Diabetes is known to alter the energy metabolism of the heart. Thus, it may be expected to affect the efficiency of contraction . The literature on the subject is conflicting. The majority of studies have reported a reduction of myocardial efficiency of the diabetic heart, yet a number of studies have returned a null effect. We propose that these discrepant findings can be reconciled by examining the dependence of myocardial efficiency on afterload.We performed experiments on streptozotocin (STZ)-induced diabetic rats (7-8 weeks post-induction), subjecting their (isolated) hearts to a wide range of afterloads . We measured work output and oxygen consumption, and their suitably scaled ratio .peak value of myocardial efficiency (14.7%) was unaffected by diabetes.We found that myocardial efficiency is a complex function of afterload: its value peaks in the mid-range and decreases on either side. Diabetes reduced the maximal afterload to which the hearts could pump (105 mmHg versus 150 mmHg). Thus, at high afterloads , the efficiency of the STZ heart was lower than that of the healthy heart (10.4% versus 14.5%) due to its decreased work output. Diabetes also reduced the afterload at which peak efficiency occurred . Despite these negative effects, the Diabetes reduces the ability of the heart to pump at high afterloads and, consequently, reduces the afterload at which peak efficiency occurs. However, the peak efficiency of the isolated working rat heart remains unaffected by STZ-induced diabetes. We elaborate this point using Figure Cardiac efficiency  has been used extensively as an index of energetics of the myocardium. In many studies of the energetics of the diabetic heart, the deterioration of cardiac performance has been linked to a reduction of cardiac efficiency -5. But, We term the afterload at which the efficiency peaks the ‘optimal afterload’, as distinct from ‘peak afterload’ where work  is zero. For the first case Figure A, comparThe objectives of our study were hence threefold: (i) to determine the effect of diabetes on cardiac mechano-energetics, (ii) to extend the single value of cardiac efficiency of the diabetic heart, as reported in the literature, to its expression as a function of afterload, and (iii) to reconcile the conflicting findings showing either a decrease, or no change, of the cardiac efficiency of the diabetic heart. We conducted experiments using streptozotocin-induced diabetic hearts isolated from rats. Each heart, under working mode, was challenged to a series of afterloads from 40 mmHg to its maximal capacity.ad libitum access to food (standard rat chow) and tap water. Blood glucose level was measured daily for the first week and once per week thereafter for 7-8 weeks. Induction of diabetes in the STZ-treated rats was confirmed by blood glucose >20 mM. Experiments were conducted in accordance with protocols approved by The University of Auckland Animal Ethics Committee.Male Sprague–Dawley rats  were made diabetic by a single tail vein injection of streptozotocin . Control (SHAM) rats were given an intravenous injection of an equivalent volume of saline. Rats in each group were housed in pairs in a cage at room temperature (20-22°C) on a 12-hr light/dark cycle with in vivo. During the surgical period, they were continuously anesthetised using inhaled isoflurane (2.5%). Under sterile conditions, each rat was surgically implanted with a blood pressure telemeter  with a solid-state pressure sensor at the tip of the catheter. The abdominal aorta was cannulated 1–2 cm rostral to the iliac bifurcation and the sensor tip of the telemeter advanced proximally 1–2 cm. Pain relief/analgesia  and antibiotic  were administered at the time of the surgery. The rats were monitored closely and analgesia given daily for up to 3 days after the surgery.From each group, 4 rats were subjected to measurement of blood pressure The arterial pressure signal was sampled at 500 Hz using an analogue–digital data acquisition card  and continuously displayed by a data acquisition programme . Heart rate, and systolic and diastolic blood pressures were derived from the arterial pressure waveform. For the calculation of the overall average level of mean arterial blood pressure, the sampled signals were averaged every 2 s. All subsequent data collection and analyses were performed using the same data analysis programme. Rats were monitored for at least 12 days to ensure they were well-recovered from surgery, with the data presented being the mean values for the last 5 days of the recordings (7-8 weeks post-injection).2), injected with heparin (1000 IU/kg), and body mass measured. Following cervical dislocation, the heart and lungs were excised and plunged into chilled Tyrode solution. The aorta was immediately cannulated for Langendorff perfusion (afterload 70 mmHg) with Tyrode solution at room temperature. The lungs were then separated from the heart. The Tyrode solution had compositions of (in mM): 130 NaCl, 6 KCl, 1 MgCl2, 0.5 NaH2PO4, 1.5 CaCl2, 10 Hepes, 10 glucose, its pH adjusted to 7.4 using Tris and was vigorously bubbled with 100% O2. Glucose at a concentration of 10 mM has been shown to be sufficient to optimise the mechanical performance of the diabetic heart [At 7-8 weeks post-injection, a rat was deeply anaesthetised with isoflurane , with their associated temperature probes, were inserted into the aortic cannula (to reside just above the coronary ostia) and the arterial cannula, for measuring the coronary arterial partial pressure of O2 (PO2) and the coronary venous PO2, respectively. Flow probes, connected to flow meters , measured the rate of aortic outflow and the rate of coronary outflow. The fully-instrumented heart was enveloped by a water-jacketed glass chamber, and the temperature elevated to 32°C. Finally, the intrinsic heart rate was measured and a unipolar stimulus electrode  was placed on the surface of the right atrium and the heart was paced at 4 Hz .The venae cavae  were ligated, as were three of the pulmonary veins, leaving one for cannulation. The pulmonary artery was also cannulated. Oxygen sensors . Data were continuously acquired and recorded using PowerLab LabChart Pro. software . In total, 16 STZ-diabetic hearts and 17 SHAM hearts were used in this study.Upon attaining steady-state of the rate of coronary flow under Langendorff mode, perfusion was then switched to working-heart mode (preload 20 mmHg and afterload 70 mmHg). Preload and afterload  were varied by changing the height, above the mid-level of the heart, of the preload chamber and the aortic outflow tubing, respectively. The afterload for the RV was fixed at 10 mmHg. When each of the measured variables had reached steady states, the afterload was altered to a new value. Afterloads were presented in random order within the range between 40 mmHg and maximal (at which point aortic flow was near zero). When the series of afterload interventions was completed, perfusion was switched back to Langendorff mode (afterload 70 mmHg) to measure the basal rate of VO2 was corrected for the trans-epicardial exchange of oxygen with the surrounding air in the glass chamber housing the heart. During the course of an experiment, the gaseous content in the glass chamber was flushed with 21% O2. Upon completion of the afterload series, the gaseous content in the glass chamber was changed to 100% O2 and the afterload was set at 50 mmHg. This resulted in an increase in the measured venous PO2 and, consequently, a decrease in the calculated steady-state rate of myocardial oxygen consumption, reflecting a diminution in the loss of oxygen from the coronary circulation across the epicardial surface. The true value of myocardial VO2 was calculated by making use of the values measured in the presence of 21% and 100% O2 in the heart chamber, as previously described [Myocardial VOescribed ,28.2 and the coronary flow, assuming an oxygen solubility of 0.0249 mL atm-1 mL-1 at 32°C [2 to be 20 J mL-1[εTotal) was defined as the ratio of the rate of performing work to the rate of total enthalpy production εMech) was calculated from total efficiency by subtracting the rate of enthalpy production in the basal state The rate of performance of work . The work, total VO2, aortic and coronary flow rates, and basal rate of VO2 were normalised to heart wet mass and thus expressed in units of J kg-1, mL min-1 kg-1 or W kg-1, where appropriate. Whereas the tissues of both ventricles are perfused (and actively contracting), the RV performs work against a negligible afterload (10 mmHg). As a result, by normalising oxygen consumption to the mass of the entire heart, we slightly underestimate the work  of the whole-heart but have no reason to expect any difference between hearts of STZ and SHAM animals.At the end of each experiment, the ventricles were opened to measure the thickness of the septum and the LV and RV walls. The heart was then blotted and its wet mass measured. Work and VO2, were plotted against afterload and the data fitted using 3rd-order polynomials. Work and total εTotal were likewise plotted against afterload and fitted using 3rd-order polynomials but with intercepts set to zero (since work is zero at zero afterload). The regression lines within a group (16 for the STZ group and 17 for the SHAM group) were averaged using the Nonlinear Mixed Model (PROC NLMIXED) of the SAS software package. Regression coefficients were assumed to have arisen from a multivariate normal probability distribution [Aortic flow, coronary flow and VOribution .2, the two-group (STZ versus SHAM) equivalent of MANOVA , prior to performing multiple ANOVAs on individual variables. Means were adjudged to be different if P < 0.05. Note that, for a 5% risk of a Type I Error, and with n = 16 or 17 observations per group, the statistical power to detect a separation of means of at least one standard deviation is 80% [Parameters of interest, estimated from each regression line defining the dependence of the measured variables on afterload , were averaged and expressed as means ± standard error (SE). The data arising from all of the dependent variables were analysed using Hotelling’s Tn is 80% .As displayed in Table in vivo levels of systolic, diastolic, and mean arterial blood pressures did not differ between STZ and control groups, but the average heart rate of the former was lower, both in vivo and in vitro .The average 2) and afterload for individual hearts (STZ and SHAM) and for the average measurements recorded from all hearts. Note the progressive increase of venous PO2 with metabolic energy expenditure, a result consistently observed in every heart. Diabetes did not alter the profile of the venous PO2-afterload relation. There was no statistical difference between the two groups in the mean values of coronary venous PO2, particularly at the specific pressures of interest: 70 mmHg and 90 mmHg (see below). Likewise, coronary arterial PO2 was constant (690 mmHg) with afterload for both STZ and SHAM cohorts (data not shown).Panels A and B of Figure Each heart was electrically stimulated at 4 Hz to avoid the confounding effects of difference in intrinsic heart rates  and total efficiency  were plotted as functions of afterload, as illustrated in Figure εTotal of the isolated working heart were both complex functions of afterload, which peak at the mid-range of afterload. (ii) Neither work nor εTotal were zero at the highest afterload that the heart could pump. This is because at the highest afterload, coronary flow rate was high despite near-zero aortic flow  was zero. (iv) Lastly, the afterloads at which the peak work was attained were not comparable to the afterloads at which the peak εTotal was reached. For example, for SHAM hearts, peak work occurred at around 110 mmHg, whereas peak εTotal appeared at around 80 mmHg.Work, total oxygen consumption ; (ii) optimal afterloads ; (iii) peak afterloads ; and (iv) values at the peak of other variables . Quantification of the first three variables is reported in Figure Given these four interesting features of the relations, we quantified four distinct variables . Mean peak εTotal was also not different between STZ and SHAM hearts, 14.7 ± 0.7% versus 14.7 ± 0.5% (B). However, the mean optimal afterload for work (C) and that for εTotal (D) were lower in the STZ hearts. The mean peak afterload for work (E) and that for εTotal (F) were also lower in the STZ hearts. In addition, we also compared the mean optimal afterload and the mean peak afterload for work with that for εTotal (comparing panels C and D). For both the STZ and SHAM hearts, the mean optimal afterload for work was greater than that for εTotal, but the mean peak afterload for work and for εTotal were not different (comparing panels E and F).Figure εTotal  did not coincide with that for  Figure B is the s Figure B, but tos Figure D. At peaVO2 of each heart at afterload 70 mmHg. There was no difference in the mean basal rate of VO2 between STZ and SHAM  intersected those of the SHAM hearts  of reporting only a single value of myocardial efficiency of the diabetic heart by reporting its behaviour as a function of afterload. Efficiency is a complex function of afterload, with values ranging from zero to a peak . It is thus incomplete, and misleading, to report only a single value. We show that the efficiency-afterload relation allows reconciliation of the conflicting conclusions in the literature regarding the effect of diabetes on myocardial efficiency.in vivo and in vitro (at 32°C). Bradycardia has been a consistent finding in STZ-diabetic hearts [A single injection of STZ at age 6-7 weeks, clearly rendered the rats diabetic 7-8 weeks later. This is demonstrated by the 4.4-fold higher concentration of blood glucose, the 30% lower body mass and the 23% lower heart mass but 11% higher ratio of heart mass to body mass . This value can be put in perspective with reference to Tune et al. [2 values from the right and left coronary veins of dogs are, respectively, 30 mmHg and 20 mmHg. It is unlikely that our observed values indicate hypoxic conditions, given the substantial coronary reserve revealed by the progressive increase of venous PO2 values with afterload  was 90 mmHg for diabetic hearts and 140 mmHg for control hearts. PO2 values above 100 mmHg exceed those associated with normoxia in vivo. Also observed in Figure The use of a crystalloid perfusate demands examination of the adequacy of oxygen supply. We exploited the inverse relationship between temperature and oxygen solubility–lowering the temperature of the perfusate to 32°C, which, in turn, allowed us to reduce the pacing frequency to 4 Hz. Thus we simultaneously increased oxygen supply and reduced oxygen demand, both of which manoeuvres enhance tissue oxygenation. As seen in Figure e et al.  and the e et al. , who repa et al. ). Note tin vivo , in accord with the finding of Joffe et al. [in vitro heart. This suggests that autoregulation of the heart, which is responsible for the relatively constant coronary flow within an afterload region between around 60 mmHg to 100 mmHg , the coronary flow rate is maximal. STZ-treatment has negligible effect on the maximum rate of coronary flow  or at the afterload that optimises either work or total efficiency. If they operate at their optimal afterloads for peak work, then they have the same total efficiency. If they operate at their optimal afterloads for peak total efficiency, then they again have the same total efficiency. But if they both operate at high afterload, then the STZ heart would have a relatively lower total efficiency , to examine the effect of diabetes, then we would have reported that the diabetic heart has a lower value of efficiency. We consider it necessary that experiments be performed at a range of afterloads since, by doing so, the optimal afterload at which the heart operates can be ascertained. If only a single value of efficiency is reported, then it is essential to report the afterload at which that value was obtained. In fact, this was done by Penpargkul et al. [Because of the complex dependencies of efficiency on afterload, it is unwise to perform experiments at only a single afterload, and to report a single value of efficiency, unless one has Streptozotocin-induced diabetes limits the ability of the heart to pump at high afterloads. A collateral consequence is a left-shift of the myocardial efficiency-afterload curve, resulting in reduced efficiency of the diabetic heart at high afterloads. However, the peak efficiency (which occurs at the mid-range of the efficiency-afterload curve) of the heart is unaffected by diabetes. These findings reconcile the conflicting reports in the literature regarding the effect of diabetes on myocardial efficiency.STZ: Streptozotocin; RV: Right-ventricle/ventricular; LV: Left-ventricle/ventricular; PO2: Partial pressure of oxygen; VO2: Oxygen consumption; εTotal: Total efficiency.The authors declare that they have no competing interests.in vivo measurement and participated in interpretation of data. KM contributed to interpretation of data and writing of the manuscript. All authors participated in critical revision and approved the final version of the manuscript.J-CH conceived and designed the study, performed experiments and was responsible for acquisition, interpretation and statistical analysis of data, drafting the manuscript and preparing the figures. DL participated in study concept and design and contributed to acquisition, interpretation and statistical analysis of data and drafting of the manuscript. SY and AT contributed to acquisition and participated in interpretation of data. CB performed the


Recent evidence suggests a link between myocardial steatosis and diabetic cardiomyopathy. Insulin, as a lipogenic and growth-promoting hormone, might stimulate intramyocardial lipid (MYCL) deposition and hypertrophy. Therefore, the aim of the present study was to investigate the short-term effects of insulin therapy (IT) on myocardial lipid content and morphology in patients with T2DM.Eighteen patients with T2DM were recruited . In 10 patients with insufficient glucose control under oral medication IT was initiated due to secondary failure of oral glucose lowering therapy (IT-group), while 8 individuals did not require additional insulin substitution (OT-group). In order to assess MYCL and intrahepatic lipid (IHLC) content as well as cardiac geometry and function magnetic resonance spectroscopy (MRS) and imaging (MRI) examinations were performed at baseline (IT and OT) and 10 days after initiation of IT. Follow up measurements took place 181±49 days after IT.Interestingly, basal MYCLs were 50% lower in IT- compared to OT-group . After 10 days of IT, an acute 80%-rise in MYCL (p = 0.008) was observed, while IHLC did not change. Likewise, myocardial mass , wall thickness in end-diastole  and concentricity, an index of cardiac remodeling, increased . In the long-term MYCL returned to baseline, while IHCL significantly decreased . No acute changes in systolic left ventricular function were observed.The initiation of IT in patients with T2DM was followed by an acute rise in MYCL concentration and myocardial mass. The pathogenesis of diabetic heart disease is multi-factorial and complex. Putative mechanisms include metabolic disturbances, myocardial fibrosis and small vessel disease Growing evidence indicates a potential relationship between chronic hyperinsulinemia in pre-diabetic patients and structural changes of the heart leading to myocardial fibrosis In a recent study we observed that insulin acutely increases MYCL content and alters cardiac function in the presence of standardized hyperglycemia/hyperinsulinemia (clamp test) in healthy subjects The study was approved by the institutional medical ethical committee  and written informed consent was obtained from all participants. All clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki.Eighteen patients with T2DM were recruited from the outpatient service of our department Table 1.1H-magnetic resonance imaging (-MRI) and spectroscopy (-MRS) examination. Thereafter, standardized IT  was initiated in patients with secondary failure to oral anti-diabetic treatment . In these patients all blood-glucose lowering agents except for metformin were discontinued simultaneously with the initiation of IT. Likely, due to the improved compliance to the oral-medication during the run-in phase glycemic control ameliorated in 8 out of 18 patients . Thus, these patients did not require standardized IT corresponding to the study protocol and only baseline MR examinations were performed in this subgroup of patients. During the course of the study no adjustments of lipid lowering and/or anti-hypertensive medication were performed. During the first 10 days of the inpatient setting standardized frequent measurements of blood glucose concentrations  allowed to quickly titrate insulin doses and achieve pre-prandial glucose concentrations of 100–120 mg/dl. Insulin doses were adjusted twice daily by experienced physicians. In addition a standardized diet with 1400 kilocalories per day (fat/carbohydrate/protein: 32%/48%/20%) was administered during inpatient treatment. All patients were advised to adhere to the diet plan after the discharge. Furthermore, structured inpatient diabetes training included recommendations for regular moderate physical activity. Ten days after the initiation of IT MRI and MRS studies were repeated. Patients were discharged on day 10. Clinical and MR follow up examinations were performed in 7 patients 181±49 days after initiation of IT.The time span between the clinical assessment in the outpatient unit and the hospitalization was 7.5±1.8 days (run-in phase). During this time period compliance with the oral medication was strongly recommended and patients were instructed that in case of persistently insufficient metabolic control the initiation of IT was intended. Additionally, patients provided standardized records of self-blood glucose monitoring until the baseline All magnetic resonance measurements were performed on a 3.0-T Tim Trio System  operated with the Syngo VB15 and VB17 user interface.3. Mid-ventricular short axis slices were analyzed for the assessment of left ventricular wall thickness 0.725×weight0.425) Visualization of cardiac function was performed employing retrospective ECG-gated cine true fast imaging with steady-state precession (TrueFISP) sequences in 2-chamber, 4-chamber and short axes orientation. Short axes images were used to quantify left ventricular global function  after manual demarcation of endo- and epicardial borders in end-systolic and end-diastolic phase via ARGUS software . Papillary muscles and trabecles were counted to the lumen of the left ventricle. Myocardial mass was determined as mean of end-diastolic and end-systolic muscle volume multiplied with a density of 1.05 g/cmCalculation of concentricity ( = left ventricular mass to end-diastolic volume ratio) 1H-MRS based on recently introduced methods 3) was placed over the interventricular septum. The acquisition of MR signal was performed during multiple breath holds using the multichannel cardiac reception coil provided by the system manufacturer  and triggered by ECG signal. For the signal acquisition in the mid-diastole trigger delay was adjusted individually. Repetition time of the sequence was given by the heart beat frequency of individual volunteer. An additional spectrum without water suppression (NS = 8) was used as the internal concentration reference. The spectra were processed by the Spectroscopy Processing tool within Syngo VB15 and VB17 user interface provided by the system manufacturer . Careful placement of the VOI, appropriate trigger adjustment and the fact that the spin-echo based sequence suppresses signal from flowing liquids makes the possible contribution of ventricular blood to the tissue water signal negligible.Myocardial lipid measurements were performed using localized 3-; 0.8–0.9 ppm] and methylene-  groups of fatty acid chains were quantified from the water suppressed spectra. The myocardial lipid content was than calculated as a ratio of the sum of intensities of methyl- and methylene- group resonances to the intensity of the water resonance. Intensities of lipid and water resonance lines were corrected for the spin-lattice (T1) and spin-spin (T2) relaxation using individual repetition time and already published T1 and T2 relaxation times of skeletal muscle at 3T Water signal intensity was quantified from the spectra without water suppression and individual spectral lines intensities of methyl- [CH1H-MRS single voxel technique using volume of interest of 3×3×3 cm3 placed in the lateral aspect of the liver. Single breath hold protocol without spectral water suppression and twelve acquisitions (NS = 4) with the repetition time of 2 sec were used. Flexible body array coil provided by system manufacturer were used for signal reception. The intrahepatic lipid content were calculated as a ratio of the sum of intensities of -(CH2)n- (1.25 ppm) and CH3- (0.8–0.9 ppm) group resonances to the intensity whole MRS signal including the water resonance. Intensities of lipid and water resonance lines were corrected for the spin-lattice (T1) and spin-spin (T2) relaxation already published T1 and T2 relaxation times at 3T The hepatocellular lipids were measured applying similar short echo time http://www.kimcl.at/).All laboratory parameters were measured by routine lab methods .All data are presented as mean ± standard error of the mean (SEM). The effect of the insulin treatment on heart function and metabolic parameters was determined by the two-sided, paired Student’s . There were no significant differences in blood glucose levels, HbA1c, and lipid profiles at the baseline between the IT- and the OT-group .The mean age was 56±2 years and the mean MYCL content was 0.58±0.09% of water signal. Interestingly, when IT was compared to OT, significantly lower MYCL content  and longer diabetes diagnosis duration  was revealed in the IT-group. Although lipid-lowering therapy was not modified, serum cholesterol concentrations diminished after short term of IT and did not rebound at follow up . (b) as well as systolic and diastolic blood pressure (c) during the inpatient treatment. At follow up (181±49 days after the initiation of IT) a reduction in HbA1c  documented improved metabolic control . Moreover, a positive correlation was found between albumin-creatinine-quotient and the following clinical features: duration of the disease , plasma glucose  and HbA1c levels  as well as MYCL concentration at day 1 .Mean blood glucose concentrations significantly decreased during IT ; . Alth. Moreover, cardiac remodeling, displayed by concentricity, emerged after the initiation of IT . However, left ventricular systolic function did not change during the study course . In 12 patients E/A ratio was below 1 indicating diastolic dysfunction, which remained stable under IT. The rise in myocardial mass persisted throughout the follow up period .Ten days after the initiation of IT alterations in myocardial mass (+13%) and wall thickness at the end-diastole (+13%) were observed . Moreove. Moreove. MoreoveAfter 10 days of IT MYCL content increased by 80%  At follow up improvement of metabolic control might have returned MYCL to baseline. These results are in accordance with previous data showing a parallel decrease in MYCL and HbA1c during treatment with pioglitazone and insulin in patients with T2DM Insulin therapy did not induce an acute rise in hepatic lipid content in the present study, suggesting that myocardial lipids are more sensitive to insulin compared to hepatic lipids. Since the muscle-type CPT1B is 10–100 fold more sensitive to malonyl-CoA compared to liver-type CPT1A In our study myocardial mass and thickness acutely increased in response to IT leading to morphological changes of the left ventricle. In accordance, investigations in animal models have shown that exogenous insulin supply induces myocardial hypertrophy and interstitial fibrosis by activation of key mitogenic signaling pathways including angiotensin, MAPK-ERK1/2 and S6K1 It is a limitation of the current study that the employed MR methods did not allow discerning the precise alterations in myocardial fuel metabolism. Since biopsies of human myocardium are not feasible in a research setting, investigations on human myocardial metabolism are limited to non-invasive techniques. In addition, we cannot exclude a potential effect of the standardized diet and the continued intake of statins on myocardial lipid content during the in-patient setting. However, withholding these treatment regiments would have been ethically unacceptable.In order to achieve adequate glycemic control insulin therapy is commonly initiated in patients with longstanding T2DM and relative insulin deficiency. The study protocol resembles standardized therapeutic regiments frequently applied in hospital setting worldwide. Thus, the present study provides a mechanistic concept potentially relevant for numerous patients on insulin therapy. We have shown that hallmark-parameters of diabetic cardiomyopathy, myocardial steatosis and hypertrophy, are acutely affected by IT in the presence of hyperglycemia. However, initiation of IT was not associated with short-term changes in myocardial function. Due to the limited number of patients and the short observation period, we cannot draw definitive conclusions or make recommendations for clinical practice on the basis of the present results. Thus, future prospective trials specifically aiming at the elucidation of insulin effects on myocardial lipid metabolism and function enrolling larger patient populations and longer evaluation periods are warranted.In conclusion, we clearly demonstrate that the initiation of insulin therapy is associated with an acute, but transient, rise in myocardial lipid content in patients with long standing type 2 diabetes and poor metabolic control. Furthermore, changes in the myocardial mass led to left ventricular hypertrophy with preservation of cardiac function in the short term.


Cardiac magnetic resonance imaging (CMR) is a powerful tool to identify the arrhythmia substrate in patients with ischemic or non-ischemic cardiomyopathy. However, the performance and diagnostic yield of CMR in pre-ablation evaluation for ventricular arrhythmia in patients without known structural heart disease was still unknown. In the present study, we sought to investigate the performance of CMR in identifying the potential structural heart disease or substrate for ventricular arrhythmia in pre-ablation patients.CMR was performed in a series of consecutive patients (average age 45.8±16.9 years) with premature ventricular contraction or paroxysmal ventricular tachycardia referred for trans-catheter ablation. None of the patients had any known structural heart disease. CMR protocol included regular cine, rest perfusion and late gadolinium enhancement imaging. CMR image was interpreted by two experienced experts who were blinded to the echocardiography findings and clinical diagnosis.The average left ventricular ejection fraction of the whole cohort was 54.9±11.1% and right ventricular ejection fraction was 45.6±15.6%. there was no significant difference in LVEDVI, LVESVI, LVMASSI,LVEF, RVEDVI, RVESVI and RVEF between patients with PVC and VT. There was 17/40(42.7%) abnormal global or regional wall motion findings by CMR cine. myocardial late gadolinium enhancement (LGE) was found in 10/40 (25%) cases. The cumulative abnormalities rate was 45% through CMR, whereas abnormal findings was only confirmed in 6/40(15%) in the same group of patients. In addition, in patients with LGE, RVEDVI, RVESVI and RVEF were significantly decreased than the patients without LGE.CMR was a powerful tool to identify the potential structural heart disease in patients with ventricular arrhythmia before ablation. Comprehensive CMR examination appeared to be more sensitive than echocardiography in detecting structural abnormalities in patients with ventricular tachycardia without known cardiomyopathy, before ablation therapy is planned.national science foundation of China (NSFC) 81271513


After ST-elevation myocardial infarction (STEMI), microvascular obstruction (MVO) can be assessed using angiographic myocardial ‘blush’ grade (MBG), subject to interoperator variability. Quantitative blush evaluator (QuBE) is a free computer-calculated algorithm, with improved reproducibility. We aimed to compare QuBE in detecting MVO and its severity in comparison to the gold standard, cardiovascular magnetic resonance (CMR).Fifty-two STEMI treated with successful primary-PCI were enrolled. QuBE values were blindly calculated on post-procedure angiogram and patients divided in tertiles (ter) according to QuBE values. All patients underwent CMR (GE 1.5T) 4-7 days after STEMI, for quantitative assessment of infarct size (IS), area-at-risk (AAR), myocardial salvage index (MSI), MVO (both as first pass MVO (FP-MVO) and delayed-enhancement MVO (DE-MVO)), and presence of intramyocardial hemorrhage on T2-weighted sequences. Indices were measured blindly by two expert readers with SMCR level 3, using ReportCard (v4.0) software. LGE infarct size was quantified using threshold >5SD, T2 sequence >2SD as previously described. MVO was manually traced, and hemorrage identified as the dark band within bright signal on T2QuBE values were inversely related to IS, both as percentage  and as mass , to DE-MVO, both as percentage  and as mass , to FP-MVO , and positively related to MSI . Moreover patients with intramyocardial hemorrhage had significantly lower QuBE values . At receiver operating characteristic (ROC) curve analysis, QuBE accounted for an area under the curve of 0.88  for both DE-MVO and haemorrhage detection. Figure This is the first report to compare quantitative computer-based assessment of angiographic perfusion with comprehensive parameters of microvascular function, infarct size and salvage on early CMR in STEMI patients. We demonstrate the important finding that QuBE values correlate strongly with microvascular obstruction, Intramyocardial hemorrage and myocardial salvage by CMR. This validates the use of QuBE for assessment of tissue reperfusion in the clinical setting, and represents and important advancement in post-procedural evaluation of reperfusion in the cathlab. Our data suggest that a quantitative evaluation of myocardial blush after STEMI will accurately risk-stratify patients, and provide useful prognostic information, better informing decisions such as the selection of patients requiring further imaging (eg by CMR).


Insulin resistance has been linked to exercise intolerance in heart failure patients. The aim of this study was to assess the potential role of coronary flow reserve (CFR), endothelial function and arterial stiffness in explaining this linkage.2peak), digital measurement of endothelial function and arterial stiffness (augmentation index), dual X-ray absorptiometry scan (DEXA) for body composition and insulin sensitivity by a 2 hr hyperinsulinemic (40 mU/min/m2) isoglycemic clamp.39 patients with LVEF < 35% (median LV ejection fraction (LVEF) 31 (interquartile range (IQ) 26–34), 23/39 of ischemic origin) underwent echocardiography with measurement of CFR. Peak coronary flow velocity (CFV) was measured in the LAD and coronary flow reserve was calculated as the ratio between CFV at rest and during a 2 minutes adenosine infusion. All patients performed a maximal symptom limited exercise test with measurement of peak oxygen uptake . Median CFR was 1.77 (IQ 1.26-2.42) and was correlated to insulin sensitivity . CFR , and arterial stiffness  were correlated to VO2peak whereas endothelial function and LVEF were not . In multivariable linear regression adjusting for age, CFR remained independently associated with VO2peak (standardized coefficient (SC) 1.98, p = 0.05) whereas insulin sensitivity  and arterial stiffness  were no longer associated with VO2peak.Fat free mass adjusted insulin sensitivity was significantly correlated to VOThe study confirms that insulin resistance is associated with exercise intolerance in heart failure patients and suggests that this is partly through reduced CFR. This is the first study to our knowledge that shows an association between CFR and exercise capacity in heart failure patients and links the relationship between insulin resistance and exercise capacity to CFR. The link between insulin resistance and heart failure is complex. Several studies have shown that insulin resistance is common in heart failure of both ischemic and non-ischemic origin. The exact mechanisms are not known but potentially include both causal and secondary associations. Insulin resistance has been linked to reduced exercise tolerance in heart failure and mechanisms may include both central and peripheral vascular dysfunction .In the absence of significant coronary artery stenosis, coronary flow reserve (CFR) is a measure of microvascular function. CFR has been shown to be reduced in patients with classic risk factors of cardiovascular disease such as hypertension , obesity2peak [2peak is one of the most important prognostic factors in CHF patients [2peak in heart failure patients. Recently, however, in a small randomized trial, 4 months of exercise training of 13 patients with primary heart failure improved both VO2peak and CFR [In healthy young volunteers CFR has been related to VO2peak ,11. VO2ppatients  and exerpatients . Few stu and CFR . This st and CFR . A possiPeak oxygen uptake, vascular function and metabolic function are all important prognostic markers in heart failure. The aim of this study was to assess the potential role of coronary flow reserve, endothelial function and arterial stiffness in explaining the link between insulin resistance and exercise intolerance.The study was a local substudy based on patients screened for inclusion to the Smartex-HF trial  in which2peak.All patients underwent an upright bicycle  exercise test with breath-by-breath gas exchange measurement . After 3 minutes of rest on the bicycle the test was initiated using either a protocol starting at 20 watt with a 10 watt increase pr. minute or starting at 40 watts with a 20 watt increase pr. minute, to ensure optimal exercise time based on an expectation of the patients exercise capacity. The patients were encouraged to continue until maximal exhaustion. A leveling off of oxygen uptake despite increasing workload and a respiratory exchange ratio (RER) > 1.05 were used as criteria for maximal oxygen uptake. The mean of the 3 highest consecutive 10-second measurements before exercise terminations were used for determining VO3-(LVEDD)3) + 0.6 g, where LVEDD is left ventricle end diastolic diameter, PWTd is posterior wall thickness in diastoly and SWTd is septum wall thickness in diastoly, and indexed (LVMi) to body surface area (BSA) calculated by Du Bois’ formula (BSA = 0.007184 x weight kg0.425 x height cm0.725).A complete transthoracic echocardiography was performed using Philips IE33  with an S5 probe with the patients in the left supine position. Left ventricle end diastolic (EDV) and end systolic (ESV) volumes and ejection fraction (LVEF) were calculated from apical 2- and 4-chamber views using the biplane Simpson model. Left ventricular mass (LVM) was calculated using the formula LVM = 0.8*(1.04*(LVEDD + PWTd + SWTd)-1 min-1. The solution was diluted so that the infusion rate was kept at 10 ml min-1. Before and during the adenosine infusion care was taken to maintain the position and angle of the probe, so measurements were done on the same segment of the LAD at the same angle. During the infusion the scale of flow velocity was changed in order to obtain optimal curves for offline measurement. CFR was calculated as the ratio between peak diastolic CFV during adenosine infusion and during rest using a mean of 3 consecutive cardiac cycles . Analyses were done offline by an investigator blinded to the other examinations. Blood pressure and ECG were monitored before and during the adenosine infusion. Interobserver variability of CFR was tested on all subjects and the mean difference in CFR was 0.07 with limits of agreement ±0.21. The coefficient of variation (CV), calculated as the within-subject standard deviation divided by the mean of the observations, was 5.5%. Intraobserver variability was tested on 10 randomly selected examinations with a mean difference of 0.03, limits of agreement ±0.29 and CV 7.5%. Figure CFR can be measured non-invasively using transthoracic Doppler echocardiography with a high success rate  and this2. Subjects met in the morning after a 12-hour overnight fast and without unusual strenuous activity for 3 days before the clamp. Blood glucose concentrations were measured in arterialized blood drawn from a catheter inserted in a dorsal hand vein. Arterialisation of the blood was achieved by placing the hand in a heating pad. Fasting blood glucose concentration was determined as the average of two blood samples, taken at t = −15 min and 0 min. Insulin was initiated by a bolus injection, and then infused continuously for 120 minutes. Glucose was measured every 5 minutes using a handheld glucose-measuring device . Insulin sensitivity was defined as the steady-state average glucose infusion rate during the final 30 minutes of the clamp . Metabolic clearance rate of glucose was calculated as the M-value divided by the prevailing blood-glucose concentration in order to facilitate comparisons between individuals at the steady-state condition.Insulin sensitivity was measured using an isoglycemic hyperinsulemic glucose clamp, with an insulin infusion rate at 40 mU/min/mA whole body dual x-ray absorptiometry scan (DEXA)  was performed for estimation of body composition (fat mass and fat free mass).Flow mediated vasodilation measurement was performed using Endo-PAT 2000  which measures arterial pulsatile volume changes in the fingertip before and after upper arm occlusion. The examination was performed in the morning in a fasting state. After 5 minutes of baseline measurements upper arm occlusion on one arm was sustained for 5 minutes using a blood pressure cuff inflated to a minimum of 200 mmHg, while the other arm served as a control. After the release of the cuff the hyperemic response was recorded and the reactive hyperemia index (RHI) was calculated as a measure of endothelial function using the automatic software taking the relative difference between basic and hyperemic blood flow on the occluded arm and dividing it with the response on the control arm, to correct for any autonomic changes in vascular diameter.Augmentation index is derived from pulse wave analyses and is a measure of arterial stiffness. A higher augmentation index indicates more arterial stiffness . Data wat-test and differences in categorical variables were assessed using chi-square test. Linear regression was used to test the relationship between variables and correlations were calculated using Pearsons correlation coefficient. A multivariable linear regression using standardized coefficients (SC) was done to identify independent predictors of VO2peak. A P value of less than 0.05 was considered statistically significant. All analyses were performed in STATA 11.1 .Unless stated otherwise values are expressed as median and inter quartile range for continuous variables and as number (percent) for categorical variables. Continuous variables were compared using Students unpaired Patient characteristics are displayed in Table 2peak was 16.2 (14.6-19.4) using total body mass and 23.5 (20.1-27.4), when using fat free mass in the calculation. No ventricular arrhythmias or signs of ischemia were seen during the test. Median test duration was 7.2 minutes (6.0-8.7) and maximum watt achieved was 90 watts (70–120). Median RER was 1.14 (1.07-1.19). VO2peak (FFM adjusted) was higher in the patients with non-ischemic vs. ischemic heart failure . There were no differences between patients with or without diabetes and atrial fibrillation.Median VO2peak (p = 0.09), but otherwise there were no differences.Median M-value was 4.8 mg/min/kg (3.6-5.6) and glucose clearance was 4.2 ml/min/kg (3.3-5.1) when using total body mass and 6.8 mg/min/kg FFM (4.9-8.1) and 6.0 ml/min/kg FFM (4.7-7.2) respectively when using fat free mass. When comparing patients with insulin sensitivity above and below the median value 6.8 , and there were no significant differences in CFR between patients of ischemic and non-ischemic origin , patients with or without type 2 diabetes , with or without mitral regurgitation  or between NYHA group II and III . There were also no differences in patients with or without previous myocardial infarction, percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) operation regardless of whether the LAD was involved or not . When comparing high and low CFR divided by the median , CFR , augmentation index  and age  . There were no significant correlations between resting  and hyperemic  CFV and VO2peak. Insulin sensitivity was correlated to resting  but not to hyperemic  CFV. There was no significant correlation between CFR and EDV, ESV and LVMi.Table 2peak . Left ventricular ejection fraction was not correlated to CFR , VO2peak  or insulin sensitivity .Unlike augmentation index endothelial function measured by Endo-Pat 2000 was not correlated with CFR , insulin sensitivity  or VO2peak  whereas insulin sensitivity  and arterial stiffness  were no longer associated with VO2peak. The same results were achieved when using glucose clearance instead of insulin sensitivity.In multivariable linear regression adjusting for age Table , CFR remThe present study confirms that exercise intolerance is related to insulin resistance in heart failure patients. The study further shows that coronary flow reserve, a measure of coronary microvessel function, is correlated to both exercise capacity and insulin resistance and supports a mediating role of CFR in explaining the link between insulin resistance and exercise intolerance. Peripheral endothelial function and arterial stiffness were not associated with exercise capacity and, notably, left ventricular function was not related to either insulin resistance, exercise capacity, coronary- or peripheral vascular function.Previous studies has shown a reduced CFR in patients with type 2 diabetes compared to patients without diabetes and an association between CFR and the severity of diabetes measured as HbA1c  and fast2peak is an important prognostic factor in this patient group. However, the link between the degree of cardiac dysfunction and exercise capacity is poorly understood, and previous studies have shown a poor correlation between VO2peak and LVEF [2peak, which has been shown previously in healthy young men but not in patients with heart failure [2peak.Exercise intolerance is the most prevailing symptom in chronic systolic heart failure and VOand LVEF . In conc failure ,11. It i2peak in heart failure patients [2peak is not completely understood. We showed that when adjusting for the effect of CFR on VO2peak, the relationship to insulin sensitivity was weakened and no longer statistically significant. A possible explanation is that increasing insulin resistance influences the cardiac microcirculation resulting in a reduced CFR, which leads to an impaired exercise capacity (Figure Insulin resistance is highly prevalent in heart failure . In accopatients ,24, whicy Figure .Our study did not show any relationship between CFR and peripheral endothelial function measured using flow mediated vasodilation. While a relationship has been shown between CFR and flow mediated vasodilation using brachial ultrasound in other patient populations , this isThe present study shows a negative correlation between CFR and augmentation index, which is as measure of stiffness in the large arteries. Only one previous study has related CFR to augmentation index . In thisPrevious studies have shown that about 50% of asymptomatic patients with type 2 diabetes have signs of diastolic dysfunction  and that2peak and insulin sensitivity, which also are well known prognostic risk factors in heart failure, suggesting that these risk factors are closely linked. Improving VO2peak and insulin sensitivity through exercise training could also improve CFR as has been shown in a recent study of heart failure patients [A reduced CFR has been shown to be an independent predictor of poor outcome in patients with dilated cardiomyopathy  and in apatients . CFR haspatients  and aftepatients . However2peak was a true maximum test as indicated by the high RER values. The cross-sectional nature of the study impedes causal inference and any conclusions regarding potential effects of intervention must therefore remain speculative. The patients had all had a LAD without significant stenosis at a previous coronary angiography or coronary CT-scan, but the examination was not repeated at the time of the study, meaning that some of the patients potentially could have developed a significant LAD-stenosis. All of the patients did however perform a maximal symptom limited cardiopulmonary exercise test at enrolment in to the study without chest pain or signs of ischemia on the ECG minimizing the chances of a significant LAD-stenosis.Limitations: Although the study is limited in size this is somewhat counteracted by the precision of the measures used: insulin sensitivity and glucose clearance were assessed by hyperinsulinemic isoglycemic clamp, the gold standard, and adjusted to fat free mass from DEXA scan. VOOur study confirms that insulin resistance is associated with reduced exercise tolerance in heart failure patients and suggests that this is partly due to reduced coronary flow reserve. This is the first study to our knowledge that shows an association between CFR and exercise capacity in heart failure patients and links the relationship between insulin resistance and exercise capacity to CFR.AI, Augmentation index; BSA, Body surface area; CFR, Coronary flow reserve; CFV, Coronary flow velocity; DEXA, Dual X-ray absorptiometry; EDV, End diastolic volume; ESV, End systolic volume; FFM, Fat free mass; ICD, Implantable cardioverter-defibrillator; IQ, Inter quartile; LAD, Left anterior descending artery; LVEF, Left ventricular ejection fraction; LVMi, Left Ventricular Mass index; NYHA, New York Heart Association; RER, Respiratory exchange ratio; RHI, Reactive hyperemia index; SC, Standardized coefficient; VO2peak, Peak Oxygen uptake.The authors declare that they have no competing interests.MS participated in the design of the study, collection of data, statistical analysis and drafting the paper. TM participated in the design of the study, collection of data and contributed to discussion. RO participated in analyzing the data and contributed to discussion. LP participated in analyzing the data and contributed to discussion. LS reviewed/edited the manuscript and contributed to discussion. HR reviewed/edited the manuscript and contributed to discussion. FD participated in the design of the study, reviewed/edited the manuscript and contributed to discussion. EP participated in the design of the study, statistical analysis reviewed/edited the manuscript and contributed to discussion. All authors read and approved the final manuscript.This work was supported by The Danish Research Council.


A higher resting heart rate is associated with an increased probability of cardiovascular complications and premature death in patients with type 2 diabetes mellitus. The impact of heart rate on the risk of developing microvascular complications, such as diabetic retinopathy and nephropathy, is, however, unknown. The present study tests the hypothesis that a higher resting heart rate is associated with an increased incidence and a greater progression of microvascular complications in patients with type 2 diabetes mellitus.P<0.001). The excess hazard was evident for both nephropathy  and retinopathy .The relation between baseline resting heart rate and the development of a major microvascular event was examined in 11 140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. Major microvascular events were defined as a composite of new or worsening nephropathy or new or worsening retinopathy. Patients with a higher baseline heart rate were at increased risk of a new major microvascular complication during follow-up (adjusted hazard ratio: 1.13 per 10 beats per minute; 95% confidence interval: 1.07–1.20; Patients with type 2 diabetes mellitus who have a higher resting heart rate experience a greater incidence of new-onset or progressive nephropathy and retinopathy.http://www.clinicaltrials.gov. Unique identifier: NCT00145925. http://www.advance-trial.com/static/html/prehome/prehome.aspURL:  Similarly, a weak, but significant and independent, association between baseline resting heart rate and urinary albumin:creatinine ratio (ACR) was recently reported in the Randomised Olmesartan and Diabetes Microalbuminuria Prevention study.14 However, not all existing data support an association between prevalent heart rate and albuminuria,15 and the cross-sectional results that are currently available cannot address the relation between heart rate and incident or progressive microalbuminuria.Although a growing volume of data supports an association between higher resting heart rate and a greater risk of macrovascular events in patients with type 2 diabetes, the impact of heart rate on the risk of developing microvascular complications, such as diabetic retinopathy and nephropathy, is unknown. There are, however, reasons to suspect that an elevated resting heart rate might predict microvascular outcomes in this setting. In patients with hypertension, a higher resting heart rate has been associated with a greater prevalence of microalbuminuria,16 and could be due to the relation between retinopathy and autonomic dysfunction. Once again, however, the importance of heart rate in the development or progression of diabetic eye disease remains unclear. Using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study , we tested the hypothesis that a higher resting heart rate would be associated with both an increased incidence and a greater progression of microvascular complications in patients with type 2 diabetes mellitus.A higher resting heart rate has been reported in patients with diabetic retinopathy18 The study made 2 randomized comparisons: (1) a double-blind assessment of the efficacy of a fixed-combination perindopril–indapamide  versus placebo and (2) an open-label evaluation of an intensive glucose-lowering regimen with modified-release gliclazide, with a target hemoglobin A1c of ≤6.5%, versus standard guideline-based glycemic control. The study was approved by the local ethics committee for each participating center, and all participants provided written informed consent. Participants were ≥55 years of age and had been diagnosed with type 2 diabetes mellitus after the age of 30 years. In addition, they were required to have a history of cardiovascular disease or ≥1 additional cardiovascular risk factor.19 Detailed study methods19 and the main results18 of the ADVANCE study have been reported previously.The ADVANCE study recruited 11 140 patients with type 2 diabetes mellitus from 215 centers in 20 countries between June 2001 and March 2003.Heart rate was measured at the same time as blood pressure with a digital monitor . Recordings were made after the patient had been resting in a seated position for a minimum of 5 minutes. Three readings were taken, and the mean of the latter 2 was used. Weight, height, urinary ACR, serum creatinine, fasting lipid levels, and glycosylated hemoglobin also were measured at baseline.The present study assesses the relation between resting heart rate and the development of a major microvascular event (a coprimary endpoint of the ADVANCE study) over the length of the trial (median follow-up of 4.4 years). Major microvascular events were defined, a priori, as a composite of new or worsening nephropathy or retinopathy. The former was defined as ≥1 of the following: the development of macroalbuminuria, defined as a urinary ACR of >300 μg albumin per milligram of creatinine (confirmed by 2 positive results); doubling of the serum creatinine level to ≥200 μmol/L ; the need for renal replacement therapy due to diabetic kidney disease, in the absence of another acute medical cause that could require transient dialysis; or death due to renal disease. Participants had their creatinine levels measured as part of the study protocol at baseline, 4 months, and 1 year and annually thereafter until completion of the study. Renal function was checked out with these time points at the discretion of their treating clinicians. Urinary ACR was measured locally as part of the study protocol at baseline, 2 years, 4 years, and completion of the study. New or worsening retinopathy was defined as ≥1 of the following: the development of proliferative retinopathy ; macular edema ; diabetes-related blindness ; or the use of retinal photocoagulation therapy. Participants underwent formal eye examination and visual acuity testing at baseline, 2 years, 4 years, and completion of the study.Secondary endpoints were the individual components of the primary outcome (new or worsening nephropathy and new or worsening retinopathy). An Endpoint Adjudication Committee, unaware of treatment allocation, reviewed source documentation for all individuals who had a suspected primary endpoint of the ADVANCE study. This included all the microvascular endpoints considered in the present analyses.20 It is possible that death during follow-up might affect the association between heart rate and the outcomes of interest. Therefore, we estimated subdistribution hazard ratios after correcting for the competing risk of death according to the methods of Fine and Gray.21 Odds ratios and 95% confidence intervals for albuminuria at baseline and microvascular diabetic eye disease at baseline among the fifths of heart rate were estimated by logistic regression. Analyses were performed in SAS v9.2 , SPSS v18 , and Stata 11 , and all reported P values are 2 sided, with the 5% threshold used to determine significance.Baseline resting heart rate was considered both as a continuous variable and after grouping into approximately equal fifths according to its quintiles. Trends in baseline characteristics across the fifths of heart rate were compared with linear and logistic regression. Cox regression analyses were used to calculate hazard ratios with 95% confidence intervals. These were performed in models adjusted for age, sex, ADVANCE study blood pressure treatment arm, and ADVANCE study glycemic control arm and in models adjusted for multiple baseline covariates . Interactions were tested by adding appropriate terms to Cox models. Linearity was assessed by comparing the categorical model with the linear trend model.Of the 11 140 patients randomized into the ADVANCE study, 2 individuals did not have their baseline resting heart rate recorded. The remaining 11 138 patients are included in the present analyses. Participants had a mean age of 66 years, and 58% were male. The mean heart rate in the study population, ± standard deviation, was 74±12 beats per minute, with a range of 33 to 140 beats per minute. The characteristics of the study population according to baseline resting heart rate are shown in P<0.001). At the time of randomization, 7376 participants (66.2%) had normal urinary albumin levels (urinary ACR <3.4 mg/mmol [<30 μg/mg]), 2861 (25.7%) had microalbuminura (urinary ACR 3.4–33.9 mg/mmol [30–300 μg/mg]), and 401 (3.6%) had macroalbuminuria (urinary ACR >33.9 mg/mmol [>300 μg/mg]). Five hundred patients (4.5%) had missing ACR data. P for trend <0.001). The age- and sex-adjusted and multivariable-adjusted odds ratios for (a) albuminuria and (b) microvascular diabetic eye disease at baseline according to fifth of resting heart rate (with the lowest fifth as the reference) are shown in At baseline, 793 patients (7.1%) had microvascular diabetic eye disease . These individuals had a mean resting heart rate of 76±12 beats per minute, compared to 74±12 beats per minute in patients without microvascular eye disease at baseline  experienced a major microvascular event. Three hundred and ninety-seven patients (3.6%) developed new or worsening nephropathy, and 575 (5.2%) developed new or worsening retinopathy. Fifteen patients were lost to follow-up  at the end of follow-up and were censored at the last follow-up assessment. In addition, 879 patients (7.9%) died during follow-up. Patients who died before the occurrence of each outcome were censored at the time of death .A higher baseline resting heart rate was associated with a greater risk of developing a major microvascular complication during follow-up . After a22).The increased risk of microvascular complications associated with a higher heart rate was observed in both sexes, in patients who had suffered a prior major macrovascular complication  and in those who had not . SimilarThe present study demonstrates that a higher resting heart rate predicts a greater risk of future microvascular complications in patients with type 2 diabetes mellitus. As far as we are aware, this has not been shown previously. The excess hazard associated with a higher heart rate is independent of many other factors that can influence heart rate and affect outcome in this setting. The association is particularly apparent for the occurrence or worsening of diabetic eye disease but is also evident for the occurrence or worsening of diabetic nephropathy.23 Indeed, we recently reported in ADVANCE that a higher heart rate was a strong and independent predictor of all-cause death and major cardiovascular complications, including cardiovascular death, myocardial infarction, and stroke.11 In contrast, there are limited prior data, almost entirely cross sectional, assessing the relation between heart rate and microvascular disease. In patients with hypertension, Bohm and colleagues12 reported that a higher heart rate is associated with increased prevalence and severity of microalbuminuria. This relation was observed regardless of treatment with β-blockers12 and irrespective of whether the patient had a history of atrial fibrillation.13 However, in a recently reported analysis of The PROspective pioglitAzone Clinical Trial In macroVascular Events, a multicenter double-blind assessment of the effects of pioglitazone versus placebo on major cardiovascular events in patients with type 2 diabetes and a history of macrovascular disease, no association was observed between resting heart rate and microalbuminuria.15 Despite this, heart rate and microalbuminuria were each independently predictive of the composite endpoint of all-cause death, myocardial infarction, and stroke in this study.15The relation between higher heart rates and major adverse cardiac events, such as myocardial infarction, cardiac death, and hospitalization with heart failure, is now well recognized.15 assessed the relation between heart rate and incident albuminuria. Two recent prospective studies have, however, identified a higher heart rate as a predictor of renal dysfunction in the general population.25 In the Atherosclerosis Risk in Communities (ARIC) Study, the hazard of developing end-stage renal disease was almost doubled among patients with a resting heart rate in the upper quarter, when compared to the remaining subjects, during a median of 16 years' follow-up.24 Similarly, in a cohort of subjects participating in a Japanese health screening program, a higher heart rate was associated with a greater risk of declining estimated glomerular filtration rate and of developing dipstick proteinuria (≥1) during 5 years of follow-up.25Neither of the aforementioned studies16 although not consistently.27 In the Wisconsin Epidemiological Study of Diabetic Retinopathy, although patients with a higher resting heart rate had a greater risk of incident macular edema and progressive diabetic retinopathy over a 4-year period, this was attenuated and was nonsignificant after correction for other factors, including age, duration of diabetes, glycosylated hemoglobin, and blood pressure.28 In contrast, in our much larger cohort, followed up for 4.4 years, we have observed strong and independent associations between resting heart rate and incident and progressive diabetic eye disease, even after correction for a wide range of potential confounding factors . Apart from differences in power, the discrepant results could reflect variances in the study populations and protocols. The Wisconsin Epidemiological Study of Diabetic Retinopathy recruited a community-based cohort with a high prevalence of younger, insulin-requiring patients, and the incidence and progression of retinopathy was determined with fundus photography.An association between a higher resting heart rate and prevalent retinopathy in patients with diabetes has been reported previously,Although a higher resting heart rate predicts a greater prevalence of albuminuria and diabetic eye disease at baseline and higher risk of subsequent microvascular events, the results could reflect an association between heart rate and other factors that might mediate microvascular disease. There are, however, several plausible mechanisms by which an elevated heart rate might predispose to such complications.12 A similar mechanism also might explain the relation between more rapid heart rates and ocular disease. An increased heart rate also has a variety of direct detrimental cardiovascular consequences. These include unfavorable effects on endothelial function and proatherosclerotic activity,29 which are important factors in the progression of nephropathy and retinopathy.32 A higher heart rate also is associated with factors such as obesity, higher blood pressure, a proatherosclerotic lipid profile, and reduced physical activity,33 all of which are associated with an increased risk of microvascular complications and are targets for intervention to improve outcome in patients with diabetes mellitus.34 Finally, a faster resting heart rate is a characteristic feature of autonomic neuropathy, which is in turn associated with an increased prevalence of other complications, such as nephropathy and retinopathy.35 It is possible, therefore, that the observed relation between heart rate and microvascular events is mediated at least in part by sympathetic overactivity, although correlations between heart rate and measures of sympathetic tone are relatively weak.36It has been suggested that a higher heart rate might promote microalbuminuria because of increased exposure of the glomerulus to arterial pressure waves.38 Intriguingly, a higher heart rate per se also has been shown to predict an increased risk of developing incident diabetes.39 This could reflect physical deconditioning and other factors that predispose to developing diabetes but reinforces the complex interrelations among heart rate, neural mechanisms, and metabolic control.When baroreflex control of heart rate is assessed by sensitive methods, abnormalities are apparent at an early stage in patients with diabetes. These changes predate obvious diabetic complications and evidence of autonomic dysfunction that can be detected by conventional methods.40 and progressive nephropathy.41 The risk attributable to this “nondipping” pattern might not be conveyed in the measured daytime blood pressure and might be magnified by a higher resting heart rate, which increases exposure of the microvasculature to the elevated pressures.It could be that the observed hazard associated with a higher heart rate is due to a combination of mechanisms and that the importance of each varies among individuals. Likewise, the mechanisms could have synergistic effects. For example, a higher heart rate might result in direct microvascular damage, but this could be accentuated by the presence of hypertension. In particular, elevated nocturnal blood pressure in diabetes is associated with incident microalbuminuriaIn summary, the mechanisms by which a higher resting heart rate predicts an increased risk of microvascular complications in type 2 diabetes mellitus are unclear, and it could be that several interrelated processes are involved. One potential method of assessing whether there might be a direct relation would be to assess the effects of a pure rate-limiting drug, such as ivabradine, on microvascular outcomes.43 Whether this reflects differing pathophysiological mechanisms, is a chance finding, or is due to the definitions used and the relatively short duration of follow-up is not clear.In this analysis, the relation between resting heart rate and the risk of developing diabetic eye disease seems stronger than the association with incident nephropathy. In addition, in contrast to retinopathy, the data suggest that the relation between heart rate and renal disease is nonlinear, with the excess hazard clearly seen only in patients with a resting heart rate in the upper fifth. Similarly, in the baseline, cross-sectional data, the increased prevalence of microalbuminuria is most obvious in patients with heart rates in the upper two fifths. This raises the possibility that the relation between heart rate and microvascular disease could vary in differing vascular beds. This is not unexpected, given that the effects of blood pressure–lowering treatment and more intensive glycemic control in the ADVANCE study were more apparent in the kidney than in the eye. Similar differential effects of treatment on differing microvascular complications have been observed in other large studies.The present study explores the relation between heart rate and future microvascular complications in patients with type 2 diabetes mellitus in a large population recruited from 20 countries and with diverse ethnic backgrounds, which was well characterized and followed up closely. The primary endpoint of this epidemiological evaluation was a coprimary endpoint of the main ADVANCE study, and all components of it were independently adjudicated according to predefined criteria. Nevertheless, it has the limitations inherent in any such post hoc analysis. Although the large study population ensures considerable statistical power and allows reliable correction for many potential confounding factors, it is not possible to fully correct for all possible confounders. In particular, autonomic function was not assessed at baseline.Patients with type 2 diabetes mellitus who have a higher resting heart rate have a greater prevalence of microalbuminuria and diabetic eye disease. They also experience a greater incidence of new-onset or progressive nephropathy and retinopathy, which suggests that an increased heart rate might be a potential mediator of these outcomes. Further work is required to assess this and to determine whether lifestyle measures or pharmacological therapies that can slow heart rate might reduce the risk of microvascular complications. In particular, the benefits of heart rate reduction in the prevention of progressive diabetic retinopathy deserve further attention.


Introduction. Paradoxical or hypokinetic interventricular septal motion has been described in patients with septal or paraseptal accessory pathways. Data regarding nonseptal pathways is limited. Methods and Results. We quantified left ventricular dyssynchrony and function in 16 consecutive children, 14.2 ± 3.7 years, weighing 53 ± 17 kg, prior to and following catheter ablation of bidirectional septal (N = 6) and nonseptal (N = 10) accessory pathways. Following ablation, the left ventricular ejection fraction increased by 4.9 ± 2.1% (P = 0.038) from a baseline value of 57.0% ± 7.8%. By tissue Doppler imaging, the interval between QRS onset and peak systolic velocity (Ts) decreased from a median of 33.0 ms to 18.0 ms (P = 0.013). The left ventricular ejection fraction increased to a greater extent following catheter ablation of nonseptal  versus septal  pathways. The four patients with an ejection fraction <50%, two of whom had left lateral pathways, improved to >50% after ablation. Similarly, the improvement in dyssynchrony was more marked in patients with nonseptal versus septal pathways  versus 1.4 ± 11.4 ms (P = 0.655)). Conclusion. Left ventricular systolic function and dyssynchrony improve after ablation of antegrade-conducting accessory pathways in children, with more pronounced changes noted for nonseptal pathways. Manifest atrioventricular accessory pathways in the so-called Wolff-Parkinson-White syndrome result in electrical and mechanical preexcitation of ventricular myocardium at their site of insertion. Earlier echocardiographic studies demonstrated that left posteroseptal accessory pathways are associated with abnormal left ventricular posterior wall motion –3 and thWe enrolled consecutive children (≤18 years of age) with a diagnosis of Wolff-Parkinson-White syndrome  referred for catheter ablation at Sainte-Justine Hospital over a 2-year period. We excluded patients with a congenital heart defect  and those in whom transthoracic echocardiograms could not be performed for logistical reasons prior to or following catheter ablation. The protocol was approved by the local institutional review board, and written informed informed consent was obtained from all patients.Electrocardiograms were performed prior to and after catheter ablation in all patients. PR intervals were measured by computed analyses. The accessory pathway location was initially classified by an established electrocardiographic algorithm in children  and subsaortic preejection delay (APD) using M-mode and pulsed Doppler modes, measured from the onset of the QRS complex to the beginning of aortic ejection  [interventricular mechanical delay (IVMD) using the pulsed Doppler mode, defined as the difference between aortic and pulmonary preejection delay  ;septal-to-posterior wall motion delay (SPWMD) using M-mode imaging  ;delay between time to peak systolic velocity at basal septal and basal lateral segments using tissue Doppler imaging  . This meCardiac dyssynchrony was assessed by the following criteria Figures , and 4:aThe left ventricular ejection fraction was quantified using the Simpson method  in the aμg/kg/min). Barring any complication, patients were discharged the following day.All catheter ablation procedures were performed under general anaesthesia. Three quadripolar catheters were advanced to the high right atrium, His position, and right ventricular apex. A decapolar catheter was placed in the coronary sinus. An initial electrophysiological study was performed to assess baseline intervals, atrial, atrioventricular nodal, accessory pathway, ventricular refractory periods, Wenckebach physiology, retrograde conduction, and inducible supraventricular tachycardia. The atrial insertion of the accessory pathway was identified as the earliest atrial signal during retrograde accessory pathway conduction. The ventricular insertion was assessed during maximum preexcitation as the site of earliest ventricular depolarization. Accessory pathways were ablated using transcatheter cryoenergy for septal and radiofrequency energy for lateral pathways (left or right). Coexisting arrhythmias, such as atrioventricular nodal reentrant tachycardia, were ablated during the same intervention. Catheter ablation was considered successful if, after 30 minutes of observation, there was no evidence of antegrade or retrograde conduction across an accessory pathway and no inducible supraventricular tachycardia with and without an isoproterenol infusion . Continuous variables are summarized by mean ± standard deviation or median and interquartile range  depending on normality of distribution. Categorical variables are represented by frequencies and percentages. Intrapatient comparisons prior to and following ablation were assessed by paired Student's N = 5), right lateral/anterolateral (N = 3), and left posterior (N = 2) connections. All patients underwent successful catheter ablation. Cryoenergy was employed in 4 patients and radiofrequency energy in 12.Overall, 16 children , age 14.2 ± 3.7 years, weight 53 ± 17 kg were systematically assessed. All had Wolff-Parkinson-White syndrome, structurally normal hearts, and evidence of sustained supraventricular tachycardia by Holter monitoring or external event loop recorders. Patient and procedural characteristics are summarized in P = 0.038) from a baseline value of 57.0 ± 7.8%. This was accompanied by a significant reduction in the difference between aortic and pulmonary preejection times . The left ventricular ejection fraction increased to a greater extent following ablation of nonseptal  versus septal  pathways. The 4 patients with a left ventricular ejection fraction <50% prior to ablation, 2 of whom had left lateral pathways, improved to >50% after ablation. By tissue Doppler imaging, the time to peak systolic velocity decreased from 33.0 ms  to 18.0 ms , P = 0.013. No significant change in septal-to-posterior wall motion delay or diastolic parameters was noted.Prior to ablation, no differences in left ventricular ejection fraction or indices of left ventricular dyssynchrony were observed in patients with septal versus nonseptal accessory pathways. P = 0.015) versus 1.4 ± 11.4 ms (P = 0.655) for nonseptal versus septal pathways, respectively. Similar to changes in left ventricular ejection fraction, the magnitude of improvement in left ventricular dyssynchrony was more marked in patients with nonseptal versus septal pathways. The difference between septal and lateral wall motion delay before and after ablation was 20.6 ± 7.1 ms  with Wolff-Parkinson-White syndrome who underwent successful radiofrequency ablation of right septal or posteroseptal accessory pathways . Prior tN = 15) compared to 62% for all other locations. Moreover, septal dyskinesia was identified in 6 patients with right septal accessory pathways and was the only factor significantly associated with a reduction in left ventricular ejection fraction. After ablation, the left ventricular ejection fraction significantly improved in these 6 patients from 42 ± 5% to 55 ± 7%. Tissue Doppler imaging was not systematically performed. In another series of 63 children with Wolff-Parkinson-White syndrome (mean age at diagnosis 5.9 years), left ventricular dysfunction was reported only in association with septal accessory pathways . The meaThe relationship between dyskinetic segments and left ventricular dysfunction is also supported by the pacemaker literature, which suggests that right ventricular apical pacing may have a detrimental effect on left ventricular function –26. RestIt may, therefore, be hypothesized that ventricular preexcitation can result in remodelling changes similar to ventricular pacing, with segmental dyskinesia leading to thinning, dyssynchrony, ventricular dilation, and, ultimately, ventricular dysfunction. Such a pattern may be produced from any site of ventricular activation remote from the normal conduction system. Our results are consistent with the hypothesis that dyssynchrony induced by nonseptal pathways may be as deleterious, and sometimes more so, than septal pathways. Further studies are required to confirm these findings and to assess the relevance of targeting accessory pathways based solely on hemodynamic effects of preexcitation .Limitations. As is often the case with pediatric case series, the study was limited by the small number of patients. Nevertheless, to minimize selection bias, all consecutive children referred for catheter ablation of Wolff-Parkinson-White syndrome were enrolled over a 2-year period. In determining dyssynchrony, echocardiographic assessment was limited to basal septal and lateral segments by means of tissue Doppler imaging. The comparative value of sampling additional segments or the use of potentially complementary imaging techniques, such as strain and strain rate, could not be assessed.In a series of pediatric patients with Wolff-Parkinson-White syndrome and absence of structural heart disease, left ventricular systolic function and dyssynchrony improved after successful ablation of antegrade-conducting accessory pathways. The more pronounced changes were observed in patients with nonseptal pathways.


Computer technology enables realistic simulation of cardiovascular physiology. The increasing number of clinical surgical and medical treatment options imposes a need for better understanding of patient-specific pathology and outcome prediction.A distributed lumped parameter real-time closed-loop model with 26 vascular segments, cardiac modelling with time-varying elastance functions and gradually opening and closing valves, the pericardium, intrathoracic pressure, the atrial and ventricular septum, various pathological states and including oxygen transport has been developed.Model output is pressure, volume, flow and oxygen saturation from every cardiac and vascular compartment. The model produces relevant clinical output and validation of quantitative data in normal physiology and qualitative directions in simulation of pathological states show good agreement with published data.The results show that it is possible to build a clinically relevant real-time computer simulation model of the normal adult cardiovascular system. It is suggested that understanding qualitative interaction between physiological parameters in health and disease may be improved by using the model, although further model development and validation is needed for quantitative patient-specific outcome prediction. The increasing number of surgical and medical treatment options in cardiovascular disease imposes a need for better understanding of patient-specific pathology and outcome prediction. Due to the complexity of the cardiovascular system, it is not always possible to understand the role of every cardiovascular parameter; additionally, prediction of the hemodynamic features can be even more challenging when several of those parameters change simultaneously. In many cases the use of simulation models can improve the understanding of both normal physiology and pathophysiology. Moreover, clinical training in simulation centres, where simulation models have been connected to mannequins responding to therapeutic measures, has proved to further increase diagnostic and therapeutic accuracy .Other authors  have pubModels focusing on particular aspects of hemodynamics such as mitral valve dynamics , remodelThe aim of this paper is to present a closed-loop, real-time, lumped parameter cardiovascular simulation model, which includes the behavior of the four cardiac chambers, interatrial and interventricular septum, pericardium, intrathoracic pressure changes, heart valves, intracardiac shunts and vascular system. The current model is based on previous publications ,9. The cThe model is presented from a normal cardiovascular physiological point of view, but a limited number of pathological scenarios will also be shown. A secondary aim is to show that the model generates valid output, which is consistent with earlier published clinical and experimental data, focusing on the behavior of the entire system rather than on single variables.The model Figure  is basedThe four cardiac chambers passive and active properties are modeled with separate time-varying elastance functions based on the “Double-Hill equation” as previously described ,14 incluBy using a continuous function through the cardiac cycle manual setting of valvular timing  is avoidThe electrocardiogram (ECG) . Inflow length l is set to a value identical to the instantaneous diameter of the valve in contrast to the constant value in Mynard et al.[Valve pressure gradients are composed of a Bernoulli resistance and an inertial term  (Equation 3), thereby stiffening during contraction, in accordance with known physiological characteristics. Additional file The interventricular septal displacement is simulated using pressure transmission through the muscular septum as previously described ,15 , the oxygen saturation (Sat) and the volume of the compartment (Volume) as in clinical routine and most catheterization laboratories [.Blood oxygen content in every compartment is calculated as a constant multiplied by the hemoglobin  and arterial vascular resistance as in Sun et al. and descThe simulator was compiled as a stand-alone software developed in Visual Basic.NET 2010  and .NET Framework 4.0 . A time step of 0.25 ms was used to assure stability. The implemented 62 differential equations were solved with an implicit Euler numerical method . Mean va3. Systolic left ventricular heart failure was simulated by decreasing the maximum elastance from 2.8 to 1.0 mmHg/ml. Diastolic left ventricular heart failure was simulated by increasing the basal passive diastolic elastance Emin from 0.05 to 0.12 mmHg/ml. Aortic stenosis was simulated by decreasing the open aortic valve area from 5.0 to 0.7 cm2. Aortic regurgitation was simulated by increasing the closed aortic valve area from 0.0 to 0.2 cm2. Simulation of a Valsalva maneuver was accomplished by increasing intrathoracic pressure from 0 to 10 mmHg for approximately 20 seconds with and without baroreceptors activated. All other parameters and settings were identical.All hemodynamic data were presented with zero intrathoracic pressure in order to resemble end-expiratory values. With the basic set of parameters presented in the supplement an adult man weighing 70 kg is described with a blood volume of 5600 ml (80 ml/kg), blood viscosity of 0.00024 mmHg · s and blood density of 1.060 g/cm-1, increased left and right ventricular contractility by 50% and increased systemic and pulmonary resistance arterial diameters by 50%. The cardiac elastance parameters α1 and α2 were scaled with the square-root of the factor changing the heart rate to preserve a realistic relation between systolic and diastolic times. The vascular damping scaling factor λ was set to 0.5 in all vascular segments and presented simulations. The oxygen saturation in the pulmonary capillaries was set to 99.4%, corresponding to a normal alveolar pO2 of 13.3 kPa and the pulmonary shunt was set to 10% of cardiac output in all presented simulations. Hemoglobin level was set to 140 g/l and systemic oxygen consumption to 250 ml/min in addition to myocardial oxygen extraction. A Young’s modulus Yinc of 3000 mmHg (= 0.40 MPa) similar to the value in Wang et al.[E0 at the vessel-specific normal mean pressure P0  mmHg, pulmonary arterial pressure 24/8(11) mmHg, mean right atrial pressure 4 mmHg and mean left atrial pressure 5 mmHg. The model output of pressures  of the ventricular pressure-volume loops . Left ventricular end-diastolic volume and filling pressures increased Figure .Simulated data of aortic regurgitation showed apparent left ventricular ejection fraction and stroke volume increase, systemic blood pressure decrease although stroke work increased (volume-load). Left ventricular end-diastolic volume and filling pressures increased Figure .The simulation of a Valsalva maneuver without and with activated baroreceptor reflex is shown in Figure The stepwise simulation of exercise is shown in Figure The presence of arteriosclerosis, simulated by increased vascular stiffness, resulted in increased systolic aortic pressure and decreased diastolic aortic pressure. A decrease in systolic ejection time during this process is indicated by the premature arrival of the reflected pressure wave changing the shape of the pressure curves in a characteristic way Figure .Blood volume was the single most important parameter in the sensitivity analysis  or suboptimal scaling of the elastance functions. It is also possible that atrioventricular (AV)-plane motion, not included in the present model, is necessary to improve ventricular filling during tachycardia in real life physiology.The algorithms for scaling of the cardiac elastance functions with changing heart rate seem efficient up to a frequency of 160 minSensitivity analysis in a non-linear model should ideally be performed for every possible set of input parameters. With many input parameters it is neither feasible to perform the calculations nor to interpret them in every possible model state. The choice of relevant parameters therefore must rely on physical and physiological model relations; however the relevance of the model is supported by the performed sensitivity analysis in normal physiology, where parameters determining cardiac filling, afterload and ventricular systolic performance are most important for cardiac flow and pressure generation  and right (gray thick) ventricular time-varying elastance functions during two heart cycles. Atrial elastance functions are shown with thin lines. The amplitude is closely related to contractile function while the volume-dependent basal level describes passive stiffness.Click here for fileThe ECG and valvular areas simulated during two normal heart beats. ECG (light blue) and area-changes during the heart cycle for aortic (red), pulmonary (yellow), mitral (brown), tricuspid (blue) valves are shown.Click here for fileModeled volume changes (black) due to pressure dependent ventricular septal volume shift from left to the right ventricle during two heart cycles. Septal stiffness values of 40, 30, 20 and 10 mmHg/ml are shown. Lower septal stiffness increases septal shift. ECG (blue) is shown as reference.Click here for fileSimulated pressure gradients over the mitral valve during diastole. The total mitral pressure gradient (thick black) is decomposed into a dominating Bernoulli gradient (grey) and an inertial component (dotted black).Click here for filePericardial pressure-volume relations. The black curve illustrates the relation used in the present model with the range used by a single heart beat in orange. Pericardial pressure is slightly negative.Click here for filePressure-volume relations in arterial vascular segments illustrating non-linear stiffness in the actual working pressure range of each vascular segment in accordance with Equation 10.Click here for fileBlood flow in left (black) and right (gray) coronary artery during two heart cycles. Left coronary artery blood flow decreases during systole due to vascular compression caused by high left ventricular wall stress.Click here for fileSensitivity analysis.Click here for filePressure changes simulated during two heart cycles in the aortic root (black), ascending aorta, proximal and distal aortic arch, descending aorta and a peripheral artery (light gray). The segments between the aortic root and the peripheral artery are shown in different shades of gray.Click here for fileFlow pulsatility in pulmonary capillaries (pink) is larger than in the systemic capillaries (green). Pulmonary valve flow (orange) and tricuspid valve flow (blue) resembling left-sided flows are also shown.Click here for filea. Intracardiac pressure-volume loops from the left ventricle (black) and right ventricle (gray). b. Intracardiac pressure-volume loops from the left atrium (black) and right atrium (gray).Click here for filewall; a resistance representing viscous chamber wall properties, Routflow; a linear chamber outflow resistance, B; a non-linear Bernoulli valve resistance, Ivalve; an inductance representing flow inertia,, R; a linear resistance, I; an inductance representing flow inertia, C; a non-linear capacitor representing vascular elasticity, Ω; a non-linear resistance term representing viscous vascular wall properties.Electrical analogue sketches showing details of the heart chambers, valves and vascular compartments. The arrows show directions of blood flow. e(t); time-varying elastance representing systolic and diastolic chamber properties, RClick here for file


Ultrasmall superparamagnetic particles of iron-oxide (SUPIO) particles can be used as a magnetic resonance imaging contrast (MRI) agent. Due to their dextran coating and small diameter (<30 nm), they are phagocytised by inflammatory cells [1].The aim of this study was to assess whether a novel acquisition/registration USPIO-MRI protocol could be used to assess myocardial cellular inflammation. Myocardial infarction and cardiac surgery was used to model myocardial inflammation [2]. An influx of macrophages can be seen in post-mortem histology, however the dynamics of in vivo patho-physiology is uncertain [3].16 patients underwent MRI 2-4 days after ST-elevation myocardial infarction (STEMI) at baseline and 24-hours after intravenous USPIO infusion  or no infusion (n=6). Between 5 and 28-days following on-pump coronary artery bypass graft (CABG) surgery, 32 patients underwent the same protocol with all patients receiving USPIO.3T-MRI  was performed to optimise USPIO sensitivity. Baseline and 24-hour multi-echo T2*-weighted sequences were spatially registered to generate an R2* (1/T2*) map to assess USPIO uptake. R2* maps were spatially registered using custom software  to late gadolinium enhancement (LGE) images to confirm USPIO localisation in the infarct zone. CABG R2* maps were analysed using a standard 17-segment modelData comparing CABG to MI cohorts was analysed by one-way and repeated measures ANOVA with Dunn's post-test. Data comparing change in R2* values within cohorts was analysed by Wilcoxon matched pairs test.Consistent with reticuloendothelial uptake, R2* values increased in the liver & spleen following USPIO administration. In the myocardial infarct, there was a large R2* increase from 41.0±12.0 (baseline) to 155±45.0 s-1 (p<0.001) at 24h. A lower magnitude response was seen in the remote myocardium from 39±3.2 to 80±14.9 s-1 (p<0.002), consistent with myocardial inflammation that occurs post infarction [4[.In CABG patients the R2* signal increased: 45±7s-1 to 118± 22 s-1 at 24h (p<0001). The increase in myocardial R2* values was greater than in the remote myocardium of patients with STEMI, but lower than the infarct zone itself (p<0.001 and p<0.05 respectively).USPIO are taken up into inflamed myocardial tissue and can be quantitatively assessed using a multi-parameter MRI acquisition protocol with optimised spatial registration analysis based on a custom mutual information algorithm.This represents a novel imaging technique of assessing myocardial inflammation, as well as providing a useful research tool in investigating tissue inflammation.Funding was provided by the Medical Research Council, Chest Heart & Stroke Scotland, the British Heart Foundation and the Scottish Universities Physics Alliance.The Welcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by NHS Research Scotland (NRS) through NHS Lothian.