Recent autopsy studies found microvascular rarefaction in remodeled myocardium of patients who died of heart failure with preserved ejection-fraction (HFpEF). This condition has not been investigated so far by non-invasive methods in patients with HFpEF. The aim was to quantify the intravascular volume (IVV) compartment by CMR in HFpEF patients.n = 6; 12 examinations) and post-myocardial infarction patients  were studied with T1-mapping (MOLLI-sequence) before and after IV bolus of 0.03 mmol/Kg of the intravascular contrast-medium (CM) Gadofosveset and 0.2 mmol/Kg of the extravascular CM Gadobutrol yielding IVV and extracellular volume (ECV), respectively. Healthy controls  were also studied with the same protocol. IVV and ECV were measured in the basal septum (without ischemic scar in post-MI patients). In post-MI patients, ECV and IVV were also measured in the ischemic scar. Left ventricular (LV) volumes, mass, and ejection-fraction were measured by standard protocol. LV global longitudinal strain (GLS) was calculated by feature tracking on long-axis cine acquisitions.In two separate CMR examinations, HFpEF patients (p = 0.005), while ECV was increased . However, IVV did not differ among HFpEF, post-MI, and healthy controls , whereas ECV was higher in HFpEF than in post-MI and healthy controls .LV mass to end-diastolic volume ratio and GLS in HFpEF were higher and lower, respectively, than in healthy controls and post-MI patients, whereas the post-MI patients showed lower LV ejection-fraction. Compared to healthy myocardium of controls, IVV in scar was reduced (0.135 ± 0.018 vs 0.109 ± 0.008, respectively, 1-mapping technique combined with an intravascular CM shows potential to measure IVV. In infarct scar with substantially increased ECV, IVV was significantly reduced. Unlike in infarct scar, in remodeled myocardium of HFpEF patients, increased ECV was not accompanied by a reduction of IVV.The T Heart failure with preserved ejection fraction (HFpEF) is a common condition with increasing prevalence and high morbidity and mortality , 2 HFpEF1 by currently available mapping technique [Based on these premises, we developed a cardiac magnetic resonance (CMR)-based approach for the quantification of the myocardial intravascular volume (IVV) consisting in the use of an intravascular gadolinium-based contrast medium (CM) combined with the quantitative measurement of myocardial Technique , 9. To technique . In addiechnique .1-mapping based extracellular volume fraction (ECV) > 28%, [1-mapping technique has been performed with regard to standardization of the method [1 mapping technique to measure the distribution volume of an intravascular CM in order to obtain IVV non-invasively. Accordingly, ECV and IVV were measured by the administration of the extravascular CM gadovist and the intravascular CM gadofosveset , respectively. In the controls, the two CMs were administered in two separate groups of 10 controls each . Post-MI and HFpEF patients were studied in a second research-dedicated CMR examination with the administration of the intravascular CM.Twenty healthy controls without cardiovascular risk factors, 6 HFpEF patients and 6 patients with previous MI were enrolled into the study. The healthy controls were recruited through local advertising and had no history or symptoms of cardiovascular disease and no cardiovascular risk factors. Patients were recruited from the clinical database of our CMR center after having performed a clinically-indicated CMR examination using an extravascular CM . HFpEF patients were selected according to the following criteria: 1) LV-EF > 40% and presence of left ventricular hypertrophy (LVH) and/or Te method –14 and ie method . In thisThe study complied with the Declaration of Helsinki and all examinations were conducted at the Lausanne University Hospital after obtaining the approval from local ethics committee. All study participants provided written informed consent.In the extravascular CMR protocol, i.e. in the clinical CMR examination, cine SSFP images were acquired for functional LV evaluation, followed by pre-contrast T2-map and T1-map acquisitions at the basal short-axis position. At ≥15-min after the i.v. bolus administration of 0.20 mmol/kg of the extracellular CM gadobutrol, the T1-map was re-acquired at the same short-axis basal position. Then, late gadolinium enhancement (LGE) imaging was performed on short axis covering the entire LV.In the intravascular CMR protocol, cine SSFP and T2-map and native T1-maps were acquired as in the extracellular CMR protocol. Then, at 3 min after the i.v. bolus administration of 0.03 mmol/kg of the intravascular CM gadofosveset, the T1-map was re-acquired at the same basal short-axis slice position. The 3-min interval was chosen to allow for a homogeneous distribution of the intravascular CM in the subjects’ blood pool, i.e. in the intravascular compartment. This protocol was performed in all patients (6 HFpEF and 6 post-MI patients) and in 10 healthy controls (as described above). In the extravascular and intravascular CMR protocol, hematocrit was measured immediately before CMR.1- and T2-mapping as well as for the LGE imaging are given in Table All studies were performed on a 1.5 Tesla system  using dedicated cardiac software, a 32-channel phased array receiver coil, and ECG triggering. The pulse sequence parameters for functional cine SSFP, TThe formula-1 below was applied to calculate the CM distribution volume after administration of the extra-cellular and intravascular CM yielding extracellular volume (ECV) and intravascular volume (IVV), respectively .\documen1-myo-pre and T1-blood-pre indicate myocardial and blood native T1 values, respectively, and T1-myo-post and T1-blood-post indicate the T1 values of myocardium and blood pool after CM administration, respectively.TECV and IVV were measured 1). in normal myocardium of controls, i.e. in the basal septum; 2). in the basal septum of HFpEF patients, and 3). in the basal septum (=non-infarcted myocardium) and in the infarcted (=LGE positive) myocardium of the post-MI patients , another ROI was drawn in the infarcted region in the native and corresponding post-contrast T1-maps. For a correct identification of the fibrotic scar on the T1-maps, a careful side-by-side comparison between T1-maps and LGE images was performed. In LGE positive patients the scar mass was quantified as myocardium with a signal intensity exceeding the mean signal intensity of remote myocardium by >6SD using a semi-automatic algorithm [All studies were saved in DICOM format and analyzed by 1 operator with > 10 years experience in CMR using GTVolume software . For all maps acquired in the basal short-axis, a region of interest (ROI) was manually drawn in the mid-layer of the interventricular septum (segment 2 and 3 according to AHA segmentation). The ROI was drawn by leaving 2 mm from each endocardial side to avoid partial volume contamination with blood pool signal. On Tlgorithm  and exprTwo-dimensional Cardiac Performance Analysis Software  was used to obtain global LV longitudinal strain derived as the mean between longitudinal strain obtained in 2-chamber, 3-chamber, and 4-chamber cine data sets. The mathematical assumptions used and the clinical validation of the feature tracking technology have been previously described . After tp value < 0.05 were considered statistically significant. All analyses were performed using SSPS version 21 .Continuous variables are expressed as mean value ± SD and categorical variables are expressed as frequency and (%). Continuous variable differences across healthy controls, HFpEF, and post-MI patients were analyzed by ANOVA, and followed by Bonferroni’s post hoc analyses when required. Categorical variable differences across the groups were assessed by Chi-squared, or by Fisher’s exact test if the expected cell count was < 5. Differences in The baseline characteristics of the healthy controls and patients are summarized in Table p = 0.005;  likely representing the well-known microvascular rarefication in scar tissue, a hallmark of dense fibrotic tissue [p < 0.001; Fig. In healthy controls, by applying formula-1, a low distribution volume in the myocardium of 0.135 ± 0.018 was obtained after intravascular CM administration, reflecting the IVV of normal myocardium. In the scar tissue of post-MI patients, IVV was reduced as compared to healthy controls , IVV of the basal septum tended to be higher in patients than in healthy controls . On the other hand, ECV of the basal septum was significantly increased in HFpEF and post-MI patients as compared to the controls .The T1-mapping after gadofosveset administration, while the extracellular compartment was expanded as compared to controls. Second, in the scar tissue of post-MI patients the intravascular compartment was significantly reduced, while the extracellular compartment was massively increased. Third, myocardial edema was not detected in the remodeled myocardium of HFpEF patients as evidenced by the normal T2 values.The main findings of the current study can be summarized as follows. First, in patients with HFpEF, there was no reduction of the myocardial intravascular compartment as derived by T1-mapping, we calculated the relaxivity of myocardium and blood pool immediately, i.e. at 3 min, after gadofosveset bolus injection, and these measurements, in conjunction with the hematocrit, were used to derive the myocardial IVV by adopting the previously published formula [1-mapping measures the effect of CM on proton relaxation, not reflecting directly the concentration of CM in the intravascular compartment. Although gadofosveset is a prevalently intravascular CM, it affects the extravascular compartment by proton (i.e. water) exchange across the vascular wall [1). For the slow exchange model, simulations found an overestimation of IVV by approximately 10–30% at a ΔR1 of 9, which is matching the ΔR1 found in our study (at 3 min after gadofosveset injection) [1 = 25 mmol.L-1.s− 1) as compared with the free fraction (r1 = 5 mmol.L− 1.s− 1) [1-maps before and at 3 min after intravascular CM bolus injection, which was demonstrated in ischemic scar versus normal myocardium of healthy controls. Reduced IVV of chronic ischemic scar is well established in the literature, and our approach was capable to correctly gauge this key feature of dense chronic fibrotic scar.By assuming that the vascular endothelium is not permeable to albumin under normal conditions, gadofosveset, which binds reversibly to albumin, behaves preferentially as an intravascular CM after intravenous bolus injection. Using T formula , 11. Thelar wall . Severallar wall . Simulatjection) . After I 1.s− 1) . The unbWhen applying the IVV measurement to non-infarcted myocardium, IVV was not reduced in HFpEF myocardium or in non-infarcted myocardium of post-MI patients. Hence, our results do not confirm some of the previous studies in HFpEF , 7. In p1 was measured at 3 min. Post CM injection, as Pedersen et al. [1 values result in elevated IVV according the formula we used (page 5). Puntmann et al. found elevated native T1 of viable myocardium of post-MI patients [1 values of non-infarcted remodeled myocardium compared to controls  and in a recent study, this MOLLI sequence performed best in measuring ECV among a set of different pulse sequences in comparison to histology [While slow water exchange was addressed as a potential confounder for measuring IVV in chronic fibrotic post-ischemic scar, additional confounders should be considered when interpreting our IVV results for non-infarcted remodeled myocardium. The concept of using an intravascular CM to quantify IVV is strictly based on the assumption that the intravascular CM does not leak into the interstitial space. In the situation of an inflammatory state of the microcirculation of remodeled myocardium as proposed in the literature , 21, lean et al.  showed mpatients  and hypepatients , which cpatients . In agreistology .2 values. Accordingly, our data on ECV, i.e. on interstitial fibrosis, are in line with other studies, which reported an expanded ECV compared to healthy controls and which correlated well with markers of HFpEF severity [While we did not observe differences in IVV between healthy controls and HFpEF patients, ECV was expanded in the later, which is very likely related to an accumulation of extracellular matrix in the cardiac interstitium, since myocardial edema was excluded by normal myocardial Tseverity . Thus, tThe small number of patients included represents an important limitation. This was due to the fact that on August 2016, the production of gadofosveset was halted due to commercial reasons not permitting the recruitment of further patients. Both, ECV and IVV were not validated against endomyocardial biopsy. Rarefaction of the microvasculature in scar tissue is well established in the literature . Therefo1-mapping in combination with the administration of an intravascular CM is able to detect a reduction of the intravascular compartment in post-infarction scar tissue. However, our study findings do not support the hypothesis of microcirculatory rarefication as a patho-mechanism in the myocardium of HFpEF patients.The proposed technique exploiting T


To study circadian rhythm aspects, national holidays, and major sports events as triggers of myocardial infarction.Retrospective observational study using the nationwide coronary care unit registry, SWEDEHEART.Sweden.283 014 cases of myocardial infarction reported to SWEDEHEART between 1998 and 2013. Symptom onset date was documented for all cases, and time to the nearest minute for 88%.Myocardial infarctions with symptom onset on Christmas/New Year, Easter, and Midsummer holiday were identified. Similarly, myocardial infarctions that occurred during a FIFA World Cup, UEFA European Championship, and winter and summer Olympic Games were identified. The two weeks before and after a holiday were set as a control period, and for sports events the control period was set to the same time one year before and after the tournament. Circadian and circaseptan analyses were performed with Sunday and 24:00 as the reference day and hour with which all other days and hours were compared. Incidence rate ratios were calculated using a count regression model.Daily count of myocardial infarction.Christmas and Midsummer holidays were associated with a higher risk of myocardial infarction . The highest associated risk was observed for Christmas Eve . No increased risk was observed during Easter holiday or sports events. A circaseptan and circadian variation in the risk of myocardial infarction was observed, with higher risk during early mornings and on Mondays. Results were more pronounced in patients aged over 75 and those with diabetes and a history of coronary artery disease.In this nationwide real world study covering 16 years of hospital admissions for myocardial infarction with symptom onset documented to the nearest minute, Christmas, and Midsummer holidays were associated with higher risk of myocardial infarction, particularly in older and sicker patients, suggesting a role of external triggers in vulnerable individuals. Ischaemic heart disease is declining in high income countries but remains the commonest cause of morbidity and mortality worldwide.Short term risk factors include, but are not limited to, emotional stress, heavy physical activity, cold weather exposure, and air pollution.We hypothesised that short term risk factors may be associated with a higher risk of myocardial infarction. Furthermore, we hypothesised that the potential risk may differ for electrocardiogram (ECG) subtypes of myocardial infarction: ST elevation myocardial infarction (STEMI) and non-ST elevation MI (NSTEMI). Our objective was therefore to study national holidays, major sports events, and circadian rhythm aspects as triggers of ECG and biomarker positive myocardial infarctions with high quality data on symptom onset documented to the nearest minute, in a large nationwide setting.We used the prospective nationwide Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry to identify cases of myocardial infarction in Sweden between 1998 and 2013. The SWEDEHEART registry has been described in detail elsewhere. Briefly, all patients with symptoms of an acute coronary syndrome admitted to a coronary care unit or other specialised facility in Sweden are enrolled.We identified all cases of myocardial infarction with symptom onset on Christmas/New Year, Easter, and Midsummer holiday. We defined Christmas/New Year holidays as Christmas Eve, Christmas Day, Boxing Day (26 December), New Year’s Eve, New Year’s Day, and the Epiphany. We defined Easter holiday as Good Friday, Easter Eve, Easter Day, and Easter Monday. Midsummer Eve and Midsummer Day  constituted Midsummer holiday . SimilarBox 1Christmas is celebrated with the immediate family, and Christmas Eve on 24 December is the main day of Christmas festivities. Celebrations continue on Christmas Day and Boxing Day .New Year’s Eve (31 December) is generally celebrated with friends. The festivities involve consuming food and alcoholic drink to excess and awaiting fireworks at midnight to share New Year’s resolutions and wish one another a happy new year.Easter celebration is the first long weekend after winter. Families and friends meet and eat. Eggs are a theme, and children dress as Easter witches.Excepting Christmas, Midsummer is the most important holiday in Sweden. On Midsummer Eve, which precedes the summer solstice, Swedes gather to celebrate by dancing around a maypole, singing, eating, and drinking, often to excess. It is associated with the Christian holiday, the Feast Day of St John the Baptist, on 24 June.2 test to assess statistical significance between categorical variables. We calculated incidence rate ratios for major holidays, sports events, day of the week, and hour of symptom onset using a Poisson regression model. Calendar week was plotted with a line graph to assess seasonality. We conducted all analyses on complete case data, and only two variables contained missing data exceeding 1%. These were time of symptom onset and smoking status, with 12% and 9% missing data, respectively. We applied family wise error rate within strata  using the Hochberg method to control for type I errors owing to multiple testing. All statistical analyses were performed using STATA version 14.1 for Macintosh . A two sided P value <0.05 was considered statistically significant.Continuous variables are displayed as mean and standard deviation. Categorical variables are displayed as counts and percentages. We used a χDuring the study period, 283 014 admissions for myocardial infarction occurred and all were included in the study. Baseline demographics are presented in A higher risk of myocardial infarction was observed for Christmas Eve, Christmas Day, Boxing Day, and New Year’s Day, but not for New Year’s Eve and Epiphany , fig 2. During the study period, four FIFA World Cup tournaments and four UEA European Championships took place. Sports events were not associated with a higher incidence of myocardial infarction, although we observed a trend for summer Olympic Games in men, but this did not reach statistical significance after adjusting for multiple testing . The risk was higher in patients aged ≥75, patients with diabetes, and those with a history of coronary artery disease. No subgroup was particularly more affected at Easter or Midsummer. We saw consistent results with higher risk of myocardial infarction on Mondays in all subgroups except for current smokers . We observed consistent results for hour of symptom onset in all subgroups . We conducted an analysis of Christmas and Midsummer holidays for all patients who had undergone coronary angiography with subsequent revascularisation with percutaneous coronary intervention or coronary artery bypass grafting versus patients who had undergone coronary angiography with no revascularisation. The associated higher risk of myocardial infarction during the holidays was limited to patients with myocardial infarction who had not undergone revascularisation (supplementary fig 2). We observed no associated risk in the sensitivity analyses exploring only the days when Sweden played in the FIFA World Cup or UEFA European Championship. The sensitivity analyses controlling for long term trends in myocardial infarction resulted in consistent results. We conducted a post hoc analysis of hour of symptom onset on Christmas Eve to investigate whether the altered risk associated with this holiday is also reflected by an altered circadian variation in myocardial infarction. Whereas most previous studies have shown an early morning peak in myocardial infarction; on Christmas Eve the peak was at 10 pm .We investigated the risk of myocardial infarction during national holidays, sports events, and various time periods using data on date and time of symptom onset, documented to the nearest minute in a large nationwide setting with 16 years of data on myocardial infarction. We observed a higher risk of myocardial infarction during Christmas/New Year and Midsummer holidays, but not at Easter. Sports events were not associated with higher risk of myocardial infarction. We observed a prominent peak incidence on calendar week 52, Mondays, and at 8 am. This is to our knowledge the largest study utilising electrocardiographic and biomarker positive myocardial infarction from a well known registry. These results are in line with previous studies using administrative data.We observed the highest risk of myocardial infarction (37% higher than during the control period) on Christmas Eve. In addition, myocardial infarctions on Christmas Eve peaked at around 10 pm, rather than in the early morning hours. Previous meta-analyses have shown that acute experience of anger, anxiety, sadness, grief, and stress increases the risk of myocardial infarction and thus possibly explains the higher risk observed in our study.We observed a 20% higher risk of myocardial infarction on New Year’s Day. This could be due to the effects of excess alcohol and food consumption, exposure to cold temperatures at night, or sleep deprivation on New Year’s Eve. The associated risk of myocardial infarction during all holidays was similar between men and women, except for Midsummer, which was associated with a trend towards higher risk in men. It is possible that men are more likely to smoke, consume alcohol, and eat to excess during this holiday than women. Although no sex specific statistics are available to support this, statistics on the sale of alcohol from a government owned monopoly chain of retail stores shows sales peaking at Christmas and Midsummer.We confirm previous studies that use administrative data and circadian and circaseptan variation in myocardial infarction.Sports events were not associated with a higher risk of myocardial infarction, which was contrary to our expectations based on previous studies.We were able to characterise myocardial infarction to a higher degree than in previous studies and this enabled us to study STEMI and NSTEMI independently, together with a wide range of subgroups. Our results showed a consistently higher risk of myocardial infarction mainly due to higher rates of NSTEMI and a greater number of patients who were elderly, had diabetes, a history of coronary artery disease, or were already taking other medication. This indicates that the “vulnerable patient,” who may have risk factors such as blood vulnerable to thrombosis and myocardium vulnerable to arrhythmias in addition to vulnerable plaques, may be more prone to these precipitators of disease.We cannot rule out the suggestion that activities and emotions associated with holidays may result in myocardial infarction secondary to ischaemia, due to an increased oxygen demand in older and sicker patients. This is supported by the subgroup analysis on the Christmas and New Year’s holiday (supplementary fig 2) that showed an incremental risk increase of myocardial infarction with each age quartile.The rationale behind our subgroup analyses of patients using previous medications was to investigate the possible inhibitory mechanisms of certain pharmacotherapies on the short term triggers of myocardial infarction. Drugs lowering heart rate, reducing blood pressure, lipid levels, and platelet aggregation might reduce plaque vulnerability to external triggers. For example, β-adrenergic inhibitors have been shown to blunt the circadian variation in myocardial infarction by reducing heart rate and blood pressure and increasing coronary blood flow by prolonging diastole.This is an observational study; therefore, causality cannot be determined as we cannot rule out unobserved confounders. Previous publications have shown a higher incidence of myocardial infarction when ambient temperatures are low. However, it is unlikely that national holidays should be associated with lower temperature to bias the results since we used control periods two weeks before and after the holidays.In this nationwide real world study covering 16 years of hospital admissions for myocardial infarction with symptom onset documented to the nearest minute, Christmas and Midsummer holidays were associated with a higher risk of myocardial infarction. Consistently, we observed a higher risk in older and sicker patients, suggesting a role of external triggers in vulnerable patients.In Western countries, cardiac mortality and hospital admission due to myocardial infarction has been observed to peak at the Christmas and New Year holidayThe risk of myocardial infarction has also been linked to football championships, hurricanes, and stock market crashesIt is therefore conjectured that factors associated with emotional stress, physical activity, and lifestyle changes may modulate the onset of myocardial infarction by acting as short term triggersIn this large study covering 16 years of clinical myocardial infarction data, a higher risk of myocardial infarction was observed during Christmas/New Year and Midsummer holidays but not during the Easter holidayThe highest risk was during Christmas Eve and in patients over 75, and those with previous diabetes and coronary artery disease Sports events were not associated with higher risk of myocardial infarction


Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The study aim was to evaluate the presence, associations, and prognostic significance of diffuse fibrosis in HFpEF patients compared to age- and sex-matched controls.We prospectively included 118 consecutive HFpEF patients. Diffuse myocardial fibrosis was estimated by extracellular volume (ECV) quantified by cardiovascular magnetic resonance with the modified Look-Locker inversion recovery sequence. We determined an ECV age- and sex-adjusted cutoff value (33%) in 26 controls.P <  0.001). Multivariate logistic regression showed that body mass index (BMI) (odds ratio (OR) =0.92 [0.86–0.98], P = 0.011), diabetes , and transmitral peak E wave velocity  were significantly associated with abnormal ECV value. During a median follow-up of 11 ± 6 months, the primary outcome  occurred in 38 patients. In multivariate Cox regression analysis, diabetes (hazard ratio (HR) =1.98 , P = 0.038) and hemoglobin level  were significant predictors of composite outcome. The ECV ability to improve this model added significant prognostic information. We then developed a risk score including diabetes, hemoglobin and ECV > 33% demonstrating significant prediction of risk and validated this score in a validation cohort of 53 patients. Kaplan–Meier curves showed a significant difference according to tertiles of the probability score (P <  0.001).Mean ECV was significantly higher in HFpEF patients versus healthy controls  contains supplementary material, which is available to authorized users. Heart failure (HF) with preserved ejection fraction (HFpEF) has been established as a major cause of cardiovascular morbidity and mortality, especially among the elderly , 2. PrevSeveral mechanisms have been implicated in HFpEF, including advanced age and cardiovascular, metabolic, and pro-inflammatory comorbidities such as hypertension, diabetes, obesity, chronic obstructive pulmonary disease), coronary disease and renal failure , 4–6. ThQuantification of extracellular volume fraction (ECV) by cardiovascular magnetic resonance (CMR) has recently emerged as a novel non-invasive diagnostic tool to assess myocardial fibrosis –14. ReceThe aim of our study was to evaluate the presence, associations, and prognostic significance of ECV, likely reflecting diffuse myocardial fibrosis, in HFpEF patients.Between December 2014 and October 2016, consecutive patients with suspected HFpEF were prospectively evaluated for inclusion in the study. The local ethics committee approved the study, and all patients gave written informed consent before study enrollment .The following criteria had to be fulfilled for study inclusion: New York Heart Association functional (NYHA) class ≥II, typical signs of HF, NT-proBNP > 350 pg/ml and/or a hospitalization for HF in the previous 12 months, left ventricular (LV) ejection fraction (EF) ≥50%, and relevant structural heart disease  enlargement) and/or diastolic dysfunction by echocardiography . Ischemi2, claustrophobia), severe valvular disease, infiltrative . Patients with severe cognitive disorder were also excluded. One patient screened for the study was excluded due to presence of unknown cardiac amyloidosis.The exclusion criteria were any contraindications to CMR  < 30 ml/min/mPatients were compared to 26 age- and sex-matched controls without history of cardiovascular disease. Controls were recruited by advertisement in the community. All subjects underwent a full clinical exam, electrocardiogram (ECG), transthoracic echocardiography and exercise stress test, which all had to be normal prior to inclusion.Controls and patients underwent blood sampling, complete transthoracic echocardiography and a CMR.All subjects underwent a two-dimensional (2D) transthoracic echocardiography at inclusion  with parasternal long- and short-axis views and apical views to assess LV and right ventricular (RV) systolic and diastolic functions and measurements of LA and right atrial (RA) volumes, as well as a valvular evaluation. Mitral valve inflow pattern (E and A velocity) and septal and lateral mitral valve annular velocities (e’) were recorded.RV function was assessed by systolic annular tissue velocity of the lateral tricuspid annulus, tricuspid annular plane systolic excursion (TAPSE), and tracing the RV endocardium in the apical four-chamber view in systole and diastole to obtain fractional area change (RV FAC%) . All meaCMR was performed using a 3 Tesla system . Briefly, after localization of the heart, to assess LV and RV myocardial function and mass, 10–12 consecutive short-axis (SAX) images and 2-, 3-, and 4-chamber long-axis images of the LV were acquired using a cine balanced steady-state free precession sequence (bSSFP). Then, mid-ventricular short-axis modified Look-Locker inversion recovery (MOLLI) images were acquired for T1 determination using an 11-image, 18-heartbeat 3-(3)-3-(3)-5 bSSFP sequence. A total dose of 0.2 mmol/kg gadobutrol  was injected, and 10–15 min after contrast injection, short- and long-axis 2D inversion recovery late gadolinium enhancement (LGE) images were acquired to evaluate focal myocardial fibrosis. Finally, 15-min post-contrast, MOLLI T1 mapping was repeated in a protocol identical to that used for pre-contrast T1 mapping. The presence of LGE was visually assessed.Pre- and post-contrast MOLLI images were processed using the open-source software MRmap v1.4  under IDEnd-diastolic and end-systolic LV and RV volumes as well as LV mass and presence of LGE were analyzed using the freely available software Segment 2.0 , as previously described. LGE was considered present if myocardial enhancement was observed on both short-axis and long-axis views. The total LGE volume was calculated by summing the LGE volume of all slices, and the ratio (%) of LGE was then calculated using the same software.Patients were prospectively followed by ambulatory visits and telephone calls at 6-month intervals. Clinical and survival status was obtained by follow up visits and by phone contact with the patients, their relatives, and their physician if necessarily. The primary outcome was a composite of all-cause mortality or a first hospitalization for HF. Vital status was ascertained by medical record review. First HF hospitalization was defined as patients treated in the emergency room or admitted to a hospital and requiring intravenous diuretics. Patients had at least one symptom and 2 signs of HF .P < 0.05 was considered statistically significant. Continuous variables were expressed as mean ± 1 SD if normally distributed or as medians (25th and 75th percentiles) if not normally distributed. Categorical variables were expressed as counts and percentages. Comparison between groups was performed using ANOVA, chi-square test, or unpaired t-tests when appropriate. We determined an ECV age and sex-adjusted cutoff value corresponding to the upper 95% confidence interval of 26 age- and sex matched volunteers (ECV ≥ 33%).Statistical analyses were performed using SPSS version 22  and STATA version 11  software. All tests were two-sided, and a P < 0.10 were proposed for inclusion in the multiple logistic regression analysis with a backward selection procedure.Logistic regression was performed to determine predictors of abnormal diffuse fibrosis . For this purpose, after univariate comparison of the two groups, parameters with a r > 0.50), only the strongest of the two covariates was proposed for inclusion into the multivariate model. After univariate Cox regression analysis, all significant variables (P < 0.10) were entered into a stepwise forward multivariate Cox regression model. Two different models were evaluated using ECV as either a continuous or a categorical variable (ECV ≥ 33%).Event-free survival was estimated using Kaplan–Meier methods and Cox regression analysis. All baseline and imaging variables were initially proposed for inclusion in a univariate Cox proportional hazard model. To avoid colinearity in the Cox regression model, the correlation coefficients between covariates were examined. In cases of colinearity  curves. This score was validated in 53 consecutive HFpEF patients recruited between October 2016 and July 2017.Between December 2014 and October 2016, a total of 118 consecutive HFpEF patients  and 26 age- and sex-matched controls  were included in the study. The demographic, clinical, and laboratory characteristics of HFpEF patients and controls are summarized in Table n = 46). By CMR, HFpEF patients had a slightly lower LVEF and higher indexed LV mass than age- and sex-matched healthy controls. Twenty-six HFpEF patients had LGE . When present, the average percentage of LGE was 5.5 ± 2.9%.Table P < 0.001), higher indexed LA volume , lower LVEF , lower TAPSE , lower FAC , and higher septal E/e’ ratio .ECV was significantly higher in HFpEF patients than in the healthy control group Fig. . Forty-nP = 0.002), had a higher body mass index (BMI) , a lower atrial fibrillation history rate , and more known ischemic cardiomyopathy  than non-diabetic HFpEF patients. Echocardiographic and CMR parameters were quite similar except for a trend to higher indexed LV mass in diabetics . Diabetic HFpEF patients presented more frequently ECV ≥33% than non-diabetic patients .Diabetic HFpEF patients were younger . There were no differences in NT-proBNP and LGE in HFpEF patients between the two groups.HFpEF patients with ECV ≥ 33% had lower BMI, lower hematocrit, higher prevalence of diabetes, higher transmitral peak E wave velocity and higher E/e’ ratio. A higher proportion of HFpEF patients with ECV ≥ 33% had an impaired RV systolic function , presence of diabetes , and higher transmitral peak E wave velocity  were significantly associated with high ECV value.In multivariate logistic regression, BMI  Fig. . The priP = 0.038) and hemoglobin level  were significantly associated with the composite outcome , as opposed to transmitral peak E wave velocity and eGFR . The ability of the model to discriminate outcome was good with an area under the curve (AUC) of 0.76. Kaplan–Meier event-free survival curves showed that HFpEF patients with ECV ≥ 33% had poorer one-year prognosis than those with ECV < 33% . Diabetes, hemoglobin, and ECV > 33% were thus used to build the risk score. ROC curves showed a better discrimination with the prognostic score and ECV  compared to LGE   in univariate analysis, in contrast to another recent study [As demonstrated in our study, the prognosis of HFpEF patients is still quite poor. Many studies have compared HFpEF and HFrEF prognosis and demonstrated the same or even a worse mortality and morbidity rate , 27 for nt study . A potenThe prognostic role of anemia has already been demonstrated in large HFpEF studies