Cardiac shockwave therapy (CSWT) might improve symptoms and decrease ischaemia burden by stimulating collateral growth in chronic ischaemic myocardium. This prospective study was performed to evaluate the feasibility and safety of CSWT.2) in an echocardiography-guided and ECG-triggered fashion. The protocol included a total of 9 treatment sessions . Clinical assessment was performed using exercise testing, angina score (CCS class), nitrate use, myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session.We included 33 patients  with end-stage coronary artery disease, chronic angina pectoris and reversible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones  and the angina symptoms diminished from CCS class III to CCS class II (p < 0.01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy  and by increased exercise tolerance at 4-month follow-up (from 7.4 ± 2.8 to 8.8 ± 3.6 min p = 0.015). No clinically relevant side effects were observed.One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (CSWT improved symptoms and reduced ischaemia burden in patients with end-stage coronary artery disease without relevant side effects. The study provides a solid basis for a randomised multicentre trial to establish CSWT as a new treatment option in end-stage coronary artery disease. Despite advances in medical and invasive revascularisation therapy a substantial number of patients show progression to end-stage ischaemic coronary artery disease with chronic refractory angina symptoms and no further revascularisation options . Long-teA shockwave is a single pressure pulse with a short (< 1 msec) positive spike with an amplitude up to 100 MPa followed by a lower amplitude tensile part lasting several microseconds . The higIn predominantly animal model studies, the following effects of shockwave therapy have been observed: Cavitation  , thermal2) on myocardial ischaemia and left ventricular function [Pre-clinical studies and limited clinical data suggest a positive effect of very low energy shockwaves , stable ischaemia-related symptoms for more than 3 months prior to the CSWT initiation without a change in medication) and were included and treated with shockwave therapy  after fu2 using the CardiospecTM device  in an echocardiography-guided and ECG-triggered fashion. Briefly, the CardiospecTM device creates shockwaves using an electrohydraulic method. An electric discharge within a water filled applicator evaporates a small portion of water that generates shockwaves. The shockwaves are reflected and focused, with a focus size of 8 mm width and 25 mm depth, by means of an applicator to the zone of myocardial ischaemia. The ischaemic regions were detected by SPECT and during treatment located by ultrasound using a transthoracic echocardiography transducer mounted on a special holder on the shockwave applicator , angina score (CCS class), nitrate use, echocardiography and SPECT at baseline (prior to first treatment session), and 1 month and 4 months after the last treatment session. Cardiac magnetic resonance imaging (CMR) was performed for safety reasons in the first 8 patients at baseline, 1 and 4 months.The safety of the shockwave therapy was assessed with continuous rhythm monitoring as well as blood pressure measurements during the intervention. Further, repeated electrocardiograms and echocardiography during and after the treatment were performed. Blood samples were taken to exclude potential myocardial damage. The clinical status of the patient was assessed and the skin controlled for burns or erythema immediately and 1 h after the procedure.Before therapy, and 1 and 4 months after shockwave therapy, a complete echocardiographic examination was performed to evaluate left ventricular systolic and diastolic function and size, segmental wall motion and valve function using Sonos 5500 ultrasound systems with S3-1 (1–3 MHz) transthoracic transducers or IE33 ultrasound systems with S5-1 (1–5 Mhz) transducers . In addition, image quality in supine position was evaluated since shockwave therapy can only be performed in the supine position. During treatment, the ischaemic zones were placed in the middle of the sector scan.As described above, diagnostic echocardiography was also performed during shockwave therapy to steer the shockwave beam to the myocardial regions of interest, as previously defined by SPECT.SPECT was performed by a one-day protocol, using either Tl-201 (111 MBq) or Tc-99 m-sestamibi  . Per pati) negative, defined as having homogenous radioactive distributions in myocardium, on both stress and rest scans, and SDS = 0; (ii) positive, defined as reversible and fixed perfusion defects. Reversible perfusion defects were considered the segments with a decreased tracer uptake at stress but with partial improvement or complete normalisation of tracer uptake at rest. Fixed pattern showed that localised segments of decreased perfusion were unchanged between the stress and rest images. Reversible perfusion defects with SDS > 1 were considered to represent myocardial ischaemia, whereas fixed perfusion defects were considered to be myocardial scar. The inter-observer variability was found to be < 10 %. For evaluation of the effect of CSWT quantitative polar maps were constructed of the stress and rest perfusion, using the Autoquant/QPS software package . This map displays the myocardial perfusion as raw counts. The pixel with the maximum raw count is set to the maximum colour scale brightness and corresponds to a value of 100. Values of the segmental counts corresponded to the average pixel value in that segment. Values of corresponding segments between stress and rest images were compared, stratifying between treated and untreated segments  in 2-, 3- and 4-chamber long axis and contiguous short axis views. Standard late gadolinium enhancement images were acquired to evaluate the presence of myocardial infarction  10 min after intravenous administration of 0.2 mmol/kg Gadolinium-DTPA . Inversion times were adjusted to null normal myocardium (200–300 ms).Patients were examined with a 1.5 T MR scanner  as previously described . Cine imCMR images were analysed with the CAAS MRV 3.0 software . Areas of myocardial infarction were visually assessed on late enhancement images. If present, areas were quantified by planimetry using a signal cut-off of > 2 SD above the mean signal intensity of remote myocardium in the same slice and expressed as a percentage of total LV mass.Blood samples were taken after the second treatment session from all patients and the following laboratory parameters were analysed to detect or exclude myocardial damage as a potential side effect of CSWT: serum creatinine kinase, (high sensitive) troponin T, aspartate aminotransferase and alanine aminotransferase.Statistical analysis was performed using SPSS software . Continuous variables with no/mild skew were presented as mean ± SD, skewed measures as median. Discrete variables were summarised as frequencies and percentages. Differences were assessed using a paired sample t-test for normally distributed data or Wilcoxon signed rank two related sampled analyses for other distributions.The study group consisted of 33 patients . The baseline characteristics of the patient population are summarised in Table CSWT was well tolerated without major side effects. Transient dizziness shortly after the first treatment session was reported from 4 patients. Creatinine kinase (106 ± 52 U/l) or TnT levels were not elevated following the treatment sessions in any of the patients. The electrocardiograms did not show any significant changes after treatment. No arrhythmias were observed and no clinical signs of dyspnoea or coughing as a sign of lung contusion were noticed. No skin erythema or burns were observed. There were no changes in medication during the treatment and the follow-up.p < 0.01). Simultaneously, angina complaints decreased by at least one CCS class in 25 patients at 1 month and in all but two patients at 4 months after CSWT (p < 0.01) (Table p = 0.015).Following CSWT, the clinical status improved significantly: The use of sublingual nitrates decreased from a median of 10 per week range 1–25) pre-CSWT to 2 per week (range 0–20) at 1 month and to 2 per week (range 0–7) at 4 months post-CSWT (5 pre-CSWp = 0.037) and 4 months (p = 0.016)  Table , Fig. 3.6) Table .The main finding of our study is that CSWT therapy is capable of improving ischaemic symptoms and reducing ischaemia burden in patients with end-stage coronary artery disease, the so called ‘no-option patients’. The beneficial effects were observed in the absence of detectable relevant side effects. Our study demonstrates an improvement of the clinical status of the patients undergoing CSWT.Moreover, our study provides mechanistic insight into the improvement of regional myocardial perfusion following CSWT, and thereby provides a solid basis for the increased exercise tolerance of these patients during follow-up of up to 4 months. The SPECT data suggest that at least part of the positive effect might be due to improved perfusion in the treated ischaemic zones at stress. Consistent with this observation and as expected, no changes in resting perfusion were detectable in treated and untreated myocardial areas nor in the stress perfusion of untreated areas.These results confirm the preliminary findings of Fukumoto et al., who investigated 9 patients with end-stage coronary artery disease . The lim2) seem to be safe [The treatment was well tolerated and not accompanied by any serious side effects known from studies on shockwave therapy in lithotripsy  or ortho be safe , 26, 29.The limited sample size and the lack of a control group are the main limitations of this study. A ‘regression to the mean’ phenomenon  as an exDecreased ischaemic burden in about two-thirds of the patients combined with alleviation of angina symptoms makes CSWT an interesting alternative in the difficult to treat group of patients with refractory angina pectoris. The main advantage of this relatively time-consuming outpatient-based method is its non-invasive character in combination with no significant side-effects. A further validation in a properly sized randomised placebo-controlled trial is needed before CSWT can be introduced into clinical routine.This work was supported in part by a ‘profileringsfonds’ of the Maastricht University Medical Centre (to J.V. and J.W.).None declared.


Ultrasound guided cardiac shock wave therapy (CSWT) is a noninvasive therapeutic option in the treatment of chronic-refractory angina. Clinical trials have shown that CSWT reduces angina symptoms, improves regional systolic function, LV ejection fraction, myocardial perfusion and quality of life parameters. Absolute measurements of myocardial perfusion before and after CSWT have not been performed so far.3 PET perfusion scan under adenosine was performed before and after CSWT treatment. CSWT was well tolerated in all patients. Absolute perfusion under adenosine of the global left-ventricular myocardium did not change under therapy or minimal coronary resistance. The treated segments, however, showed in terms of both perfusion and resistance a mild but significant improvement, by 11 and 15 %, respectively, whereas no change could be observed in the remote segments. Considering a threshold of increased perfusion of 5 %, 10 (77 %) out of 13 patients with a better target perfusion improved in their CCS class, whereas 3 (43 %) out of 7 patients without improved target perfusion improved in their CCS class too.We studied a total of 21 CCS III patients with history of CAD and multiple interventions who suffered from disabling angina despite individually optimized medical therapy. An N-13 NHStandard CSWT has the potential to improve myocardial perfusion of the therapy zone and clinical CAD symptomatology without affecting global myocardial perfusion. As a noninvasive and well tolerated therapeutic option, these data suggest the use of CSWT in patients with end-stage CAD. Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality in industrialized countries. Several therapeutic options for chronic CAD are available. They include medical treatment, percutaneous coronary intervention (PCI), and coronary artery bypass surgery. Despite excellent interventional results, an increasing number of patients with advanced CAD not suitable for any intervention suffer from chronic angina inspite of optimal medical therapy , 2. It hUltrasound guided cardiac shock wave therapy (CSWT) is another noninvasive therapeutic option in the treatment of chronic-refractory angina. Physically, a shock wave pulse is a single sharp pressure pulse with amplitude up to 100 MPa, followed by a tensile part of several microseconds with lower amplitude.Animal studies have suggested that CSWT promoted angiogenesis in ischemic myocardium by mRNA expression of vascular endothelial growth factor (VEGF), endothelial cell proliferation, and endothelial nitric oxide synthase (eNOS) expression , 9. FurtClinical trials demonstrated that CSWT may reduce angina symptoms, improve regional systolic function, LV ejection fraction, myocardial blood flow and quality of life parameters –14.3 PET perfusion imaging under adenosine induced hyperemia the effects of CSWT treatment on absolute perfusion in the target region and in the entire left myocardium in patients with chronic-refractory angina.In this context myocardial perfusion has been evaluated with SPECT imaging at rest , under lWe studied a total of 21 patients with history of CAD and multiple prior interventions  who suffered from disabling angina despite individually optimized medical therapy  scale was assessed in all patients before and after therapy. Additionally, echocardiography and, if feasible, ergometry were performed.Patients gave their written informed consent to CSWT and the clinical PET studies. The data analysis was approved by the local ethics committee of the Ruhr-University Bochum (Reg. No. 60/2013).Patients were investigated with an ECAT-951 R scanner  and, after a change of the device, with a Biograph mCT . Directly before the PET acquisition, a transmission scan was performed with an ECAT-951 R scanner and a low-dose CT with the Biograph mCT for attenuation correction.Adenosine was infused intravenously at a constant rate of 0.14 mg/kg/min over 6 min. During the stress phase, heart rate and blood pressure were recorded every 2 min, starting with the onset of the adenosine infusion until completion of after 6 min. Mean arterial blood pressure was calculated from the average values of all four time points and minimal coronary resistance as mean arterial blood pressure/global perfusion.3 were injected as an intravenous bolus. Image acquisition over 15 min was started simultaneously with the bolus injection. A consecutive set of 20 frames was reconstructed for quantification of perfusion.Two minutes after the onset of the adenosine infusion, on average 600 MBq N-13 NH3 scans was based on an irreversible two-compartment model [Quantification of the N-13 NHnt model . Correctnt model . A validnt model . The quant model .The CSWT target zone was assigned to the anteroseptal wall in 8 cases, to the inferolateral wall in 6, to the inferior wall in 6, and to the apex in 1 case. The reference wall was defined as the remote wall opposite to the CSWT target zone. In the case of the apical CSWT target, the anterior wall served as the reference. For quantitative analysis, perfusion values of the segments of the parametric polarmaps representing either the target or the remote wall were averaged.2, with a focus size of 8–9 mm and a length of 25 mm to ensure transmural coverage. The focus could be set up to a depth between 4 and 15 cm. During the procedure, patients lay in supine position. ECG, blood pressure and vital signs were monitored continuously.A detailed description with illustration of the device and the CSWT protocol has been given elsewhere . In brieThe target region previously defined with the PET scan was adjusted with the ultrasound probe. Shock wave release occurred with an R-wave ECG trigger.The CSWT scheme was performed over 3 months (93 ± 34 days) in blocks of 3 sessions applied every other day during the treatment weeks, with 6 weeks intervals . The target region previously defined with PET was divided into a basal, midcavity, and apical zone. During each treatment, these zones were targeted with the ultrasound probe, progressing from the basal zone in week 1 (sessions 1–3) to the midcavity zone in week 2 (sessions 4–6), and the apical zone in week 3 (sessions 7–9). Patients received 300 shocks (when starting) to 500 shocks (after verification of tolerance) per treatment session. Thus, during the 9 shockwave sessions, a total of 2700–4500 individual discharges were delivered. Troponin I was controlled several hours after each application.Resting two-dimensional echocardiography was performed at baseline and follow-up with a 1.7/3.3 MHz multifrequency probe in harmonic imaging mode using commercially available echo equipment . The classical two apical views (2- and 4-chamber views) were applied to measure biplane LVEF and both the endsystolic and enddiastolic volumes.The bicycle test was performed in the upright position . Depending on the patient’s condition, ergometry was started at 25 W or 50 W, and was increased by 25 W each minute. The test was stopped when typical chest pain, significant ST depressions, or exhaustion of the leg muscles occurred.For the sample size estimation, a power of 90 % and a significance criterion of 0.05 were chosen. The minimum expected difference between the two means and the standard deviation were estimated to 10 mL/min/100 g each. Accordingly, about 20 patients had to be enrolled .t test.Data are given as mean value ± standard deviation. In the first step, the paired parameters were tested for normal distribution with the Kolmogorov–Smirnov test. As all parameters were normally distributed, post hoc comparisons were performed with a paired The contingency between change in CCS class (unchanged or better) and change in perfusion (increase <5 % and increase ≥5) was examined using Fisher’s exact test.Differences were considered statistically significant at values <0.05 (two-sided). For the analyses, the statistical software package IBM SPSS (version 20) was used.The baseline clinical characteristics of the patients and their cardiac medication are shown in Tables CSWT was well tolerated in all patients. No patient showed an increase in troponin I beyond the reference level after the applications, and no therapy course had to be stopped prematurely.All patients were in CCS class III at baseline. At follow-up, a downstaging was observed in 13 patients, such that 13 were in CCS class II and 8 remained in CCS class III .The perfusion data are listed in Tables Considering a threshold of improvement in perfusion of 5 %, based on an estimated error of measurement of 5 %, 10 (77 %) patients out of 13 with a better perfusion of the target segments improved in their CCS class, whereas, 3 (43 %) patients out of 7 without better perfusion of the target segments improved in their CCS class, too  increase of local shear stress by the collapse of microbubbles, and (2) stimulation of local angiogenesis by angiogenesis-related growth factors and recruitment of endothelial progenitor cells , 9, 24.Several studies demonstrated that CSWT is able to improve clinical symptoms, and quality of life parameters , 12, 14.In the present study, we could demonstrate a significant increase in absolute myocardial perfusion in the treated segments, whereas no change in perfusion occurred in the remote segments. Coronary resistance showed a concordant behavior indicating that the perfusion changes were not exclusively related to improvements in hemodynamics and has to be assigned to further factors directly affecting myocardial perfusion. CSWT-induced neoangiogenesis may be one potential component, but the extent to which it contributes required additional morphological studies.Normal absolute myocardial perfusion under hyperemia is usually assumed >200 mL/min/100 g . AgainstIn terms of global myocardial perfusion and minimal coronary resistance, no significant changes were found during the 4 months between the observation periods. These results are in accordance with the echocardiographic measurements indicating that no significant change of the disease occurred during this period. Nevertheless, a treatment of the leading ischemic area seems to be beneficial with respect to the CCS classification, although no significant changes in exercise tolerance were observed. To what extent this improvement in CCS classification is a net effect of reduced ischemic burden, and thus a relief of angina symptoms, or is driven by changes in individual perception needs further clarification. The present data indicate that suggestive factors are likely to play a role as 38 % of those patients with no better perfusion of the target segments experienced a CCS class downstaging.Another issue of interest is the duration of the improvements, with the concept for future therapeutic courses having to evaluate the frequency and duration of CSWT and, finally, patient outcome.The results of the present study are in line with former imaging studies and demonstrate absolute effects of CSWT on myocardial perfusion of the target zone . The cliTo summarize the results of the present study: CSWT has the potential to improve myocardial perfusion of the target therapy zone and CAD symptomatology without affecting global myocardial perfusion and morphologic ventricular parameters. As a noninvasive and well tolerated therapeutic option, our data suggest the use of CSWT in patients with end-stage CAD.From a statistical point of view, the patient number is sufficient to identify differences in perfusion with PET imaging and mildly larger than in other studies with nuclear medicine imaging. Nevertheless, larger patient cohorts with longer follow-ups are needed to further evaluate the efficacy of CSWT. A placebo-controlled group is missing. However, the intraindividual comparison of treated vs nontreated zones tried to circumnavigate this issue.


The optimal timing of pulmonary homograft valve replacement (PVR) is uncertain. Cardiopulmonary exercise testing (CPET) and cardiac magnetic resonance (CMR) are often used to guide the clinical decision for PVR in operated tetralogy of Fallot (TOF) patients with significant pulmonary regurgitation (PR). We aim to study the relationship between exercise capacity and CMR in these patients.The study is a single-centre retrospective analysis of 36 operated TOF patients  with significant PR on CMR who underwent CPET within 15 [median 2.0 (interquartile range 0.8-7.2)] months from CMR. CPET parameters were compared with 30 age- and sex-matched healthy controls .2max)  and peak oxygen pulse  were significantly lower in TOF group versus control. Univariate analyses showed negative correlation between PR fraction and anaerobic threshold. There was a positive correlation between indexed left (LV) and right (RV) ventricular end-diastolic volumes, as well as indexed LV and effective RV stroke volumes, on CMR and VO2max and Mets achieved on CPET. These remained significant after adjustment for age and sex.Peak systolic blood pressure , Mets , peak oxygen consumption (VO2max and peak oygen pulse achieved compared to controls. Increased PR fraction in TOF subjects was associated with lower anaerobic threshold. Higher indexed effective RV stroke volume, a measure of LV preload, was associated with higher VO2max and Mets achieved, and may potentially be used as a predictor of exercise capacity.TOF subjects have near normal exercise capacity but significantly lower Mets, VO Long-term outcomes of patients with tetralogy of Fallot (TOF) have improved with advances in surgical techniques. HoweverThe optimal timing of pulmonary homograft valve replacement (PVR) in operated TOF patients with significant PR is unclear. The decision for PVR is usually a fine balance between avoiding permanent remodeling of the right ventricle, 6 and r2). Patients with residual pulmonary stenosis pressure gradient on Doppler echocardiography, associated atrioventricular septum defect, double outlet right ventricle of Fallot type, pulmonary atresia with ventricular septum defect, TOF with absent pulmonary valve, or patients who had undergone pulmonary valve replacement (PVR) were excluded. Clinical data were obtained from review of patients’ case-files and electronic medical records.CMR and CPET data were recorded. CPET data were also obtained from age- and sex-matched healthy controls. The study was approved by the SingHealth Centralised Institutional Review Board .Study subjects underwent CMR on a 1.5 T Avanto scanner (Siemens). In each patient, fast imaging in steady-state precession (trueFISP) cine MR images were acquired in the left ventricular (LV) long axes , RV outflow tract (RVOT)  planes as well as a parallel contiguous stack of 8 mm ventricular short-axis cine slices. Retrospective ECG-triggering was employed, achieving typical frame rates of about 25 per cardiac cycle. Throughplane flow measurements in planes across the aortic root and main pulmonary trunk were performed using velocity-encoded gradient-echo pulse sequences.Calculation of left and right ventricular end-diastolic (EDV) and end-systolic (ESV) volumes, LV mass and ejection fractions (EF) was performed using CMRTools . All volumes and LV mass measurements were then indexed to body surface area. The presence of RVOT aneurysm, defined as akinesia or dyskinesia (outward movement) during systole of part of the RVOT assessed from the basal ventricular short-axis cine images, was recorded. PR fraction (diastolic reverse flow expressed as a percentage of forward flow) was assessed from anterograde and retrograde flow in the main pulmonary artery . Effective right ventricular stroke volume (RVSV) was calculated as the difference between the total RV forward flow and the pulmonary regurgitant flow, 16. Res2), minute ventilation (VE), and carbon dioxide output (VCO2) were measured breath by breath. The anaerobic threshold (AT) was chosen as the VO2 at which respiratory exchange ratio reached 1.0 and when there was a sudden and sustained precipitous rise in VCO2. Peak VO2 was defined as the value of averaged data during the final 15 seconds of exercise. The VE/VCO2 slope was determined as the linear regression slope of VE and VCO2.Cardiopulmonary exercise tests were performed on a Hewlett-Packard Cosmos treadmill machine. A maximal ramp protocol with fixed treadmill speed but constantly increasing incline gradient to provide an increasing workload was employed. Exercise speed was determined at the performing physician's discretion. Patients were encouraged to exercise until symptoms were intolerable, i.e. when Rating of Perceived Exertion reached 18/20. Heart rate was monitored continuously, and non-invasive blood pressure was taken every 2 minutes with both manual and automatic blood pressure. Oxygen saturation was monitored by a finger probe pulse oximeter. Oxygen uptake . Significant relationships were subsequently assessed by multiple linear regression technique adjusting for age and gender. Scatter plots with linear fit were produced. For all analyses, a two-tailed P value of <0.05 was considered significant.Data was analysed using STATA version 11.1 . All values were presented as median and interquartile range for continuous data and frequency and percentage for categorical data. Comparisons between groups were made with Mann–Whitney U test, or the Fisher’s exact test as appropriate. The linear correlation, Of the 119 TOF patients on clinical follow-up at our institution at the beginning of the study, 36 had significant PR on echocardiography. The latter underwent CPET and CMR testing and were included in this study. Thirty controls were also recruited. There was no significant difference in age, sex and indexed body mass between patients and controls. Six TOF patients had NYHA II functional status; the rest of the study TOF population were either asymptomatic or NYHA I , Mets , peak oxygen consumption  and peak oxygen pulse pressure . These differences were significant even after adjusting for age and sex. There were no significant difference in the rest of the CPET parameters  and the median time from surgical repair was 21.4 years (IQR 16.4-26.4). Ten patients (27.8%) had undergone transannular patch repair (Table .3-6.9 an2 (IQR 142.5-178.5), 87.2 ml/m2 (IQR 75.8-98.4), 45.6% (IQR 39.2-50.0), 73.5 ml/m2 (IQR 61.8-82.9), 41.1 ml/m2 (37.9-44.3) and 45.0% (IQR 35.5-52), respectively. The median LVEDVi, LVESVi, LVEF and LVSVi were 73.1 ml/m2 (IQR 66.6-82.5), 30.4 ml/m2 (IQR 26.9-35.3), 58.7% (IQR 52.9-62.3) and 43.1 ml/m2 (IQR 39.0-48.1), respectively. All patients had LVEF >40%, with five (13.9%) patients having LVEF between 40-50%. Twenty-six (72.2%) had restrictive RV physiology; and 20 (55.6%), RVOT aneurysms , RVESVi  and LVEDVi  were associated with significantly higher Mets achieved during exercise testing. Larger RVEDVi  and LVEDVi  were associated with higher peak oxygen consumption achieved during exercise testing. Larger LVSVi  and effective RVSVi  were associated with significantly higher Mets achieved. Larger LVSVi  and effective RVSVi  were associated with significantly higher peak oxygen consumption. Greater PR fraction was associated with lower AT (see Table The median time between CPET and CMR was 2.0 months (IQR 0.8-7.2); there was no change in clinical status between CPET and CMR for all patients. Larger RVEDVi (Our operated TOF patients with significant PR had near normal exercise capacity, albeit lower than that of normal healthy controls. Although direct comparison is difficult because of differences in cohort characteristics, the exercise capacity in our operated TOF patients with significant PR is fairly similar to a published series and bettWe demonstrated a negative correlation between PR fraction and AT, implying a possible deleterious effect on exercise capacity of worsening PR per se. The AT is decreased in patients with heart disease and is an important functional limit: physiological responses to exercise are different above and below the AT. While lIn our study, we found that higher effective RV stroke volume correlated significantly with higher Mets and peak oxygen consumption. In contrast, we found no significant correlation between exercise capacity and either RVEF or RV stroke volume, which is in keeping with reported studies, 20. In That LV preload may play an important role in determining exercise capacity is further supported by the observation that both RV and LV end-diastolic volumes - both indirect estimates of LV preload - showed positive correlation with Mets achieved and peak VO2, albeit not as strong a correlation as effective RVSVi. This appears to be counter-intuitive to the commonly held notion that increasingly dilated ventricular volumes equates with worsening exercise capacity. However, our results are by no means unique. There was a trend towards higher peak VO2 with increasing biventricular diastolic volumes in another study. SimilarQuestions have been raised regarding the use of RV size as a primary parameter in deciding the timing of PVR. Studies have found that exercise capacity and stroke volume are preserved late after tetrology repair, despite severe right ventricular dilation. There aIn our study, we have shown that effective RVSVi significantly correlates with exercise capacity and maybe a potentially useful additional parameter in the decision for PVR. Nevertheless, the decision for timing of PVR is a complex one and should not be based primarily on a single parameter. Rather, each case should be considered individually: balancing the need to intervene before the point of irreversible remodeling against the likelihood for repeat procedures in future. The use of ventricular volumes alone may not take into account the degree of compensation of ventricular function. Many factors may also influence the poorer exercise performance in operated TOF patients: not only residual PR, but also residual right ventricular outflow tract obstruction, impaired biventricular function and presence of ventricular or atrial arrhythmias.Abnormal cardiac function and and haemodynamic abnormalities secondary to residual PR and other residual defects may only appear after longer periods of follow-up. As time passes, PR leads eventually to worsening right ventricle enlargement and dysfunction, with consequent biventricular dyssynchrony, progression to heart failure, and poor performance at physical exercise. The challenge is to identify the optimal timing prior to irreversible decompensation for intervention. Presence of arryhythmia is another important consideration in the decision for PVR. Ventricular and atrial arrhythmias occur not uncommonly after correction of TOF and are one of the causes for sudden cardiac death in this group of patients, 26. BotThe strength of our study lies in the unique set of data on exercise capacity in operated TOF patients with significant PR, which provides insights into the relationship between exercise capacity and CMR findings in this group of patients. The main limitations of our study is its retrospective and cross-sectional design, with lack of longitudinal CPET and CMR data. The longitudinal relationship between exercise capacity and biventricular volumes and function were not addressed and are best studied in a prospective cohort. The retrospective nature of our study also did not allow us to collect data on exercise habits and behavior which may be significant in this group of young patients and could better help explain our findings. Further, most subjects had near normal exercise capacity, which limits extrapolation of the findings to TOF cases with end-stage symptoms. Finally, our study had been performed in a single centre with relatively few patient number. This could have inadvertently introduced some bias and affect the generalizability of our results.2max and peak oygen pulse were significant lower than controls. Increased PR fraction in TOF patients was associated with lower AT. Indexed effective RV stroke volume, which we postulate to be a measure of LV preload in the presence of significant PR, was positively associated with VO2max and Mets achieved. This may potentially be used as a predictor of exercise capacity in repaired TOF with significant PR.Although the majority of our TOF subjects had near normal exercise capacity; objective measures of Mets achieved, VO


Left ventricular late gadolinium enhancement (LV-LGE) is a known incidental cardiac magnetic resonance (CMR) finding in atrial fibrillation (AF) patients and has recently been associated with increased mortality . While LA 1:2 observational case-control study was conducted with a dataset of cases with new onset ischemic stroke after 1st CMR scan and controls matched by age and sex. Cases and controls were selected from a database of 762 AF patients without any prior history of MI who underwent cardiac MRI exams between June 2006 and January 2013. We manually reviewed the electronic medical records of all patients with CMR and sequentially selected the first identified age and sex matched controls (subjects without stroke event after their CMR scan). Two experienced readers scrutinized the CMR scans of cases and controls for presence of left ventricular delayed enhancement. We then collected all comorbidities and conducted univariate (Chi-square test/t-test as appropriate) and multivariate analyses to examine the association between LV-LGE and occurrence of stroke.Out of 762 patients, we identified 14 cases (1.8%) with new onset ischemic stroke after the first MRI scan. Of these cases, 2 (14%) were found to have LV-LGE. We age and sex matched these 14 cases with 28 controls in a 1:2 fashion. Description of demographic variables and univariate measures of association are presented in Table In this case-control study of AF patients without a history of MI, an incidental finding of LV-LGE is shown to predict the risk of stroke, especially in the case of patients with a higher CHADS2 score.Not applicable.


The Carpentier-Edwards Perimount Magna mitral valve bioprosthesis  is a low-profile version of the earlier Perimount valve that uses the ThermaFix process for enhanced calcium removal. The Magna valve has been in use since 2008, yet no publication, until now, has verified its intermediate-term safety and efficacy.From 2008 through 2011 (our 4-year study period), 70 Magna valves were implanted in the mitral position at a single institution (the Cleveland Clinic). Echocardiograms were prospectively interpreted. For this study, we reviewed patients’ charts; endpoints included hemodynamic measurements, in-hospital morbidity and mortality, valve-related events, resource utilization, and 5-year survival rates.P = 0.003). Per their final echocardiogram during our study period, 98 % of surviving patients had trivial or no MR, one patient had mild MR, and one patient had severe MR.The mean patient age was 68 years; 43 % of the patients had New York Heart Association (NYHA) class III or IV disease, and 51.4 % had moderately severe, or worse, mitral regurgitation (MR). For 43 % of the patients, the Magna valve implantation was a reoperation. For 83 %, the Magna valve implantation also included a concomitant cardiac procedure. The median survival rate was 4.7 years and 90 % of patients were free from significant structural valve degeneration at 5 years. Preoperative atrial fibrillation, ischemic MR, intraaortic balloon pump placement, cardiogenic shock, cardiac arrest, and renal failure were associated with increased mortality. Right ventricular systolic pressure decreased from 50 mmHg preoperatively to 40 mmHg postoperatively, according to our matched-pair analysis (Our 5-year experience indicates that the Magna valve offers excellent intermediate-term durability and substantial echocardiographic improvement; its low-profile design make it ideal for reoperations and for concomitant cardiac procedures, including valve replacement. Each year, more than 20,000 mitral valve operations are reported to the Society of Thoracic Surgeons database . DespiteA mitral valve bioprosthesis avoids anticoagulation, but is associated with a higher reoperation rate than a mechanical valve. For patients older than 70 years and for patients with a contraindication to anticoagulation, a mitral valve bioprosthesis is the preferred replacement option , 5–8. SeIn 2008, Edwards Lifesciences modified that initial Perimount model to provide a lower profile and to enhance removal of calcium-binding sites through its ThermaFix process. This modified model is referred to as the Carpentier-Edwards Perimount Magna mitral valve bioprosthesis, or the Magna valve for short. It protrudes less into the left ventricular outflow tract (LVOT) than its predecessor, so it is appealing for patients with small ventricles undergoing multiple valve procedures or reoperations. It is also predicted to have less structural valve deterioration, thanks to the ThermaFix process.The Magna valve, building on the proven durability of the initial Perimount model, has now been implanted in centers around the United States. Yet no publication, until now, has verified its short- and intermediate-term safety and efficacy. Herein, we report our 5-year outcomes with the use of the Magna valve in 70 patients implanted between 2008 through 2011 at a single center (the Cleveland Clinic)—including short-term in vivo echocardiographic data, which can be used as a reference for outcomes analyses and for future valve modifications.For our study, we queried the Cardiovascular Information Registry (Cleveland Clinic), a prospective database approved for use in research by the Institutional Review Board. Included in our study population were patients who underwent mitral valve replacement with the Magna valve from 2008 through 2011 (our 4-year study period)  ≥40 mmHg, per echocardiography findings.Endpoints were postoperative hemodynamic measurements, in-hospital morbidity and mortality, valve-related events, resource utilization, clinically significant structural valve degeneration and intermediate-term survival rates. To define in-hospital morbidity , we used the Society of Thoracic Surgeons national Adult Cardiac Surgery database. For surviving patients, we used hospital length of stay as a surrogate marker for resource utilization. Clinically relevant structural valve degeneration was defined as the need for reoperation or severe regurgitation or stenosis preceding death.For the echocardiography findings, we retrieved the last available transthoracic study from our server for each patient; for all quantifications, we used Syngo software , with interpretations made by two experienced echocardiologists (A.S and W.S.). For the 2D echocardiography analysis of LVOT diameter, left ventricular ejection fraction (EF), and stroke volume (SV), we used the biplane method of disks (modified Simpson’s rule). We also recorded RVSP, peak and mean transmitral gradients (mmHg), left atrial (LA) size, left ventricular internal diameter (LVID), and effective orifice area (EOA).To calculate the LVOT systolic velocity time integral (VTI), we used the mean of three waveforms acquired by LVOT pulse-wave Doppler; then, to calculate SV, we multiplied LVOT diameter by LVOT VTI. If systolic LVOT VTI was not available, we obtained SV by using the biplane method of disks (modified Simpson’s rule).To calculate the peak transmitral gradient, we obtained measurements from mitral diastolic continuous-wave Doppler assessment and then used the simplified Bernoulli equation. To calculate the mean transmitral gradients, we obtained measurements from the diastolic waveform VTI. For both the peak and mean measurements, we used the mean of three waveforms.1/2) method (MVA = 220/t1/2). To calculate the mitral EOA, we divided SV by the mitral diastolic VTI. To calculate the EOA index, we divided the EOA by body surface area.To calculate the mitral valve area (MVA), we used the pressure half-time  after Magna valve implantation, we used the Kaplan-Meier method, with censoring . To assess freedom from structural valve degeneration we used the Kaplan-Meier method . To analyze the relationship between dichotomous variables and survival, we used the 2-tailed Fisher exact test.Continuous demographic variables are expressed as the mean ± the standard error of the mean (SE); categorical values are expressed as the n (percentage). To compare pre- and postoperative echocardiography findings, we used the paired Student Preoperative demographic and clinical characteristics are reported in Table Operative factors and findings are summarized in Table Thirty eight patients had at least some MAC documented in the operative note. Moderate to severe MAC was noted in 29 of these cases (57 %). MAC involved the anterior annulus in 22 cases (57 %) and the posterior annulus in 36 cases (94 %). In 17 cases (44 %) the MAC was left undisturbed.Twelve cases (31 %) required at least some debridement and nine cases (23 %) required extensive debridement. Annular reconstruction with a patch was used to avoid AV rupture if adipose tissue was visible on the ventricular side of the annulus after debridement. Three cases (8 %) used a bovine pericardial patch and 1 case (3 %) used a felt patch. Only one case required an additional bypass run for mild-moderate perivalvular regurgitation to reinforce a separation along the anterior rim. The rest had either no or trivial MR at the conclusion of the replacement.Postoperative complications are detailed in Table P = 0.02) suggesting, at minimum, that no penalty was incurred for Magna valve implantation in patients with moderate pulmonary hypertension.The average clinical follow-up was 16 months . The 2- and 5-year survival rates were 84 and 40 % respectively. The median survival was 4.7 years  or everting  suture techniques depending on anatomy and ease of placement. We favor inverting sutures in the setting of MAC which places the sewing ring on the atrial side of the mitral annulus. If everting sutures are used then the valve may sit slightly intra-annular. We will infrequently construct a neo-inner annulus as described by Di Stefano and colleagues to avoid debridement in the setting of severe MAC . The preThe favorable hemodynamic profile of the Magna valve is further supported by the significant reduction we observed in RVSP. It is anticipated that a persistent reduction in RVSP could correlate with improved long-term survival, but we did not have a large enough sample size or long enough follow-up to definitively show any correlation . The sugOur study supports the use of the Magna valve as a replacement option, but we acknowledge several important limitations. First, echocardiographic follow-up was not as standardized as it is for repairs and not all patients had echos at their longest follow-up interval. Echocardiography was generally obtained if a clinical indication was met. Thus, our review of structural valve degeneration was limited to the causes of death, reoperation and the last available echo prior to these events. The Magna valve design is based on the previous Perimount model, which is associated with 14 years’ worth of data showing freedom from explantation and from structural valve deterioration, so we are confident that the newer model will do at least as well. Additionally, the prospective evaluation of the echocardiograms by two experienced cardiologists was crucial as it standardized the valve’s performance measures. But it was limited to a mean follow-up of 5 months with a broad range of intervals. We elected to evaluate the last echos to avoid an unfair advantage from early postoperative performance. We noted a high interobserver variability for the calculation of the EOA index in our series, making it difficult to reach conclusions about the actual value for any given Magna size. However, we were able to make statistical comparisons for changes in the EOA index across valve sizes. Our study was underpowered for a multivariate analysis, although trends were established by univariate measures.The peak gradient for the 25, 29 and 31 mm valves gradually decreased as expected. However, the peak was higher for the 29 mm valve than the 27 mm valve. Similarly, the 25, 27 and 31 mm mean gradients gradually decreased as expected. But the mean for the 29 and 25 mm valves were not statistically different. Peak and mean gradients can be affected by various transient factors such as cardiac output, heart rate, and volume status. In addition, the patient population was heterogeneous and we did not have an equal distribution of patients throughout the various valve sizes. Thus, we can conclude that the peaks and means decreased in our series with larger valve sizes as expected but we cannot give definitive estimates of these relative gradients that would translate to a broader population.In conclusion, this is the first published report on outcomes after implantation of the Magna valve. Modifications are regularly made to valves; it is important that at least short-term results are made available. In our 5-year study, we found excellent freedom from structural valve degeneration, excellent short term survival, good hemodynamics at even the lowest valve sizes, substantial echocardiographic improvement, and minimal valve-related events. The Magna valve’s low-profile design and ThermaFix process make it ideal for patients who have small ventricles, extensive comorbidities, or complex valve disease, as well as for those who need reoperations and concomitant cardiac procedures, including valve replacement.


A 52-year-old man presented after one episode of effort angina, normal treadmill electrocardiogram (ECG), and clearly positive adenosine cardiac magnetic resonance (aCMR) for reversible perfusion defects in the left anterior descending (LAD) coronary artery territory. Contrast high-dose dipyridamole (0.84 mg/kg per 6 min) stress echocardiography (cSE) demonstrated normal myocardial perfusion (MP) and wall motion at rest, while perfusion defects were shown in the lateral and apical segments after dipyridamole. Wall motion at stress was completely normal and stress/rest Doppler diastolic velocity ratio on the LAD demonstrated reduced flow reserve. In this case, cSE was the provocative test detecting both the LAD and circumflex obstructive lesions, thanks to MP analysis, while wall motion assessment was negative, not different from treadmill ECG, and aCMR highlighted only the LAD disease.In spite of the low sensitivity of wall motion assessment during stress-echocardiography to detect coronary artery disease (CAD) in patients with multivessel disease and balanced ischemia, the addition of cSE with myocardial perfusion assessment, is not only able to overcome this limitation of false negative rate on a per-patient basis, but may also depict multivessel myocardial perfusion defects more efficiently than aCMR, as in the reported case, thanks to high spatial resolution.Myocardial perfusion assessment during cSE, although not always technically feasible, has a very high spatial and temporal resolution which can easily demonstrate multivessel subendocardial perfusion defects during maximal vasodilation, which is often the only detectable marker of multivessel, balanced CAD.It is known that wall motion analysis during pharmacologic stress may result in falsely negative multivessel disease; in these cases perfusion imaging or Doppler measurement of coronary flow reserve may be helpful to detect multivessel obstructive CAD, which is a significant and dismal prognostic finding. aCMR is assumed as the perfect imaging modality for CAD detection, but in selected cases, such as the one presented, an advanced echocardiographic method in experienced hands can provide even more comprehensive results. The combination of myocardial perfusion (MP) imaging and dipyridamole or dobutamine real-time contrast echocardiography improves the sensitivity to detect coronary artery disease (CAD), particularly multivessel CAD. Patients with diffused CAD have the worst prognosis and hence false-negative results represent Achilles heel of stress echocardiography, when performed in its standard fashion, aiming only for reversible wall motion abnormalities without perfusion imaging or left anterior descending (LAD) Doppler coronary flow reserve measurement A 52-year-old man presented after one episode of effort angina, normal submaximal treadmill electrocardiogram (ECG), and clearly positive aCMR for reversible perfusion defects in the LAD coronary artery territory (rest A and strVideo 1http://dx.doi.org/10.1530/ERP-14-0013-v1Coronary angiography (LAD and circumflex arteries). Download Video 1 via Download Video 1Video 2http://dx.doi.org/10.1530/ERP-14-0013-v2Coronary angiography (RCA). Download Video 2 via Download Video 2Video 3http://dx.doi.org/10.1530/ERP-14-0013-v3Echocardiography: four 4 chamber view (flash-replenishment sequence at rest depicted from left to right). Download Video 3 via Download Video 3Video 4http://dx.doi.org/10.1530/ERP-14-0013-v4Perfusion defects in the lateral and apical segments after dipyridamole. Download Video 4 via Download Video 4Video 5http://dx.doi.org/10.1530/ERP-14-0013-v5Wall motion at stress (left ventricular end diastolic image) and wall motion at stress (left ventricular end systolic image). Download Video 5 via Download Video 5Video 6http://dx.doi.org/10.1530/ERP-14-0013-v6Stress/rest Doppler diastolic velocity ratio on the LAD (color Doppler and pulsed-wave tracings). Download Video 6 via Download Video 6In this case, cSE was the provocative test detecting both the LAD and circumflex lesions thanks to MP analysis, while treadmill ECG was negative and aCMR highlighted only one territory, i.e. the LAD disease. Nonetheless, wall motion during cSE resulted falsely negative in this case of three-vessel disease. Doppler coronary flow reserve, non-invasively measured on the LAD, was reduced, confirming its significant additive diagnostic role, as wall motion analysis during cSE may result falsely negative in multivessel disease and perfusion imaging is not always technically feasible.See panel and linked videos showing results of coronary angiography, aCMR, and cSE.Single-photon emission computed tomography using radionuclide agents is the most widely used MP technique for the assessment of CAD, although the use of first-pass contrast magnetic resonance is increasing for this purpose.Myocardial contrast echocardiography (MCE) can evidence perfusion defects (relative decrease in contrast enhancement or prolonged time to reach contrast enhancement of one region compared with other adjacent regions). A contrast defect is usually observed first in the subendocardium and rarely extends over the full thickness of the myocardium. When analyzing loops obtained with real-time imaging, judgment of wall motion and MP is often combined. A subendocardial perfusion defect makes a wall motion abnormality much clearer and vice versa. Thus, assessment of myocardial contrast often helps by increasing the diagnostic confidence of dubious wall motion analysis. During stress echocardiography, concordant findings in wall motion and perfusion increase our confidence when assessing a dubious wall motion abnormality.Contrast echocardiography significantly improves the image quality during rest and stress echocardiography and at the same time provides additional information on MP Reversible perfusion defects may help diagnose more comprehensively the extent and territorial distribution of functionally significant CAD, in cases of multivessel disease In the reported case, cSE with additional perfusion assessment helped diagnose CAD in the two mainly affected territories (LAD and circumflex), with confirmation by Doppler assessment of reduced flow reserve on the LAD. Unfortunately, cSE is not robust enough for ideal perfusion assessment, rarely reliably assessed in the entire left ventricle, leaving uncertainties in few segments.aCMR has a better coverage of the whole left ventricle, but as shown in this case, it also has drawbacks that can sometimes limit its diagnostic value in multivessel disease. aCMR and adenosine MCE have been compared in one of the previous studies Independently from the imaging method utilized, in case of multivessel disease, the use of vasodilator stress may hamper the detection of perfusion defects in territories subtended by less severe coronary stenosis, due to relatively smaller flow reduction: aCMR is not immune to this mechanism of false-negative results. In these cases, a second imaging provocative test may be synergistic.


A novel method for 3D interleaved T1 and T2 mapping of the whole left ventricular myocardium within one breath hold, 3D-QALAS, has recently been developed [In this feasibility study, eleven patients from an ongoing study were consecutively included . The 3D-QALAS sequence which measures T1 and T2 relaxation times in 13 slices with a resolution of 2mm x 2mm x 6mm was run twice on a Philips Ingenia 3T scanner both pre and post Gd in all patients except for one patient were only native data was collected, due to poor renal function. For comparison, three  2D 3-3-5 MOLLI acquisitions [T1 and T2 relaxation times obtained with 3D-QALAS correlate well with reference methods, MOLLI for T1  and Multi Echo GraSE for T2 . Data are visualized in Bland-Altman plots in figure The preliminary results from this ongoing study indicate that 3D T1 and T2 mapping in the left ventricle is feasible in one breath hold for patients with different pathologies using 3D QALAS. The method shows a good correlation in relaxation times measurement with existing 2D T1 and T2 mapping methods.Partly funded by the Swedish Heart and Lung Foundation.


There is considerable disagreement over the effects of percutaneous coronary intervention (PCI) on left ventricular diastolic function that has necessitated the investigation of diastolic indices. The present study was conducted to evaluate left ventricular diastolic function and its indices, three months after performing the PCI procedure in patients with coronary artery disease (CAD).In a quasi-experimental clinical trial study (before and after), 51 patients with CAD scheduled for elective PCI were investigated provided that their Ejection Fraction (EF) was > 30%. Before and three months after PCI, echocardiography was carried out to evaluate left ventricular diastolic indices including the E/Ea as the most important criteria for diagnosis of diastolic heart failure (DHF).Based on the E/Ea indices and after PCI, the number of patients with DHF decreased significantly: 40 patients (78.4%) before PCI versus 28 patients (54.9%) after PCI (p<0.05). The Mean and Standard error of deceleration time (DT), isovolumic relaxation time (IVRT), early diastolic mitral annulus velocity; Ea (E’), E/Ea and left ventricular ejection function (LVEF) indices underwent significant changes. In addition, MVA dur/PVA dur, PVs/PVd, and E/Ea indices had changed significantly after PCI in both genders. However, no significant difference was reported for the other indices.The E/Ea ratio as an important criterion for diagnosis of DHF was improved after PCI. Improvement of several other diastolic indices was observed after the PCI procedure. It can be concluded that PCI can be an effective treatment modality in patients with left ventricular diastolic indices. Coronary Artery Disease (CAD) is one of the major causes of death in the world that kills many people annually . FrequenAzizi, Rahmani, Emami, Mirmiran, Hajipour, Madjid et al., 2002).PCI is a procedure performed to relieve ischemic symptoms in patients with CAD. The application of this method to prevent heart failure can be as effective and efficient as coronary artery bypass grafting (CABG). Coronary artery stenosis can result in a heart failure and consequently systolic and diastolic heart failure, in case it is disregarded . DiastolIn a study conducted on patients with kidney dysfunctions, diastolic indices like Deceleration Time (DT) and E/Ea significantly decreased, while intervention had no impact on E/A and Isovolumic Relaxation Time (IVRT) . In another study carried out on the coronary arterypatients, improvement was observed only for E/A and E’ indices with no significant changes in diastolic indices for other cases  conducted in Imam Ali educational research center .Based on a study conducted in Iran and the rates of IVRT, Mitral EV and Mitral AV indices, the maximum sample size was estimated for 51 patients considering the changes in Mitral EV  . PatientExclusion criteria were well-known factors of left ventricular diastolic dysfunctions, including high blood pressure (over 140/90 mmHg), hypertrophic cardiomyopathy, left ventricular hypertrophy, high creatinine, bundle branch block, ventricular fibrillation, ventricular arrhythmia, severe valvular disease, complete heart block and previous CABG. The participants underwent left ventricular diastolic analysis using echocardiography according to the guidelines of American Echocardiography Association before PCI was performed.IVRT (ms), E/A Ratio of Mitral Inflow Velocity (E/A ratio), MVA duration, PVA duration, Pulmonary vein systolic flow/Pulmonary vein diastolic flow (PVs/PVd), Deceleration Time (DT) and Ea (E’) parameters were determined using Tissue Doppler Imaging (TDI). E/Ea and Left Ventricular Ejection Fraction (LVEF) indices were also determined . DiastolThe study received the approval from the ethical committee of Kermanshah University of Medical Sciences. Before the study, all patients signed the consent form to participate in the study, and thereafter PCI was performed.The obtained data were fed into SPSS software (version 16) and analyzed by Fisher test, paired sample t-test and independent t-test. p <0.05 was considered significant.The study included 51 patients. Thirty-six (70.6%) patients were males and the rest were females. The mean and standard deviation obtained with the age range of 40–77 was 59.61±8.76. In terms of risk factors, 30 (58.8%) patients had high blood pressure followed by 19 (37.3%) patients with high blood lipid. Smokers comprised 25.5% of the total (13 patients) and diabetics accounted for 17.6% of the population (9 patients). The results of the angiography carried out before PCI indicated that 27 (52.9%) had one-vessel, 17 (33.3%) had two-vessel, and 7 (13.8%) had three-vessel coronary artery disease.As for DHF and taking the E/Ea ratio into account, 11 (21.6%) of the participants were healthy but 40 (78.4%) of them were sick before the intervention. However, the number of healthy people almost doubled to 23 (45.1%) and the number of sick patients dropped to 28 (54.9%), (p=0.014), .Among the indices of diastolic performance of the heart, the mean and standard error for DT, IVRT, Ea (E’), E/Ea, and LVEF indicated significant change after PCI followed by medication. However, E/A, MVA dur/PVA dur, and PVs/PVd remained unchanged. The pattern of these changes showed a decline for DT, IVRT, and E/Ea indices and an increase for the other indices .After PCI, the mean and standard errors of MVA dur/PVA dur, PVs/PVd, and E/Ea indices changed significantly in both genders; MVA dur/PVA dur increased in male and PVs/PVd increased in both genders. In contrast, E/Ea index decreased in both males and females (p<0.05). For DT, IVRT, E/A, Ea(E’), and IVEF, however, there was no statistically significant difference in terms of gender. DT and IVRT decreased in both genders. Other indices (except E/A) showed an increase in males (p>0.05) .DHF has been reported in over 35–42% of the patients with heart failure symptoms . DHF hasAccording to The diastolic performance indices were analyzed three months after PCI. The findings demonstrated a decrease in the mean and standard error of DT, IVRT, and E/Ea indices. E/A, MVA dur/PVA dur and PVs/PVd levels did not show any significant changes. Inan analysis of the effect of angioplasty or PCI on the diastolic performance of patients with renal insufficiency, Namazi et al, (2010) have not demonstrated a significant impact of PCI on the E/A index, which is in line with the findings of the present study. They also indicated a decline for DT and E/Ea indices. Although they did not report any significant change in the IVRT index, in the present study, it decreased significantly. This difference may be justified bya longer reevaluation time in which their patients were investigated six months after PCI in comparison with the three-month period of the present study . ContrarAccording to our findings, Ea (E’) and IVEF levels increased after intervention. In the studies conducted by Surucu et al and Moreover, after PCI, Beitnes et al. have concluded that LVEF as a diastolic index increased in the first three months and then decreased in the second three months and the following six months. However, this decrease was not statistically significant, which probably confirms the effect of time on diastolic indices after PCI .The limitation of this study is proving an association in a quasi-experimental study of this nature with an n=51  and this should be considered in future studies with a larger sample size.Among the variables analyzed after intervention, DT, IVRT, Ea (E’), E/Ea Ratio and LVEF indices showed an improvement. The E/Ea index, thought to be the main criterion to determine DHF was also improved. From the findings of the present study, it can be argued that PCI in patients with CAD can ameliorate the compromise in diastolic heart function. As an effective step in clinical management, decreasing the E/Ea index using the PCI method in patients with CAD may decrease the chance of DHFThe role of confounding factors including medication use before & after PCI, high mean age of the participants, smoking, hypertension, diabetes and high blood lipid that can affect diastolic performance after PCI is important and needs to be considered in the future studies. Furthermore, future studies are advised to employ larger study samples and longer follow-up periods, which help eliminate the effects of confounding factors to investigate the symptoms in different patient groups according to the ejection fraction (EF).


CMR has become an increasingly valuable tool in the diagnosis and risk stratification of patients with non-ischaemic dilated cardiomyopathy (DCM) due to its assessment of left ventricular systolic function and tissue characterization ability and may have a role in early identification of cardiomyopathy. Some of the changes associated with early DCM (left ventricular dilatation and mild reduction in LV ejection fraction) can also occur in patients with a history of significant aerobic exercise, known as "athlete's heart". Using standard echocardiographic and CMR parameters it may be difficult to differentiate between DCM and normal physiological athletic adaptation, which may have significant implications for the patient. We hypothesized that use of CMR tagging and T1 and T2 mapping might be useful to differentiate between patients with left ventricular dilatation due to DCM and athlete's heart.105 male patients  underwent a comprehensive CMR protocol including tagging, T1 and T2 mapping and calculation of extracellular volume (ECV) using a 1.5T scanner.GCS was significantly decreased in both athletes and sedentary patients with compared to controls  while there was a trend to lower GLS in athletes compared to controls. Native T1 and ECV were significantly increased in sedentary mild DCM patients compared to both healthy controls  and athletes . Using multivariable logistic regression native T1 was the only significant parameter to differentiate between athletes and sedentary patients with early DCM (AUC 0.91).T1 mapping is potentially a useful tool for differentiating between athlete's heart and patients with early DCM. T1 mapping could be used whenever differentiation between these two phenotypes is inconclusive using alternative techniques.N/A.


New York Heart Association class improved at 4 months  as did ventricular filling . In contrast, relaxation  and filling pressures  did not change. Slope of EDPVR did not change with CRT. Such finding, together with an unmodified Klv/EDV and a 7 ± 18 % reduction in EDV (p = 0.001), suggested reverse remodelling towards a smaller equilibrium volume. Finally, end-systolic LV volume decreased from 147 ± 59 to 125 ± 52 ml and ejection fraction increased from 0.26 ± 0.07 to 0.32 ± 0.09 (both p < 0.001). Using a Cox regression model we found that only changes (Δ) in diastolic, but not systolic indexes, correlated with the composite clinical endpoint, with increments in ΔEDV20 and ΔE/DT, single or combined, greatly increasing risk of heart failure and/or cardiac death (p = 0.003). Ventricular reverse remodelling, together with improvement in ventricular filling, rather than improvements of systolic function, predict clinical prognosis long-term post-CRT.Conflicting data exist about the effects of cardiac resynchronization therapy (CRT) on diastolic function (DF). Aim of the study was to assess if and how CRT affects DF in systolic heart failure patients. We also investigated potential relations between CRT-induced left ventricular changes and the composite clinical endpoint of progressive heart failure and cardiac death over 3 years follow-up. 119 CRT patients underwent clinical evaluation and echocardiography before CRT and 4 months later. DF was quantified by transmitral velocities , early diastolic mitral annulus velocity (E′), E/E′ ratio and 2-D speckle tracking strain rate during isovolumetric relaxation . End-diastolic pressure–volume relationship (EDPVR) was also assessed noninvasively using a single-beat method. Overall stiffness was quantified by ventricular stiffness (K Cardiac resynchronization therapy (CRT) improves functional capacity, left ventricular systolic function and survival in patients with chronic heart failure and left bundle branch block . Not mucload-dependent as well as relatively load-independent parameters. In addition, we analyzed the passive phase of ventricular diastole by the end-diastolic pressure–volume relationship (EDPVR) using a single-beat approach that uses noninvasively-estimated diastolic pressure and volume data  .Finally we assessed ventricular re (EDP) , 7. Acco4·E/E′)] . Values lv, which was determined from DT according to the following equation (Klv = 1.28exp[−0.008DT]); this approach has been validated by invasive methods in a group of comparable cardiomyopathic patients  plus an ΔE/DT [−0.05 cm/s2 (−18 % relative to pre CRT)] entire population median basis. Thus, 3 groups were created according to the values of ΔEDV20 and ΔE/DT compared to the related medians .In order to confirm that ΔEDVp = 0.001). Group 3 event-free survival was half of that of group 1 at the end of follow-up. Furthermore, group 3 event-free survival rapidly decreased in the first 500 days after CRT. In contrast, group 1 event-free survival was maintained around 90 % until the end of the observation period. The difference, based on a post hoc Holm–Sidak test was statistically significant (p < 0.006). Group 2 exhibited an intermediate trend, with improved event-free survival as compared with group 3 (p < 0.03), but worse relative to group 1, although not at a significant level . The results could not be explained by differences in the drug distribution among the three groups. The percentage of patients treated with beta-blockers , diuretics  and ACE inhibitors/AT1 antagonists  was not dissimilar among the 3 groups (p = 0.995).Event-free survival curves for the three groups, shown in Fig. ivr), nor filling pressures (E/E′ and E/SRivr) in patients affected by dilated cardiomyopathy and systolic heart failure at 4-month follow-up. CRT, however, induces left ventricular reverse remodelling, resulting in a smaller ventricle with improved filling characteristics. Both dyssynchrony and systolic function improve after CRT, as demonstrated by TUS index and ejection fraction increments versus systolic volume decrements, but such changes do not seem to influence patients’ outcome long-term in a significant way.Our study demonstrates that CRT does not significantly affect relaxation phase  were significantly improved only in responders, defined as patients with a reduction >15 % in LV systolic volume at 12-month follow-up. In contrast to Waggoner et al., they concluded that reverse remodelling induced by CRT was associated with an improvement in both relaxation and filling pressures. Along the same line of thinking, Aksoy et al. [Jansen et al.  evaluatey et al.  documentPorciani et al.  classifiivr and E/SRivr ratios, obtained with speckle-tracking analysis, improved only in responders, suggesting that CRT has beneficial effects on both relaxation and filling pressures.Shanks et al.  evaluateload-dependent. In contrast with data in literature, however, neither relaxation parameters (E′ and SRivr) nor indirect filling pressure descriptors (E/E′ and E/SRivr) showed statistically significant improvements. Only IVR increased significantly.Retracing Shanks’ study, our aim was to evaluate DF in patients with dilated cardiomyopathy and to verify if and how improvements after CRT, if any, affect patients’ outcomes. In line with previous studies, we documented an improvement in transmitral flow parameters, which are As mentioned before, ventricular diastolic relaxation is influenced by both myocardial inactivation and asynchrony . Since a10, EDV20 EDV30 and Klv/EDV we can conclude that CRT induces reverse remodelling with no change in slope of EDPVR . There was, instead, a significant interaction (p = 0.002) between time changes in Vp and CRT when ΔE/DT <>18 % was used as a grouping criterion (−2.4 ± 15.2 vs. +10.3 ± 11.2 cm/s). Such findings are compatible with ventricular overfilling in patients doing badly after CRT and do not conflict with the hypothesis of a modest increment in apical gradient in those improving after CRT [In our study, the reverse remodelling effect of CRT was associated with no statistically significant change in filling pressures, but with an improvement in the filling profile that seems to have prognostic relevance. Survival analysis, in fact, proves that patients with reduction in ΔE/DT greater than 18 % post-CRT exhibit better survival based on the composite clinical endpoint of worsening heart failure or cardiac death Fig. . The comfter CRT , 30.Operator-dependency of all the measured echocardiographic measurements is an unavoidable limitation. In practical terms, this limits the reliability of the data acquisition process. In this regard NMR data would have been more reliable, but difficult to obtain in this patients’ population.ivr in those patients with an inadequate apical 4-chamber and/or 2-chamber view. Thirdly, DF was not evaluated via invasive measurements of pressure and volume but exclusively inferred from echocardiographic parameters. It should be considered, however, that the estimate of EDPVR from a single beat has demonstrated a good correlation with EDPVR measured with invasive techniques, as reported by Klotz et al. [10–20–30 can be considered as a reliable parameter for describing the ventricular passive properties and can be used to describe the process of reverse remodeling after CRT as long as the original input is correct. Given the limitations of E/E′-based measurements of filling pressures in patients with conduction abnormalities or undergoing pacing [lv/EDV as another parameter, beyond single-beat EDPVR, in order to confirm the changes in ventricular characteristics post-CRT.The experimental data were partly biased by not calculating SRz et al. , 7. Thusg pacing , we usedAnother limitation to be taken into consideration is the relatively small sample size and short follow-up time at which echocardiographic data were obtained. Expansion of the patients’ population and another echocardiographic assessment, after 6 or 12 months, would have allowed verification of the positive trend in the filling profile and echocardiographic parameters of relaxation. In this regard it has to be underlined that the use of the E–E′ time interval, instead of the indexes here considered, could have been better descriptor of the relaxation behavior pre/post-CRT . Unfortup = 0.017), ischemic etiology (p = 0.007) and worsening in LV filling characteristics (ΔE/DT% p = 0.033) predicting HF exacerbations or death during follow-up. The statistical weight of ΔEDV20% decreased slightly (p = 0.068), There was no contribution at all from ΔESV% (p = 0.658), QRS duration (p = 0.533) and presence of diabetes and/or chronic renal insufficiency (p = 0.138).Also the time of first evaluation and diagnosis of heart failure and patient’s comorbidity Table  may be oOur study demonstrates that CRT improves systolic function and ventricular dyssynchrony and in particular it positively affects DF through a reverse remodeling process due to a left shifting towards a smaller equilibrium volume, with no change in the slope of EDPVR. Such evolution is associated with a favorable impact on the filling profile, although direct indexes of improved active relaxation are not significantly affected.Finally, short-term changes in DF, together with ventricular volume shrinkage, rather than improvement in systolic function, predict clinical prognosis long-term post-CRT. Such a combination (improved filling coupled with reverse remodelling), rather than amelioration in systolic pump performance, seems to modulate long-term follow-up in these patients.


CKD), but the underlying mechanisms contributing to this complex phenotype are incompletely understood. Myocardial deformation analyses (ventricular strain) of patients with mild CKD have recently been reported to predict adverse clinical outcome. We aimed to determine if early myocardial dysfunction in a mouse model of CKD could be detected using ventricular strain analyses. CKD was induced in 5‐week‐old male 129X1/SvJ mice through partial nephrectomy (5/6Nx) with age‐matched mice undergoing bilateral sham surgeries serving as controls. Serial transthoracic echocardiography was performed over 16 weeks following induction of CKD. Invasive hemodynamic measurements were performed at 8 weeks. Gene expression and histology was performed on hearts at 8 and 16 weeks. CKD mice developed decreased longitudinal strain  and diastolic dysfunction  compared to controls as early as 2 weeks following 5/6Nx. In contrast, ventricular hypertrophy was not apparent until 4 weeks. Hearts from CKD mice developed progressive fibrosis at 8 and 16 weeks with gene signatures suggestive of evolving heart failure with elevated expression of natriuretic peptides. Uremic cardiomyopathy in this model is characterized by early myocardial dysfunction which preceded observable changes in ventricular geometry. The model ultimately resulted in myocardial fibrosis and increased expression of natriuretic peptides suggestive of progressive heart failure.Uremic cardiomyopathy is responsible for high morbidity and mortality rates among patients with chronic kidney disease ( Patients with chronic kidney disease (CKD) have an estimated 10‐ to 100‐fold increased risk of cardiovascular mortality than their peers  and diastolic dysfunction are recognized features of uremic cardiomyopathy in adults  during diastole to allow myofilament relaxation. Reuptake of iCa2+ into the SR during diastole occurs primarily via the SR calcium ATPase (SERCA2a). SERCA2a dysfunction resulting in accumulation of iCa2+ during diastole and consequently incomplete myofilament relaxation, has been implicated in the impaired relaxation of cardiomyocytes (CM) isolated from failing hearts in humans  or sham surgeries (n = 11) under inhaled isoflurane (2%) anesthesia, in a two‐stage approach. In the first stage, the left kidney was exposed via flank incision and decapsulated to avoid ureter and adrenal damage. The upper and lower poles of the left kidney were resected via selective cauterization with a high‐temperature fine tip cautery . After 1 week recovery, the entire right kidney was removed via a right flank incision. Sham surgeries involved flank incision, exposure of kidneys, but no removal of tissue at the same timing as 5/6Nx surgeries. Mice were fed 2018 Teklad Global 18% Protein Rodent Diet  ad libitum. All animal experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals using protocols approved by Emory University Institutional Animal Care and Use Committee. Renal function was assessed by measuring urea nitrogen concentration via colorimetric assay  and Cystatin c concentration using an ELISA assay  in plasma samples.Male 129X1/SvJ mice  age 5–6 weeks were randomly assigned to undergo five‐sixth nephrectomy (5/6Nx) surgery (Echocardiographic studies were performed at baseline (prior to surgeries), then every 2 weeks through 8 weeks of CKD, and every 4 weeks thereafter until 16 weeks . M‐mode and Doppler measurement data represent 4–5 averaged cardiac cycles from at least two scans per mouse.TM Analysis . Global strain measurements in the longitudinal and radial directions were quantified using B mode cine images in the LV parasternal long‐axis view. All strain data were measured and averaged over at least three heart beats.Strain analyses were conducted by the same trained investigator (RJ) for all images using speckle tracking software, VevostrainBlood pressures (BP) were measured using noninvasive tail‐cuff measurements  at baseline and every 4 weeks until endpoint Fig. A. BP meaInvasive hemodynamic measurements were performed at 8 weeks following surgery in a separate cohort of mice. Mice were anesthetized with inhaled isoflurane, intubated and ventilated using a small animal volume‐controlled ventilator . A 1F pressure‐volume conductance catheter  was inserted into the left ventricle via apical puncture. Data were analyzed using LabChart analysis software .μm thickness.Hearts were removed, flushed with phosphate‐buffered saline, submerged in 100 mmol/L KCl to arrest in diastole, then fixed in 10% buffered formalin. Fibrosis quantification was performed in ImageJ . RNA was isolated from ventricular homogenates using miRNeasy mini kit . Complementary DNA was generated using High Capacity cDNA Reverse Transcription Kit  according to manufacturers’ instructions. See Table TM real‐time PCR system (ThermoFisher Scientific). Relative gene expression was calculated using the ΔΔCt method normalized to the housekeeping gene Rn18s, and is presented as fold change compared to expression in Sham samples at each time point.Left ventricles were dissected from excised hearts and preserved in RNAlaterμmol/L Fura‐2AM (ThermoFisher Scientific) for 20 min at room temperature then placed in the stimulation chamber and perfused with Tyrode Buffer for 30 min to allow for de‐esterification of the dye. Cells were paced by field stimulation at 0.5, 1, and 2 Hz, and imaged with a dual‐excitation fluorescence photomultiplier system  allowing for simultaneous recording of sarcomere length and Fura‐2 emission ratio throughout each beat. Calcium transients were analyzed using IonWizard software .Mouse ventricular myocytes were isolated by enzymatic dissociation. The hearts of anesthetized mice were excised and perfused with Krebs‐Ringer solution followed by an enzymatic solution (Worthington Type II) for 17–25 min. The left ventricle was dissected and placed into a KB (storage) solution. The tissue was then minced and triturated to separate individual myocytes and filtered to remove large, undissociated fragments. Sarcomere shortening and calcium transients were measured as we have previously described  for data with normal distributions. Nonparametric tests (Mann–Whitney) were performed for data that did not have a normal distribution. Data with normal distribution are presented as means with standard deviation, and those with non‐normal distribution are graphically presented as geometric means with 95% confidence intervals. A P‐value < 0.05 was considered statistically significant.Unpaired, two‐tailed P = 0.02) that persisted throughout the study  consistent with CKD. Cystatin‐c levels were also elevated in mice undergoing 5/6Nx compared to sham controls at 2 weeks  and remained elevated throughout the study. Systolic BP were increased compared to controls and remained stable throughout the 16‐week study  in the 129X1/SvJ mouse strain. Mice undergoing 5/6Nx developed elevated plasma urea nitrogen levels at 2 weeks following surgery  early (2 weeks) following partial nephrectomy and progressed to reversal (ratio < 1) indicating severe diastolic dysfunction by 16 weeks of CKD . LV mass , anterior wall thickness , and RWT  were not significantly different between the groups at baseline. Surprisingly, LV remodeling was first detectable (4 weeks) after the development of ventricular dysfunction based on absolute anterior wall thickness , RWT  and remained so over the course of the experiment . Consistent with this finding, the rate of ventricular relaxation (dP/dtmin) was significantly lower in CKD mice . Neither ejection fraction nor the rate of LV pressure rise during systole (dP/dtmax) was significantly different between the groups  in CKD mice , but were significantly shorter in cells from mice at 8 weeks of CKD . Despite the shorter diastolic sarcomere length, CMs isolated from CKD mice at 8 weeks did not display accumulation of diastolic calcium  was not significantly altered in the hearts collected at 8 or 16 weeks (Fig. SERCA2a dysfunction resulting in accumulation of diastolic calcium has been implicated in diastolic dysfunction (McMahon et al. This study presents a detailed examination of the longitudinal changes in cardiac structure and function in an experimental model of CKD. Uremic cardiomyopathy in this model is characterized by early myocardial dysfunction as demonstrated by altered indices of ventricular relaxation and myocardial deformation, which preceded observable changes in ventricular geometry. The model ultimately resulted in myocardial fibrosis and increased expression of natriuretic peptides suggestive of progressive heart failure. To our knowledge, this is the first published report of myocardial deformation analysis in a mouse model of uremic cardiomyopathy.Ventricular stiffness has classically been considered a direct consequence of ventricular hypertrophy, so we were surprised to see impaired diastolic function as the earliest detectable change during uremic cardiomyopathy. Diastolic dysfunction has recently been noted to precede the development of LVH and elevation in BP in young adults with genetic predisposition for hypertension (Aeschbacher et al. It remains unclear if the altered myocardial deformation detected by ventricular strain analysis is directly related to LVH or diastolic dysfunction (Kasner et al. Impaired myocyte calcium handling and consequent accumulation of cytosolic calcium during diastole have been implicated in the pathogenesis of early diastolic dysfunction in models of diabetic cardiomyopathy (Lacombe et al. Our model ultimately resulted in cardiac fibrosis and expression of BNP, which are associated with progressive heart failure and likely represent more “permanent” changes in cardiac structure and ventricular dysfunction. Determining the precise point at which compensatory hypertrophy converts to heart failure remains a challenge in the field of cardiovascular biology and is beyond the scope of this report.Similar to our model, impaired myocardial deformation has been detected prior to the classical measures of systolic function in patients with mild CKD (Nasir et al. None declared.


Previous studies have demonstrated that an increase in extracellular volume measured on MRI is directly proportionate to myocardial fibrosis. Myocardial extracellular volume is proportionate to partition coefficient (λ) and extracellular volume = λ × (1-hematocrit). λ can be measured by assessing the T1 relaxation time before and after injection of contrast medium. The goal of this study is to assess the accuracy and precision of several T1 mapping sequences using a phantom at 1.5 and 3.0T.Experiments were performed on two magnets; a 1.5T magnet  and on a 3.0T magnet  with a 32 phased array cardiovascular coil. phantoms were built using 15 separate tubes to produce similar T1 and T2 values of myocardium and blood before and after gadolinium administration. All sequences were tested with an ECG simulation at heart rates 40, 60, 90, 120. To assess the standard T1 value for each tube, we used a tubo spin echo inversion-recovery sequence . The T1 value was assessed using an ECG gated single shot modified Look Locker inversion recovery (MOLLI) and several different schemes of Short MOLLI: at 1.5T  and at 3.0T . We calculated errors in the MOLLI T1 estimation according to Error T1 (%) = ((T1MOLLI-T1reference)/T1reference)x100. We assessed the effect of T2 value, T1 value, heart rate and MOLLI schemes on T1 errors.At 1.5 and 3.0T, the under estimation of T1 with MOLLI sequence was important, highly dependent on heart rate and increased significantly from 40 to 120 bpm. Using ShMOLLI sequences, the effect of heart rates was lower than 1% at 1.5T (Figure ShMOLLI sequences provide an accurate assessment of T1 at 1.5T and 3.0T.This study was supported by the PHRC 2011-A00887-34.


Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). We hypothesized that chronic vagus nerve stimulation (VNS) could prevent left ventricular (LV) remodeling and dysfunction in a canine HF model induced by chronic mitral regurgitation (MR).After the MR inducing procedure, 12 survived canines were randomly divided into the control (n = 6) and the VNS (n = 6) groups. At month 2, a VNS stimulator system was implanted in all canines. From month 3 to month 6, VNS therapy was applied in the VNS group but not in the control group. At month 6, compared with the control group, the canines in VNS group had significantly higher cardiac output , and end-systolic stiffness constant . NT-proBNP and C-reactive protein were decreased significantly in the VNS group. However, no statistical difference was found in LV ejection fraction, LV end-diastolic dimension, LV end-diastolic volume, myocyte cross-sectional area, or collagen volume fraction between two groups.Chronic VNS therapy may ameliorate MR-induced LV contractile dysfunction and improve the expression of biomarkers, but has less effect in improving LV chamber remodeling. One of the key features of chronic heart failure (CHF) is the autonomic sympathetic/parasympathetic imbalance, which is usually characterized by excessive sympathetic drive accompanied by parasympathetic withdrawal ,2. It diCardiac sympathetic activation is increased in patients with CHF due to mechanical overload. By suppressing cardiac sympathetic activities, β-blockade had been demonstrated to be an effective treatment for contractile dysfunction caused by valvular heart disease . HoweverThe study was performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health  and was approved by the animal research committee of Fuwai hospital, Peking Union Medical College.Mitral valve regurgitation was induced by chordae rupture using a fluoroscopic guided catheterization method in 16 conditioned, 17 to 24 kg, male/female mongrel canines. Twelve canines survived at week 1 after the procedure and were randomized into the control (n = 6) and VNS (n = 6) groups. At the month 2, a bipolar cuff electrode was implanted around the right cervical vagus nerve and connected to a customized implantable pulse generator  in all canines. All animals were then closely monitored for a month without VNS therapy to allow sufficient recovery from the implantation procedure. At the month 3, consistent contractile dysfunction was observed in all 12 animals, which is consistent with previous reports . The VNSMitral regurgitation was created using the close-chest chordae rupture technique as described previously ,10. BrieRight cervical vagus nerve stimulators were implanted in both groups as previously described . BrieflyCanines were anesthetized with intravenous injection of pentobarbital (25 mg/kg). Then, animals were mechanically ventilated with oxygen (2 L/min) and anesthesia was maintained with halothane after intubation. Right or left femoral artery was used for catheterization. Two pigtail catheters were introduced into the LV and the ascending aorta. Mercury calibrated water-filled transducers were connected to the pigtail catheters. A multilumen thermodilution catheter was inserted into the left jugular vein and positioned in the pulmonary artery to measure cardiac output, pulmonary artery and pulmonary capillary wedge pressures. A 25-mm balloon catheter was introduced into the inferior vena cava through the same vein to monitor LV volume and pressure by inflating and deflating the balloon during ventriculography. After baseline measurements, a standard left ventriculogram using nonionic contrast (iohexol) was performed. After a 15-min equilibration, a second ventriculogram was taken and synchronized with balloon deflation so that beat-by-beat increases in both LV pressure and volume were recorded simultaneously . The preContractility is the inherent capacity of the myocardium to contract independently of changes in the preload or afterload. In vivo contractile function was assessed using the end systolic stiffness constant (K index). The K index has been investigated extensively in the past and its limitations are relatively well known. It has correlated well with an independent standard of contractile function-sarcomere function in isolated cardiomyocytes ,12. Dataa-SVf)/SVa] × 100, where SVa is stroke volume measured by angiography and SVf is forward stroke volume derived from actual cardiac output measured by thermodilution and heart rate. Wall stress was calculated using Mirsky’s formula [Ceκln(1/H), where ơ is end-systolic wall stress, C is a constant, κ is the end-systolic stiffness constant and ln(1/H) is the natural logarithm of the reciprocal of wall thickness [LV volume and mass were determined by the area-length method which was previously demonstrated to be able to provide accurate LV volume and mass in dogs with MR . The reg formula . The endhickness .Transthoracic 2-dimensional echocardiography was performed when canines were consciously lying on the table in the left lateral decubitus position. Standard 2-dimensional short- and long-parasternal views, as well as 4-chamber, 2-chamber, and 3-chamber apical views were obtained via standard procedure using a 3S transducer coupled to a Vivid 7 echocardiographic machine . LV end-diastolic and end-systolic volume, and ejection fraction were measured three times using a Simpson’s biplane method. The averages were used in the final data processing.Venous blood samples were collected and placed in ice-chilled tubes coated with EDTA. Plasma was separated for 15 minutes by 3000 rpm centrifugation at 4°C and stored at −80°C. The levels of NT-proBNP and CRP were measured by enzyme-linked immunosorbent assay .Paraffin-embedded tissue samples were cut at 5 μm thickness and stained with hematoxylin and eosin (H&E). The cardiomyocytes of which cross-sections contain a centrally located nucleus with intact cellular membrane  from H&EEpicardial and endocardial sections from the mid-LV wall were obtained and paraffin-embedded after the fixation, 5-μm thick paraffin sections were stained with Sirius red F3BA. Interstitial collagen was identified using light microscopy at high power . To evaluate the collagen volume fraction(CVF), about 3 sections from each animal were picked and 30–40 randomly selected fields in each section were used to calculate the mean ratio of connective tissue area to the total tissue area . The dout-test were performed using SPSS 16.0 statistical software). Proper and necessary data transformations (logarithmic or square root) were applied for non-normal distributed data prior to the statistical analysis. P value less than 0.05 was considered to be statistically significant in the test.Data are expressed as mean ± SEM. Both two-sided One-way ANOVA and two-sided Holm-Sidak post hoc max, LV end-diastolic volume (LVEDV) than those of the VNS group. There was no significant difference systemic blood pressure and RF between two groups at all observation periods.All canines were survived through the 6 months experimental period. The related LV function and hemodynamic data were summarized in Table The summary of LV ejection fraction (LVEF), K-index, cardiac output (CO) and forward stroke volume was showed in Figure The plasma NT-proBNP levels increased significantly in both the control group and the VNS group compared to the baseline while no significant changes between both groups at month 3 after the MR. However, at month 6, the NT-porBNP levels were significantly lower in the VNS group than the levels in the control group.Plasma CRP level also increased at 3 months of MR compared to the baseline while no significant difference between both groups. However, the CRP level was lower in the VNS group compared with the the control group at 6 months significantly Figure .Figure 2As shown in Figure The present study investigated the effects of chronic VNS on HF development in a chronic MR induced HF canine model. There were two major findings of this study. Firstly, VNS preserved LV contractile function and favorably altered cardiac biomarkers. To our best knowledge this is the first time to report that VNS is effective in the treatment of contractile dysfunction result from experimental chronic MR. Secondly, VNS in the present study failed to prevent the LV from hypertrophic and eccentric remodeling.max and K-index compared to non-treated control group after three month chronic MR. Furthermore, the PCWP and plasma NT-proBNP level were were remarkably decreased in the VNS group at month 6 compared with controls.The results from several pre-clinical investigations -7 supporConflicting results on the usage of renin angiotensin system (RAS) blockade and β-blockade therapy in MR model have been reported previously ,17. The Some of previous pre-clinical work  suggesteOne of the limitations of the present investigation is that it did not provide clear mechanisms on how VNS preserved LV systolic function during CHF with MR. In general, CHF is characterized by a deregulation of the immune response, and autonomic imbalance accompanied by concomitant abnormalities of reflex cardiorespiratory control. VNS can reverse autonomic sympathetic/parasympathetic imbalance and improve ventricular function and pumping efficiency by slowing HR. A previous study found that β-blockers ameliorate LV contractile dysfunction in experimental chronic MR by restoring cellular contractile elements . HoweverPrevious studies also suggested that VNS can suppress systemic inflammatory response through “the cholinergic anti-inflammatory pathway” ,22, whicCurrently, there is no single or multiple drug therapies available for the treatment of chronic MR that prevents adverse LV remodeling . In the The canine MR model is characterized by absence of fibrosis and dissolution of the fine collagen weave . The impA limitation to translating the present investigations to the clinical setting is creating MR by chordae rupture in our experimental model. This model may not similar to more gradually produced MR which might occur in rheumatic heart disease.Chronic VNS therapy ameliorates MR-induced LV contractile dysfunction and improves biomarkers of NT-proBNP and CRP. These findings provided additional supportive evidence for VNS therapy as promising therapy for CHF. In addition, the VNS might preserve LV systolic function by slowing HR during CHF.