic VEBs. Thus far, 18-months follow-up, she has been asymptomatic and doing physical exercises.In our current patient, we used RDN as a synergistic method to attenuate the sympathetic overactivity, which is narrowly linked to VEBs appearance. Our case report highlighted that RDN may become a potential adjuvant treatment for VEBs in the future. Sympathetic overactivity exerts a crucial role in the development, continuation, and exacerbation of ventricular arrhythmias.RDN may become a potential adjuvant treatment for VEBs in the future.1 Overall, VEBs in the structurally normal heart are considered benign. Nonetheless, they have been related to a >2-fold higher risk of cardiovascular events, comprising stroke and cardiac death. Reentry is the probable mechanism for VEBs rising from areas of fibrosis or infiltration in cardiomyopathies, e.g., ischemic cardiac disease, arrhythmogenic right ventricular cardiomyopathy, sarcoidosis, Chagas disease, hypertrophic cardiomyopathies, primary dilated cardiomyopathies, valvular cardiomyopathy, congenital cardiac disease, muscular dystrophies, and metabolic disorders. VEBs can also occur due to reentry around surgical scars. Either small reentry circuits involving the fascicles,,6 or triggered or boosted automaticity can provoke fascicular VEBs.Ventricular ectopic beats (VEBs) are very common, particularly in hypertensive or obese individuals, as well as in patients presenting with either sleep apnea or structural cardiac disease.2 necessity, autonomic dysregulation, modifications in intracellular Ca2+ handling, and different heart rate (HR) dynamics.,9 Even though VEBs are somewhat infrequent and asymptomatic in most cases, some individuals may sense VEBs more frequently and its symptoms . The range of benign outflow tract VEBs varies from single VEBs to recurring nonsustained ventricular tachycardia to paroxysmal sustained ventricular tachycardia (VT). Short-coupled right ventricular outflow tract (RVOT) VEBs hardly ever initiate polymorphic VT, whereas even shorter-coupled VEBs frequently coming from the fascicular structure or papillary muscles may trigger ventricular fibrillation.,12 Currently, it remains elusive which medical therapy option for treating polymorphic and refractory VEBs may be most beneficial. Possible treatment options involve mapping and ablating them one by one or attempting a novel, alternative, or even adjuvant therapy, aiming to blunt or eliminate different targets.VEBs have recently been identified as a crucial source for deteriorating left ventricular (LV) systolic function, and heart failure in numerous subjects presenting diverse conditions . The pathogenesis of cardiomyopathy mediated by VEBs is unclear, and theories consist of ventricular dyssynchrony, hemodynamic impairment, intensified O Recent studies have reported the relevance of sympathetic activation in patients with ventricular arrhythmias and suggested a potential role for catheter-based renal denervation (RDN) in reducing the arrhythmic burden.Sympathetic overactivity plays a crucial role in the development, continuation, and exacerbation of ventricular arrhythmias.2After obtaining written informed consent from the participant for the publication of this case report, we here describe a 38-year-old female patient presenting with a high incidence of polymorphic VEBs on a 24-hour rhythm monitoring (Holter) referred to our Cardiology Service. At the time of presentation, the patient was complaining of fatigue in response to minor and medium efforts and not tolerating any physical activity, and episodes of tachycardia associated with dyspnoea, pre-syncope, and syncope. This was associated with LV hypertrophy on her echocardiogram. She was hospitalized twice due to events of syncope. The episodes started ∼1.5 years ago. She was on bisoprolol 10 mg/d since the beginning of her VEBs. However, her attending physician tried to prescribe metoprolol which she did not tolerate because of her low blood pressure (BP)  mm Hg, also occurring when she was prescribed sotalol or verapamil. Subsequently, amiodarone was started, but she presented with ophthalmological side effects , and the antiarrhythmic medication was discontinued.3, standard range between 62 and 88 mL/mm3; and 33.1 mL/mm3, standard range varying between 19 and 30 mL/mm3, respectively). Her RV ejection fraction was 40% , while her LV ejection fraction was 58.8% . No signs of myocarditis, fibrosis, or myocardial necrosis were detected. A 24-hour Holter on bisoprolol 10 mg/d was performed at baseline , the right ventricle (RV) end-diastolic volume index and the RV end-systolic volume index were reduced  we detected the highest precocity point at the RVOT (intracavitary electrogram 30 ms earlier than VEBs). We performed thermo-controlled radiofrequency (RF) applications in the region Fig. , and 30 After 4 months post-ablation, we scheduled the second procedure. The patient underwent general anesthesia by the anesthesiologist and presented sinus rhythm with frequent VEBs originating from LV. Electrocardiographically, VEBs morphology suggested the free lateral wall of the LV as their site of origin. We performed a transseptal puncture, and positioned the decapolar catheter in the LV, performing the electro-anatomical mapping and reconstruction of this cavity using the aforementioned mapping system. We mapped the LV and found the point of highest precocity on its free lateral wall Fig. . SubsequThree months post-procedure, she underwent another 24-hour Holter off all concurrent medication Table . Also, h3 Renal afferent nerves are varied and heterogeneous with myelinated and nonmyelinated fibers.,16 Two principal forms of renal afferents relay information to the central nervous system, mechanosensitive , and chemosensitive receptors . From a functional perspective, the renal afferent fibers can be categorized into pressor, reno-renal, and depressor types, which means that some of them when activated increase the sympathetic tone, while others depress the sympathetic tone. Preclinical and clinical data support this, pointing out that stimulation of the renal arteries can provoke different responses, including BP elevation.–21 Recently, the SPYRAL HTN-OFF MED trial reported that the higher baseline HR was associated with RDN success, which may indicate that RDN works better in patients with a high sympathetic drive (assessed in the absence of interfering drugs), and thereby may also have utility in mitigating arrhythmias through autonomic mechanisms.Catheter-based RDN is an approach to modulate central afferent input. Renal afferent and efferent nerves work in a reflex loop where afferent input from the kidney to the central nervous system regulates the efferent sympathetic nerve output to the heart and back to the kidney. Both types of renal nerves are mostly situated in the adventitia layer, 1.5 to 2 mm from the lumen of the renal artery.,24 In a swine model of ischemia, RDN decreased the number of spontaneous VEBs and VF similarly to β-blocker treatment. Also, RDN effects on ventricular electrophysiology seem happen regardless of its effects on BP as shown in initial preclinical and clinical studies. The primary clinical experience with RDN and ventricular arrhythmias has also been encouraging.,28 The principal multicenter series of cases, involving 13 subjects with refractory VT, has demonstrated that freedom from VT was assignet to RDN without occurring intraprocedural complications over 3-month follow-up.Ablation of renal nerves may reduce both systemic and cardiac catecholamine levels, as well as reduce heart fibrosis through modulation of the renin-angiotensin-aldosterone system. was employed effectively. However, based on the physiopathology mentioned above, we used additional RDN as a synergic method targeting to attenuate the sympathetic overactivity, which is closely linked to the appearance of VEBs. Our findings, with all limitations of a single case report, suggest that RDN may be a useful adjuvant treatment in this context, a proposition that needs to be adequately tested in the future.The gold-standard technique for treating ventricular arrhythmias, which is the endocardial ablation,Conceptualization: Marcio Galindo Kiuchi, Shaojie Chen.Data curation: Marcio Galindo Kiuchi, Shaojie Chen.Formal analysis: Marcio Galindo Kiuchi, Humberto Villacorta, Revathy Carnagarin.Investigation: Marcio Galindo Kiuchi, Shaojie Chen, Revathy Carnagarin.Methodology: Marcio Galindo Kiuchi, Shaojie Chen.Project administration: Marcio Galindo Kiuchi.Software: Marcio Galindo Kiuchi, Revathy Carnagarin, Vance Bruce Matthews.Supervision: Humberto Villacorta, Vance Bruce Matthews, Markus Peter Schlaich.Validation: Marcio Galindo Kiuchi, Shaojie Chen, Revathy Carnagarin.Visualization: Humberto Villacorta, Vance Bruce Matthews, Markus Peter Schlaich.Writing – original draft: Marcio Galindo Kiuchi, Humberto Villacorta, Vance Bruce Matthews.Writing – review & editing: Revathy Carnagarin, Markus Peter Schlaich.


This issue of the Netherlands Heart Journal contains two articles on management of heart failure , 2. The One of the recently developed tools for monitoring patients, the CardioMEMS, is an implantable sensor that continuously monitors the pressure in the pulmonary artery as an indicator of cardiac filling pressures.However, the benefit of advanced diagnostics such as continuous pressure monitoring in the pulmonary artery relies on the ability to avert the worsening it predicts. In recent years, we have seen an increased number of options to intervene pharmacologically, such as the recently added combination of angiotensin receptor blockade with neprilysin inhibition . Last yeVeenis and Brugts summarise the evidence for remote monitoring of heart failure patients, which shows the challenges to demonstrate significant gain . This miIn this same issue, Brugts and colleagues describe a national prospective study, the MONITOR HF trial, to assess the potential benefit of continuous remote monitoring of pressure in the pulmonary artery in heart failure patients . This haTo obtain data from a similar study in the Netherlands is of great value. First of all, in the CHAMPION trial the main benefit at 15 months was decreased admissions for worsening heart failure without a mortality benefit. Roughly speaking, CardioMEMS decreased the number of admissions by one or two admissions per patient per year. Therefore, a relevant question is whether—apart from the obvious patient benefit—the costs of the device and its continuous monitoring are offset by saving admissions. This is not obvious since costs of admission differ considerably across countries, so the cost-benefit equation of this effect may not be similar across all countries.In addition, the ability to predict imminent decompensation and how to intervene also differs across countries. Therefore, the added role of remote monitoring may differ between, for example, the US and the Netherlands. In the Netherlands, the existing heart failure outpatient clinics form a tightly woven fabric that provides high-quality care to guide and monitor each heart failure patient. This may decrease the ability of added remote monitoring to further improve upon this. In countries where this type of care cannot be as tightly organised, for instance due to large distances and a different health-care system, the added benefits of remote monitoring may differ significantly.Therefore, it will be of great interest to see how the continuous measurement of pulmonary artery pressures is translated into clinical decisions in the Dutch health-care system and whether this will lead to similar benefits as experienced elsewhere. Finally, whether it will be successful will, to a considerable extent, depend on how doctors respond to increasing filling pressures and whether their immediate interventions (e.g. increase diuretics) actually translate into longer term beneficial effects.


Severe AS is defined by a mean pressure gradient of 40 mmHg occurring at any time during the test when aortic valve area remains < 1.0 cm2.Low-dose dobutamine stress echocardiography (DSE) is indicated in patients with low flow  by tissue Doppler imaging and peak LV outflow tract (LVOT) velocity as markers of LV intrinsic contractile function during DSE in a patient with low flow low gradient AS and reduced EF prior to transcatheter aortic valve implantation (TAVI).Mitral annular S′ and peak LVOT velocities are reliable markers of LV intrinsic contractile function and should be incorporated into routine low-dose DSE. This case is of clinical interest for physicians and sonographers who perform DSE in patient with classical low flow low gradient AS to assess contractile reserve, the patterns of flow normalization and the hemodynamic severity of AS. However, the incorporation of mitral annular S′ and peak LVOT velocity into low dose DSE may provide additional information on the LV intrinsic contractile function and the potentials for recovery of LV function following valve intervention.A 82-year-old male with known coronary artery disease , diabetes type II, hypertension and hypercholesterolemia, and smoking-induced chronic obstructive pulmonary disease (FEV1 69%) was referred to our heart valve clinic for assessment of AS. An echocardiogram 2 years earlier had shown LVEF of 60% and a moderate AS. He had experienced progressive dyspnea over the past 4 weeks (NYHA function class III).His medications included vildagliptin 50 mg twice daily, empagliflozin 25 mg once daily (OD), liraglutid 1.2 mg s.c. OD, aclidinium bromide/formoterol fumarate dehydrate inhalation 340/12 μg twice daily, aspirin 75 mg OD, metoprolol depot 50 mg OD and atorvastatin 40 mg OD.2. On physical examination, there was a systolic murmur, grade 4/6 on the right and left 2nd intercostal space, with the preserved second heart sound. His blood pressure was 124/79 mmHg.His body surface area was 1.80 m2), sodium (139 mmol/L) and potassium (4.3 mmol/L).Laboratory tests: Apart from non-fasting serum glucose (11.3 mmol/L) and NT-pro-BNP (260 ng/L), all other blood tests were normal including troponin T (9 ng/L), creatinine (67 μmol/L), eGFR . No new obstructive lesions were revealed. Heart CT showed a tricuspid aortic valve with Ca score of 2140 Agatston units.An ECG showed sinus rhythm with heart rate of 58 beat per minute, and a Q-wave in leads II, III and AVF.2. AS was mild by peak aortic jet-velocity (2.6 m/s), but severe by aortic valve area (0.9 cm2). A mild aortic and mitral regurgitations were noted. There was no sign of right-sided valvular heart disease or pulmonary hypertension. A low-dose DSE  was indicated to assess contractile reserves and the severity grade of AS, i.e. differentiate true severe from pseudo-severe [2 to 43 ml/m2 (34% increase), aortic jet velocity from 2.6 m/s to 3.4 m/s and aortic valve area from 0.93 cm2 to 1.07 cm2. LVEF increased from 42 to 50%, peak LVOT velocity from 0.69 m/s to 1.04 m/s (51% increase), septal mitral annular S′ from 6 cm/s to 8 cm/s (33% increase) and lateral mitral annular S′ from 7 cm/s to 12 cm/s (71% increase)  showed reduced LVEF 42%) and hypokinesia in the ventricular septum and inferior wall following previous myocardial infarction. The Aortic valve was heavily calcified Fig. . Flow ra% and hyp2, peak LVOT velocity to 1 m/s . SVi further increased to 55 ml/m2, a borderline cut-off between moderate and severe. Aortic valve was heavily calcified with a Ca score of 2140 Agatston units by CT, indicating a hemodynamically severe AS. In order to restore LV function and treat symptoms, the removal of valvular resistance/stenosis by TAVI was essential. It is known that the prognosis of moderate AS is no longer benign [In routine clinical practice, a low dose DSE is essential for subcategorization of classical low flow low gradient AS into true severe and pseudo-severe, and assessment of contractile reserves, reflected by > 20% increase in SVi. Low dose DSE is a relatively safe and tolerable investigation, and provides valuable information on LV contractile reserve, which has important implications in terms of surgical risk stratification . During r benign . We haver benign .Table 22 during DSE pre TAVI, remained at 35 ml/m2 post TAVI, but further increased to 55 ml/m2 6 weeks after TAVI. In a previous study of severe AS by Lindqvist et al. septal annular S′ increased from 5.8 cm/s before TAVI to 7.0 cm/s 1 week after TAVI, and remained largely unchanged 6 months after TAVI (7.2 cm/s) [LVEF and SVi are the conventional markers of heart pump function and may not necessarily reflect the true intrinsic contractile function of the LV. This case report illustrates that besides the traditional contractile reserves as assessed by > 20% increase in SVi, other routine echocardiographic parameters such as mitral annular S′ by tissue Doppler and peak LVOT velocity may also provide important clinical information on the recovery of LV function following valve intervention. During DSE, the septal S′ increased by 33% to 8 cm/s, lateral annular S′ by 71% to 12 cm/s, and peak LVOT velocity increased by 51% to 1.04 m/s  immediately after TAVI, it further increased to 55 ml/m2 at 6-weeks follow-up, which indicates early reverse LV remodeling. Mitral annular S′ may be a better immediate marker of LV recovery after pressure unloading compared with SVi. However, this is our experience from this particular case report and we therefore suggest that the clinical significance and prognostic value of mean change in mitral annular S′ and peak LVOT velocities from rest to peak stress in patients with low flow low gradient AS should be explored in future prospective studies.Both Tissue Doppler S′ and peak LVOT velocities are easy to measure during routine echocardiography. Tissue Doppler S′ is a robust marker of systolic LV function, particularly in the longitudinal axis, and correlates well with strain and markers of myocardial fibrosis such as late gadolinium enhancement on cardiac MR . ReducedThis case report demonstrates that mitral annular S′ and peak LVOT velocities are reliable markers of LV intrinsic contractile function, correlate well with the indices of transaortic flow (SVi and flow rate) and may be true markers of LV recovery after unloading AS by TAVI.We suggest the incorporation of tissue Doppler S´ and LVOT velocities into routine low-dose DSE.


FGF4 retrogene on CFA 12 have opened up new areas of investigation to further define the pathophysiology of premature IVDD. While preliminary data from studies investigating FGF4 retrogenes in IVDD implicate FGF4 overexpression as a major disease factor, they have also highlighted knowledge gaps in our understanding of intervertebral disc herniation which is a complex and multifactorial disease process.Premature degeneration of the intervertebral disc and its association with specific chondrodystrophic dog breeds has been recognized for over a century. Several lines of evidence including disease breed predisposition, studies suggesting heritability of premature intervertebral disc degeneration (IVDD) and association of a dog chromosome 12 (CFA 12) locus with intervertebral disc calcification have strongly supported a genetic component in IVDD in dogs. Recent studies documenting association of IVDD with an overexpressing  The list of inherited neurological disorders in companion and production animals is ever expanding. There are over 120 known genetic variants for neurological disorders in dogs alone . Beyond FGF4 associated with insertion of FGF4 retrogenes on CFA12 and CFA18 appear to have broader influences on limb length across many breeds and are the only genes to have been implicated in body size in across-breed association studies  and has been used to describe extreme differences in limb length in several dog breeds, such as the Basset Hound, Dachshund, and Pekingese . Historiral disc .Fibroblast Growth Factor 4 is most highly expressed in the embryonic ectoderm, axial, paraxial, and lateral plate mesoderm, and tail bud   for Hansen Type I intervertebral disc disease  and polyA tracts (class 1 templated sequence insertion polymorphism) , 3534, 3orphism) .FGF4 retrogenes have been associated with clinical phenotypes in dogs.Retrocopies have historically been considered to be inactive in most cases due to lack of appropriate regulatory elements as well as genetic alterations that remove open reading frames, and documented association with disease states is relatively uncommon. However, retrotransposition is believed to play an important role in genome evolution  and as tFGF4 retrogene is 3,209 bp long (Gen Bank accession no. MF040221) and consists of the parental chromosome 18 FGF4 exons  with common 5′ UTR and exons but a shorter 3′ UTR and is inserted within a LINE element on the parental chromosome 18]. The CFA12 FGF4 retrogene is transcriptionally active resulting in a 20-fold increase in FGF expression in neonatal intervertebral disc from dogs homozygous for the CFA12 FGF4 retrogene insertion compared to disc from neonatal dogs with just the parental FGF4 genes  appeared and produced an obvious phenotype, strong selection was likely applied to retain them.Although we have little ancient historical data documenting IVDD prior to the late nineteenth century , we do kFGF4 retrogenes generally reflects the morphological phenotype and susceptibility to IVDD we recognize in clinical practice (FGF4 retrogene copy (CFA12 or CFA18) tend to have skeletal dysplasia with moderately short limbs, while those carrying both copies, such as Dachshunds, Corgis and Bassett Hounds, have the most severe form of disproportionate dwarfism. The breeds with a higher frequency of the CFA12 FGF4 insertion are the same breeds identified in the last 50 years as being predisposed to IVDD , it does not appear to be directly associated with development of IVDD since several of the highly susceptible short legged breeds carrying the CFA12 FGF4 retrogene such as Beagles, French Bulldogs and Cocker Spaniels do not carry the CFA18 FGF4 retrogene and interestingly contrast with the short legged breeds such as Cairn Terriers and West Highland White Terriers that are rarely reported to have IVDD and carry only the CFA18 FGF4 retrogene . Sunsertion , 42.FGF4 retrogene was present in 40 breeds, the CFA18 FGF4 retrogene in 32 breeds and both retrogenes in 23 breeds  in the general population of breeds such as Beagles, Dachshunds, French Bulldogs, and most spaniel breeds, and not surprisingly, this frequency increases when looking at the population of dogs that present with clinical IVDD . Consistent with the skeletal dysplasia phenotype common to both retrogenes, presence of 1 or 2 copies of either the CFA12 or CFA18 FGF4 retrogenes was also associated with “smaller” dogs (based on body weight).Genotyping of over 3,000 dogs from 75 breeds showed that the CFA12 3 breeds  42). Th. ThFGF4 FGF4 retrogene is associated with a younger age of presentation for decompressive surgery (mean 6.1 vs. 8.5 years) (FGF4 retrogene had a significantly younger age at surgery (median 3.7 years) compared to other breeds homozygous for the CFA12 FGF4 retrogene such as Dachshunds (median age 6.5 years)   42). In. InFGF4 5 years) , 52 thatFGF4 retrogene frequency also described dogs with calcified (Type I) IVD to be significantly smaller (median 8.1 vs. 25 kg) and to have a significantly younger age at presentation for surgery (5.5 vs. 9 years) compared to non-calcified IVD (Type II) dogs  compared to surgically treated animals with fibrous/non-calcified disc herniation/protrusion   dogs . Supporty 0.149) .FGF4 retrogene (84.8%) compared to 1 copy of the CFA12 FGF4 retrogene (63.8%) compared to zero copies (18.5%)  . Multivao 1 copy . Presencfication .FGF4 retrogene location on chromosome 12 was done using high vs. low radiographic calcification scores in Dachshunds  Dachshunds. This population would be necessary for a successful genome mapping study and is consistent with the CFA12 FGF4 retrogene dosage effects on radiographically apparent calcification subsequently demonstrated following identification of the CFA12 retrogene , relative risk for IVDD  associated with the CFA12 FGF4 retrogene ranged from 5.5 in Chihuahuas to 15.1 in mixed breed dogs.Prospective data determining the risk for IVDD associated with presence of the CFA12 erformed . LookingFGF4 retrogene. Clarification of these pathophysiological and clinical variables in the presentation of IVDD is important if genotyping is to be used as a tool for reduction in disease incidence. A more comprehensive picture will also increase breeder and owner confidence for eradication strategies that may potentially require major alterations in breed standards for those breeds with high allele frequencies.Several aspects of the clinical presentation of IVDD in dogs are not easily explained by a simple presence or absence of the CFA12 FGF4 retrogene allele frequency  as the major determinant of ratio changes. However, several genetic factors are likely to be contributing to conformation including CFA12 and 18 FGF4 retrogenes. Clinically affected Dachshunds were reported to have longer epaxial muscle fascicle lengths in one study, which could be a secondary effect of clinical IVDD; however, it is interesting to note that FGF4 is also a key signaling molecule in the development of myofibers and tendon of epaxial muscles arising from somitic mesoderm  length were associated with increased risk in one study  while a mesoderm , 68.FGF4 retrogene status of dogs within the Standard Wire Haired population which can be inferred from the successful GWAS mapping using this Dachshund subtype (FGF4 retrogene (FGF5 gene (likely loss of function based on recessive inheritance)  , 70. Altng limbs , 71. Redng limbs  and it iPO2 gene . RSPO2 sPO2 gene , an impoPO2 gene  and downPO2 gene .FGF4 retrogene presence and other factors) based on breed has been reported  gene associated with screw tail and brachycephaly  would provide further insight into the relative effects of the two retrogenes.Co-expression of the CFA12 and CFA18 e modest , potentie modest . The CFA the IVD  althoughFGF4 retrogenes documented to date may facilitate its expression in other chromosomal locations as well. This provokes the question of how many other times the FGF4 gene has been retrotransposed and then eliminated by selective breeding, or if additional retrocopies remain in some breeds and are responsible for other morphological phenotypes or contribute to IVDD.The location of a large CpG island in the two FGF4 retrogene were found in 12% (46/378) of dogs presenting for IVDD related surgery and with documented presence of calcified intervertebral discs  are defined, may have specific molecular mechanistic similarities to FGF4 overexpression and IVDD  in dogs. However, less definitive data are available regarding genetics of IVDD and associated low back pain and sciatica in the general human population. Heritability of risk factors for IVDD in humans was initially established using twin studies  may sometimes conflict with dog breeding phenotypic goals.The most critical unanswered question relating to the CFA12 FGF4 retrogene has been seen in almost all IVDD affected breeds, even those with high allele frequencies. In breeds with a high degree of segregation it should be possible to reduce or eliminate the retrogene from the population.Positively, some degree of segregation of the CFA12 FGF4 retrogenes. In high IVDD risk breeds such as Dachshunds, Bassets, Corgis and Pekingese that have both the CFA12 and CFA18 FGF4 retrogene, breeding away from the CFA12 FGF4 retrogene, while still maintaining the aesthetically desirable shortness in stature contributed by the CFA18 FGF4 retrogene is possible.Even in high allele frequency breeds, such as the Dachshund, there are frequency differences between populations [0.98 in USA/UK samples and 0.94 in Swiss samples ], indicaFGF4 retrogene, so that the allele frequency can be reduced.The dominant nature of the CFA12 FGF4 retrogene on IVDD and the very high allele frequency in some breeds means that eradication may be challenging. The Wire Haired Dachshund was developed through crossbreeding with Schnauzer and Terrier breeds which may explain the lower frequency of the CFA12 susceptibility locus and lower incidence of IVDD in some wire haired populations. Long term strategies may require a combination of testing and selection of heterozygous dogs, outbreeding, cross breeding, and alteration in breed standards, maybe with inclusion of additional CFA12 FGF4 retrogene-negative phenotypes within the breed standards. Whatever the future holds, from a veterinary perspective, current data suggest that breeding priorities should be for dogs with fewer copies of the CFA12 All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Guanidinoacetic acid  is a naturally-occurring derivative of glycine and a direct metabolic precursor of creatine, a key player in high-phosphate cellular bioenergetics. GAA is found in human serum and urine, with circulating GAA likely reflects an equilibrium between its endogenous production and utilization/excretion. GAA deficiency (as indicated by low serum GAA) has been reported in various conditions yet this intriguing clinical entity appears to be poorly characterized as yet, either as a primary deficit or a sequel of secondary disease. This minireview article summarizes the inherited and acquired disorders with apparent GAA deficiency and discusses a possible relevance of GAA shortfall in clinical medicine. About 85 years ago, Dr. Clarence J. Weber from the University of Kansas School of Medicine was arguably the first who isolated GAA  from the urine of two patients with pseudo-hypertrophic muscular dystrophy and the urine of normal humans collected during the period of fasting Figure 1), a fact confirmed in further studies L-arginine:glycine amidinotransferase , the most likely control enzyme in the pathway and the committed step in the formation of creatine N-methyltransferase . GAMT transfers the methyl group from S-adenosylmethionine to GAA to form creatine and S-adenosylhomocysteine. Creatine is finally discharged into the bloodstream from where it can be absorbed by miscellaneous energy-demanding tissues, while residual GAA likely been excreted via the kidney Guanidinoacetic acid , and act as an oxidant-antioxidant tuner Figure 2), with GAA deficiency perhaps singled out as a novel clinical entity. Although this member of the guanidine family has been identified as a naturally occurring compound in the human biofluids way back to the 1930s, GAA deficiency actually remains poorly addressed in experimental and clinical medicine up to this point. Here, we summarize inherited and acquired disorders characterized by GAA deficiency, and discuss the possible clinical relevance of this deficit; only human studies that provided data for circulating GAA concentrations were included in this analysis after a detailed search of published papers from scientific journals indexed in PubMed, Scopus, and Web of Science. This includes kidney and thyroid dysfunctions, neurological diseases and post-traumatic GAA deficit, along with L-arginine:glycine amidinotransferase deficiency, ornithine aminotransferase deficiency and urea cycle disorders; we also put forward criteria for normal and abnormal GAA levels, and clinical features of GAA deficiency.Besides serving as a direct precursor of creatine, GAA appears to have no other major physiological roles e.g. blood urea ranging from 62 to 325 mg/100 mL) and patients undergoing maintenance hemodialysis. Tofuku and co-workers  vs. 1.5 ± 0.1 μmol/L). Similar results were found in non-dialyzed men and women with chronic renal insufficiency e.g. creatinine clearance, CCR < 10 mL/min) experienced the most prominent reduction (~ 49.8 %) in circulating GAA as compared to control group (2.6 ± 0.5 μmol/L vs. 1.4 ± 0.6 μmol/L). A Japanese group e.g. from 3.3 μmol/L in healthy adults to 2.1 μmol/L in CGN patients). The authors also demonstrated that patients with nephropathy induced by non-insulin dependent diabetes mellitus (DM) experienced a significant drop in circulating GAA, with a degree of GAA deficit CCR-dependent, and the authors implied that GAA deficiency might be a reason of muscle wasting in this clinical population. Besides diminished production, GAA deficiency in renal failure could be aggravated by augmented GAA urinary excretion perhaps as a consequence of defective transmethylation extrarenally, with children with nephrotic syndrome encountered a tremendous increment (~ 900%) in 24 h urinary excretion of GAA Since the kidney is among the main organs of GAA synthesis, any persistent and severe renal disorder could jeopardize GAA output and instigate GAA deficiency. Sawynok and Dawborn per seA group led by Dr. Bart Marescau from the University of Antwerp analyzed circulating guanidino compounds in a large group of patients with common thyroid gland disorders vs. 2.1 μmol/L) which perhaps implies a hypoactive GAA metabolism in neurological patients. In addition, circulating GAA appears to be less reduced in a subpopulation of epileptic patients treated with appropriate medication as compared to serum GAA levels found in patients with uncontrolled epilepsy (2.2 μmol/L vs. 1.6 μmol/L). These findings suggest that common medicines given to neurological patients might improve GAA turnover and tend to restore normal GAA equilibrium that could contribute to the overall benefit. However, not all human trials found GAA deficiency in neurological patients. A recent study reported that plasma GAA concentrations in 9 patients suffering from acute stroke or transitory ischemic attacks were comparable to those measured in healthy humans vs. chronic pathologies) that might alter GAA homeostasis in a dissimilar manner.The first case of GAA deficiency in common neurological disorders was described almost 30 years ago. Shiraga and co-workers An interesting study from Manchester University Medical School L-arginine:glycine amidinotransferase. The syndrome primarily affects the brain and skeletal muscle, and patients with AGAT deficiency have mild to moderate pathology that includes mental retardation, developmental delay, muscle weakness and epilepsy AGAT deficiency  is a very rare inherited disorder of creatine metabolism, characterized by the lack of GAA-synthesizing enzyme, Another inherited disease with pertinent GAA shortfall is ornithine aminotransferase (OAT) deficiency. This rare inborn error of ornithine metabolism  is caused by decreased activity of ornithine aminotransferase, an enzyme that is involved in the formation of proline from ornithine. OAT deficiency is clinically characterized by myopia which progresses to night blindness, subcapsular cataract and elevated levels of ornithine in the blood vs. 1.7 μmol/L). The authors advanced the use of plasma GAA as a practical and relevant parameter to consider in the follow-up of patients with UCDs.Urea cycle disorders (UCDs) results from inherited deficiencies in any one of the six enzymes or two transporters of the urea cycle pathway, with the clinical presentation and severity influenced by the importance of the defective compound (for a detailed review see Ref. 35). Typically characterized by hyperammonemia, loss of appetite, vomiting, lethargy, and behavioral abnormalities, distinct types of UCDs can impede GAA synthesis due to the overproduction of ornithine (presented as hyperornithinemia) and concomitant inhibition of AGAT. Arias and co-workers vs. 3.2 μmol/L), with bedridden elderly had even lower GAA levels (accompanied by lighter muscle mass) than their ambulatory peers (1.8 μmol/L vs. 2.8 μmol/L). This might be due to age-dependent suppression of AGAT activity modulated by dietary and hormonal factors Besides the above pathologies, a transient or long-standing GAA deficiency becomes evident in several non-clinical populations, including elderly or healthy men and women exposed to heavy exercise. Matsumura and co-workers vs. subjects older than 15 years). Unfortunately, no means or variation indices were presented in this study, although children tended to show lower plasma GAA levels as compared to their older counterparts while no significant difference was observed between genders. Another study vs. stable‑isotope dilution GC-MS measurement). This highlights the need to establish a gold-standard protocol to evaluate serum or plasma GAA in laboratory medicine. For the time being, a serum GAA < 0.04 μmol/L is highly suggestive of severe GAA deficiency, as seen in AGAT defect The normal levels of circulating GAA in healthy humans are evaluated in a handful of studies. The most recent trial known to the author reported plasma GAA for healthy subjects to be 2.6 ± 0.8 μmol/L Although GAA and creatine metabolism are tightly interconnected, GAA deficiency and low serum GAA does not go along with creatine deprivation on every occasion. As an example, a reduced circulating GAA level is accompanied by normal serum creatine in patients with chronic renal insufficiency Either as a disorder that could be due to a root cause of GAA shortage (e.g. AGAT deficiency) or triggered by a condition that provokes GAA diminution (such as trauma-driven kidney failure), GAA deficiency likely entails clinical attributes of low levels of energy output due to its role in energy metabolism Many issues on GAA deficiency need to be addressed before recognizing it as an authentic clinical entity. First and foremost, more studies are needed to define the reference ranges for GAA deficiency in various clinical disorders. The largest population study so far described the GAA reference values in a population of 6334 French patients with neurological symptoms GAA deficit has been found in many pathologies, from very rare creatine deficiency syndrome and urea cycle defects to more common conditions, including traumatic injuries, chronic kidney disease, and neurological disorders. Characterized by the reduced serum GAA, GAA deficiency seems to reflect a disbalance between its endogenous production and utilization/excretion in disorders that primarily affect GAA-pivotal organs, such as the kidney, liver and skeletal muscle. Due to somewhat divergent specificity to creatine turnover, GAA deficiency might be considered as a unique metabolic feature in the follow-up of various diseases. To validate its possible clinical significance, additional well-sampled studies are warranted to describe GAA dynamics in large cohorts of patients and evaluate possible GAA deficiency features across the continuum of GAA values and conditions.


The contradictory findings of recent prospective randomized controlled trials assessing the impact of percutaneous edge-to-edge repair in patients with functional or secondary mitral regurgitation have triggered a lively discussion about an “integrated” echocardiographic approach for grading severity of mitral regurgitation. In the MITRA-FR trial, the COAPT trial and the REDUCE-FMR trial echocardiographic assessment of the severity of mitral regurgitation was consistent with principles set forth by the current echocardiographic guidelines and analysed in its best settings by expert international leaders in the field of echocardiography. However, serious inconsistencies appeared in the presented echocardiographic assessments regarding cardiac output and regurgitant fraction. A new term “disproportionate functional mitral regurgitation” was introduced describing a situation where the increase of effective regurgitant orifice area exceeds the enlargement of the left ventricular end-diastolic volumes. Further discussion resulted in the idea of a “new conceptional framework” for distinguishing “proportionate” and “disproportionate” functional mitral regurgitation. The aim of this viewpoint is to dispute conclusions based on the term “disproportionate” mitral regurgitation. A “disproportionate” FMR is highly questionable because disproportionateness of flow in communication vessels cannot exist. In addition, a proposal of echocardiographic assessment based on a conventional comprehensive transthoracic echocardiography is given to avoid obvious hemodynamic contradictions. Taken) trials –7. The s) trials , 9. Thus) trials  is in do) trials –7, 10–23The first objective of this viewpoint is to discuss whether a “disproportionate” FMR can be possible anyway with the conclusion that disproportionateness of flow in communication vessels cannot exist. The second objective is to propose an extended transparent echocardiographic protocol focusing on hemodynamic plausibility to improve the grading FMR severity.tot can be measured at the level of the LVOT as well as at the level of the stenotic orifice area by Doppler echocardiography, because volume flow has to be the same at both levels [MV is the calculated difference LVSVtot − LVSVeff. Thus, if forward stroke volume LVSVeff is known, the interrelationship between effective regurgitant orifice area (EROA) and regurgitant flow can be calculated due to physical laws of rheology  severity based on the physical laws of conservation of mass and energy. These principles cannot be neglected meaning that blood flow velocities at defined orifices are proportional in a system of communicating tubes. If we assume “pure” aortic valve stenosis (AS), and if cross sectional areas are known at the level of the left ventricular outflow tract (LVOT) as well as at the level of the stenotic orifice area, LVSVh levels , 25. In ogy Fig. .Fig. 1Ileff, heart rate (HR) and body surface area (BSA) should be the basis of the physiological thinking in echocardiography. Further important cardiac parameters are the LV end-diastolic volume (LVEDV) and the LV ejection fraction (LVEF) to interpret the cardiovascular physiology. Normal CO is defined within ranges of 4.0 to 4.5 l/min or a CI of about 2.5 l/min/m2. A CI < 2.2 l/min/m2 is a criterium for cardiogenic shock (CO < about 4 l/min). A normal heart rate at rest—and the target heart rate for cardiovascular patients with optimal medical treatment (OMT)—is within the ranges of 50 to 70/min. With respect to these values of a normal cardiovascular physiology a borderline region to differentiate between normal conditions and cardiac decompensation can be marked in a LVSVeff − LVEDV diagram with respect to different LVEF  and the cardiac index (CI) determined by the LVSVtot and LVEDV of the recent TMVR trials [tot, the RegVolMV is only 8 ml, revealing a difference of 51 ml RegVolMV (RegVolMV = LVSVtot − LVSVeff) or a difference of 51 ml LVSVtot (LVSVtot = LVSVeff + RegVolMV) in the device group, which is not explained by the COAPT authors .In all figures two dots are presented for the COAPT trial. The two dots are explained by the values reported in the literature about COAPT , 4. The d values . If 51 mMV, LVEDV, LVEF and LVSVtot are not conclusive and plausible, the following conclusions can be drawn: RegVolMV is obviously overestimated and planimetry-derived LVEDV is obviously underestimated. Thus, either the methods used should not be applied anymore or they should be applied correctly.With respect to hemodynamic implausibility of the echocardiographic data presented in the recent TMVR trials –3 it migMV by measuring improper PISA radius at false time points and/or at the VC instead of the entry of the EROA [MV/VTILVOT) seems to be suitable for a grading approach of MR severity, if the sample volumes are properly positioned, ultrasound beam alignment is parallel to the blood flow, MV stenosis or aortic valve regurgitation as well as mitral annular dilatation and atrial fibrillation is absent [tot, LVSVeff and RegVolMV in a similar approach as currently used in cardiac magnetic resonance, CMR [tot, LVSVeff and RegVolMV, the most likely explanation are obviously measurement errors due to methodological factors.The assessment of MR severity by the echocardiographic “integrated approach” described by the current guideline recommendations is primarily based on semiquantitative analysis of semiquantitative parameters describing MR severity , 9, 23. the EROA . The shathe EROA . The intthe EROA . The rats absent . Due to nce, CMR –33. If eIn HF patients with FMR recently two “hemodynamic pathways” have been described to characterize pathophysiological differences . FirstlyMV has to be proportional to EROA in a system of communicating vessels  of the LVOT. In patients with combined aortic valve disease the LVSVeff can be determined by Doppler calculations of SV using cross sectional area the right ventricular outflow tract (RVOT) and the respective PW-Doppler VTI of the RVOT which is not common use in clinical routine echocardiography. As illustrated LV volumes and RegVolMV can be correctly calculated by the differences of LVSVtot and LVSVeff or RVSVeff, and in few cases, in which the 2D-PISA method can adequately be used, the calculated RegVolMV corresponds to the RegVolMV determined by the 2D-PISA method (Figs. The quantitative approach of FMR assessment by echocardiography is challenging. The quantitative assessment of LV volumes is highly criticized because of the necessity to determine several parameters, which are all prone to measuring errors that are squared in the respective calculations , 9. Neveod Figs. , 7, 8, 9The inconsistencies of the echocardiographic characterization of FMR severity make interpretations about FMR characteristics or generation of algorithms based on the trial results difficult.The term “disproportionate FMR” is not in line with the physical laws of conservation of mass and energy and can only be explained by inconsistent echocardiographic data. Thus, the term is confusing and should therefore be avoided because a “disproportionate FMR” with inconsistent hemodynamics is not possible anyway.tot, LVSVeff, RegVolMV and individual RF by echocardiography should be discussed in future recommendations.A quantitative approach of FMR grading that includes the accurate quantitative assessment of LVSV