The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.We present the first  This report describes myocardial perfusion reserve abnormality in Freidreich's ataxia (FA), a heritable disorder whose major manifestations are neurological and myocardial disease. In more than 90% of cases, this autosomal recessive condition results from excess of DNA triplet repeats (GAA) in the first intron at the end of exon 1 leading to suppression of FRDA (frataxin) gene expression. Around 5% of patients have a point mutation in the frataxin gene; both forms result in a deficiency of the protein frataxin that is located in the inner mitochondrial membrane, neitherA 26 year-old nonsmoking Middle Eastern woman presented for evaluation of exertional chest pain and shortness of breath. The past medical history was notable for genotype-proven Friedreich's ataxia (FA) diagnosed at age 19 that had produced ambulatory limitation with frequent falls due to her ataxia. Genotyping showed 846GAA repeats  consistent with FA. Family history revealed extensive affected members and carriers  with a 12-channel phased array coil. Resting steady-state free precession cine imaging showed normal left ventricular (LV) size and systolic function, with LV end-systolic volume 21 cc/mBased on the reproduction of chest pain with adenosine stress and accompanying perfusion abnormality, she was referred for invasive coronary angiography. This showed angiographically normal epicardial coronary arteries Figure  and normIn summary, we identified impaired microcirculatory reserve in FA using CMR that occurred in the absence of epicardial coronary artery disease. Friedreich's ataxia is a neurodegenerative condition frequently accompanied by cardiomyopathy due to a mutation in the gene frataxin, resulting in intra-mitochondrial accumulation of iron. The predilection for neuromuscular and myocardial involvement in FA reflects the high energy demands of both systems.et al. using positron emission tomography; their work suggested that compensation for impaired energetics in FA occurs by increasing myocardial oxygen consumption rather than myocardial blood flow, though this study was conducted under resting conditions only[Prior magnetic resonance-based evaluation of FA cardiomyopathy has focused on cardiac magnetic resonance spectroscopy  or quantions only.The detection of subendocardial perfusion abnormality afforded by adenosine CMR is similar to that described in other conditions such as syndrome X and coarctation of the aorta,7, thougThe author(s) declare that they have no competing interests.


Left ventricular hypertrophy (LVH) is common in patients with end-stage renal disease (ESRD) and an independent risk factor for premature cardiovascular death. Left atrial volume (LAV), measured using echocardiography, predicts death in patients with ESRD. Cardiovascular magnetic resonance (CMR) imaging is a volume-independent method of accurately assessing cardiac structure and function in patients with ESRD.Single-center prospective observational study to assess the determinants of all-cause mortality, particularly LAV, in a cohort of ESRD patients with LVH, defined using CMR imaging.2 (men) or >74.6 g/m2 (women) based on published normal left ventricle dimensions for CMR imaging. Maximal LAV was calculated using the biplane area-length method at the end of left ventricle systole and corrected for body surface area.201 consecutive ESRD patients with LVH  who had undergone pretransplant cardiovascular assessment were identified using CMR imaging between 2002-2008. LVH was defined as left ventricular mass index >84.1 g/mCMR abnormalities, including LAV.All-cause mortality.2 . Patients were grouped into high (median or higher) or low (less than median) LAV. There were no significant differences in heart rate and mitral valve Doppler early to late atrial peak velocity ratio. Increased LAV was associated with higher mortality. Kaplan-Meier survival analysis showed poorer survival in patients with higher LAV (log rank P = 0.01). High LAV and left ventricular systolic dysfunction conferred similar risk and were independent predictors of death using multivariate analysis.54 patients died (11 after transplant) during a median follow-up of 3.62 years. Median LAV was 30.4 mL/mOnly patients undergoing pretransplant cardiac assessment are included. Limited assessment of left ventricular diastolic function.Higher LAV and left ventricular systolic dysfunction are independent predictors of death in ESRD patients with LVH. Patients with end-stage renal disease (ESRD) have an increased risk of premature cardiovascular disease.LVH is present in approximately 67% of patients with ESRDPrevious studies measuring left ventricular mass index (LVMi: defined as left ventricular mass corrected for body surface area [BSA]) in patients with ESRD have used echocardiography. However, estimation of LVMi is inaccurate because of changes in intravascular volumes during the inter- and intra-dialytic period and during dialysis and geometric assumptions that rely on intraventricular diameter to calculate LVMi using conventional echocardiography.Left atrial dilation (corrected for BSA or height) measured using echocardiography is an independent predictor of mortality in the general population, and in patients with hypertension and ESRD.This was a single-center prospective observational study to assess the determinants of all-cause mortality, particularly LAV, in a cohort of patients with ESRD with LVH defined using CMR.The Renal Transplant Unit at the Western Infirmary, Glasgow, provides transplant services to a population of 2.8 million people in the West of Scotland.Since 2002,All patients receiving maintenance hemodialysis therapy from our unit were studied on a nondialysis day with the aim to perform all investigations at the individuals' “dry weight.” Only patients with evidence of LVH on CMR imaging were entered into the study. To ensure that only nonvalvular causes of left atrial dilation were assessed, patients with mild to severe mitral valve disease on echocardiography, based on American Society of Echocardiography guidelines,All-cause mortality was the principle outcome in this study. To characterize factors associated with death, demographic information, past clinical history (at time of CMR scanning), and CMR measurements were recorded.www.medical.siemens.com) to assess LVM and function.Non–gadolinium-enhanced CMR imaging was performed using a 1.5-Tesla magnetic resonance imaging scanner  or >76.4 g/m2 . LVSD was defined as left ventricular ejection fraction <55%, and left ventricular dilation was defined as end-diastolic volume (EDV)/BSA >111.7 mL/m2  or >99.3 mL/m2  or end-systolic volume (ESV)/BSA >92.8 mL  or >70.3 mL .LVM and LAV were analyzed by 2 observers (R.K.P. and A.G.M.J.) blinded to patient clinical characteristics. LVM was measured from short-axis cine loops using manual tracing of epicardial and endocardial end-systolic and end-diastolic contours, calculated using analysis software , and indexed for BSA (thus providing LVMi). According to established normal values,The biplane area-length method for ellipsoid bodies was used to measure LAV.Echocardiography was performed by an experienced echocardiographer (A.F.C.) using an Acuson Sequoia C512 machine . Diastolic function was assessed using pulsed-wave Dopplerwww.spss.com).Data are described as mean ± standard deviation for normally distributed data) or median and interquartile range (IQR) for non-normal data. Survival data including survival time (mean ± SD) are shown as Kaplan-Meier graphs . These data were also analyzed using Cox multivariate survival analysis to assess the influence of multiple clinical and cardiac variables on outcome. Variables identified as significantly influential on outcome by univariate analysis were entered into a backward stepwise regression model. All analyses were performed using SPSS, version 15.0 .Seventy-one patients received a kidney transplant during the study period. There were 54 (26.9%) deaths during a 6.65-year follow-up period. Eleven deaths occurred after kidney transplantation. Overall survival at 12, 24, 36, 48, and 60 months was 92%, 87%, 79%, 77%, and 74%, respectively. Median LAV/BSA was 30.4 mL/mTo identify determinants and consequences of increased LAV, we divided patients into high LAV  or low LAV  patients had LVSD and 49 (24.4%) had left ventricular dilation. Doppler mitral valve inflow velocity measurement showed a mean peak E wave velocity of 0.74 ± 0.2 cm/s, mean peak A wave of 0.75 ± 0.2 cm/s, and E:A ratio of 1.04 ± 0.5.Examining the entire cohort , mean heWe also compared structural CMR imaging and mitral valve echocardiography Doppler results between the low- and high-LAV groups. There were no significant differences between heart rate during CMR imaging, ejection fraction, left ventricular myocardial mass, EDV/BSA, ESV/BSA, and number of patients with LVSD or left ventricular dilation between groups. As a basic marker of diastolic function, Doppler mitral valve inflow velocity measurement showed no difference in E:A ratios between the low- and high-LAV groups.P = 0.01. Furthermore, increasing LAV was associated significantly with poorer prognosis (P = 0.01).We initially examined the effect of left atrial and ventricular abnormalities on patient survival. Divided into quartiles, increasing LAV was significantly associated with higher mortality: quartile (Q)1, 5 (10.0%) deaths; Q2, 13 (26.0%) deaths; Q3, 17 (34.0%) deaths; and Q4, 19 (37.3%) deaths; P = 0.02). Left ventricular dilation was associated with a non-significant decrease in patient survival .Similarly, LVSD was associated with a significant reduction in mean survival time  was less common in male patients. This differs from previous studies that have shown removal of sex-related differences in LAV when corrected for body size. Neither sex nor BSA had an effect on survival in our analyses. There was no significant difference in cardiovascular disease history between groups (greater or less than median LAV). Furthermore, heart rate, LVEF, LVMi, and left ventricle chamber size (at end-diastole and end-systole) were similar in both groups. This suggests that left atrial size was not a marker of reduced diastolic filling time or impaired left ventricular systolic emptying.In the survival analysis, higher LAV was significantly associated with poorer survival A. MultivThese data confirm previous studies investigating LAV and survival.In the present study, LAV was not significantly correlated with LVM, suggesting that increased LAV is not caused solely by impaired atrial emptying into a large, poorly compliant, left ventricle. In other patient populations, increased LAVs are considered to reflect the long-term effects of increased ventricular filling pressures.A decrease in LAV has been achieved in patients with mitral valve disease and atrial fibrillationWe have previously shown that LVSD is associated with (often asymptomatic) ischemic heart disease and, in turn, poorer survival.In contrast to previous studies using echocardiography to assess left ventricular dimensions,We accept that this study has some limitations. Patients recruited to this study were being assessed for kidney transplantation and may not be representative of all patients with ESRD. However, since these patients were considered healthy enough to be considered for a kidney transplant, we believe these results would be relevant to other patients with more significant comorbid conditions. In addition, we obtained limited information regarding ventricular diastolic function in our cohort and hopefully, as more detailed methods  are utilized, these data will become available.In conclusion, in ESRD patients with LVH, increased LAV and the presence of LVSD are independent predictors of death and may provide novel factors that may be amenable to modification to improve cardiovascular prognosis.


Self-gated dynamic cardiovascular magnetic resonance (CMR) enables non-invasive visualization of the heart and accurate assessment of cardiac function in mouse models of human disease. However, self-gated CMR requires the acquisition of large datasets to ensure accurate and artifact-free reconstruction of cardiac cines and is therefore hampered by long acquisition times putting high demands on the physiological stability of the animal. For this reason, we evaluated the feasibility of accelerating the data collection using the parallel imaging technique SENSE with respect to both anatomical definition and cardiac function quantification.Findings obtained from accelerated data sets were compared to fully sampled reference data. Our results revealed only minor differences in image quality of short- and long-axis cardiac cines: small anatomical structures  and left-ventricular (LV) remodeling after myocardial infarction (MI) were accurately detected even for 3-fold accelerated data acquisition using a four-element phased array coil. Quantitative analysis of LV cardiac function (end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass) in healthy and infarcted animals revealed no substantial deviations from reference (fully sampled) data for all investigated acceleration factors with deviations ranging from 2% to 6% in healthy animals and from 2% to 8% in infarcted mice for the highest acceleration factor of 3.0. CNR calculations performed between LV myocardial wall and LV cavity revealed a maximum CNR decrease of 50% for the 3-fold accelerated data acquisition when compared to the fully-sampled acquisition.We have demonstrated the feasibility of accelerated self-gated retrospective CMR in mice using the parallel imaging technique SENSE. The proposed method led to considerably reduced acquisition times, while preserving high spatial resolution at sufficiently high CNR. The accuracy of measurements of both structural and functional parameters of the mouse heart was not compromised by the application of the proposed accelerated data acquisition method. In view of increasing availability of genetically engineered strains, mouse models of human disease have become important tools for the study of pathophysiological mechanisms and the evaluation of novel therapies. A remarkable number of such transgenic models have been developed mimicking aspects of cardiovascular pathologies such as heart failure and myocardial infarction (MI). Phenotyping of disease models commonly includes investigation of the morphology and function of the heart, preferentially using non-invasive imaging methods such as cardiovascular magnetic resonance (CMR), computed tomography (CT)  and echoCardiac MR images can be acquired following two different strategies: either using the prospective approach -9, i.e. In recent reports, self-gated cardiac imaging methods have been demonstrated to be a valuable tool for cardiac MR imaging in small rodents ,13, sincAccelerating self-gated cardiac imaging is therefore of high interest as demonstrated in clinical studies . So-callIn this work the feasibility of accelerating self-gated cardiac imaging for assessing ventricular function in mice has been evaluated. In a first step, SENSE accelerated self-gated CMR has been adapted and optimized in order to assess morphological and functional parameters of the normal mouse heart. Subsequently, the method has been applied to self-gated CMR in mice subjected to experimental MI one week prior to the examination. The sensitivity of non-accelerated (fully sampled) self-gated retrospective CMR data in detecting structural and functional alterations due to MI was compared with that of accelerated acquisitions. Acceleration factors of up to 3.0 were investigated, resulting in a substantial decrease of the data acquisition time . For detailed comparison, contrast-to-noise ratios (CNRs) of myocardial wall as well as functional heart parameters such as left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass have been calculated and compared between datasets derived from non-accelerated (acquisition time: 18.7 min) and accelerated scans (acquisition time: 6.2 min for three-fold acceleration).All animal experiments were carried out in strict adherence to the Swiss law for animal protection. CMR acquisitions were performed in eight healthy and six infarcted female C57Bl/6J mice showing average body weights of 24.0 ± 2.1 g. MI was induced by permanent ligation of the left anterior descending coronary artery. The surgical intervention was performed as described in detail in literature ,17. The 2 (4:1) and positioned on a cradle made of PMMA comprising a built-in warm water circuit. Animals were freely breathing and carefully positioned with the heart resting on the center of the RF receive coil. Body temperature was measured using a rectal temperature probe . Special care was taken to maintain body temperature at 36 ± 0.5°C. During the experiments anesthesia was maintained using a reduced level of isoflurane (1.6%). Mean heart and mean respiratory rates of the animals were estimated retrospectively form the acquired navigator signal yielding 498 ± 46 beats/min and 85 ± 16 breaths/min, respectively.For CMR experiments, mice were anesthetized with an initial dose of 3% isoflurane  in air:O2, total outer dimensions: 26 × 21 mm2) for signal reception. The coil elements were bent to a cylindrical surface (radius = 10 mm) with the axis parallel to the main magnetic field direction. The proximity of the four coil elements allowed large acceleration factors (up to three-fold acceleration) without considerably degrading image quality as each part of the imaging slice provided enough signal in all four coil elements.All experiments were performed using a Bruker Pharmascan 47/16  small animal MR system operating at 200 MHz with a gradient system capable of switching 350 mT/m in 200 μs. A volume resonator  operating in quadrature mode was used for excitation and a four element (2 × 2) phased array surface coil  = 1.6/5.2 ms, number of repetitions (NR) = 200, total acquisition time = 18.7 min. Inflowing blood was saturated in a slice of 5.0 mm thickness parallel to the imaging stack with a saturation pulse angle of 60° and carefully placed at the inflow tract of the ventricles with a gap of 0.5 mm between saturation slice and first imaging slice. In addition, the navigator signal was derived from the saturation slice prior to the excitation of the cardiac imaging slices. Cardiac data were collected either in a non-accelerated manner (full k-space sampling) or accelerated in phase encoding direction (reduced k-space sampling). Acceleration factors (R) used were 1.5, 2.0, 2.5 and 3.0, resulting in total acquisition times of 12.4 min, 9.4 min, 7.5 min and 6.2 min, respectively.Scout images of the heart anatomy were acquired for accurate planning of the subsequent cine cardiac scans. Black-blood short-axis images covering the entire left ventricle were acquired using the self-gating technique IntraGate , which is based on a fast low-angle shot (FLASH)  multisli2, matrix dimension = 288 × 288, spatial resolution = 83 × 83 μm2, slice thickness = 1.0 mm, pulse angle = 15°, echo/repetition time (TE/TR) = 2.7/10 ms, number of repetitions (NR) = 300. The navigator slice was positioned at the same location as the imaging slice with a slice thickness of 1 mm. Heart data were acquired for acceleration factors of 1.0, 2.0 and 3.0, corresponding to scan durations of 14.4 min, 7.2 min and 4.8 min, respectively.In addition, the feasibility of accelerated data collection was investigated for cardiac cine images acquired in cardiac long axis orientation using a self-gated bright-blood sequence with the following parameters: FOV = 24 × 24 mmCardiac cine images were reconstructed by using the collected navigator information within the IntraGate software to assign the acquired k-space lines to ten cardiac frames and one respiratory frame, retrospectively.2, matrix dimension = 154 × 50, spatial resolution = 162 × 500 μm2, slice thickness = 1.0 mm, pulse angle = 10°, TE/TR = 1.4/4.1 ms, NR = 130, total scan time = 1.6 min. Calculation of sensitivity maps was performed by dividing the time-averaged single coil images by the corresponding reference images. To exclude regions of mere noise from the calculation process and for extrapolation of sensitivity maps by region growing, a signal mask was calculated using a noise level adapted threshold according toCoil sensitivity maps utilized for the SENSE reconstruction process were estimated from separate gradient echo low-resolution scans: FOV = 25 × 25 mmMEAN(SNoise) and SD(SNoise) represent mean and standard deviation of signal originating from a region-of-interest (ROI) placed in an image region exhibiting pure noise.where As the volume resonator could only be operated in transmission mode, the magnitude of the reference image was calculated as the sum-of-squares (SOS) of the single coil images and the corresponding phase according to the method proposed by de Zwart et al. . The noiValidation and optimization of the proposed accelerated CMR acquisition and reconstruction method was first performed in the healthy animals: CNR analyses as well as the calculation of EDV, ESV, SV and EF were carried out in order to investigate the possible effects of accelerated data collection on image quality and on the accuracy of image derived cardiac parameters. Subsequently, the optimized acquisition and reconstruction parameters were utilized to investigate the sensitivity of the proposed accelerated CMR method in assessing myocardial remodeling induced by MI in six diseased animals.0.6 • MEAN(SLeft Ventricle), where MEAN(SLeft Ventricle) represents the average signal intensity of the whole left ventricle. The threshold value for intensity based image segmentation was optimized by comparing the LV volumes obtained from the MR data with references volumes from literature  were performed for the LV functional parameters EDV, ESV, SV, EF and LV mass.where Finally, in order to assess reproducibility of our proposed method, inter- and intra-observer variability measurements were performed by two independent observers as well as twice by one observer for all investigated cardiac functional parameters for R = 1.0 and R = 3.0.2) and excellent contrast between LV myocardial wall and LV cavity were obtained for all investigated acceleration factors. Representative images of a mid-ventricular short-axis view of the left and right ventricle of a healthy mouse heart are shown in Figure High-resolution short-axis cardiac black-blood images depicting the heart anatomy with high anatomical definition  and valve (AV) as well as the pulmonary artery (PA) for all investigated acceleration factors R. In particular, the good definition of the AV is remarkable as illustrated by the magnified views  was carried out in eight healthy animals. The analyzed parameters were calculated for each animal and for all investigated acceleration factors Table . Deviati2 = 0.85 and 0.75 have been obtained for LV cavity areas during end-diastole and end-systole, respectively, with corresponding slopes of regression line of 0.99 ± 0.02 and 1.02 ± 0.03  from the reference values obtained from the R = 1.0 reference datasets was analyzed for all investigated acceleration factors according to Eq. [3]. Using the absolute value of differences, i.e. Eq. [3], allowed to avoid possible averaging effects when calculating the mean values of the different LV parameters. The results are summarized in Figure PLV of 6% was found for the ESV for an acceleration factor of R = 3.0. All other mean deviations estimated for EDV, SV and EF were found to be < 5% demonstrating that acceleration of data acquisition did not significantly compromise the accuracy of morphometric measurements.Finally, the mean deviation of the various functional parameters  are summarized in Figure PLV were found for the SV and EF for an acceleration factor of R = 3.0 amounting to 8.4% and 8.1%, respectively. The maximum mean deviations estimated for EDV and ESV were found to be 2.9% and 3.2%, respectively, for an acceleration factor of R = 3.0. The higher ΔPLV values for SV and EF are due to the fact, that relatively high EDV (84 - 88 μl) and ESV (66 - 68 μl) values were obtained from the LV function assessment, whereas SV (17 - 19 μl) and EF (22% - 24%) values, which were derived from the difference of EDV and ESV and the ratio of SV and EDV, resulted to be relatively small and hence led to comparatively large deviations ΔPLV.The mean deviations of the functional parameters  could be found for all calculated cardiac functional parameters.Self-gated CMR has been shown to yield accurate structural and functional measures of the mouse heart ,13. Yet,CNRWall-Cavity calculated between LV myocardial wall and LV cavity  derived from accelerated acquisitions from values obtained from fully-sampled data  allowing for high spatial resolution in all three dimensions would have beneficial effects on the depiction of the cardiac anatomy and the derivation of cardiac functional parameters by minimizing partial volume effects. On the other hand, increasing spatial resolution has the drawback of increased scan durations, making the application of the proposed accelerated acquisition method even more attractive. In plane spatial resolution in the current study was 83 × 83 μmThe sensitivity issue can be addressed by applying the SENSE based accelerated data acquisition method to 4D self-gated retrospective CMR. Furthermore, the spatial encoding efficiency of a receiver array is enhanced for 3D imaging since acceleration can be done in both phase encoding directions . FinallyIn conclusion, we have demonstrated the feasibility of accelerating self-gated retrospective CMR in mice using the parallel imaging technique SENSE in combination with a four-element phased array surface coil for signal detection. The accuracy of the accelerated acquisition allows identification of small anatomical heart structures such as the papillary muscles and the aortic valve as well as a reliable quantification of left ventricular function. Accelerating data collection using SENSE led to considerably reduced acquisition times (up to factor 3.0), while preserving high spatial resolution at sufficiently high CNR, a prerequisite for accurate calculation of cardiac functional parameters. Finally, quantitative analysis of cardiac function and assessment of myocardial remodeling in infarcted animals was successfully performed demonstrating the feasibility of the developed method to follow disease progression and therapy.The authors declare that they have no competing interests.DR and CB were responsible for study design, implementation of the accelerated self-gated CMR method, for data acquisition and analysis and for manuscript preparation. CD was responsible for inducing myocardial infarction in the investigated animals. MR has supervised the project and contributed to the manuscript. All authors have read and approved the final version of the manuscript.


Trastuzumab (Herceptin), an antagonist to the human epidermal growth factor 2 (HER2) receptor significantly decreases the rates of breast cancer recurrence and mortality by 50%. Despite therapeutic benefits, the risk of cardiotoxicity with trastuzumab ranges from 10–15% when administered sequentially following anthraycline chemotherapy. Little is known about the utility of cardiac magnetic resonance (CMR) in the assessment of trastuzumab mediated cardiomyopathy.Between 2005–2006 inclusive, 160 breast cancer patients were identified at a single tertiary care oncology centre. Of the total population, 10 patients (mean age 40 ± 8 years) were identified with trastuzumab induced cardiomyopathy, based on a LVEF less than 40% on serial MUGA or echocardiography. CMR was performed in all patients to determine LV volumes, systolic function and evidence of late gadolinium enhancement (LGE). At the time of diagnosis of trastuzumab induced cardiomyopathy, the mean LVEF was 29 ± 4%. Subepicardial linear LGE was present in the lateral portion of the left ventricles in all 10 patients.LGE-CMR is a novel way of detecting early changes in the myocardium due to trastuzumab induced cardiotoxicity. Breast cancer is a major public health concern that affects 1 in 7 women in their lifetime . Recent Serial multiple gated acquisition scans (MUGA) are widely used to monitor cardiac dysfunction in breast cancer patients. However, with the improvement in both spatial and temporal resolution of cardiac magnetic resonance (CMR) over the past decade, it has now become the gold standard for the non-invasive assessment of left ventricular (LV) systolic dysfunction. Additionally, late gadolinium enhancement (LGE) can detect myocardial scarring. Although frequently used in the assessment of dilated cardiomyopathies secondary to ischemia or myocarditis , little Between 2005–2006 inclusive, 160 breast cancer patients who received trastuzamab in addition to anthracyline based adjuvant therapy were identified at a tertiary care oncology centre. All patients received FEC  for a total of 6 cycles. The mean duration between completion of chemotherapy and initiation of trastuzumab was 2 ± 1 months. Of the total population, 10 patients were identified with trastuzumab induced cardiomyopathy based on LV ejection fraction less than 40% on either serial MUGA or echocardiography. The medical records of all 10 patients were extensively reviewed for baseline demographic data. The retrospective study was approved by the local institutional review board.CMR was performed on all 10 patients using a 1.5 T scanner . Morphologic images in the cardiac short axis, 4 chamber long axis and 2 chamber long axis planes were acquired using IR-prepared dark blood HASTE sequences . In the same planes, cine-CMR was performed using a breath-hold balanced steady state free precession sequence . The cine-CMR short-axis images encompassed the entire LV from the base to the apex  to obtain a left ventricular ejection fraction (LVEF). Late gadolinium enhancement was performed after 10 minutes of 0.2 mmol/kg injection of Gadolinium  using a T1-weighted IR-prepared multislice TrueFISP sequence with magnitude and phase sensitive reconstruction. Images were acquired sequentially in the short axis, followed by horizontal and vertical long axis images .The total population included 10 patients  with normal LVEF at baseline and preserved systolic function following administration of anthracycline based chemotherapy using serial MUGA scans  is a relatively new chimerized monoclonal antibody that targets the extracellular portion of the HER2 membrane protein. Previous studies have demonstrated that trastuzumab provides considerable therapeutic benefits, when added to conventional anthracycline chemotherapy, in decreasing the rates of disease recurrence and death in HER2 overexpressed metastatic breast cancers -6. DespiVarious theories have been suggested regarding the possible pathogenetic origin of trastuzumab induced cardiomyopathy. These include potentiation of anthracycline induced cardiotoxicity and immune mediated destruction of cardiomyocytes . There iThe use of CMR for the non-invasive characterization of trastuzumab induced myocarditis is novel. Whereas CMR has become the standard diagnostic test in the evaluation of suspected myocarditis ,12, to dLate gadolinium enhancement using CMR is a novel way of detecting early changes in the myocardium due to trastuzumab induced cardiotoxicity. Future studies are required to validate identification of positive delayed enhancement using CMR as a subclinical marker for future LV dysfunction in this select population. Early detection of LV dysfunction using LGE-CMR may allow one to adjust treatment with trastuzumab prior to the development of irreversible heart failure.The author(s) declare that they have no competing interests.


Cardiac allograft rejection and vasculopathy are the main factors limiting long-term survival after heart transplantation.In this pilot study we investigated whether non-invasive methods are beneficial to detect cardiac allograft rejection (Grade 0-3 R) and cardiac allograft vasculopathy. Thus we compared multi-slice computed tomography and magnetic resonance imaging with invasive methods like coronary angiography and left endomyocardial biopsy.10 asymptomatic long-term survivors after heart transplantation  were included. In a blinded fashion, coronary angiography and multi-slice computed tomography and ventricular endomyocardial biopsy and magnetic resonance imaging were compared against each other.2 = 0.85, p < 0.05) with the histological diagnosis of transplant rejection revealed by myocardial biopsy. None of the examined endomyocardial specimen revealed cardiac allograft rejection greater than Grade 1 R.Cardiac allograft vasculopathy and atherosclerosis were correctly detected by multi-slice computed tomography and coronary angiography with positive correlation (r = 1). Late contrast enchancement found by magnetic resonance imaging correlated positively (r = 0.92, rA combined non-invasive approach using multi-slice computed tomography and magnetic resonance imaging may help to assess cardiac allograft vasculopathy and cardiac allograft rejection after heart transplantation before applying more invasive methods. Since the development of heart transplantation for treatment of end-stage heart failure, the early diagnosis of transplant rejection has become essential. Regular follow-up contributes to detection of complications like coronary allograft vasculopathy and chronic transplant rejection which can result in significant graft coronary artery disease or myocardial fibrosis with loss of contractility. Coronary allograft vasculopathy is usually clinically silent and therefore presents a diagnostic challenge; because of continued denervation in the majority of heart transplants, any occurrence of myocardial ischemia in those grafts is asymptomatic with angina being rarely. They might manifest sequelae of coronary artery disease, including signs of congestive heart failure or loss of transplant function, or they may experience arrhythmias or sudden death.Current diagnostic standards for the diagnosis of cardiac vasculopathy are invasive coronary angiography and for acute or chronic transplant rejection endomyocardial biopsy . EndomyoOur present pilot study was performed to analyze the relationship between the results from magnetic resonance imaging and those from endomyocardial biopsy respectively the end-points cardiac transplant rejection and its degree of severity. Further we conducted this study to investigate the relationship between the results from coronary angiography and those from the multi-slice spiral computed tomography respectively the end-points cardiac transplant vasculopathy and its degree of severity. The results should clarify if the non-invasive approach is reliable and could be superior in long time survivors after heart transplantation.The routine follow-up consisted of clinical examination, blood testing, electrocardiogram and echocardiography and chest X-ray every three months.Routine blood testing consisted of red and white blood count with differential haemogram and cardiac enzymes (creatinin-kinase with its isoenzyme CK-MB and Troponine I). The parameters for liver , renal function  and coagulation  were part of the routine. Further serum analyses were lipids , electrolytes  and CRP. To rule out any infectious diseases virologic analyses with PCR were performed to detect cytomegaly virus, hepatitis A-E virus, herpes simplex, varicella zoster virus and human herpes virus 4. Finally the serum levels of the immunosuppressive drugs (cyclosporine A or mycophenolate) were analysed.This summarizes analyses of sputum, pharyngeal smear and urine to assess any bacterial, viral or fungal infections.A 12-lead electrocardiogram was part of the basic follow-up.To assess the patient's heart valves, ejection fraction and to rule out any vegetations and pericardial effusion patients were examined lying on their left side on the examination table. The images were displayed on a monitor and were recorded. Ultrasound device and probe Chest X-ray was routinely performed to evaluate the chest wall, lungs and heart.Transvenous endomyocardial biopsying was performed only as clinically indicated for systematic control or in case of suspected rejection. The systematic controls were performed at the following rates: at two-week intervals for the first four months following transplantation, then at monthly intervals until the end of the first year and finally at two-month intervals during the second year. After this period biopsying was performed in two year intervals.2. 4/10 patients had an impaired renal function with serum urea levels between 50 and 100 mg/dl and serum creatinine levels between 1.2 and 1.7 mg/dl. 5/10 patients were still carrying out their professions on a daily base of 6-8 hours. The basic medication of all patients consisted of β-blockers, angiotensin converting enzyme inhibitors, statins, diuretics and the antiplatelet agent acetyl salicylic acid 100 mg per day. The immunosuppressive medication consisted in 8/10 patients of cyclosporin A and 2/10 patients received mycophenolate additionally. All patients were free of glucocorticoids.10 patients  were included in our study  a myocardial biopsy was obtained within one week of magnetic resonance imaging; 2) no intravenous treatment for acute rejection had been given in the week preceding magnetic resonance imaging or in the period between magnetic resonance imaging and myocardial biopsy; and 3) the patients were not identified as having a chronic transplant rejection at the time of these investigations.Further in the present study the relationship between the results from coronary angiography and those from the multi-slice spiral computed tomography, multi-slice spiral computed tomography investigations were retrospectively selected according to the following criteria: 1) coronary angiography was performed within one week of multi-slice spiral computed tomography; 2) no intravenous treatment for acute rejection had been given in the week preceding multi-slice spiral computed tomography or in the period between multi-slice spiral computed tomography and coronary angiography; and 3) the patients were not identified as having a chronic transplant rejection at the time of these investigations.Cardiologists performing the coronary angiography and endomyocardial biopsy, radiologists performing the multi-slice spiral computed tomography and magnetic resonance imaging and the pathologists performing the immunohistochemical analyses on the endomyocardial biopsies were blinded to the results of the different examinations.Standard (X-ray) coronary angiography was performed according to standard procedures. Stenosis severity was evaluated by quantitative coronary analysis . Coronary angiography was performed in all patients.Diffuse atherosclerosis was defined by wall irregularities in coronary angiography. Lesions with a diameter stenosis > 50% were considered to be significant and classified as a significant stenosis or coronary artery disease.3 under X-ray guidance. The obtained specimens were fixed in formaldehyde.Left ventricular endomyocardial biopsying (3 specimens per patient) could be performed in 9/10 patients. Endomyocardial biopsies were gained from three different regions of the left ventricular apex with a Cordis™ biotome with a jaw volume of 5.20 mmThe fixed biopsies were embedded in paraffin, stained with Masson's trichrome and hematoxylin-eosin and examined by light microscopy. For immunohistological identification of cardiac immune cells 5 μm tissue sections were treated with avidin-biotin immunoperoxidase , applying monoclonal antibodies: CD3 , PGM1, HLA-DR . Graft rejection was classified according to the working formulation of the International Society for Heart and Lung Transplantation (ISHLT) [Multi-slice spiral computed tomography was performed by using a Sensation 16 Speed 4 D™  scanner. This technique allows the application of dedicated spiral algorithms that provide up to 185 ms of temporal resolution. electrocardiogram-gated heart phase selective imaging reconstruction was used in all patients. As all our heart transplant patients received β-blockers, no further β-blockade prior to the multi-slice spiral computed tomography scan was performed. After a low dose precontrast spiral scan  with simultaneously recorded electrocardiogram signal, a test bolus of 20 ml of contrast medium and a chaser bolus of 20 ml of physiological saline solution were injected through an 18-gauge catheter into an antecubital vein to determine the circulation time. The following scan protocol was used: 0.75 mm collimation, caudocranial scan direction, 80 cc contrast media (400 mg Iodine/cc) with a biphasic injection protocol (50 ml at 4 ml/s and 30 ml at 2.5 ml/s), gantry rotation time 370 ms, temporal resolution 185 ms, effective slice thickness 1.0 mm, 120 kV, approximately 650 mAs. All scans could be performed within one single breath-hold (15-20 s). Algorithms optimized for retrospective electrocardiogram-gated multi-slice spiral computed tomography were used for reconstructing the raw data. Image reconstruction was performed in the diastolic phase with a relative retrospective gating between 20% and 75% of the RR-interval. Multi-slice spiral computed tomography radiation dose was approximately 6 mSv.The reconstructed data of the multi-slice spiral computed tomography were transferred to a computer workstation for further processing The scans were evaluated by two independent radiologists blinded to clinical data coronary angiography and biopsy results in a joint reading. Data were analysed on an offline workstation for postprocessing . Coronary calcifications were assessed on native scans and quantified by determining the total calcium mass expressed in mg of calcium hydroxyapatite (CaHa). Morphological changes with resulting narrowing of the coronary artery diameter served as another criterion to assess coronary artery disease. Lesions with a diameter stenosis > 50% were considered to be significant and classified as a significant stenosis or coronary artery disease.Magnetic resonance imaging could only performed in 7/10 patients includes into this study. 3 patients were excluded due to contraindications (implanted pacemakers). Total measurement time for magnetic resonance examinations was within 45 minutes in all patients. Electrocardiogram-triggered cardiac magnetic resonance examinations were performed on a 1.5T MR scanner . Cine images , T1 weighted turbo spin echo images  and T2 weighted turbo spin echo images , as well as delayed enhancement images using an inversion recovery-TurboFLASH sequence  were acquired in the three main cardiac axes. Cine short axis sections were recorded from base to apex for subsequent functional evaluation. For post contrast/delayed enhancement images there was a delay of 15 minutes between injection of 0.15 mmol Gadolinium-DTPA/kg body weight  and image acquisition. Inversion time was adjusted in order to minimize signal of normal myocardium.The scans were evaluated by two independent radiologists blinded to clinical data, multi-slice computed tomography, coronary angiography and biopsy results in a joint reading. Electrocardiogram-triggered cardiac magnetic resonance imaging examinations were performed on a 1.5 Tesla magnetic resonance scanner . Ejection fraction was calculated using short axis cine images. T1 weighted images, T2 weighted images and late contrast enhancement images were assessed later ,7. The fContinuous variables are described as means and standard error of mean. We used Prism 5.0™  for the analyses. Comparisons between discrete variables and comparisons between proportions were made by calculating the Pearson product-moment correlation coefficient. For all tests, a p value ≤ 0.05 was considered to be indicative of a significant difference.By coronary angiography and multi-slice spiral computed tomography lesions in the epimyocardial vessel segments could be correctly detected in all patients Table . 2 patieThe results of coronary angiography and multi-slice spiral computed tomography correlated positively with a Pearson coefficient r = 1.2 = 0.1, p = 0.4).No significant correlation could be demonstrated between the Calcium mass and the degree of severity of the coronary lesion  mild transplant rejection (Grade 1 R) was evident. In none of the patients a rejection greater than Grade 1 R existed2 = 0.85, p < 0.05).There was a significant correlation between the results of the magnetic resonance imaging late left ventricular enhancement sequences and the left ventricular endomyocardial biopsies (p < 0.05). Furthermore, the endomyocardial biopsy results respectively the histologically determined degree of rejection correlated positively with the late left ventricular enhancement confirming fibrosis .Another significant correlation existed between the results of the magnetic resonance imaging late left ventricular enhancement sequences and the number of prior acute transplant rejections -diethyltriaminepentaacetic acid (Gd-DPTA) does not accumulate in the intracellular or interstitial space. Gd-DPTA accumulation may reflect an increase of interstitial space of inflammatory and fibrotic tissue as well as different wash-out kinetics in those areas. Gd-DPTA late enhancement is a tissue- or necrosisspecific staining technique or a ligand binding to specific receptors ,7,22. GaOur current study is a pilot study including only 10 patients with a mean time after heart transplantation of 72.7 ± 11 months. In these long-term survivors after heart transplantation acute cardiac allograft rejections according Grade 2 R and higher are not frequent as in the first years after transplantation. We could only detect mild chronic transplant rejection in our study population equivalent to Grade 1 R (ISHLT). Patients with cardiac pacemakers could not be evaluated by magnetic resonance imaging.In this pilot study multi-slice spiral computed tomography proved to be equal to coronary angiography to detect cardiac allograft vasculopathy in epimyocardial vessel segments in patients after heart transplantation. The results of multi-slice spiral computed tomography and coronary angiography showed a high positive correlation. In regard of complications multi-slice spiral computed tomography proved superior to coronary angiography enabling it without any hospital stay underlining its cost-effectiveness.Magnetic resonance imaging revealed left ventricular fibrosis which seems to correlate with the histological findings of the endomyocardial biopsy showing a mild cardiac allograft rejection Grade 1 R according to the ISHLT working formulation.A combined non-invasive approach seems to be useful, cost-effective and less harmful for the patient for detection of cardiac allograft vasculopathy and cardiac transplant rejection before applying invasive methods. Larger studies should be performed to improve the sensitivity detecting cardiac allograft rejection and possibly reduce, if not eliminate, the need for endomyocardial biopsy especially in patients with acute and severe cardiac allograft rejection with at least Grade 2 R.The authors declare that they have no competing interests.EU carried out the routine follow-up examinations, echocardiographies and participated in the study design and coordination. EU performed the statistical analysis. CB, SS and UH carried out the echocardiographies, coronary angiographies and endomyocardial biopsying. Andreas F K carried out the multi-slice computed tomography and magnetic resonance imaging and participated in their analyses. HA and GZ conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.


We report an unusual and interesting case of a 24-year-old woman with nephropathic cystinosis in association with concomitant isolated noncompaction of the left ventricle. Left ventricular noncompaction usually presents with reduced exercise tolerance as a consequence of ventricular dysfunction, the result of embolus or with palpitations and syncope due to arrhythmia. There is no specific treatment directed at isolated noncompaction. Treatment is focused on the cause of presentation, with medication aimed at improving ventricular dysfunction, as well as treating and preventing thrombosis and arrhythmia.Our patient presented with an episode of decompensated heart failure. Trans-thoracic echocardiography demonstrated excessive trabeculation with inter-trabecular recesses in the left ventricle typical of noncompaction of the left ventricle. The patient's admission was complicated by a cardiac arrest precipitated by ventricular tachycardia for which she subsequently underwent implantation of an automatic implantable cardioverter defibrillator.This is, as far as we know, the first case report of the co-existence of nephropathic cystinosis and isolated noncompaction of the left ventricle. It highlights the importance of being vigilant to the diagnosis of left ventricular noncompaction. Isolated noncompaction of the left ventricle (LV) is increasingly being recognized as a distinct entity with a significant associated morbidity and mortality; however, definitions are still being debated. A diagnosis can be made with the commonly available modality of echocardiography but is still often overlooked. The co-existence of noncompaction of the LV together with nephropathic cystinosis has not been described previously.A 24-year-old woman with cystinosis complicated by end-stage renal failure, for which she was receiving intermittent haemodialysis, was admitted with generalized malaise and weight loss. In May 2001, she had undergone trans-thoracic echocardiography because of increasing shortness of breath on exertion, and this had shown a moderately dilated LV with globally reduced systolic function , consistent with dilated cardiomyopathy.The patient was referred for cardiology consultation following a period of increased breathlessness and a cardiac arrest precipitated by ventricular tachycardia from which she was successfully DC cardioverted. Her medication at that time included perindopril 4 mg once daily (od), carvedilol 3.125 mg twice daily (bd), prednisolone 5 mg od, levothyroxine 200 mcg od, folic acid 5 mg od, darbepoetin 80 mcg per week, mercaptamine (Cystagon) 150 mg four times per day (qds), calcium carbonate 500 mg three times daily (tds), aspirin 75 mg od and alfacalcidol 1.5 mcg od.On examination, the patient's blood pressure was 86/50 mmHg and she was in sinus rhythm at 76 bpm. She had some facial oedema, mild ankle oedema and bi-basal crackles on chest auscultation. Heart sounds examination revealed a soft apical pansystolic murmur. The remainder of the examination was unremarkable. Echocardiography revealed a dilated LV with globally impaired systolic LV function (EF Simpsons biplane = 25%). There was marked trabeculation of the LV, most prominent at the apex and lateral wall at the mid-ventricular level; six trabeculae were more than 2 mm in diameter. The noncompacted to compacted ratio was 2.2 at the thickest part of the lateral wall on the parasternal short-axis view. Multiple inter-trabecular recesses in communication with the LV cavity were demonstrated by forward and reverse flow of blood on colour flow mapping Figure . These fThe first cases of cystinosis were reported in 1903 . There iThree variants have been described. These are the nephropathic, the adolescent, and the benign adult forms. Our patient had the nephropathic variant.Skeletal muscle involvement has been widely reported. Muscle cystine concentrations approximately a thousand-fold greater than normal values are reported . CystineIsolated ventricular noncompaction is increasingly recognised as a distinct entity with an associated significant morbidity and mortality. It was the third most commonly identified primary cardiomyopathy in an epidemiological survey of Australian children, after dilated and hypertrophic cardiomyopathy . HoweverIsolated noncompaction may occur sporadically or be inherited. Familial adult and neonatal forms have been described. The familial adult forms of the disease are transmitted as an autosomal, dominant trait in the majority of cases . NeonataClinically, patients may present with a triad of symptoms, related to LV dysfunction, arrhythmia presenting as palpitations and syncope, or with the consequences of systemic thrombo-embolism. Others may be asymptomatic and identified incidentally. LV systolic dysfunction is one of the most commonly occurring features ,10-13. TDiagnosis is most commonly made by two-dimensional and colour Doppler echocardiography. Commonly used criteria include the identification of excessive (more than three), prominent (more than 2 mm diameter) trabeculae with inter-trabecular recesses that penetrate deeply into the myocardium, from which blood flows directly into and out of the ventricular cavity (which is demonstrated using colour Doppler imaging), in the absence of other structural heart disease.More objective criteria have been validated by Jenni et al. . This grAreas of noncompaction are found predominantly in the apex and midventricular regions of the inferior and lateral walls, with the trabeculae most frequently coursing from the free wall to the ventricular septum . HypokinAlternative conditions with reported prominent trabeculations include hypetrophic cardiomyopathy, endocardial fibroelastosis and metastatic disease involving the myocardium. More than three prominent trabeculations is unusual in the normal ventricle .Prognosis is variable. Patients not uncommonly experience sudden death, progression of their ventricular dysfunction, arrhythmias such as ventricular tachycardia, or atrial fibrillation. Thrombo-embolic complications, secondary to atrial fibrillation or thrombus in the deep recesses, are common. Many patients may also remain asymptomatic.Management is as for heart failure, including arrhythmia management, and more liberal use of prophylactic anticoagulation agents. Increased awareness of possible complications will allow earlier institution of correct therapies. AICD therapy for haemodynamically significant arrhythmia and cardiac transplantation should be considered.This is the first report to our knowledge of LV noncompaction in a patient with cystinosis. It highlights the importance of being vigilant to the diagnosis of LV noncompaction in such patients.AICD: automatic implantable cardiovertor defibrillator; bd: twice daily; EF: ejection fraction; LV: left ventricle/ventricular; od: once daily; qpd: four times per day; tds: three times daily.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.IA reviewed the literature and was a major contributor in writing the manuscript. TP reviewed the patient case history and contributed to the writing of the manuscript. GL made the diagnosis of nephropathic cystinosis and provided expert opinion on the diagnosis and management of cystinosis. MF made the diagnosis of LV noncompaction and made a large contribution to the final draft of the manuscript.


The severity of aortic regurgitation (AR) can be determined by invasive or echocardiographic methods. We systematically compared quantitative invasive and echocardiographic data with semiquantitative invasive grades in a prospective series of patients. Using Doppler-echocardiography we determined the cardiac output over the aortic, pulmonary and mitral valve in 27 patients . Aortic regurgitant volume was calculated as the difference between the cardiac output over aortic and pulmonary valve/ mitral valve. During angiography the severity of AR was assessed semiquantitatively by aortography and the regurgitant volume was calculated invasively as the difference between the left- and right ventricular cardiac output. The echocardiographically and invasively determined regurgitant blood volume correlated closely (R≈0.8). The regurgitant volume increased with higher angiographic grade but there was significant overlap between adjoining qualitative grades. In patients with AR, quantitative echocardiographic and angiographic measurements of the regurgitant volume correlate closely. The natural history of aortic regurgitation (AR) is characterized by an asymptomatic period of left ventricular compensation followed by decompensation with eventually irreversible left ventricular dysfunction. The management of patients with AR and in particular the timely indication of valve surgery is therefore dependent on a reliable estimation of the severity and progression of regurgitation and LV function . The sevBetween July ‘90 and May ‘93 we examined 136 consecutive patients who were referred to the color imaging laboratory of the Philipps-University-Marburg for further evaluation of suspected valvular disease. All patients had undergone 2D and conventional Doppler studies before referral. Informed consent was obtained according to institutional guidelines. The study was approved by the Philipps-University Marburg. Fourty-four patients were excluded from the final analysis for the following reasons: no reliable visualization (n=2), pulmonary valvular disease or combined aortic valve disease (n=6), mitral valve disease (n=24), atrial septal defect (n=9), ventricular septal defect (n=3). Of the remaining 92 patients, only those 27 patients that were examined by cardiac catheterization and echocardiography within 24 hours were included in this study. Twenty of these patients had AR and 7 did not. The patients with AR had no concomitant, significant aortic stenosis . The 7 patients in the control group had the following diseases: dilated cardiomyopathy (n=2), CAD (n=2), HTN (n=2), mitral valve prolapse without regurgitation (n=1).Access was established using the Seldinger technique from a femoral artery. After coronary angiography a 7F pigtail catheter was placed in the mid left ventricle. A left ventriculogram was recorded in the 30 degree RAO projection over several cardiac cycles. The catheter was then withdrawn into the ascending aorta for the aortography in a 30 degree RAO projection. For both ventriculography and aortography, 40 ml of contrast material were injected with a flow of 14 ml/sec.The semiquantitative grading of AR was done according to established guidelines . Grade 1The images of the ventriculogram were analyzed off line. End-diastolic and end-systolic frames were chosen for planimetry. The pictures were projected from a projector Tagano 35 CX) onto a calibrated screen. The heart base, the maximal length of the ventricular cavity and the left ventricular circumference were manually traced on the screen. The left ventricular stroke volume (LV) was calculated according to the area-length method  CX onto . The resvia a femoral vein with a pulmonary artery flotation catheter. The tip of the catheter was positioned in the main stem of the right pulmonary artery. Through the proximal sidehole 10 ml 0.9% NaCl at room temperature were injected. At the thermistor at the distal end of the catheter the temperature were recorded.The right heart catheterization was performed The right ventricular (RV) cardiac output was calculated semiautomatically according to the Stewart Hamilton equation ,8.The invasive regurgitant volume (RVinvasive) was calculated as the difference between the left- and right-ventricular cardiac output (LVCO/RVCO) determined by ventriculography (LVCO) and thermodilution (RVCO).All examinations were performed by an experienced physician sonographer, who was blinded to the results of the cardiac catheterization. The examinations were performed with a Sonotron Vingmed CFM750 machine, equipped with an imaging transducer of 3.5 or 2.75 Megahertz for the M-mode and 2D images. The echo-machine was connected online with a Macintosh Apple III personal computer equipped with an image processing software package. For off line analysis, the images were stored on optical disk and also printed on paper and recorded on a video recorder.3).The examination was performed in a left decubitus position. Complete 2D, conventional Doppler and color Doppler study with evaluation of all valves and ventricular function were performed according to ASE standards. The cross sectional areas (CSA) of the aortic, pulmonic and mitral valve were determined using the formula CSA = πr2 as follows: The maximal diameter of the left ventricular outflow tract (LVOT) was measured from a 2D-parasternal long axis view. The maximal diameter of the pulmonary artery (PA) was measured from a 2D-parasternal short axis view at the level of the pulmonic valve. The maximal diameter of the mitral valve (MV) was measured from a 2D apical 4-chamber view at the level between the mid and distal third of the valve leaflets .The flow velocity was measured by pulsed Doppler. It was measured in a parasternal short axis view for the pulmonary valve with the sample volume directly distal of the valve. For the aortic valve it was measured from an apical 5-chamber view with the sample volume in the LVOT . For the mitral valve flow velocity was measured from a apical 4-chamber view with the sample volume at the level of the mitral valve, respectively  was calculated semiautomatically by planimetry. For each valve, 3 representative cycles that followed a sinus beat were analyzed, and the results averaged. The stroke volume was calculated according to the formula -13.The cardiac output (CO) was calculated by multiplying stroke volume (SV) and heart rate (HR):The regurgitant volume (RVecho1) was calculated as the difference between the cardiac output of the aortic and pulmonary valve .RVecho2 was calculated as the difference between the cardiac output of the aortic and mitral valve .For all measurements the mean, standard deviation and ranges are described.Comparisons of the results were made by paired and unpaired t-test for paired and unpaired data, respectively. Simple linear regression analysis was employed to test the relation between two continuos parameters. Spearman rank correlation was used for the comparison of discrete angiographic grades and continuos parameters.Mean age was 49.4±12.6 (23-69) years. Eighteen (66.7%) patients were male. Mean EF was 60.5±17.8%. LVEDd was 5.9±1.1 cm (4.1-7.7), LVESd was 4.0±1.01 cm (2.4-6.4). All patients were in normal sinus rhythm at the time of examination. The mean heart rate during catheterization was 73.9±14.4 bpm and during echocardiography 70.3±20.2 bpm.In the 20 patients with AR the cardiac output over the aortic, pulmonary, and mitral valve were: 9.4±3.2 l/min (5.5-17.0), 4.72±1.1 l/min (2.7-7.3), and 5.1±1.1 l/min (3.3-7.4), respectively.In the 7 patients without AR the cardiac output over the aortic, pulmonary, and mitral valve were: 5.3±1.2 l/min (3.7-7.1), 5.1±1.1 l/min (3.5-7.3), and 5.1±1.4 l/min (3.3-7.8), respectively.The calculated regurgitant volume in patients with AR was 4.7±2.7 (1.4-10.8) for the comparison of the aortic and pulmonary valve (RVecho1) and 4.3±2.6 (0.01-10.3) for the comparison of the aortic and mitral valve (RVecho2).The calculated regurgitant volume in patients without AR was 0.2±0.8 (-0.8-1.6) for the comparison of the aortic and pulmonary valve (RVecho1) and 0.3±0.9 (-0.7-1.7) for the comparison of the aortic and mitral valve (RVecho2).Semiquantitative grading of aortic regurgitation by aortography showed grade 0 in 7 patients (26%), grade 1 in 1 patients (4%), grade 2 in 8 patients (30%), grade 3 in 9 patients (33%) and grade 4 in 2 patients (7%).In the 20 patients with AR the right-and left-ventricular cardiac output were 5.9±1.3 l/min (3.6-9.0) and 10.7±3.8 l/min (6.0-19.8), respectively.In the 7 patients without AR the right-and left-ventricular cardiac output were 5.0±0.9 l/min (3.5-6.6) and 5.1±1.7 l/min (2.7-7.3), respectively.In the 20 patients with AR the calculated regurgitant volume was 4.7±3.3 l/min (0.81-12.8).In the 7 patients without AR the calculated regurgitant volume was 0.06±1.1 l/min (-1.9-1.3).Comparison between Echocardiographic and Invasive MethodThe regurgitant volume calculated from aortic and pulmonary valve (RVecho1) was compared to the regurgitant volume calculated from aortic and mitral valve (RVecho2). For the entire group, the correlation was 0.98; p<0.0001; y= 0.93x-0.011; SE= 0.038.The echocardiographic regurgitant volume RVecho1  and RVecho2  were compared with the angiographic regurgitant volume (RVinvasive). For RVecho1 the correlation was 0.8; p<0.0001; y=0.69x+1.07; SE= 0.10.For RVecho2 the correlation was 0.78; p<0.0001. y=0.64x+0.99; SE=0.10.1 shows the comparison of the RV calculated by echocardiographic and invasive method and the angiographic grades. There was a significant correlation between higher grades of severity and increased RVecho 1 , RVecho2 , and RVinvasive .Table However, because of a wide range of the regurgitant volume in each grade, no significant differences of the echocardiographic RV was found between angiographic grades 2 and 3. In this study we systematically compared quantitative echocardiographic, quantitative invasive and semiquantitative invasive data determining the severity of aortic insufficiency. We found a high correlation (R=0.98) between two quantitative echocardiographic methods quantifying the regurgitant volume over the aortic valve (RVecho1 and RVecho2). Although the correlation between angiographic and echocardiographic quantitative methods was good, the correlation between semiquantitative angiographic grades and RV was only moderate and semiquantitative grading could not differentiate grade 2 and 3 because of significant overlap between grades.Echo and semiquantitative grades , with significant overlap between grades. Rokey et al. examined 6 patients with isolated AR and 19 patients with isolated MR [These results have important implications for the approach to patients with AR. The angiographic semiquantitative classification has been the historical “gold standard” for estimating severity of AR and grade 3 has been used as a cutoff point above which to consider valve surgery. Our results suggest that angiographic grades 2 and 3 do not reliably differentiate groups with different hemodynamically active regurgitant volume. This is consistent with results of previous studies. Kitabatake examined 10 patients with isolated AR, 13 with additional valve disease and 10 control patients . Using dlated MR . Mitral lated MR . The autThese and other studies  describePrevious studies generally report a good correlation between echocardiographic, szintigraphic and invasive quantitative methods determining RV: Kitabatake calculated the regurgitant fraction (RF) invasively from right ventricular stroke volume, determined by thermodilution and left ventricular stroke volume determined by ventriculography . A closeIn calculating the cardiac output over individual valves by multiplying the velocity time integral (VTI) and the outflow tract area several technical limitations have to be considered: The calculation of the outflow tract area from one measured diameter assumes a circular shape during systole. Several studies have shown a nearly circular anatomy of the aortic and pulmonary valves and a constant valve area during systole -20. On tThe goal of our study was to compare noninvasive, echocardiographic quantification of aortic insufficiency versus quantitative and qualitative invasive methods. We did not perform a comparison of the described echocardiographic quantitative method to a comprehensive echocardiographic evaluation as performed typically in clinical practice. This typically includes flow mapping to determines the spatial extension of the regurgitant jet -31, the However, as quantification of flow events has more recently been described using three dimensional echocardiography ,39 and mqualitative results obtained with 2D Echo and quantitative echocardiographic results and clinical findings is therefore necessary.The small number of patients is a major limitation of our study. Also, the regurgitant volume is dependent on hemodynamic conditions. Therefore the time delay between echocardiographic and invasive examination may have affected the correlation between echocardiography and angiographic grades. In order to minimize that influence we included only patients who had the two examinations within 24 hours. The results of the RV calculated in patients without AR show a relative large range with both echocardiographic and invasive calculation. A careful comparison of The results of our study show a good correlation between echocardiographic and invasive quantitative calculations of the regurgitant volume in patients with aortic insufficiency. The comparison to the semiquantitative angiographic grades show that grades 2 and 3 do not reliably differentiate groups with significant different regurgitant volume. Although angiographic grading of severity is considered the traditional “gold standard”, management decisions in patients with aortic regurgitation should therefore not rely on angiographic grades alone but incorporate a quantitative assessment of the hemodynamically active regurgitant volume.


Myocardial involvement is an important prognostic factor in patients with systemic sclerosis, and early diagnosis and staging of the disease have been sought after. Since myocardial damage is characterized by connective tissue disease, including fibrosis and diffuse vascular lesions or microcirculation, nuclear myocardial perfusion imaging has been a promising option for evaluating myocardial damages in early stages. In addition to the conventional stress-rest perfusion imaging, the current use of quantitative electrocardiographic gated imaging has contributed to more precise evaluation of cardiac perfusion, ventricular wall motion, and diastolic function, all of which have enhanced diagnostic ability of evaluating myocardial dysfunction. Abnormal sympathetic imaging with Iodine-123 metaiodobenzylguanidine might be another option for identifying myocardial damage. This paper deals with approaches from nuclear cardiology to detect perfusion and functional abnormality as an early sign of myocardial involvement as well as possible prognostic values in patients with abnormal imaging results. The role of nuclear cardiology in the era of multiple imaging modalities is discussed. Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse vascular lesions and fibrosis, and it systemically involves various organs such as skin (scleroderma), heart, lung, kidney and gastrointestinal tracts –6. Of th201Tl) myocardial perfusion imaging [SSc is usually classified into two subsets of diffuse and limited cutaneous types (dcSSc and lcSSc) . The maj imaging . A resea imaging . It was  imaging –13.In nuclear cardiology, myocardial perfusion imaging has been used extensively for evaluating coronary artery disease, which includes diagnosis of ischemic heart disease, physiological assessment of known coronary stenosis, viability assessment after acute coronary syndrome, reevaluation after coronary intervention, and risk stratification for future cardiac events . The dia201Tl perfusion imaging with circumferential profile analysis that added quantitative support [201Tl [201Tl defects [201Tl and Technetium-99m (99mTc)-labeled radiopharmaceuticals have shown that either stress-induced ischemia or persistent perfusion defects occur in SSc patients [201Tl SPECT in patients with SSc and systemic lupus erythematosus showed a high incidence of (82%) of abnormal findings by 201Tl SPECT [In more than three decades of history of nuclear medicine in cardiology, an early finding of myocardial perfusion abnormality in SSc was documented in 1984 by planar  support , 17. Cort [201Tl . The autpatients –24. AfteTl SPECT . The aut201Tl myocardial perfusion: the mean number of segments with perfusion defects decreased from resting condition after dipyridamole [201Tl myocardial perfusion with nifedipine in patients with progressive systemic sclerosis [Based on a pathophysiological viewpoint, abnormalities of microcirculation seemed to play an important role leading to myocardial damages . Focal mridamole . The samclerosis . In cont201Tl scanning, except for subtle abnormality [201Tl perfusion defects appeared to be related to left ventricular function, which showed that patients with perfusion defect had scores above the median value. In contrast, several patients with diffuse scleroderma had prominently abnormal EF at rest with further prominent deterioration during exercise [Resting left ventricular ejection fraction (EF) and its response to exercise also appeared to be unrelated to the findings on ormality . Howeverexercise . Thus, a99mTc methoxy-isobutyl-isonitrile (MIBI) study with ECG-gating of 16 frames per cardiac cycle in 34 patients with SSc [In a Japanese population, we performed a stress with SSc . Comparewith SSc , 31. A dwith SSc , 33. Diastolic dysfunction as detected by either gated myocardial perfusion imaging or radionuclide ventriculography was not specific to the findings of SSc. Diastolic dysfunction may have occurred even without any systolic dysfunction in patients with ischemic heart disease, hypertrophic cardiomyopathy, hypertensive heart diseases, and secondary cardiomyopathies –37. In pThus, we postulate that myocardial perfusion SPECT abnormality is correlated to the severity of cardiac dysfunction. In mild dysfunctional patients, even when left ventricular contractility is normal, diastolic dysfunction may be related in some cases. A stress myocardial perfusion scan might show reversible perfusion defect in patients with mild to moderate severity. In patients with more advanced severe dysfunction, fixed perfusion defects and regional wall motion abnormality would occur accompanied by global decrease in EF. However, whether or not the slight degree of perfusion abnormality and diastolic dysfunction would result in further deterioration of cardiac function should be investigated in a long-term follow-up study.The reason for the relatively low incidence of perfusion abnormality in our study might be explained by the selection bias of our study population, which might not have included the severer type of SSc. As for another possible reason, it might have been caused by differences in the sex and race of the patients, since ethnic differences have also been demonstrated in a Japanese population , 39.Our experience with SSc patients has shown that large perfusion defects and induced ischemia do not seem to be so common as described previously. Instead, small regional abnormality has become evident by the help of quantitative analysis. Current nuclear cardiology technology uses sophisticated computer-aided diagnosis for quantification. As an example, a patient with SSc is shown in 99mTc MIBI using stress-rest protocol. During exercise, only a slight decrease in perfusion was observed in the apical anteroseptal walls. A polar map display, with a 17-segment model overlaid, showed a localized decrease in perfusion in the anteroseptal region. The summed stress score and rest score namely, semi-quantitative defect scores during exercise and at rest were 3 and 1, which was judged as only a slight abnormality. In the polar map, wall motion and systolic thickening were apparently reduced in the anteroseptal region, particularly after exercise. A three-dimensional ventricular contour display showed apical anterior hypokinesis. A volume curve by gated SPECT showed characteristics of diastolic dysfunction. The time to peak filling rate (TPFR) as defined from the time points from end-systole to peak filling rate was prolonged to 352 msec ). The early diastolic parameter of 1/3 mean filling rate was 0.94 /sec ) [A 66-year old male patient diagnosed with dcSSc was referred to our department for nuclear cardiology for the purpose of evaluating possible cardiac involvement. His onset of disease was Raynaud's phenomenon 5 years ago prior to his visit. Scleroderma progressed since 2 years ago extending from hands, forearms, anterior chest to abdominal skin, and the MRSS indicated moderate severity (score 25 of 51). Significant pulmonary fibrosis was observed by X-ray computed tomography (CT). Myocardial perfusion SPECT was performed with 0 /sec)) . Instead123I-metaiodobenzylguanidine (MIBG) studies [123I-MIBG is known as an analogue of norepinephrine and shares its metabolic pathways with catecholamine uptake and excretion. Sympathetic abnormality has been detected by decreased uptake and rapid clearance from the heart. Initial experiences of MIBG support its use in ischemic heart diseases, typically shown as regional denervation of the heart in acute coronary syndromes and cardiomyopathies. Currently, 123I-MIBG has been used for patients with heart failure as well as neurological disorders involving Lewy-body diseases [Myocardial perfusion imaging is fundamental for evaluating myocardial damage. In addition, patients with SSc have a high frequency of diastolic dysfunction and sympathetic abnormality as shown by  studies , 42. 123diseases –45. It hdiseases ). MIBG wdiseases ). In condiseases , 48. How123I-MIBG provided additional discrimination in analyses of interactions between B-type natriuretic peptide, LVEF and H/M ratio. Although pathophysiological evidences of heart failure in the study could not be readily applicable to SSc patients, the MIBG imaging may provide new insights into the nature and prognosis of myocardial damage in SSc.The use of MIBG imaging has also been validated by a large prognostic multicenter trial in patients with heart failure of New York Hear Association (NYHA) functional class II/III and LVEF of 35% or less . The two111In-antimyosin antibody, which was a marker of the myocardial damage or necrosis [An article reported a case of systemic sclerosis with a subacute episode of myocardial disease assessed by necrosis . However201Tl perfusion defect. A study followed up 48 patients who underwent a perfusion scan in the 1980s. Notably, the survival information over the last 10 years revealed that the size of the initial defect was the best predictor of later adverse events compared with other disease-related features. These kinds of long-term prognostic study, which has been accumulating in the field of coronary artery disease, should also be conducted in SSc patients both retrospectively and prospectively.Large-scale prospective cohort studies have been performed extensively in the field of coronary artery disease, although such prognostic studies are still limited in patients with SSc. However, it has been recognized that cardiopulmonary involvement has been considered to be a poor prognostic factor since renal involvement is no longer a major cause of death in SSc, , 27, 51.Although we have focused on nuclear cardiology methods, echocardiography remains the mainstream tool for heart evaluation in SSc patients , 27, 53.When cardiac abnormalities are suspected by the initial screening tests, the next step would be diverse, depending on the clinical problems in the individual patient. In patients with pulmonary arterial hypertension (PAH), guidelines from both the American College of Chest Physicians (ACCP) and European Society for PAH recommended chest-X-ray, ECG and Doppler echocardiography as evidence-based approaches , 55. TheAccording to our study, it is apparent that all patients diagnosed with SSc are not indicated for a SPECT study. Based on our study population, it is noteworthy that patients with the lcSSc type or MRSS less than 10 showed neither significant perfusion defect nor ventricular dysfunction . TherefoThe best diagnostic approach or decision tree for cardiac evaluation has not been defined yet, although chest X-ray and echocardiography would be the first-step imaging method readily available in any hospital. While several possible diagnostic approaches have been proposed, some of them might have practical values for diagnosis, and others may provide pathophysiological insight or prognostic information. The determination of the appropriate role of imaging is of great concern in the era of multimodality cardiac imaging.Myocardial involvement as part of diffuse organ fibrosis and vascular changes is commonly observed in SSc. Even when severe fibrosis as evidenced by myocardial perfusion defects is not observed, perfusion reserves or functional abnormality might be detected as an earlier sign of myocardial damage. The aid of computer-assisted diagnosis will enhance the diagnostic ability for identifying abnormalities. The relationship of nuclear imaging and prognosis should be evaluated to confirm the role of functional imaging for patients with SSc. Finally, the roles or effectiveness of various current imaging modalities remain to be defined.


Few data exist regarding the direct effects of caffeine and smoking on cardiac function. We sought to explore the acute effects of caffeine assumption, cigarette smoking, or both on left ventricular (LV) and right ventricular (RV) function in a population of young normal subjects.a), early diastolic Ea, and late diastolic (Aa) velocity of mitral annulus were measured by pulsed Tissue Doppler, and left atrioventricular plane displacement was determined by M-mode. Tricuspid annular velocities and systolic excursion (TAPSE) were also determined. Measurements were performed at baseline and after oral assumption of caffeine 100 mg in group 1, one cigarette smoking in group 2, and both in group 3.Forty-five healthy subjects aged 25 ± 2 years underwent echocardiography. Fifteen of them were non-smokers and habitual coffee consumers (group 1), 15 were smokers and not habitual coffee consumers (group 2), and 15 were smokers and habitual coffee consumers (group 3). Peak systolic , tricuspid Sa  and TAPSE , and a decrease in the mitral Ea/Aa ratio . Sequential caffeine assumption and cigarette smoking in group 3 was associated with an acute increase in mitral Aa  and tricuspid Aa  and a reduction in mitral Ea/Aa ratio  tricuspid Ea  and tricuspid Ea/Aa ratio . In a two-way ANOVA model controlling for hemodynamic confounding factors, changes in the overall population remained significant for mitral Aa and Ea/Aa ratio, and for tricuspid Aa and Ea/Aa ratio.No changes in ventricular function were observed in group 1 after caffeine administration. In group 2, cigarette smoking yielded an acute increase in mitral AIn young healthy subjects, one cigarette smoking is associated to an acute impairment in LV diastolic function and a hyperdynamic RV systolic response. Caffeine assumption alone does not exert any acute effect on ventricular long-axis function, but potentiates the negative effect of cigarette smoking by abolishing RV supernormal response and leading to a simultaneous impairment in both LV and RV diastolic function. Both caffeine assumption and cigarette smoking are well known to yield considerable changes in cardiovascular hemodynamics. Increases in blood pressure and heart rate related to dietary intake of caffeine and cigarette smoking -3 as welNonetheless, few evidences exist regarding the direct effects of caffeine and smoking on cardiac function. Studies on animal models suggest that intravenous caffeine may acutely affect left ventricular (LV) relaxation without altering contractility , althougThe aim of this study was to analyze the acute effects of caffeine assumption, cigarette smoking, or both, on LV and RV performance in a population of young healthy subjects.The study population included a total of 45 young healthy volunteers (mean age 25 ± 2 years) free of cardiovascular or systemic diseases. Of them, 15 were non-smokers and habitual coffee consumers (group 1), 15 were smokers and not habitual coffee consumers (group 2), and 15 were smokers and habitual coffee consumers (group 3). Ten non-smokers and non habitual coffee consumers were considered as controls. None of patients were assuming any medication.Informed written consent for the participation to the study was obtained from all participants. All subjects were asked to abstain from smoking, coffee, and other foods or beverages containing caffeine  for a wash-out period of at least 12 hours before examinations. Baseline systolic blood pressure, diastolic blood pressure, and heart rate were measured after 5 minutes of resting in the supine position, using standard procedures. Arterial oxygen saturation was also measured using a digital pulse oximeter.a), early diastolic (Ea), and late diastolic (Aa) mitral annulus velocities were determined. The Ea/Aa and E/Ea ratios were calculated, and used as indices of LV filling pressures [Echocardiographic examinations were performed using high-quality machines  equipped with 2.5 MHz probes. LV diameters and thicknesses, LV mass, end-diastolic LV relative wall thickness, end-diastolic RV diameter were determined in accordance with current ASE recommendations . LV voluressures -24. Pulsressures . Left atThe study design is summarized in Figure A second clinical and echocardiographic examination was performed after a total of 45 minutes from caffeine assumption in group 1, after 15 minutes from beginning of cigarette smoking in group 2, and after 45 minutes from caffeine assumption  in group 3. During these periods, patients were asked to rest quiet in the sitting position. The second examination included measurement of systolic blood pressure, diastolic blood pressure, heart rate, arterial oxygen saturation, mitral inflow indices, mitral annulus velocities and AVPD averaged over four annular sites, lateral tricuspid annulus velocities, and TAPSE.The experimental setting Figure  includedData were expressed as mean ± standard deviation. Between-group comparisons at baseline were performed using the Kruskal-Wallis test for continuous variables and the chi-square test for categorical variables. Within-group comparisons between baseline values and those obtained after caffeine assumption, cigarette smoking, or both were performed using the Student t test for paired samples. Repeated measures two-way ANOVA was also performed by considering groups and status  as the main variables within a 3 × 2 factorial design, using a mixed model adjusting for heart rate, systolic blood pressure, and diastolic blood pressure. The P value for the main effect of status was used to express the significance of the effect of caffeine and smoking on ventricular function in the overall population, whereas the interaction P value was considered to explore for differences in the effect of testing across groups. A P value < 0.05 was considered for statistical significance. All tests were two-tailed. Analyses were performed using the SPSS  software Release 11.5.Baseline clinical and echocardiographic characteristics were similar among the four study groups Table . Changesa, tricuspid Sa, and TAPSE, and a reduction in the mitral annulus Ea/Aa ratio were observed after cigarette smoking  and Ea/Aa ratio (p = 0.0022), and for tricuspid Aa (p = 0.010) and Ea/Aa ratio (p = 0.019). For these 4 variables, significant interaction P values were found , suggesting differences in the effect of testing across groups. Significant interaction P values were also observed for tricuspid Sa (p = 0.038) and TAPSE (p = 0.049).In a two-way ANOVA model adjusting for hemodynamic confounding factors, changes in long-axis function observed in the overall population remained significant for mitral AThe results of this study show that: 1) caffeine assumption does not yield any significant change in ventricular long-axis function; 2) cigarette smoking is associated with an acute impairment in LV diastolic function and an increase in RV long-axis systolic indices; 3) caffeine assumption followed by cigarette smoking is associated with an acute impairment in both LV and RV diastolic function.a/Aa ratio – an index of LV diastolic function that correlates with LV filling pressures [a and a reduction in the Ea/Aa ratio similar to that observed after cigarette smoking alone  and cigarette smoking should be avoided.This study has limitations. A lager sample size would have added statistical solidity to our results. The study population included young healthy subjects, so that caution is required in extending results to other populations. The choice of an interval of 45 minutes between baseline and second examination in group 1 and 3 was based on a general estimate of the time necessary to reach the peak plasmatic concentration of caffeine after oral assumption, but a considerable inter-individual variability in caffeine kinetics exists . SimilarIn summary, one cigarette smoking acutely impairs LV diastolic function and is associated to a hyperdynamic RV systolic response in young normal subjects. Concomitant caffeine assumption may enhance the negative effect of cigarette smoking by abolishing RV hyperdynamic response and favouring simultaneous impairment in both LV and RV diastolic performance.The author(s) declare that they have no competing interests.All authors participated to the design of the study. EP, EG, GB, and VZ were responsible for collection of data and drafting of manuscript. PB performed the statistical analysis and revised the manuscript critically for important intellectual content. SM conceived the study and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.


New sensors for intelligent remote monitoring of the heart should be developed. Recently, a cutaneous force-frequency relation recording system has been validated based on heart sound amplitude and timing variations at increasing heart rates.To assess sensor-based post-exercise contractility, diastolic function and pressure in normal and diseased hearts as a model of a wireless telemedicine system.We enrolled 150 patients and 22 controls referred for exercise-stress echocardiography, age 55 ± 18 years. The sensor was attached in the precordial region by an ECG electrode. Stress and recovery contractility were derived by first heart sound amplitude vibration changes; diastolic times were acquired continuously. Systemic pressure changes were quantitatively documented by second heart sound recording.Interpretable sensor recordings were obtained in all patients (feasibility = 100%). Post-exercise contractility overshoot  was more frequent in patients than controls . At 100 bpm stress heart rate, systolic/diastolic time ratio  was > 1 in 20 patients and in none of the controls (p < 0.01); at recovery systolic/diastolic ratio was > 1 in only 3 patients (p < 0.01 vs stress). Post-exercise reduced arterial pressure was sensed.Post-exercise contractility, diastolic time and pressure changes can be continuously measured by a cutaneous sensor. Heart disease affects not only exercise systolic performance, but also post-exercise recovery, diastolic time intervals and blood pressure changes – in our study, all of these were monitored by a non-invasive wearable sensor. Telemonitoring heart failure patients is a very promising way of managing several complex and costly healthcare issues . Recent A new cutaneous force-frequency relation recording system has recently been validated in the stress echo lab, based on heart sound amplitude and timing variations at increasing heart rates. Expert monitoring of the heart – via a chest wall accelerometer – can reliably and non-invasively sense the contractile force and the filling function of the heart -6.The systolic force-frequency relation. An increased heart rate progressively increases the contractile force of the heart  . HoweverA significant correlation was found between post-exercise hypotension and recovery S2 undershoot Fig. . In thisCongestive heart failure (HF) is a serious public health problem due to its prevalence, high mortality, high morbidity, and the expense of ongoing therapy .Several strategies to control fluid volume status are used in the practice. Clinic visits for assessment of filling pressure by physical examination, multiple types of non-invasive measurements, and repeated cardiac catheterization may be employed. There is considerable cost and inconvenience for the patient associated with these strategies and, more importantly, these methods represent pressure and volume status only as one discrete point in time without the perturbance of daily activities or stress. A system of frequent monitoring could alert clinicians to early signs and symptoms of decompensation, providing the opportunity for intervention before patients become severely ill and require hospitalization .Implantable hemodynamic monitors that are capable of measuring chronic right ventricular oxygen saturation and pulmonary artery pressure are currently being developed  .Cardiac resynchronization therapy/defibrillators and implantable cardioverter defibrillators with continuous intrathoracic impedance monitoring capabilities  have recently been introduced and may provide an early warning of thoracic fluid retention . HoweverAs technologies such as micro-technologies, telecommunication, low-power design, new textiles, and flexible sensors become available, new user-friendly devices can be developed to enhance the comfort and security of the patient. Since clothes and textiles are in direct contact with about 90% of the skin surface, smart sensors and smart clothes with non-invasive sensors are an attractive solution for home-based and ambulatory health monitoring . All theExpert monitoring of the heart – via a chest wall sensor – can reliably and non-invasively sense the contractile force and the diastolic function of the heart. Dichotomy patterns: upsloping vs flat FFR, stress-induced "systolic-diastolic mismatch (yes/no), post-exercise contractility overshoot (yes/no), post-exercise diastolic time overshoot (yes/no), post-exercise normal hypotension (yes/no) are easily recognized by sensor-based intelligent monitoring Table . MonitorOur research will continue to optimize features of both the sensor and algorithm, and will develop an engineering model for industrialization, aiming at the device's eventual use in long-term home monitoring for tailoring drug treatment and preventing re-hospitalization.Contractility can be continuously measured by a cutaneous accelerometer during the post-exercise phase. Knowledge of the recovery overshoot phenomenon could be helpful for recognizing advanced failing patients in home monitoring systems. Diastolic duration time can be monitored during the post-exercise phase and a recovery diastolic time overshoot phenomenon can be easily assessed by the sensor. S2 amplitude monitoring is a method for assessing acute post-exercise blood pressure reduction. The daily life of both healthy subjects and patients involves periods of rest alternating with physical activity; and activity consists of mild to severe exercise with obviously subsequent recovery periods. Heart disease affects not only peak exercise systolic performance, but also post-exercise recovery, diastolic time intervals and blood pressure changes – all of which can be monitored by a non-invasive wearable sensor.g: acceleration unit (9.8 m/sec2); HF: heart failure; HIMO: implantable hemodynamic monitor; HR: heart rate; S2: second heart sound; SBP: systolic blood pressure; SVR: systemic vascular resistance; WMSI: wall motion score indexBSA: body surface area; DBP: diastolic blood pressure; CAD: coronary artery disease; CHF: congestive heart failure; CO: cardiac output; DCM: idiopathic dilated cardiomyopathy; EaI: effective arterial elastance index; EDV: end-diastolic volume; EF: ejection fraction; ESV: end-systolic volume; FFR: force-frequency relation; FHS: first heart sound; The authors declare that they have no competing interests.TB designed this study, performed the data analysis, and drafted the manuscript; EPa, LP and MP were responsible for data collection and revised the manuscript; VG, EB, FF and MG were responsible for technology development and digital signal processing; GA and RS contributed to data discussion; EPi contributed to preparation of study design, data discussion, and critical revision of the manuscript.