Although subjective differences have been observed between radial artery (RA) and long saphenous venous (LSV) grafts, these have not been quantified. This study assessed and compared the flow characteristics and E) and volume flow (FE) were then calculated. A further 7 patients underwent in-vivo graft flow responses assessments to adenosine, acetylcholine and isosorbide dinitrate (ISDN) using intravascular Doppler.Angiograms from 52 males taken 3.7 ± 1.0 months after CABG surgery were analyzed using adjusted Thrombolysis in Myocardial Infarction (TIMI) frame count. Graft and target coronary artery dimensions were measured using quantitative coronary angiography. Estimated TIMI velocity (VE for RA grafts was significantly greater than LSV grafts (P = 0.002), however there was no difference in volume FE (P = 0.20). RA grafts showed positive endothelium-dependent and -independent vasodilatation, and LSV grafts showed no statistically significant response to adenosine and acetylcholine. There was no difference in flow velocity or volume responses. Seven RA grafts (11%) had compromised patency (4 (6%) ≥ 50% stenosis in the proximal/distal anastomoses, and 3 (5%) diffuse narrowing). Thirty-seven (95%) LSV grafts achieved perfect patency and 2 (5%) were occluded.The VThe flow characteristics and flow responses of the RA graft suggest that it is a more physiological conduit than the LSV graft. The clinical relevance of the balance between imperfect patency versus the more physiological vascular function in the RA graft may be revealed by the 5-year angiographic follow-up of this trial. Basal velocity was significantly greater in RA versus LSV grafts, but volume flow was similar. RA grafts, but not LSV grafts, showed endothelium-dependent vasodilatation.We compared 3-month post-operative flow characteristics and Interest in the radial artery (RA) as a coronary artery bypass graft has grown over recent years, driven by a desire to replace vein grafts with arterial grafts. Numerous observational series have shown favourable early and longer-term patency results, summarized in a recent review . Furtherin-vivo flow responses in RA grafts have not been compared with LSV grafts. The aim of this study therefore was to examine the resting flow characteristics and dynamic flow responses in RA and LSV aorto-coronary bypass grafts to a single coronary artery territory.The success of arterial grafts has been attributed to more physiological flow characteristics and adaptability to the coronary arterial bed by a process of autoregulation . LSV graPatients undergoing myocardial revascularization surgery aged 40–70 years with significant stenosis (≥ 70%) in the circumflex territory as identified on preoperative angiograms, and a negative Allen's test  were enrolled. Exclusion criteria were poor LV function (EF <25%), severe diffuse peripheral vascular disease or bilateral varicose venous disease and inability to comply with the angiographic follow-up at 3 months or/and 5 years.in vivo graft flow sub-study were obtained from the Royal Brompton Hospital Ethics Committee. Written informed consent was obtained from all patients preoperatively.Ethics approvals for both the randomized study and the The Radial artery versus Saphenous Vein Patency (RSVP) trial is a prospective randomized trial to compare angiographic patency rates of RA and LSV grafts to the native LCx territory. Phase 1, the results of which are presented here, was designed as a safety/efficacy assessment to address any early technical problems associated with using RA to the ascending aorta and involved the first 100 patients returning for 3 month post-operative angiography. A subgroup of these patients also underwent physiological assessment of the randomized graft at angiography (described below). Randomization was 2:1 in favour of RA to increase the RA graft dataset. Phase 2 involved recruitment of additional patients, and patients from phase 1 and 2 will undergo assessment of long-term angiographic graft patency at 5 years.All vasoactive medications such as β-blockers, calcium antagonists, nitrates, angiotensin converting enzyme inhibitors and statins were stopped 24 hours prior to study. Angiograms were performed using 5 or 7 French angiographic catheters with Omnipaque contrast medium. Frame acquisition was 25 frames/s. Heart rate and blood pressure were recorded throughout the study. Angiographic endpoint was graft patency graded to the following scale: P1 , P2 , P3 , P4  or P5 . All stenoses were assessed using quantitative coronary angiography . Graft diameter and length and target coronary artery diameter were also analyzed using QCA as previously described . AnalysiE) was derived using the following equation [Flow characteristics in both grafts were assessed using the TIMI frame count. This is a reproducible and semi-quantitative measure of coronary flow index represented as time in seconds (TIMI frame count/25 frames = seconds)  and prevequation :E) (ml/s) was calculated by multiplying VE with cross-sectional area [Flow volume estimate  and LCx grafts, patients were heparinized and a 0.014 inch Doppler wire  was positioned in the proximal third of the randomized obtuse marginal or RCA grafts. A continuous trace of average peak blood flow velocity was recorded together with arterial blood pressure, heart rate and ECG.-7 and 10-6 M. The Doppler wire was then withdrawn and inserted into the second graft (either the LCx or RCA graft) and the above infusions repeated. Finally an intra-graft bolus of ISDN (300 μg) was given. The Doppler wire was then re-introduced into the first graft and the ISDN infusion repeated.After equilibration, an intra-graft bolus of the endothelium-independent vasodilator adenosine (30 μg) was given via the guiding catheter, followed by two 2-minute infusions of the endothelium-dependent vasodilator acetylcholine 10Velocity was measured at peak velocity response or 2 minutes after commencement of infusion. Angiograms were performed at baseline and at peak velocity response to each vasoactive substance. There was a rest period of at least 1 minute between each infusion to allow all measured parameters to return to baseline.in-vivo graft data were analyzed as a within patient comparison using a paired Student's t test. Because of the difference in territory compared for the in-vivo graft data, the percentage dilatation achieved was divided by the grafted coronary artery diameter response to isosorbide dinitrate. Significance was set at 5%. Data are expressed as mean ± SEM.Nominal data and patency rates between the two grafts were analyzed using Chi square test for proportions. Continuous variables were analyzed using unpaired t-tests with significance at p < 0.05 and are expressed as mean ± SEM. TIMI flow data were analyzed using unpaired Student's t test and One hundred patients underwent early angiographic graft patency assessment at mean of 3.7 ± 1.1 months after surgery. Sixty-one patients were randomized to RA grafts (aged 58.7 ± 0.8 years) and 39 to LSV grafts (aged 59.4 ± 1.3 years), with no difference in patient characteristics between groups . Operative and post-operative details such as bypass and cross-clamp times, intensive care stay and duration of hospital stay were not statistically different.All RA grafts were patent with no incidence of complete occlusive disease. Fifty-four (89%) patients had RA grafts that were perfectly patent (grade P1), however 7 patients (11%) had compromised patency with 4 (6%) in grade P3 , and 3 (5%) in grade P4 . Thirty-seven (95%) LSV grafts achieved grade P1 and 2 (5%) were completely occluded (grade P5). There were no intermediate grades seen in the LSV graft group. There was no significant difference between the two groups in each of the grades.Intra-graft nitrate was infused down all compromised RA grafts. This did not affect the degree of anastomotic narrowing of RA grafts in grade P3 but all of the RA grafts with string-sign exhibited a small degree of dilatation. Grade P3 RA grafts all had good rapid flow of angiographic contrast through the grafts, despite significant anastomotic narrowings (>75%). All patients with occluded or compromised grafts were clinically well and symptom free. There were no major adverse events related to graft occlusion or graft stenosis.RA graft diameters were significantly smaller than LSV grafts , and graft-coronary diameter difference (0.19 ± 0.07 vs 1.34 ± 0.13 mm) and cross-sectional area difference were significantly smaller for RA grafts than LSV grafts , however the mean volume FE was not significantly different . Heart rate and mean ascending aortic pressure during angiography were not significantly different between the 2 groups .Angiograms from 52 patients were suitable for analysis of TIMI flow characteristics. There was no difference in patient characteristics between groups . Others were excluded from analysis due to a variety of technical considerations such as incomplete opacification of the whole graft. Mean V-6 mmol . Mean vascular reactivity data of RA and LSV grafts in response to pharmacological challenge are presented in Table l Figure .-7 M in RA grafts (P = 0.05), and a trend at acetylcholine 10-6 M (P = 0.08) but no such trend in LSV grafts (both P = 0.7 and 0.1 respectively). Resistance decreased significantly from baseline in response to adenosine in both arterial and venous grafts, and to nitrate in LSV grafts, but there was no significant difference between graft types. There was no difference in coronary flow reserve for the two graft types . Heart rate and mean blood pressure did not change significantly throughout the procedure (75 ± 14 bpm and 114 ± 17 mmHg respectively).While velocity percent changes from baseline were slightly higher in LSV grafts, and slightly higher in RA grafts with respect to flow, there was no statistically significant differences in velocity or flow responses between RA and LSV grafts to any intervention. Adenosine induced significant increases from baseline in blood flow velocity and volume flow in both arterial and venous grafts, and both significantly increased flow from baseline in response to nitrate. Interestingly, there was a significant flow increase from baseline to acetylcholine 10This single-centre randomized study compares the patency, early flow characteristics and flow responses to pharmacological stimulation of flow in arterial and venous grafts. Prospectively randomizing the patient to receive RA or LSV grafts and controlling for disparities in native coronary anatomy by assigning the randomized graft to a single (the LCx) territory, ensures meaningful clinical comparisons can be made. We showed that RA grafts are better matched in both structure and function to the native coronary artery than LSV grafts. TIMI velocities were greater but flows were no different in RA versus LSV grafts consistent with adequate revascularization at rest. Pharmacological challenge revealed preserved endothelium-dependent vasodilatation in RA but not LSV grafts 3 months post-CABG surgery.Early RA graft patency rates were comparable to LSV graft patency, in line with published case series . There wThere was a much better size match to the target LCx with the RA. It is possible (but very unlikely) that the size of an individual's RA is approximately the same as the largest branch of the LCx coronary artery. However, it is likely that the RA graft, with its preserved endothelial function, is capable of autoregulating its size to adapt to the target coronary circulation, as was reported with the pedicled left internal mammary artery graft .The haemodynamic effects of the internal diameter disparity between native coronary arteries and respective vein grafts has not been well studied. Stoel and colleagues calculated flow in the native LCx of 67 ml/min after giving intracoronary nitrate, which is similar to our nitrate-induced RA flow (63 ml/min) but quite different from the LSV flow (93 ml/min) in our patients . This raIntra-graft infusions of adenosine and acetylcholine resulted in divergent effects on graft diameters; RA grafts dilated to both drugs whereas there was a slight but statistically non-significant diameter decrease to adenosine and acetylcholine in LSV grafts. After adjusting for disparities in native coronary artery studied, this difference was statistically significant at the higher dose of acetylcholine. A dilatory response to acetylcholine indicates a functioning endothelium in RA grafts at 3 months after surgery, as previously reported 5 years post-operatively . The inaRA graft TIMI flow velocities were significantly greater than LSV grafts, similar to previously published data ,12, althTIMI-derived volume flow was not statistically significantly different between graft types, perhaps reflecting the similar target territory (LCx coronary artery) and distal run-offs, but were comparable to those measured previously using intra-operative volume flowmetry . AlthougPercentage increases in volume flow from baseline in response to pharmacological agents were similar in both groups indicating that RA grafts, despite their smaller size, are capable of delivering a similar volume of blood as the LSV grafts to meet myocardial oxygen demand. As endothelial function is preserved in RA grafts, we propose that they provide a more physiological autoregulation of flow compared with LSV grafts.The limitations of the TIMI frame count for estimating flow and velocity have previously been discussed . VariablLength of both grafts was measured with quantitative coronary angiography and this may vary according to geometry and spatial position of the grafts and cardiac cycle, which may contribute to some degree of error in the measurement obtained. To overcome this, only the longest measurement of length of the graft in the left anterior oblique view at diastole was taken. Another limitation was that native coronary flow velocity was not estimated nor directly measured in this study and the data used in the discussion were referenced from other studies .Due to the complexity of the protocol we were only able to enroll a small number of patients into the pharmacological challenge part of the study. It is possible that some of the trends shown may have shown significance if larger numbers were able to be included.The 3 month follow-up of the RSVP trial showed confirms excellent, although not perfect, early patency of RA grafts as compared to those of LSV grafts. There were no occluded RA grafts in the present series and an absence of any significant post-operative complications arising from using the RA as a coronary conduit. Our findings suggest that the RA is a more physiological conduit than the LSV, exhibiting flow characteristics that are comparable to the native coronary system with intact endothelial function 3 months after CABG surgery. The clinical relevance of the balance between imperfect patency versus the more physiological vascular function in the RA graft may be revealed by the 5-year angiographic follow-up of this trial.


Left ventricular hypertrophy is an important risk factor in cardiovascular disease and echocardiography has been widely used for diagnosis. Although an adequate methodologic standardization exists currently, differences in measurement and interpreting data is present in most of the older clinical studies. Variability in border limits criteria, left ventricular mass formulas, body size indexing and other adjustments affects the comparability among these studies and may influence both the clinical and epidemiologic use of echocardiography in the investigation of the left ventricular structure. We are going to review the most common measures that have been employed in left ventricular hypertrophy evaluation in the light of some recent population based echocardiographic studies, intending to show that echocardiography will remain a relatively inexpensive and accurate tool diagnostic tool. The diagnosis of left ventricular hypertrophy (LVH) has been incorporated in the clinical practice as an important marker of cardiovascular disease. Its prevalence depends on classification criteria and specific population characteristics, ranging from 3% in normotensive community-based samples  to aboutEchocardiography has been clinically employed for more than 30 years, becoming one of the most important non-invasive imaging methods in the evaluation of cardiac morphology and dynamics. However, the apparent simplicity in LVH evaluation by echocardiography conceals several intrinsic and usually unrecognized critical steps that may limit its clinical validity.This manuscript introduces the basic principles of left ventricular mass (LV mass) estimation by echocardiography, focusing on the potential limitations and discrepancies of such measurement, in order to provide the appropriate background for understanding the rather complex issue of defining the cut-off values for LVH diagnosis in populations. Although advances in echocardiographic techniques has minimized the impact of many of the methodological details discussed here, an understanding of these topics is important, since most of the clinical and epidemiologic studies currently published are based on the echocardiographic criteria here described. We also intend to give a critical evaluation of the diagnostic performance and clinical validation of this imaging method.Left ventricular mass is generally calculated as the difference between the epicardium delimited volume and the left ventricular chamber volume multiplied by an estimate of myocardial density. Following this principle, several methodologies have been used to calculate left ventricular mass and to define hypertrophy with its own flaws and strengths on each step Table , resultiBoth M-mode and two-dimensional imaging can be employed to calculate left ventricular mass. M-mode imaging allows better endocardial border definition as it has greater resolution due to higher frame-rate, as long as adequate ultrasound beam positioning is ensured and ventricle shape approaches normality. Two-dimensional imaging, on the other hand, depicts the "real" ventricular shape and identifies regional motion abnormalities. However, the quality of two-dimensional imaging may be limited due to both lower lateral resolution and frame-rate. Additionally this option is more time consuming, limiting its use in epidemiological studies. Two-dimensional images are usually acquired both in paraesternal and apical views, depending on the geometrical formulas that are used.Technological advances have joined both methods and partially minimized their limitations There are standardized and validated recommendations for the clinical use of two-dimensional determination of LV mass , HoweverA relevant degree of variability in LV mass determination could be attributed to online measurement inaccuracies due to lower imaging resolution of older equipment, which could reach 10% of parietal thickness. Nowadays, variability due to on-line or off-line analysis of digitalized images calculations is of considerably smaller magnitude .We will focus our discussion on M-mode estimation of LV mass, since most epidemiological reports use this imaging modality. Preference for M-mode is based on its technical feasibility and availability at the time when most studies were performed. However, despite adequate correlation with two-dimensional measurements , M-mode Determination of left ventricular volumes is accomplished using formulas that fit ventricular shape to primary geometric figures. Ellipse, cylinder, cone, and truncated polyhedrons have been employed and validated in normally shaped ventricles, although most studies have limited sample sizes . Some geIf a two-dimensional approach is used, both area-length and truncated-ellipsoid models are feasible and reasonably accurate, with validated formulas . Among oThe method of cubed formulas, which incorporate only one dimension of the left ventricular cavity and assume an ellipsoid geometry, is the most widely used to calculate left ventricular volumes and mass in noninvasive laboratories worldwide. The broad acceptance of M-mode derived estimation relies on the fact that it was the first method that was validated and also on its technical simplicity. The one-dimensional approach, however, imposes more strict geometrical assumptions and amplifies the risk of inaccuracy, as measurement errors are cubed.Ultrasound signals are reinforced where surfaces change density, allowing definition of limits between surface layers. The inclusion or exclusion of these echoes from interfaces of the left ventricular cavity or myocardial wall can cause significant discrepancies in the overall measurements . InitialIn the past few years, spatial resolution of transthoracic echocardiography has greatly enhanced, leading to major improvements in image quality. Most of this progress can be attributed to second harmonic imaging, that significantly increases signal-to-noise ratio by receiving only harmonic frequencies. Although this technology is now widely available in most ultrasound equipment, its potential accuracy to evaluate LVH remains poorly characterized. A recent study suggests that LV mass estimations using second harmonic imaging can cause as much as a 26% increment in mean LV mass index corrected for body surface area, when compared to standard fundamental imaging using similar formulas and conventions . This isThe most commonly used formulas to estimate LV mass are all variations of the same mathematical principle, based in the volume formulas stated above. Original calculations from Troy and coworkers were the first to be recommended as standard to estimate LV mass from M-mode measurements (Formula 1) .3- [LVIDD]3) g.Formula 1: LV mass(Troy) = 1.05 . Their prediction equation in this pivotal study was derived from necropsy findings of 34 patients .3- [LVIDD]3) -13,6 g.Formula 2: LV mass(Penn) = 1.04 )+ 0,6 g.Formula3: LVmass(ASE): 0.8 .Obesity has been shown to be independently associated to LVH , particuLV mass progressively increases during aging , particuLVH is particularly prevalent in African-Americans ,62,69-72Several factors have been shown repeatedly in epidemiologic studies to associate with LVH. Investigation and prognostication based on LVH should take these factors in the account.Numerous population based studies have unequivocally shown an association between hypertension and LVH ,5,65,75.Together with obesity and hypertension, diabetes has been implicated as an important determinant of left ventricular mass in most population-based studies ,62,81,82An adaptive response has been shown to diverse degrees of altered carbohydrate metabolism, as in Cardiovascular Health Study  and in TA gender difference in the left ventricular response to diabetes, with an increase in parietal thickening, rather than hypertrophy, being prominent in women has been suggested ,85,87.LV mass increase is also seen in individuals with other known risk factors, as in those linked to the metabolic syndrome ,88., wheA multitude of other factors have been shown to be independently related to LV mass. It should be emphasized that estimates of the relative magnitude of these factors varies according to the degree of adjustment for other known risk factors in statistical modeling. Primary valvular and myocardial disease are clearly related to LV mass increase but will not be subject of our review.Environmental exposures such as alcohol consumption , salt inClinical validity and impact of such factors is controversial, but it may be important to consider them as relevant potential confounders in epidemiological studies investigating the role of novel risk factors in LVH and the role of LVH in disease prediction.Each step in LV mass measurement is a potential source of variability. In M-mode measurement, differences of approximately 5% may translate into differences in LV mass between 8% and 15% , which cIntraobserver M-mode measurements may vary about 5% between echocardiographic studies, while interobserver variability may reach 15%. Some trials retesting patients found differences of up to 30 g between tests ,101. WheAutopsy is classically employed as the gold standard in heart hypertrophy studies, because it objectively measures LV mass. However, use of reported data is complicated by the fact that macroscopic LVH definition criteria are usually more varied than those used in non-invasive testing -105, as From a histological point of view, myocytes hyperplasia is uncommon in adults. Pathologic studies and animal models suggest evaluating hypertrophy suggest that myocytes keep their integrity and functionality until an increase up to 50 -70% above normal . This isLV mass can also be calculated from angiography. Although diverse formulas have been employed and validated , correla99mTc-Sestamibi has been employed to estimate LV mass. Its accuracy is limited by image construction and processing variability, resulting in a limited correlation with echocardiographic LV mass [99mTc-tetrofosmin myocardial perfusion and echocardiographic based LV mass estimations, using an automated quantitative software.Radioisotopic gated myocardial perfusion imaging with  LV mass . However LV mass  found a Newer imaging methods have been employed in LV mass determination. Computed tomography has a good correlation with necropsy findings (r = 0.97). In vivo intrareader variability was estimated to be equivalent to 19 g and intereader 28 g . MagnetiReal time three-dimensional echocardiography is still experimental, but has incorporated technical advantages in image acquisition and processing. This method may permit accurate real time LV mass measurement without the caveats of geometrical assumptions. Preliminary data suggest that real time three-dimensional echocardiography is at least as accurate and reproducible as MRI calculations . ContrasLV mass estimation and LVH diagnosis role in cardiovascular disease management is based on epidemiological research and also on clinical grounds. Despite more than 30 years of use echocardiography-based LVH calculation and definition are still variable among ultrasound technicians and laboratories around the world, leading to inconsistency among epidemiological studies and possibly limiting its clinical application. Several technical aspects of the echocardiographic exam can generate substantial errors in LV estimations, some of them equivalent in size to those expected to result from pathophysiological processes and therapeutic strategies. Also, adequate indexing for body size seems to be a critical point in defining pathological hypertrophy. LV mass is closely related to the other known cardiovascular risk factors, that must be taken into account concomitantly. Finally, since the risk associated to LV mass appears to be progressive, without a clear threshold, additional input can be added at different baseline risks, defined by the prevalence of other known cardiovascular risk factors. The addition of multiple newer markers, however, leads to a small increment in risk stratification capacity over formulas applying only classical risk factors . Despite2.7greater than 51g/m2.7 appears to be a reliable criteria to define LVH, and the inclusion of a measurement of relative wall thickness, individually or classified as geometric patterns improves the identification of the adaptive mechanisms involved.Considering all the aspects reviewed, use of echocardiography in clinical studies must be standardized applying already defined criteria. In delineating a study, if two-dimensional is impractical, then two-dimensional guided M-mode, using ASE criteria and Devereux modified formula, will allow estimation of LV mass with an acceptable level of accuracy. Additionally, adequate adjustment of related covariates must be undertaken. LHV/HtEchocardiography is widely available all over the world and major technical improvements have been achieved in the last two decades. Given careful attention with respect to the technical aspects appraised in this review, echocardiography will remain a safe, inexpensive and accurate tool for both the clinical diagnosis and epidemiologic investigation of left ventricular hypertrophyThe author(s) declare that they have no competing interests.All authors contributed equally to this work, read and approved the final manuscript.


We aimed to assess whether we could identify a graded association between increasing number of components of the metabolic syndrome and cardiac structural and functional abnormalities independently of predicted risk of coronary heart disease by the Framingham risk score.We conducted a cross-sectional study on a random sample of the urban population of Porto aged 45 years or over. Six hundred and eighty-four participants were included. Data were collected by a structured clinical interview with a physician, ECG and a transthoracic M-mode and 2D echocardiogram. The metabolic syndrome was defined according to ATPIII-NCEP. The association between the number of features of the metabolic syndrome and the cardiac structural and functional abnormalities was assessed by 3 multivariate regression models: adjusting for age and gender, adjusting for the 10-year predicted risk of coronary heart disease by Framingham risk score and adjusting for age, gender and systolic blood pressure.There was a positive association between the number of features of metabolic syndrome and parameters of cardiac structure and function, with a consistent and statistically significant trend for all cardiac variables considered when adjusting for age and gender. Parameters of left ventricular geometry patterns, left atrial diameter and diastolic dysfunction maintained this trend when taking into account the 10-year predicted risk of coronary heart disease by the Framingham score as an independent variable, while left ventricular systolic dysfunction did not. The prevalence of left ventricular diastolic dysfunction, and the mean left ventricular mass, left ventricular diameter and left atrial diameter increased significantly with the number of features of the metabolic syndrome when additionally adjusting for systolic blood pressure as a continuous variable.Increasing severity of metabolic syndrome was associated with increasingly compromised structure and function of the heart. This association was independent of Framingham risk score for indirect indices of diastolic dysfunction but not systolic dysfunction, and was not explained by blood pressure level. The metabolic syndrome is associated with an increased risk of coronary heart disease  which inGiven the increasing prevalence of heart failure and its consequences – impaired quality of life , frequenThere has been much debate about the putative usefulness of the metabolic syndrome in cardiovascular risk prediction, namely whether it adds information to that provided by its individual components and, on the other hand, whether it adds to alternative risk prediction tools -14, amonThe aim of this study was therefore to assess whether we could identify a graded association between increasing number of components of the metabolic syndrome and cardiac structural and functional abnormalities in a cross-sectional study of urban Portuguese adults. Additionally, we intended to investigate whether this association was independent of predicted risk of coronary heart disease by the Framingham risk score.As part of a health and nutrition survey of a representative sample of the adult population of Porto, Portugal, all participants aged ≥ 45 years and recruited from January 2001 to December 2003 were assessed with a systematic evaluation of parameters of cardiac structure and function. A detailed description of the study has been published . In brieParticipants were invited to visit our Department for an interview, which included questionnaires on demographic, behavioural and clinical data. After a 12-hour fast, a venous blood sample was collected. Serum glucose level was determined using routine enzymatic methods, and cholesterol and triglyceride levels were determined using standard enzymatic colorimetric methods ,19. HDL 3 - (LV end-diastolic diameter)3] - 13.6 [2.7 and fat-free mass, estimated according to the equations reported by Kuch et al [Echocardiograms were done by four cardiologists, using the same equipment (HP Sonos 5500) and recorded on videotape for later review by a single experienced cardiologist (C.A.L.), blinded to clinical data. Measurements of wall thicknesses and chamber dimensions were obtained according to the Penn convention and left ventricular mass was calculated as 1.04  - 13.6 . Left vech et al  using hech et al : IVRT > Participants were classified according to the stages of heart failure defined by the American College of Cardiology and American Heart Association : Stage AFeatures of the metabolic syndrome were defined according to the Adult Treatment Panel III of the National Cholesterol Education Program (ATPIII-NCEP) :1. Waist circumference > 102 cm in men and > 88 cm in women;2. Fasting serum triglycerides ≥ 150 mg/dl;3. High-density lipoprotein (HDL) cholesterol < 40 mg/dl in men and < 50 mg/dl in women;4. High blood pressure: systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg or antihypertensive drug treatment;5. High glucose levels: fasting serum glucose ≥ 110 mg/dl or clinical diagnosis of diabetes.Due to missing data on key variables for the definition of the metabolic syndrome , only 684 participants were available for analysis.th and 75th centiles for clearly non-normally distributed variables. Counts and proportions are reported for categorical variables. We studied cardiac structural and functional abnormalities among participants according to the number of components of the metabolic syndrome. The association between the degree of the metabolic syndrome and cardiac structural and functional abnormalities was assessed by calculating mean values of the dependent cardiac variables by linear regression, adjusting first for age and gender, then for 10-year predicted risk of coronary heart disease by Framingham risk score (continuous variable) and finally for age, gender and systolic blood pressure, considering that the reported association might be explained by increasingly high blood pressure. Likewise, adjusted proportions of categorised cardiac variables were estimated using logistic regression by applying population averages of the cofactors to the regression coefficients derived in the regression model. To analyze a graded effect, we included the concurrently present number of syndrome components as a continuous independent variable in the multiple regression models.Data are described as mean and standard deviation for normally, or as median and corresponding 25Table Concurrence of various components of the metabolic syndrome increased significantly with age and was more frequently found in women. It was also significantly and strongly associated with predicted 10-year risk of coronary heart disease by the Framingham score.There was a positive association between the degree of the metabolic syndrome – assessed as number of concurrently present components – and parameters of cardiac structure and function, with a consistent and statistically significant trend for all cardiac variables considered Table . These aThe prevalence of left ventricular diastolic dysfunction, and the mean left ventricular mass, left ventricular diameter and left atrial diameter increased significantly with the number of features of the metabolic syndrome when additionally adjusting for systolic blood pressure as a continuous variable Figure .In this study, we found an association between systolic and diastolic dysfunction and the degree of metabolic syndrome, with the frequency and/or the severity of systolic and diastolic dysfunction increasing with the number of features of the metabolic syndrome. Importantly, early asymptomatic stages of cardiac dysfunction increased progressively with the severity of the metabolic syndrome, independently of systolic blood pressure.Previous studies demonstrated an association between insulin resistance and heart failure . In a neFrom the clinical and public health perspective, it has been questioned whether metabolic syndrome improves cardiovascular risk prediction, beyond previously used tools such as the Diabetes Predicting Model for type 2 diabetes or Framingham risk score for coronary heart disease -14, 32--32-34. SIn comparison with previous studies, this study additionally shows that the association is not fully explained by the level of blood pressure, and that the metabolic syndrome may help predict an increased cardiovascular risk beyond that predicted by the more frequently used tool Framingham risk score.The main limitation of the present study is the relatively small sample size expectedly leading to few outcomes in certain categories, such as left ventricular systolic dysfunction, and weakening assessment of interactions between the factors of the metabolic syndrome, which would be most relevant in trying to document synergistic effects. The cross-sectional design is also not the ideal approach to assess causality. Advanced cachectic heart failure patients have a particularly high fatality rate and are most likely underrepresented in a dwellers sample like ours (length bias) and less likely to participate if selected . An overestimation of the strength of the association with heart failure could also result from the "reverse epidemiology" of cardiovascular risk factors , becauseIn summary, symptomatic heart failure and several cardiac structural and functional abnormalities regardless of symptoms increased progressively with increasing degree of metabolic syndrome. This association was independent of 10-year predicted risk of coronary heart disease by Framingham risk score for indirect indices of diastolic dysfunction but not systolic dysfunction.The author(s) declare that they have no competing interests.AA, PB, ACS, CAL, HB have made substantial contributions to conception and designAA, PB, PBA, ACS have made substantial contributions to acquisition of dataAA, PB, CAL, HWH, HB have made substantial contributions to analysis and interpretation of dataAA, HWH, HB have been involved in drafting the manuscript and revising it critically for important intellectual contentPBA, ACS, CAL have been involved in revising the manuscript critically for important intellectual contentAll authors have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:


Danio rerio is an important model system for drug discovery and to study cardiovascular development. Using a laser-scanning confocal microscope, we have developed a non-invasive method of measuring cardiac performance in zebrafish embryos and larvae that obtains cardiovascular parameters similar to those obtained using Doppler echocardiography in mammals. A laser scan line placed parallel to the path of blood in the dorsal aorta measures blood cell velocity, from which cardiac output and indices of vascular resistance and contractility are calculated.The zebrafish This technique, called laser-scanning velocimetry, was used to quantify the effects of pharmacological, developmental, and genetic modifiers of cardiac function. Laser-scanning velocimetry was applied to analyze the cardiovascular effects of morpholino knockdown of osmosensing scaffold for MEKK3 (OSM), which when mutated causes the human vascular disease cerebral cavernous malformations. OSM-deficient embryos had a constricted aortic arch and markedly increased peak cell velocity, a characteristic indicator of aortic stenosis.These data validate laser-scanning velocimetry as a quantitative tool to measure cardiovascular performance for pharmacological and genetic analysis in zebrafish, which requires no specialized equipment other than a laser-scanning confocal microscope. Danio rerio are widely used in genome-wide screens to identify genes that regulate the development and function of the vertebrate cardiovascular system [The zebrafish r system -3. Zebrar system ,5. A beaWe first demonstrate that laser-scanning velocimetry is a sensitive and precise tool for measuring the physiological changes during normal cardiovascular development and drug-induced cardiotoxicity. We then use laser-scanning velocimetry to evaluate the cardiovascular function of zebrafish embryos with reduced expression of osmosensing scaffold for MEKK3 (OSM) – a scaffold protein, whose mutation in humans leads to the development of a vascular disorder called cerebral cavernous malformations . Using mLinescans are images constructed with laser-scanning microscopes by repeatedly imaging a one pixel-wide line. Whereas traditional two-dimensional images provide spatial information in both the x- and y-dimensions, linescans contain spatial information in the x-dimension and temporal information in the y-dimension. When the scan line is placed across a vessel, either perpendicular or parallel to the flow of blood, the resulting linescan images contains information about the dynamics of circulation Figure . BecauseMany diagnostic indices of cardiac function can be calculated from a continuous measurement of the velocity of blood cells flowing through the dorsal aorta Table . While cA scan line placed in the middle of the vessel was found to be optimal for velocimetry measurements because the flux of cells crossing the line is much higher than at the extreme periphery  yielded velocity-versus-time profiles similar to those obtained by continuous-wave Doppler echocardiography in mammals Figure  and 2b. Stroke volume, the volume of blood ejected by the heart in one beat, can be determined by integrating the continuous velocity versus time graphs obtained by laser-scanning velocimetry and multiplying by the cross-sectional area of the aorta. Since the heart is a pump, stroke volume is an excellent functional measure of cardiac performance. Estimates of stroke volume decreased significantly over a concentration range of tricaine that caused little change in heart rate Figure  and 2f. Absolute measurements of stroke volume can be obtained when the scan line is placed along the outflow tract prior to any arterial branches. While it is not always possible to image the outflow tract prior to arterial branching, an estimate of stroke volume can be obtained by measuring cellular velocities along the dorsal aorta immediately caudal to the fusion of the lateral dorsal aortas Figure . RelativDanio rerio matures into an adult-like morphology by five days post fertilization (dpf). We used laser-scanning velocimetry to correlate differences in cardiac function with developmental changes in heart structure . Quantification of cell flux using perpendicular linescan images indicated that erythrocyte flux in OSM-deficient embryos was reduced to 55% that of control embryos, and this phenotype was almost completely restored by co-injection of ccm2/osm mRNA . One characteristic change observed in patients with aortic stenosis is an increase in peak velocity because the constricted passage acts as a nozzle to increase the velocity of blood flowing through it . Laser-sDespite the widespread use of zebrafish for understanding cardiac development and function, few quantitative tools exist to measure functional cardiovascular phenotypes in embryos. Laser-scanning velocimetry meets this need, using a standard laser-scanning confocal microscope for non-invasive measures of cardiac function. High-resolution ultrasound has been used to measure cardiovascular performance in adult zebrafish , and tecLaser-scanning velocimetry provides quantitative and precise measures of several indices of cardiac performance  embryos used for velocimetry measurements and morpholino injections were obtained by natural spawning of a wild-type AB* line. Embryos were raised at 28.5°C in 30% Danieau solution2, 1.5 mM HEPES pH 7.6). Zebrafish were handled in accordance with IACUC approved protocols.Zebrafish (Embryos for imaging were placed in a 4-well coverglass-bottom chamber slide (Lab-Tek) in 30% Danieau solution containing the anaesthetic tricaine at a final concentration of 100 μg/ml or as indicated. After a three-minute delay to ensure a steady-state level of anaesthesia, images were captured using an Olympus Fluoview FV1000 laser-scanning microscope with an Olympus PlanApo N (60 ×/1.42 oil) lens using DIC optics. Scan lines were oriented parallel to the flow of blood within the dorsal aorta, just above the yolk ball. Approximately 15,000 lines were acquired per sample at a rate of 0.488 ms/line allowing a maximum velocity of 4.10 cm/s to be measured. Using a 20 μm line and the optical system described above, a minimum scan rate of 8 ms/line is required to record the maximum cellular velocity of 0.25 cm/s observed in these experiments. Cell paths within parallel linescans were traced using the NeuronJ plugin v.1.1.0 for ImageJ v.1.37 . High-quA single zebrafish embryo at 30 hpf was placed in a coverglass-bottom chamber slide containing 30% Danieau solution without tricaine. Parallel linescans were acquired from the free-floating, non-anesthetized embryo to obtain baseline values of an untreated embryo. After a baseline image was collected, the 30% Danieau was sequentially replaced with 30% Danieau solutions containing increasing concentrations of tricaine from 300 μM to 1 mM. After each solution change, the embryo was allowed to equilibrate with the drug for three minutes prior to imaging.Aaorta.) by the distance blood is pumped along the aorta in one beat (dx) (Equation 1).Borrowing principles from human ultrasonic Doppler Imaging, stroke volume and cardiac output were extracted from linescans of the dorsal aorta close to the heart, where there is little influence from peripheral vessels. Stroke volume (SV), the volume of blood ejected by the ventricle in one heartbeat, was determined by multiplying the cross sectional area of the aorta (daorta.) was measured from the x-dimension of the perpendicular linescan.Assuming a circular dorsal aorta, the cross-sectional area is given by Equation 2, where the diameter of the aorta .Substitution of Equations 2 and 3 into equation 1 gives the final equation for stroke volume (Equation 4).v(t)dt was approximated by calculating the area under the curve of a plot of velocity as a function of time for each heart beat using Origin v.6.0 . Cardiac output, the volume of blood ejected by the heart in one minute, was calculated by multiplying the stroke volume by the heart rate (Equation 5).The integral of Heart rates were determined by dividing 60 seconds by the average duration of a heart beat, which was measured by the average peak-to-peak distance of the velocity-versus-time profile.Danio rerio ccm2/osm mRNA were purchased from Gene Tools, Inc. Two OSM-specific morpholinos were used . Morpholino sequences were designed from the +75 to -25 bp region surrounding the initiating ATG of Danio rerio ccm2/osm cDNA (IMAGE Clone 7396516) by Gene Tools, Inc. A non-targeting morpholino or 1× Danieau solution 2, 5 mM HEPES pH 7.6) were used as controls. Unless otherwise specified, morpholinos were dissolved to 2 ng/nl in 1× Danieau solution. Approximately 5 nl of morpholino solution were injected into embryos between the 1- and 4-cell stage. Repression of OSM protein was confirmed by immunoblotting using a rabbit polyclonal anti-OSM antibody produced against recombinant full-length mouse OSM [Morpholino oligonucleotides targeting the translation initiation site of the ouse OSM .ccm2/osm mRNA was synthesized using Mmessage Mmachine T7 kit (Ambion) from the coding region of a Danio rerio OSM cDNA (IMAGE Clone 7396516). Embryos between the 1- and 4-cell stages were injected with 5 nl ccm2/osm mRNA (20–100 pg/nl) together with an OSM morpholino that targets the 5' UTR (MO#1) at 2–4 ng/nl).Capped, in vitro transcribed silico microangiography is an image processing approach to representing motion in a series of two-dimensional images. A DIC movie of cells flowing through the vasculature of anesthetized embryos at 28 or 48 hpf was collected as a set of 100 12-bit tiff images recorded at 15 ms intervals .t. Using Metamorph IP software (Molecular Devices) a difference image stack was created by dividing adjacent time points; that is, for time t = n, Difference.n = .n+1. *1000/.n.. The resultant difference stack has intensity values only where changes occurred from one time point to the next. Maximum intensity projections through the differences stack produce an image correlating to blood cell movement over the duration of the original movie.In in silico microangiography, and assisted in drafting the manuscript. LS performed zebrafish husbandry and morpholino knockdown experiments. KH assisted in developing image acquisition protocols. EL assisted with zebrafish husbandry and morpholino knockdown experiments. GLJ participated in the design of the study, coordinated essential collaborations, and assisted in drafting the manuscript. All authors read and approved the final manuscript.MHM and NS conceived of the study. MHM performed zebrafish husbandry, morpholino knockdown and drug treatment experiments, acquired images, wrote the laser-scanning velocimetry data analyzer software, analyzed linescan images and drafted the manuscript. NS developed image acquisition protocols, processed images for linescans, performed position effects. Dependence of cardiac performance measurements on scan line positionClick here for filecardiovascular analysis of OSM morphant. Decreased circulation in OSM-deficient embryos only affects the aortic archClick here for filerestricted circulation movie. Restricted blood flow through constricted aortic arch of control and OSM morpholino-injected embryoClick here for file


The most recent treatment option of medically refractory heart failure includes cardiac resynchronization therapy (CRT) by biventricular pacing in selected patients in NYHA functional class III or IV heart failure. The widely used marker to indicate left ventricular (LV) asynchrony has been the surface ECG, but seems not to be a sufficient marker of the mechanical events within the LV and prediction of clinical response. This review presents an overview of techniques for identification of left ventricular intra- and interventricular asynchrony. Both manuscripts for electrical and mechanical asynchrony are reviewed, partly predicting response to CRT. In summary there is still no gold standard for assessment of LV asynchrony for CRT, but both traditional and new echocardiographic methods have shown asynchronous LV contraction in heart failure patients, and resynchronized LV contraction during CRT and should be implemented as additional methods for selecting patients to CRT. The most recent treatment option of medically refractory heart failure includes cardiac resynchronization therapy (CRT) by biventricular pacing in selected patients in NYHA functional class III or IV heart failure (HF) caused by idiopathic dilated (DCM) or ischemic cardiomyopathy, with QRS duration ≥ 130 milliseconds, left ventricular (LV) end-diastolic diameter ≥ 55 mm, and ejection fraction ≤ 35% . HoweverThe acute improvement of LV performance by CRT was demonstrated by reduction of capillary wedge pressure and an improvement in peak dp/dt without increase in myocardial oxygen consumption -14. LongThe main focus of this manuscript is to review LV asynchrony, and to present an overview of techniques for identification of left ventricular intraventricular and interventricular asynchrony.The widely used marker to indicate LV asynchrony has been the surface ECG. The rational for that, is that the electrical delayed stimulation may lead to a mechanical delay of the respective LV areas. In LBBB the lateral free wall is activated later than the interventricular septum and thus leads to a delayed contraction of LV free wall. This surrogate marker represented by LBBB is one of the criteria indicating implantation of CRT . It is sIn 29 patients Alonso et al showed that reducing the QRS duration by CRT correlated to a positive clinical response suggesting a hemodynamic improvement associated with narrowing of QRS indicating reduction of the mechanical asynchrony of LV contraction. The study concluded even that the optimal placement for hemodynamic LV improvement of the right and LV leads would be those sites that could induce the greatest shortening of QRS duration . HoweverAn additional method to elucidate the intraventricular activation pattern in HF patients eligible for CRT is electroanatomical activation mapping.  In 26 patients Peichl et al. showed that the surface ECG is of limited value to describe the complex conduction disturbance of the LV . They foAlso Yu et al. showed that endocardial electrical LV activation sequences was variable among 7 HF patients with LBBB . LambiasAsynchronous contraction of LV was demonstrated in patients with DCM with intraventricular conduction delay by Curry et al., who used MRI . MRI is  By using gated equilibrium radionuclide angiography and Fourier phase analyses Fauchier et al. demonstrated in 103 patients  with DCM that QRS duration was related to both interventricular and intraventricular asynchrony . FurtherAnother radionuclide angioscintigraphy study by Toussaint JF et al.  in 21 patients showed that resynchronization by CRT between LV apex and base which persisted up to 12 months was also associated with a persisting improvement in LV systolic function . The samKerwin et al. used gated blood pool scintigraphy in 13 patients to demonstrate asynchronous contraction of LV and to show the resynchronizing effect of CRT . DCM witEchocardiography is an essential method to diagnose HF and is also used to evaluate the effect of treatment to improve cardiac performance. The echocardiographic measurement of LV fractional shortening by M-mode and EF measured from two-dimensional images by using Simpsons method in accordance with the recommendations of the American Society of Echocardiography Committee, are widely used parameters for cardiac evaluation . An addi150 ms  predicted response to CRT in terms of > 15 % reduction of left ventricular end-systolic volume index in 79% of the patients. The authors demonstrated the prediction of reverse remodelling by septal-to-posterior wall motion delay to be more precise than the QRS duration (accuracy 85% vs. 65%) Using the septal-to-posterior wall motion delay in M-mode recordings from the parasternal short axis view Pitzalis et al. demonstrated in 20 patients that a septal-to-posterior wall motion delay  of  ≥ 130 ms and QRS duration   ≥. The samThe septal-to-posterior wall motion delay in M-mode recordings can also be examined in the parastrenal long axis view and a decrease of the posterior delay during CRT can be shown .The measurement of interventricular electromechanical delay using pulsed Doppler imaging was examined by Rouleau  et al in 35 patients with DCM . A QRS wVarious echocardiographic parameters of ventricular asynchrony were examined by Bordachar et. al in 41 patients undergoing CRT. Changes in interventricular asynchrony, defined as the difference between the aortic and pulmonary pre-ejection delays and determined as the time from the onset of the QRS complex to the beginning of each respective systolic ejection by pulsed wave Doppler imaging were not correlated with changes in cardiac output, whereas several TVI modalities could confirm high correlation with hemodynamic changes .The use of pulsed tissue velocity Doppler imaging by Ansalone et al in 21 non ischemic patients receiving CRT demonstrated a reduction of asynchronous contraction of LV basal segments. After CRT, LV performance improved significantly in patients with better LV resynchronization evaluated by TVI, whereas the QRS narrowing was not predictive of this functional improvement .The effect of inflow based AV optimization adopted from use in DDD pacing  showed iFunctional mitral regurgitation is reduced by CRT in patients with HF and LBBB shown in 24 patients by Breithardt et al, explained by a more coordinated LV contraction and due to the increased closing force (left ventricular systolic pressure rise) .A new echocardiographic method based on contrast variability imaging was used in 10 patients by Kawaguchi et al. to quantify asynchrony and magnitude of resynchronization achieved by CRT . The metA semiautomatic border detection method based on the fact that each region of the ventricular endocardial wall undergoes a periodic cycle of inward and outward displacement was performed in 34 patients by Breithardt et al. The authors showed a septal-lateral resynchronization during CRT by using this echocardiographic phase analysis of radial endocardial wall motion predicting an acute hemodynamic response (dp/dt) .Three dimensional (3 D) echocardiography has been used by Kim et al. to document hemodynamic improvement by CRT  and additionally to identify LV segments with asynchrony . The latThe excellent time resolution of c-TVI by using a postprocessing procedure is used in several studies to demonstrate the regional time aspect of LV contraction. In addition to the high time resolution another main advantage of c-TVI method is the possibility of comparing the contraction pattern of different LV regions simultaneously from the recording. Synchronicity of LV contraction pattern in the structurally normal heart is demonstrated  and compared to HF patients with bundle brunch block  showing a significant asynchrony within the LV in the HF patients ,47. FigComparing surface ECG with the mechanical contraction pattern in HF patients showed that neither QRS duration nor QRS pattern predicts the mechanical asynchrony. Even HF patients with normal QRS width can have significant LV asynchronous contraction ,49. The Using c-TVI has shown resynchronization during CRT, both as measurement of regional contraction timed to the QRS complex  by Yu et al. and measured as an absolute resynchronization of the contraction of LV septum and the lateral free wall by Schuster et al. and by Bax et al -54. One The measurement of LV segment shortening or lengthening (strain) is also used to demonstrate resynchronization during CRT, but the more angle dependency of strain compared to TVI allows only the measurement of relative resynchronization because of the fact that the different regions have to be examined in separate recordings. However a resynchronization effect by CRT is shown using the strain method by Breithardt et al .The above mentioned manuscripts deal partly with concordance or disconcordance of electrical and mechanical markers of asynchrony. Despite the findings of angioscintigraphic asynchrony related to the QRS complex , in summ


Ca2+ ions enter through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions "trigger" the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle.In the standard accepted concept, contractility is the intrinsic ability of heart muscle to generate force and to shorten, independently of changes in the preload or afterload with fixed heart rates. At molecular level the crux of the contractile process lies in the changing concentrations of Ca2+ entry via voltage-gated Ca2+ channels provides cardiac cells with a highly sophisticated short-term system for the regulation of intracellular Ca2+ homeostasis. An increased stimulation rate increases the force of contraction: the explanation is repetitive Ca2+ entry with each depolarization and, hence, an accumulation of cytosolic calcium. As the heart fails, there is a change in the gene expression from the normal adult pattern to that of fetal life with an inversion of the normal positive slope of the force-frequency relation: systolic calcium release and diastolic calcium reuptake process is lowered at the basal state and, instead of accelerating for increasing heart rates, slows down. Since the force-frequency relation uncovers initial alteration of contractility, as an intermediate step between normal and abnormal contractility at rest, a practical index to measure it is mandatory.In the past, several attempts were made to transfer the pure physiological concept of contractility, expressed in the isolated myocardial fiber by the maximal velocity of contraction of unloaded muscle fiber (Vmax), to the in vivo beating heart. Suga and Sagawa achieved this aim by measuring pressure/volume loops in the intact heart: during a positive inotropic intervention, the pressure volume loop reflects a smaller end-systolic volume and a higher end-systolic pressure, so that the slope of the pressure volume relationship moves upward and to the left. The pressure volume relationship is the most reliable index for assessing myocardial contractility in the intact circulation and is almost insensitive to changes in preload and after load. This is widely used in animal studies and occasionally clinically. The limit of the pressure volume relationship is that it fails to take into account the frequency-dependent regulation of contractility: the frequency-dependent control of transmembrane CaMeasuring end-systolic elastance for increasing heart rates is impractical: increasing heart rates with atrial pacing has to be adjunct to the left ventricular conductance catheter, to the left ventricular pressure catheter, to the vena cava balloon, and to afterload changes. Furthermore, a noninvasive index is needed. Noninvasive measurement of the pressure/volume ratio for increasing heart rates during stress in the echo lab could be the practical answer to this new clinical demand in the current years of a dramatic increase in the number of heart failure patients. When ~3,500,000,000 years ago prokaryotes appeared, the selection of an intracellular messenger preceded the appearance of ionic channels of enveloping lipid membranes.2+ channels were activated by mechanical stimuli, present but slow and low efficient in reactions. But faster reactions are essential for survival.Calcium had conformational and stechiometric advantages to be chosen as an intracellular messenger (=good messenger and modulator of intracellular processes), due to its high coordination number and irregular coordination geometry. If calcium was the first intracellular messenger, ionic channels for calcium had to appear for the cells to maintain constant intracellular calcium concentrations . Ionic cWhen ~1,500,000,000 years ago the hydrosphere became aerobic and the primitive unicellular organisms developed mechanisms of energy production, eukaryotes developed active transport and voltage-gated channels as a result of selection for faster signaling .2+ channels subsequently extends the effect to the entire cell by voltage gated Ca2+ channels.When in this new evolutional cell a mechanical stimulus involving a portion of the membrane hits the cell, a depolarization produced by the mechanic-sensitive Ca2+ channels would increase the speed of the depolarizing wave, but would have compromised the role of Ca2+ as modulator of intracellular function.With the appearance of multicellularity, even faster signaling had to appear for life competition. As a possible solution to this new requirement, increase in density of Ca+ channels, capable of carrying greater ionic fluxes without interfering with intracellular processes, would be evolutionarily favorable. And, in fact, this model was the one chosen by evolution in nerve cells: earlier selection of Na+ channels to sustain potential changes [2+ channels mediated maximum velocity is equal to 0.10 m/sec. For Na+ channels mediated max. velocity is 3 m/sec.The appearance of Na changes . In fact2+ ions for contraction came from outside the cell.In primitive muscle fibers all the activating Ca2+ channels would increase the speed of the depolarizing wave and at the same time would speed up the activation of the contractile machinery.High density of Ca2+ ions for contraction, muscle fibers acquired the capability of stronger contraction with less energy consumption. As for force of contraction, also signaling speed was a problem in muscle cells: but in these cells less pronounced advantages are provided by an exclusively Na+-channels-based membrane potential changes. The simultaneous presence of fast Na+ channels for conduction function and slow Ca2+ channels for beginning the contraction mechanism through inward calcium flow was maintained [But with the evolutionary appearance of intracellular calcium stores (sarcoplasmic reticulum) in supplying Caintained .At the present evolutionary state, once the impulse has formed in the sinus node, it spreads very rapidly throughout the atrium to reach the atrioventricular (AV) node and ventricles. In atrial tissue, the pattern of the action potential is dominated by a fast sodium channel. The action potential duration of atrial tissue is short when compared to that of ventricles, and the inward flow of calcium ions is less, with a lower force of contraction developed in the atria and lower activity of L-type calcium channels. Conduction of the wave of depolarization is rapid through conduction tissues where the action potential goes through fast sodium channel activity, whereas conduction is lower through the ventricular myocardium, where there is chiefly calcium channel activity with a slower rate of depolarization.2+ entry via voltage-gated Ca2+ channels provides mammalian cardiac cells with a highly sophisticated short-term system for regulation of intracellular Ca2+ homeostasis.Ultimately developed, the frequency-dependent control of transmembrane Ca2+ entry through Ca2+ channels by high rates of beating (HFIUR of ICa) is involved in the frequency-dependent regulation of contractility: this process is crucial in adaptation to exercise and stress [Up-regulation of Cad stress ,5. This 2+ ions in the myocardial cytosol.The crux of the contractile process lies in the changing concentrations of Ca2+ ions through the voltage-sensitive L-type Ca2+ channels, acting as a trigger for the release of Ca2+ ions from the sarcoplasmic reticulum (SR).Crucial features are  entry ofRelatively small amounts of calcium ions actually enter and leave the cell during each cardiac cycle, whereas much larger amounts move in and out of the sarcoplasmic reticulum. Calcium-induced calcium release explains most of the current available data. This process elevates by about tenfold the concentration of calcium ions in the cytosol. The result is the increasing interaction of calcium ions with troponin C to trigger the contractile proteins  Fig. 2)2).2+ ions arrive at troponin C (TnC). As more and more myofibers enter the contracted state, pressure development in the left ventricle proceeds. The interaction of actin and myosine increases, and cross-bridge cycling augments. As long as enough calcium ions are bound to troponin C, many repetitive cycles of this nature occur. The enhanced force development in response to a greater calcium ion concentration is due to recruitment of additional cross bridges.Left ventricular pressure starts to builds up when the arrival of calcium ions at the contractile proteins starts to trigger actin-myosine interaction. The thin actin filament interacts with the myosin head when CaWhen calcium ions depart from their binding sites on troponin C, cross-bridge cycling cannot occur and the diastolic phase of the cardiac cycle sets in.2+ ATPase) pump that constitutes nearly 90% of the protein component of the SR. Calcium taken up into the SR by the calcium uptake pump is stored within the SR before further release. To balance the small quantity of calcium ions entering the heart cell with each depolarization, a similar quantity must leave the cell. First, calcium can be exchanged for sodium ions entering by the Na+/Ca2+ exchange and, second, an ATP-consuming sarcolemmal calcium pump can transfer calcium into this extra cellular space against a concentration gradient.At the end of systole, calcium stops interacting with troponin C and calcium ions are taken up into the SR by the activity of the SERCA  when the fiber is stretched and the sarcomere length increases, for any given number of Ca2+ ions binding to TnC, there is greater force development. Length sensitization of the sarcomere explains how the sarcomere can "upgrade itself" to a higher force-length curve [The preload is the load present before contraction has started, at the end of diastole. When the preload increases, the left ventricle distends during diastole, and the stroke volume rises according to Starling's law . The proth curve .The afterload is the systolic load on the left ventricle after it has started to contract.Increased afterload means that an increased intraventricular pressure has to be generated first to open the aortic valve and then during the ejection phase .In the nonfailing heart, the left ventricle can overcome any physiological acute increase in load ."Contractility is the inherent capacity of the myocardium to contract independently of changes in the preload or afterload. Whatever the problems of measuring it, contractility remains an essential corner concept to separate the effects of a primary change in loading conditions from an intrinsic change in the force of contraction ". It is - The myocardial fiber number involved in the contraction process.- The maximal velocity of myocardial fibers shortening.Increased contractility, is reflected in higher myocardial fiber shortening velocity, with a more highly developed tension peak and a steeper pressure rise, when preload, afterload, and heart rate are constant: in the cytosol calcium release is more and faster from SR with a higher cytosol calcium concentration in systole: more troponin is activated from higher levels of calcium with more acitn-myosin cross-bridges in the time unit, and ultimately myocardial fiber contraction is more and faster.Decreased contractility is reflected in lower myocardial fiber shortening velocity, with a lower tension peak and a blunted pressure rise, when preload, after load, and heart rate are constant: in the cytosol calcium release is less and slower from SR with a lower cytosol calcium concentration in systole: less troponin is activated from lower levels of calcium with less actin-myosin cross-bridges in time unit, and ultimately myocardial fiber contraction is less and slower.Contractility expressed in the isolated myocardial fiber is the maximal velocity of contraction of unloaded muscle fiber (Vmax). This value is defined as the maximal velocity of contraction, when there is no load on the isolated muscle. This strictly preload and after load independent index, fulfills the theoretical requirements for contractility quantification and greatly contributes to this research field ,10. NeveIn the past attempts were made to transfer the purely physiological concept of contractility expressed in the isolated myocardial fiber by the maximal velocity of contraction of unloaded muscle fiber (Vmax), to the in vivo beating heart. Suga and Sagawa achieved this aim by measuring pressure/volume loops in the intact heart: during a positive inotropic intervention, the pressure volume loop reflects a smaller end systolic volume and a higher end-systolic pressure, so that the slope of the pressure volume relationship (Ees) moves upward and to the left ,12. Ees This is widely used in animal studies and occasionally clinically .A now-time conductance catheter is used for human studies . The metFocusing on cytosol calcium concentrations along the pressure-volume loop, Fig  in diastMore highly developed systemic pressure simultaneously with lower end-systolic volume is typical of higher contractility. Counter-directional changes identify compromised contractility.If end-systolic volume is measured for different end-systolic pressure values, sequential end systolic pressure/volume values can be recorded . The upper left corners  of the loops define the LV end-systolic pressure-volume relation (ESPVR). Fig.  The ESPVContractility is quantified by the angular coefficient (or slope) of the ESPVR relation: the Ees (end systolic elastance) Fig. .The heart contractility dependence on increasing heart rates has been established in most mammalians.The inherent ability of ventricular myocardium to increase its strength of contraction independently of neurohormonal control, in response to an increase in contraction frequency is known as frequency treppe  Fig. 6)6). In huHeart rate is a leading determinant of cytosol calcium concentration, and strictly linked to the contractility levels. In the healthy heart, a frequency increase up to 180 beats per minute provides systolic faster calcium SR release (increased contractility or developed force) and diastolic faster SR calcium reuptake (positive lusitropic effect).2+ entry through Ca2+ channels by high rates of beating (HFIUR of ICa) is involved in the frequency-dependent regulation of contractility: this process is crucial in adaptation to exercise and stress [Up-regulation of Cad stress . This reThis property has been definitively established in the human heart in experimental settings using cardiomyopathic myocardial strips.Measurements of twitch tension in isolated left-ventricular strips from explanted cardiomyopathic hearts compared with non-failing hearts show reduction in peak rates of generation and relaxation of twitch tension and a decrease in slope of tension rate vs. contraction frequency ,16 Fig..negative treppe at contraction frequencies above about 100 bpm.The FFR of these failing groups both exhibit a Presence of a negative treppe in the working range of heart rates may constitute an additional liability beyond mere depression of the wall tension since this may contribute to an accelerated progression of heart failure. In patients in end stage failure the peak of the FFR occurs at such a low frequency that there is a negative treppe over the entire in vivo range of heart rates. The contraction frequency at which the FFR begins its descending limb ("optimum stimulation frequency") declines progressively in the order: atrial septal defect, coronary artery disease, diabetic myopathy, mitral regurgitation, dilated cardiomyopathy. This suggests that a correlation between severity of myocardial disease and optimum contraction frequency may exist ,16.In more severe heart failure the peak of the FFR is shifted sufficiently to lower frequencies so that it has a negative slope over the entire range of in vivo heart rates . The weakening of contractile strength as heart rate rises suggest the possibility that in vivo, a sudden increase in heart rate could predispose the ventricle to being stretched by venous return.While the FFR is well known in the physiological lab ,17,18, w"As the ventricle fails, there is a change in the ventricular gene expression pattern from the normal adult pattern to that normally observed only during fetal life. There is a down regulation of the calcium uptake pump (SERCA2) and of the fast-contracting myosin heavy chain. The fetal program may be activated from cytosolic calcium overload, by adding phosphate groups to enzymes that normally inhibit the fetal program " Fig. 88.+/Ca2+ exchange, so that the diastolic levels rise, as does the diastolic tension.Changes in the calcium cycle are fundamental to the impaired contractile performance of the failing heart. The SR calcium stores are severely depleted because of the combined effects of depressed calcium uptake into the SR resulting from decreased SERCA activity, both down-regulated and inhibited. Thus, the calcium ions entering with depolarization are unable to trigger the release of enough calcium to generate a normal calcium transient Fig. . There iMuscle strips prepared from patients with severe heart failure behave very differently from normal muscle, in that there is hardly any response to an increased stimulation frequency. Whereas in strips from normal hearts, optimal force development is reached at rates of about 150 to 180 beats/min, in patients with cardiomyopathy an increased heart rate produces a decreased twitch tension Fig. . In addi2+ entry via voltage-gated Ca2+ channels provides mammalian cardiac cells with a highly sophisticated short-term system for regulation of intracellular Ca2+ homeostasis.This standard, historically accepted, rest-assessed contractility, is limited because it is an invasive index, but especially because it fails to take into account frequency-dependent regulation of contractility: ultimately developed in the evolutional scale, as a typical feature of more advanced mammalian species, absent in fetal life and in adults with heart failure-induced regression of the contractile mechanism, the frequency-dependent control of transmembrane CaThe impossibility of separating the cellular mechanism of contractility changes from those of load or heart rate is now clear. "Thus, there is a clear overlap between contractility, which should be independent of load or heart rate, and the effects of load and heart rate on the cellular mechanism. Hence, the traditional separation of inotropic state from load or heart rate effects as two independent regulators of cardiac muscle performance is no longer simple now that the underlying cellular mechanisms have been uncovered ." This tSince end-systolic elastance (Ees), expressing the slope of the in-vivo, end-systolic ventricular pressure vs chamber volume relation, is the most "foolproof' window into in vivo myocardial contractility, Ees should be measured at each heart rate step increase, as made by Liu and coworkers  Fig. 1010.But measuring Ees for increasing heart rates is impractical: increasing heart rates obtained with temporarily pacing has to be adjunct to the LV conductance catheter, the LV pressure catheter, the vena cava balloon, and to afterload changes. Proof of this is that only Liu  adopted If assessment of Ees is difficult under clinical conditions at fixed heart rates, assessment of Ees for increasing heart rates is much more difficult.A simpler approach was utilized by Feldman and co-workers  in DCM pNon-invasive methods -30 have This method is similar to the previously proposed ones but is totally noninvasive, with echocardiography used to assess LV volumes during exercise and cuff blood pressure to estimate peak systolic pressure as an index of end-systolic pressure -33.During  stress echocardiography continuous 2D echo monitoring is performed by protocol and blood pressure, ECG and left ventricular volumes are obtained at each step, providing the basic information required to build a force-frequency relation over a wide range of frequencies .This approach is based on serial assessment of these variables at different exercise steps so that the force-frequency pattern  can be assessed Fig .The patient undergoes transthoracic echocardiography at baseline and at each 10 beat frequency increase during stress. This is performed using conventional two-dimensional echocardiography and tissue harmonic imaging, and digitized on-line into a quad screen, cineloop format. Images are also recorded on half-inch S-VHS videotape. Left ventricular end-diastolic and end-systolic volumes are measured from apical four and two chamber view, by an experienced observer using the biplane discs-method ,36 Fig.. Only reOne investigator records all blood pressures at rest and during exercise during the study. The blood pressure recording is made using a manometer sphygmomanometer and the diaphragm of a standard stethoscope Fig. .To build the force-frequency relationship, the force is determined at each step as the ratio of the systolic pressure (cuff sphygmomanometer)/end-systolic volume index (biplane Simpson rule/body surface area). The force frequency relation is built off line Fig. . The sloThe critical heart rate (or optimum stimulation frequency) is the human counterpart of the treppe phenomenon; "in situ, the optimal heart rate is not only the rate that would give maximal mechanical performance of an isolated muscle twitch, but also is determined by the need for diastolic filling " Fig. 1This proposed approach allows the assessment of a theoretically robust and sophisticated index of left ventricular contractility with an absolute minimum extra-burden of data acquisition and analysis, since all the basic parameters  are routinely acquired during exercise stress echo testing . The extThese are all prerequisites for a larger scale testing in the clinical subsets in which the contractility information can be more important – such as patients with latent ventricular dysfunction  or advanNoninvasive measurement of pressure/volume relation (the Suga index) ,26,31 fo


Although a small percentage of patients with critical aortic stenosis do not develop left ventricle hypertrophy, increased ventricular mass is widely observed in conditions of increased afterload. There is growing epidemiological evidence that hypertrophy is associated with excess cardiac mortality and morbidity not only in patients with arterial hypertension, but also in those undergoing aortic valve replacement. Valve replacement surgery relieves the aortic obstruction and prolongs the life of many patients, but favorable or adverse left ventricular remodeling is affected by a large number of factors whose specific roles are still a subject of debate. Age, gender, hemodynamic factors, prosthetic valve types, myocyte alterations, interstitial structures, blood pressure control and ethnicity can all influence the process of left ventricle mass regression, and myocardial metabolism and coronary artery circulation are also involved in the changes occurring after aortic valve replacement. The aim of this overview is to analyze these factors in the light of our experience, elucidate the important question of prosthesis-patient mismatch by considering the method of effective orifice area, and discuss surgical timings and techniques that can improve the management of patients with aortic valve stenosis and maximize the probability of mass regression. Left ventricular pressure overload due to aortic valve stenosis (AS) leads to a marked hypertrophic response of the myocardium, which is probably an adaptative reaction aimed at normalizing the increased wall stress. Although a small percentage of patients with critical AS do not develop left ventricle (LV) hypertrophy, increased LV thickness is widely observed in conditions of increased afterload and is usually accompanied by a parallel deposition of new sarcomers. This compensatory response seems to maintain cardiac performance despite the high intracavitary systolic pressure ,2.AS is a common disorder and the most frequent acquired valvular disease in developed countries. The natural history of symptomatic patients is dismal, and even asymptomatic subjects with a significant stenosis face a risk of sudden death that has been reported to be ~1% per year ,4. Hyperfavorable remodeling) or deteriorate (adverse remodeling).What follows is an experience-based review of the factors involved, and the extent to which the myocardium itself may recover  and, as the majority of patients suffering increased mortality and morbidity due to aortic valve disorders are elderly , it is e75 years , and Gau finding . Using m surgery , but thee course . Univarie course ,19.et al. found that the LV hypertrophy index of females was less likely to regress incompletely [et al., female gender is a neutral factor whereas male gender adds one point: i.e. it increases the risk of post-AVR mortality and morbidity [et al. found that male gender was an independent predictor of LV mass regression after AVR with stentless bioprostheses [et al, using another type of stentless xenograft, found that it negatively affected LV mass regression [et al. indicate that 1-year LV mass index normalization is unrelated to gender [It is known that there is a gender-related difference in the development of pressure overload-induced LV hypertrophy: after adjusting for body surface area, females have less mass, more concentric hypertrophy, less wall tension, fewer alterations in passive elastic properties, higher ejection fractions and smaller LV volumes -22. The mpletely , and we mpletely ,19. In torbidity . On the ostheses  althoughgression . Howevergression ,21,25,26o gender .The hemodynamic advantage of AVR arises from its ability to minimize postoperative gradients and favor the normalization of LV mass and function but, although it intuitively seems to be quite important, the influence of hemodynamic variables on the extent of LV mass regression is controversial.2/m2. However, in clinical practice, post-AVR indexed EOA be less than this for a number of reasons: the size of the aortic annulus may be reduced because of calcifications, fibrosis, hypertrophy in the LV outflow tract, or because the structural support of the valve prosthesis may be quite bulky  and create a relative obstruction to flow. Moreover, the procedures for implanting an adequate prosthesis in a small and severely calcified aortic root  can be technically more difficult and often require a longer period of aortic cross-clamping. They may also be contraindicated in some situations: for example, the presence of heavy and extended calcifications around the coronary ostia does not allow root replacement and coronary artery reimplantation. Consequently, the perceived balance between the increased preoperative risk of the more complex operation needed to avoid a potentially suboptimal late clinical outcome due to a small prosthesis, and the chances of the patient experiencing meaningful long-term survival and quality of life determines the surgeon's choice of prosthesis type and size.A PPM is considered such when the effective orifice area (EOA) of the implanted prosthesis is less than that of the normal human valve: i.e. too small in relation to body surface area (BSA). This is a crucial parameter when evaluating the performance of valve substitutes: some authors have found that PPM leads to higher mortality rates ,28 and oThe true incidence of PPM can only be discovered using the EOA method to evaluate the prosthesis performance. This has repeatedly shown that the presence of PPM seriously hampers LV mass regression ,23, wher2/m2: for example, if the BSA is 1.7 cm2/m2, the minimum EOA is 1.7*0.85 = 1.44 cm2. The next step is verifying which of the available prostheses have the same or a larger EOA by looking at the widely available published data reported in the literature or provided by the manufacturers (Tab.1) [In conclusion, even in the presence of PPM, surgery usually improves hemodynamics. The extent of the improvement can be quite important and it is likely that the best results can be expected if PPM is completely avoided. Moreover, the relationship between gradients and indexed EAO is curvilinear, and the implications for a given patient are directly related to his/her original and final positions on the indexed EAO-gradient curve ,31. One  (Tab.1) ,30. In tet al. have reported the relative positions of different types of biological aortic valve substitutes on the exponential curve linking the transvalvular gradient and indexed EOA [2/m2 and are therefore on the steep portion of the curve, where the gradients are relatively high, whereas most patients with a stentless prosthesis and almost all of those undergoing an aortic homograft or pulmonary autograft have a larger indexed EOA and are on the flat portion of the curve, where the gradients are relatively low [et al. very recently [et al. found that the type of prosthesis did not predict the extent of postoperative LV mass regression in a long-term prospective study comparing stented porcine valves, stented pericardial prostheses, stentless porcine valves, and tilting and bileaflet mechanical prostheses [et al. found that 1-year normalization of the LV mass index studied by means of 3-D echocardiography was not related to valve type [et al. revealed no substantial advantage of stentless over stented valves in terms of the rate of LV mass regression [Pibarot exed EOA . The majvely low ,35. It irecently , Hanaymaostheses ; furtherlve type , and a tgression . Also ingression . In factet al. attributed pre-AVR findings of a reduced ratio at rest to myocardial stress and ischemia: i.e. a hypertrophy-induced imbalance between myocardial oxygen supply and demand. Consequently, a recovery in the post-AVR myocardial PCr-ATP ratio accompanied by a reduction in the LV mass index  may indicate that the reduced pressure overload has decreased the metabolic demand of the myocardium and improved coronary blood flow. The same authors also reported a statistically significant correlation between myocardial high-energy phosphate metabolism and LV diastolic function [It has been shown that LV hypertrophy can be accompanied by alterations in myocardial high-energy phosphate metabolism , but it function .et al. after 89 ± 21 months have shown that diastolic function normalizes only late after AVR [and interstitial fibrosis) is slow and may allow diastolic normalization only after its completion. Hess et al. previously made another important contribution based on endomyocardial biopsies obtained before and after surgery, and simultaneous echocardiography and pressure measurements, which showed that diastolic alterations persist after AVR due to increased myocardial stiffness [et al. because the follow-up of their study was longer.Doppler echocardiographic alterations in LV diastolic function occur early under conditions of pressure overload and precede the increase in LV mass. It is not clear whether the early reduction in afterload immediately after AVR (when hypertrophy is still present) also leads to improved diastolic function. Assessments of the time constant of relaxation, peak filling rate and the constant of myocardial stiffness by Villari fter AVR . This intiffness . Their fet al., who assessed the effect of residual pressure overload on the regression of LV hypertrophy and its relationship to diastolic function two months and four years after AVR [Another contribution comes from Ikonomidis fter AVR . Isovolufter AVR .et al. [vs 13%; p = 0.27), but increased after 10 years . Although the findings regarding the degree of LV mass reduction agree with those of other investigators [et al. did not make a specific analysis in relation to PPM (see Hemodynamic factors), but the patients with the worst diastolic function after 10 years had a significantly higher prosthesis gradient [In a recent longer follow-up study of a large and representative population of patients with a mean age of 67 ± 8.6 years, Gjertsson et al.  evaluatetigators ,40, the gradient . This inet al. performed transmural biopsies during AVR and found that the preoperative LV ejection fraction (EF) inversely correlated with myocyte nucleus volume and the fibrous tissue, muscle cell and LV mass indices. The LV mass index 18 months after AVR was significantly related to the above mentioned morphological parameters, thus suggesting that favorable remodeling after the removal of the hypertrophy trigger may be predetermined by profound changes in hypertrophied myocytes and ventricular fibrosis in many patients [et al. consistently found that LV mass index studied by means of 3-D echocardiography was less likely to normalize one year after AVR in patients with a reduced preoperative EF [et al. also failed to find any difference in preoperative EF between the patients with a normal or abnormal LV mass index after a longer follow-up [The effect of LV systolic function on mass regression has rarely been investigated in detail. Lund patients . Kühl etative EF . Our ownollow-up ,19. Howeollow-up .et al. have recently reported that CAD also has a negative impact on reverse remodeling, as revealed by means of the very promising method of intramyocardial MR imaging [Epicardial coronary arteries are larger in patients with aortic valve disease, but it has been reported that the appropriateness of their cross-sectional areas normalized on the basis of muscle mass is inadequate, and this contributes to explain the anginal symptoms that occur in AS: after AVR, reduced LV hypertrophy and smaller coronary arteries allow a more adequate match of coronary size and muscle mass . However imaging . They in imaging .et al. have conducted many studies in this field and, in 1998, published an interesting paper in which the findings from transmural biopsies taken during AVR were related to instrumental results after 18 months and to medium/long-term clinical outcomes [et al. can estimate this potential because of its significant correlation with the LV mass index and long-term survival [Many factors are recognized as influencing the sequence of biological events that lead to the development of LV hypertrophy. Hemodynamic load is the fundamental stimulus, but genotype, gender and other not fully determined genetic and environmental factors regulate the growth of LV mass by means of proto-oncogenes, growth factors, neurohormones and cytokines . The degoutcomes . Generaloutcomes . In partoutcomes . The potsurvival .et al. have recently found that, in addition to male gender, the extent of preoperative hypertrophy was the most important predictor of incomplete mass regression in a large study group and, like Gaudino et al. and Lund et al. previously [We have also searched for preoperative factors affecting absolute LV mass regression and, after an intermediate follow-up, we found that a higher preoperative LV mass was an independent non-hemodynamic predictor of greater regression (p < 0.0001), a finding that was also confirmed in patients with PPM ,19. Thiseviously ,17, sugget al. [Over the last 50 years, aortic valve surgery has made enormous strides towards the durable and physiological performance of aortic valve prostheses, thus allowing the restoration of normal LV structure and function. Interactions between surgeons and physicians have not only led to improvements in operative techniques and results, but have also facilitated a better knowledge of LV pathophysiology. We now understand much more about the nature of myocardial adaptation to pressure overload and myocardial responses to AVR, but some limitations need to be considered. The literature pertaining to the effects and efficacy of surgery largely consists of heterogeneous studies of relatively small populations, and differences in terms of patient selection, evaluated outcomes, operative interventions, and the timing of postoperative follow-up examinations limit their general applicability. Even the apparent simplicity of evaluating LV hypertrophy by means of echocardiography hides some intrinsic and largely unrecognized critical steps that may sometimes limit its clinical validity . One poset al. .Other often-overlooked factors affecting the postoperative course are now emerging, such as ethnicity or arterial hypertension ,48,52,53Post-AVR residual hypertrophy is a complex and important phenomenon and, although its incidence is decreasing, it still represents a vexing problem that has an impact on morbidity and, probably, mortality. There is no doubt that meticulous blood pressure control and an optimized drug regimen are fundamental, but the curative potential of surgery in AS may only be fully revealed by adopting a different timing for AVR. Earlier surgery can also be considered for asymptomatic patients with moderate AS and a low expected operative mortality who show a marked hypertrophic myocardial response to the increased afterload. No clinical trial has yet compared an early surgical strategy based on the degree of myocardial hypertrophic remodeling with the traditional timing mainly based on symptoms and valve parameters, although the former makes sense as it has been shown that preserved or supranormal LV chamber performance can mask myocardial tissue dysfunction and surgery could hypothetically prevent it. However, surgery has already improved the prognosis of patients with AS, and many intraoperative options are now available to tailor the right operation for each patient. In our experience, every effort should be made if a small projected indexed EOA is expected to choose a prosthesis with the best projected indexed EOA and implant it adequately by adding other procedures, such as myotomy-myectomy, that allow favorable remodeling and the long-term benefits of LV mass regression.The author(s) declare that they have no competing interests.All authors contributed to the paper and meet the criteria for authorship. All authors read and approved the final manuscript.Myectomy-myotomy before prosthetic valve implantation. .Click here for file