The survival rate of adrenal Cushing syndrome patients has been greatly increased because of the availability of appropriate surgical and pharmacological treatments. Nevertheless, increased possibility of a heart attack induced by a cardiovascular event remains a major risk factor for the survival of affected patients. In experimental studies, hypercortisolemia has been found to cause cardiomyocyte hypertrophy via glucocorticoid receptor activation, including the possibility of cross talk among several hypertrophy signals related to cardiomyocytes and tissue-dependent regulation of 11β-hydroxysteroid dehydrogenase type 1. However, the factors are more complex in clinical cases, as both geometric and functional impairments leading to heart failure have been revealed, and their associations with a wide range of factors such as hypertension are crucial. In addition, knowledge regarding such alterations in autonomous cortisol secretion, which has a high risk of leading to heart attack as well as overt Cushing syndrome, is quite limited. When considering the effects of treatment, partial improvement of structural alterations is expected, while functional disorders are controversial. Therefore, whether the normalization of excess cortisol attenuates the risk related to cardiac hypertrophy has yet to be fully elucidated. Since Harvey Cushing initially reported a 23-year-old woman with a pituitary adenoma in 1910, 50% of affected patients have died within five years of diagnosis, mainly because of a heart attack-inducing cardiovascular event, as a normal history of Cushing syndrome (CS) ,5. NeverSince the 1990s, subclinical adrenal CS, which features autonomous secretion of excess cortisol without detectable related physical characteristics , has gaiCardiac hypertrophy is a well-known condition that indicates the possibility of hypercortisolemia-inducing ACS. Because of its relationship with induction of heart failure and cardiac death, timely detection of such an alteration can lead to early diagnosis and contribute to reducing mortality. However, there are few literature reviews regarding related experimental mechanisms or the clinical features of hypercortisolemia. The aim of the present study was to provide an updated review of findings obtained in both experimental and clinical medicine investigations showing the influence of excess cortisol on heart structure and function, as well as to summarize the effects of therapeutic interventions on cardiac impairment in affected patients.The effects of bioactive cortisol, which is synthesized in the adrenal cortex, are exerted following connection to a glucocorticoid (GC) receptor (GR) or mineralocorticoid receptor (MR). GR belongs to a ligand-dependent transcription factor nuclear receptor superfamily that is comprised of three functional domains: an N-terminal transactivation domain (NTD), central DNA-binding domain (DBD), and C-terminal ligand-binding domain (LBD) . Nearly To produce an appropriate effect of cortisol and aldosterone, 11β-hydroxysteroid dehydrogenase type 1 and 2  play essential roles ,33. 11β-Endogenous GC contributes to maintain heart performance for regulating the life cycle of cardiomyocytes involved in growth, differentiation, metabolism, and apoptosis . GC actiH6PDH activity has been identified in cardiomyocytes and fibroblasts in rats ,52, whilRegarding the effects of excessive GC in therapeutic and pathologic conditions, abundant knowledge showing its influence with exposure to the heart has been accumulated. For example, antenatal corticosteroid therapy, known to reduce neonatal death , has beeOn the other hand, intracellular sodium kinetics in ischemia, heart failure, and hypertrophy has been considered ,71,72,73When considering local regulation of GC, its association with 11β-HSD1 is another related issue. Nishiyama et al. recently confirmed the influence of 11β-HSD1 in mouse tissues showing persistent GC excess . Two weeIn clinical cases, the pathophysiological relationship of hypercortisolemia with cardiac hypertrophy is complex and studies that assessed the structural alterations of cardiac muscle including hypertrophy in CS patients have been presented. Although patients with adrenocorticotrophic hormone (ACTH)-dependent and -independent CS participated in those investigations, few studies have focused on overt adrenal CS, while knowledge regarding cardiac hypertrophy in ACS cases is also quite limited .n = 53, 11.5 ± 2.9 mm, p < 0.01) or primary aldosteronism . Interestingly, posterior wall thickness (PWT) diameter at end-diastole was relatively mild in all groups . Furthermore, a significant higher ratio of IVST to PWT (IVST/PWT) exceeding 1.3 was seen only in the CS group, suggesting existing asymmetric septal hypertrophy (ASH). Such disproportional hypertrophy is uncommon in both essential hypertension   . Indeed,= 0.045] , while a= 0.045]  potentia= 0.045] . Additio < 0.05) . Togethep < 0.05) [p < 0.05; hypertensive: 16.4 ± 0.28% vs. 18.8 ± 0.47%, p < 0.05) [p < 0.01), as was stress-adjusted endocardial FS [p < 0.001) and hypertension , while no significant difference was observed in regard to endocardial FS. In a comparison of LV diastolic function between CS patients and controls, a reduced ratio of E/A velocity , along with decreased E velocity  and prolonged E-wave deceleration time  were observed. Notably, analysis regarding the association of those diastolic parameters to CS and hypertension revealed that E-wave deceleration time was independently associated with CS  but not with hypertension , while E/A ratio was independently associated with both CS  and hypertension . Finally, the authors concluded that the cardiac structural alterations described above are associated with attenuation of both systolic and diastolic performance, such as mwFS, E/A ratio, and E-wave deceleration time, which may partially explain the high risk of heart attack occurring in patients with CS.In addition to structural alterations, cardiac dysfunction in CS patients is another factor for consideration. Toja et al. found no significant difference for left ventricular ejection fraction (EFLV), or ratio of early (E) and late (A) wave diastolic filling velocity between CS cases and a control group with normotension , while a significant attenuation of EFLV was only observed in the CS group with hypertension as compared with the controls with hypertension  . In addi < 0.05) . Muiesanrdial FS . Additio2 vs. 22.4  mL/m2, p = 0.002; RV; 36.6  mL/m2 vs. 27.1  mL/m2, p = 0.012), though end-diastolic volume was not significantly different. Therefore, stroke volume index was significantly smaller in the RV  mL/m2 vs. 41.9  mL/m2, p = 0.033) and tended to be smaller in the LV  mL/m2 vs. 44.8  mL/m2, p = 0.079), and lower EF values were also observed % vs. 64.3 %, p < 0.01; EFRV: 49.3 % vs. 60.0 %, p < 0.01). Additionally, left atrial (LA) parameters showed a significant increase in minimal volume ) mL/m2 vs. 15.6  mL/m2, p = 0.042) but not in maximal volume; consequently, EFLA was markedly lower in the CS patients as compared with the controls % vs. 56.1 %, p < 0.01). Finally, end-diastolic LV segmental thickness shown in basal, midventricular, and apical slices was markedly increased  mm vs. 7.99  mm, p < 0.01; 10.3  mm vs. 7.26  mm, p < 0.01; 8.45  mm vs. 5.90  mm, p < 0.01, respectively). Furthermore, late gadolinium enhancement testing, which depicts dense myocardial fibrosis [Cardiac magnetic resonance (CMR) imaging testing has been shown to provide results that are useful for highly accurate and comprehensive evaluations of cardiac geometry and function, as well as myocardial fibrosis ,102,103,fibrosis , revealen = 50) conducted by Takagi et al. demonstrated that serum cortisol (24.3 ± 16.6 µg/dL) and potassium (3.8 ± 0.6 mEq/L) levels independently contributed to LVMI , while hemoglobin A 1c (HbA1c) (6.2 ± 1.6%) and serum potassium levels independently contributed to EFLV  [p < 0.05 for RWT) [p = 0.5), RWT , or all-day BP values [It is rather surprising that the associations of serum and urinary cortisol levels with cardiac hypertrophy in humans have yet to be clarified. A multivariate analysis of patients with adrenal CS (ctively) . They alctively) , noradrectively) , and thectively) , as wellctively)  and accectively) . Moreovefor RWT) . The autfor RWT) ; (2) thefor RWT) ; (3) 24 P values ; and (4)P values . Present2.7-adjusted LVM, which is more sensitive for detecting LVH in patients with obesity [p = 0.01; 49.7 ± 10 g/m2.7 vs. 47 ± 8 g/m2.7, p = 0.05; respectively). The results suggested that epicardial fat shown in echocardiogram findings was a non-invasive marker of earlier cardiac abnormalities in patients with adrenal incidentaloma. Interestingly, LVMh2.7 and LVM were obviously greater in mild CS patients than in patients with non-functional adenomas , whereas epicardial fat thickness was not significantly different (8.0 ± 0.7 mm vs. 7.9 ± 0.9 mm). On the other hand, Evran et al. found no echocardiographic differences in five patients (mean age 49.60 ± 8.64 years) with adrenal ‘subclinical CS (SCS)’, defined based on non-suppressive cortisol level (>50 nmol/L) in post-DST results, and ACTH < 10 pg/mL as compared to 76 patients (mean age 52.09 ± 9.78 years) with nonfunctional adrenal incidentaloma (NFAI) [n = 33), both the SCS and NFAI groups showed larger waist circumference (p = 0.00) and impaired glucose metabolism profiles , and higher triglyceride level (p = 0.01). The differences in hormonal parameters between the patients with SCS and NFAI reflected pathology, with no differences for basal serum level of cortisol, ACTH, or dehydroepiandrosterone sulfate (DHEAS), but a higher post-DST cortisol level in the SCS group . When assessing echocardiographic measurements between the SCS and NFAI groups, there were no differences found for IVST (11.20 ± 2.49 mm vs. 10.38 ± 1.47 mm), PWT (10.80 ± 1.78 mm vs. 10.31 ± 1.45 mm), or end-diastolic diameter (49.00 ± 2.00 mm vs. 47.5 ± 3.49 mm).There is only limited knowledge regarding alterations of heart structure and function associated with ACS, though its association with a high risk of heart attack-inducing cardiovascular events has been noted. Iacobellis et al. examined 46 consecutive patients  with incidentaloma, including 40 with non-functional incidentaloma (mean age 61.6 ± 10.7 years) and six with mild adrenal CS (mean age 69.3 ± 12.5 years), defined when two or more of the following abnormalities were present: urinary-free cortisol level > 70 µg/day, >5 µg/dL of serum cortisol after 1 mg DST, and ACTH level < 10 pg/mL in the morning (08:00) . The stu obesity , were oba (NFAI) . None ofn = 37) underwent 2 mg-DST. Only 3 patients showed suppressed cortisol (≤50 nmol/L) and 34 were within a range of 51–138 nmol/L, considered to be pACS; thus, the remaining 37 were categorized as having a non-functioning adenoma (NFA). Their clinical and biochemical characteristics at the baseline were similar, such as mean age 68 (57–73) years in the pACS group vs. 67 (60–72) years in the NFA group, male sex percentage 38.2% vs. 29.7%, and BMI 26.7 (22.6–29.3) vs. 25.9 (23.7–31.2), while other metabolic or electrocyte profiles and cardiovascular risk factors were also similar, except for adenoma diameter (27.4 (23.4–31.5) mm vs 20.2 (17.2–23.1) mm, p = 0.004). As for hormone parameters including baseline serum cortisol, ACTH, aldosterone/renin ratio, 17OH progesterone, DHEAS, urinary free cortisol, androstenedione, urine metanephrine, and lower levels of ACTH (18 (15–20) pg/mL vs. 25 (19–31) pg/mL, p = 0.028) and DHEAS (37.5 (18–54) µg/dL vs. 77.8 (45–189) µg/dL, p = 0.012) were observed in the pACS group. A covariance model with fixed age, BMI, sBP, LDL cholesterol, and HbA1c, revealed geometric and functional differences as follows. (1) IVST and PWT were significantly thicker in the pACS as compared with the NFA group (10.7 (95% CI: 10.2–11.2) mm vs. 9.9 (95% CI: 9.4–10.4) mm, p = 0.015; 9.1 (95% CI: 8.5–9.6) mm vs. 8.4 (95% CI: 7.9–9.0) mm, respectively; p = 0.047), while LV end-diastolic diameter (LVDd) and RWT were not. (2) There was a greater increase in LVMI for both LV massh2.7 and body surface area (BSA)-adjusted LVM (LVMBSA) confirmed in the pACS group (46.1 (95% CI: 42.5–49.6) g/m2 vs. 36.2 (95% CI: 32.8–39.6) g/m2, p = 0.01; 95.3 (95% CI: 88.0–102.5) g/m2 vs. 76.6 (95% CI: 69.6–83.6) g/m2, p = 0.001, respectively). (3) LVEF was similar between the two groups, while tricuspid annular plane systolic excursion (TAPSE), which partially represents RV function, was slightly reduced in the pACS patients, though the mean value was not highly suggestive of so-called RV dysfunction (<17 mm) (20.2 (95% CI: 18.9–21.6) mm). (4) Significantly higher values for septal and mean  E/e’ were found in the pACS group (10.3 (95% CI: 9.0–11.6) vs. 8.3 (95% CI: 7.2–9.5), p = 0.028; 8.85 (95% CI: 7.8–9.8) vs. 7.4 (95% CI: 6.6–8.3), respectively; p = 0.044), though the difference for E/A was not significant. Furthermore, a stepwise method showed the main contributor to LVMI to be post-DST cortisol level, which accounted for 13.7%, followed by sBP (9.9%) and HbA1c (8.1%). When considering these findings, the higher prevalence of diastolic function abnormality, especially in septal E/e’, found in the pACS patients is notable. Elevation of E/e’ value generally follows a re-increase in E wave velocity after reduction in both E and e’ velocities. In this study, lateral, septal, and mean e’ were not significantly different between the pACS and NFA cases, though there was a tendency of relaxation impairment shown by septal and mean e’ values observed in the pACS group (7.4 (95% CI: 6.4–8.2) cm/s vs. 8.5 (95% CI: 7.7–9.3) cm/s, p = 0.059; 8.3 (95% CI: 7.4–9.2) cm/s vs. 9.4 (95% CI: 8.6–10.2) cm/s, respectively; p = 0.067), suggesting that the pACS patients might have been above a certain level of diastolic dysfunction.Of note, a recent study by Sbaedella et al. disclosed a mild correlation between serum cortisol level especially in post-DST and LVH in echocardiography in patients with pACS . Seventyn = 25) as compared with those with a non-functioning adrenal adenoma  , while no significant differences for either e’ velocity or E/e’ between the groups have been confirmed . These findings might be useful in regard to early detection of ACS, though accumulation of additional cases is needed.On the other hand, A-wave velocity has received focus as a predictor of arterial stiffness  and alsoAn adrenalectomy is recommended as standard care for overt adrenal CS, especially in unilateral CS cases, only a few studies with small populations have demonstrated low to very low levels of evidence regarding surgery for ACS . SurgicaNevertheless, structure alterations of the human heart in CS have been reported to be partially reversible after remission. Sugihara et al. followed nine patients after surgery for periods from three months to six years three months . ConsequSince the severity of LVH is correlated with cardiovascular risk, normalization of excess cortisol may contribute to reduce mortality. Nevertheless, additional studies focused on long-term outcomes of cured adrenal CS patients, including differences between surgery and conservative treatment, such as steroidogenesis inhibitor administration, are needed, while results of investigations of adrenal ACS cases are also crucial.In summary, excess cortisol has been experimentally shown to induce cardiomyocyte hypertrophy via activated GC signaling through GR. On the other hand, the pathophysiology in humans is more complex, indicating associations with several different factors including hypertension. Based on this literature review, it is concluded that a hypertensive state may exacerbate LVH in CS patients, though is possibly dependent, at least in part, on duration or severity. Furthermore, both systolic and diastolic function impairments were found to be independently associated with CS and hypertension. When considering treatment, partial improvement of structural alterations is expected after normalization of excess cortisol, whereas the possibility of improvements in functional disorders remains controversial. Although to what extent these findings are related to mortality of patients with overt CS or ACS remains vague, evidence presented in this review strongly demonstrates that hypercortisolemia itself has a relationship with geometric and/or functional alterations, as shown in clinical results as well as experimental findings. Nevertheless, the findings of this investigation require further elucidation regarding whether such alterations in pre-symptomatic state contribute to early diagnosis of hypercortisolemia, while evaluations of the effects of treatment on long-term mortality are also necessary.


Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented.n = 15) by occlusion of the circumflex coronary artery, associated with acute volume overload and increases in arterial blood pressure by vasoconstrictor infusion. After onset of ADHF, animals received 48-h iv infusion of either serelaxin (n = 9) or placebo (n = 6). The pathophysiology and progression of ADHF were described by combining evaluation of hemodynamics, echocardiography, bioimpedance, blood gasses, circulating biomarkers, and histology.Myocardial infarction (MI) was induced by occlusion of left anterior descending coronary artery in 17 male pigs (34 ± 4 kg). Two weeks later, ADHF was induced in the survived animals (p < 0.01 vs. baseline). Other ADHF-induced alterations in hemodynamics, i.e., increased central venous and pulmonary arterial pressures; respiratory gas exchanges, i.e., respiratory acidosis with low arterial PO2 and high PCO2; and LV dysfunction, i.e., increased LV end-diastolic/systolic volumes, were observed (p < 0.01 vs. baseline). Representative increases in circulating cardiac biomarkers, i.e., troponin T, natriuretic peptide, and bio-adrenomedullin, occurred (p < 0.01 vs. baseline). Finally, elevated renal and liver biomarkers were observed 48 h after onset of ADHF. Mortality was ~ 50%. Serelaxin showed beneficial effects on congestion, but none on mortality.During ADHF, animals showed reduced left ventricle (LV) ejection fraction < 30%, increased thoracic fluid content > 35%, pulmonary edema, and high pulmonary capillary wedge pressure ~ 30 mmHg  contains supplementary material, which is available to authorized users. Acute heart failure (AHF) is characterized by a gradual or rapid onset of new or worsening signs and symptoms of heart failure (HF), usually requiring hospitalization for urgent therapy. Indeed, AHF is the most common cause for hospital admission in patients over 65 years, with approximately 1 million hospitalizations per year in the USA and Europe, and a high burden of costs, i.e., over $60 billion/year .Lung congestion leading to dyspnea is the main reason for hospitalization in patients with acute decompensated heart failure (ADHF). Although, the majority of patients respond readily to loop diuretics, achieving complete decongestion can be challenging, so that a significant proportion > 30%) are discharged with persistent evidence of congestion. Residual congestion is associated with a high risk of early rehospitalization and death. Among patients discharged from the hospital for ADHF, only 32.9% are alive and have not been rehospitalized after 1 year 0% are di.Over the years, several animal models have been employed in order to discover disease mechanisms and to develop new therapies for AHF –14. AmonThus, the aim of the present study was to set up a novel, highly reproducible, and preclinically relevant porcine model to mimic the common pathophysiological clinical condition observed in ADHF patients , 15, 16.All procedures involving animals and their care were in conformity with national and international laws and policies (Legislative Decree n° 76/2014-B). Approval of the study was obtained by the governmental review board committee and governmental institution .Sus scrofa domesticus pig weighing 34 ± 4 kg were used. Animals were obtained from the same breeder and were housed in the animal facility of the Veterinary Teaching Hospital, University of Milan, Lodi, Italy. Pigs were housed in pairs before the experiment, and individually after, under controlled temperature, humidity, and illumination condition, and with food and water being available ad libitum. Environmental enrichment was used. Animals were allowed a minimum of 4 days to adapt to housing conditions before undergoing any manipulation.For the study, 17 male The experimental design is detailed in Fig. 2 of 0.21 . Respiratory frequency was adjusted to maintain the end-tidal PCO2 (EtCO2) between 35 and 40 mmHg, monitored with an infrared capnometer  [Seventeen pigs were fasted the night before the experiment except for free access to water. Anesthesia was induced by intramuscular injection of ketamine (20 mg/kg) followed by intravenous administration of propofol (2 mg/kg) and sufentanil (0.3 μg/kg) through an ear vein access. Anesthesia was then maintained by continuous intravenous infusion of propofol (4–8 mg/kg/h) and sufentanil (0.3 μg/kg/h). A cuffed tracheal tube was placed, and animals were mechanically ventilated with a tidal volume of 15 mL/kg and FIORx, USA) . To measRx, USA) .First AMI was induced in a closed-chest preparation by intraluminal occlusion of the LAD. A 6F balloon-tipped catheter  was inserted from the right common carotid artery and advanced into the aorta, then into the LAD, beyond the first diagonal branch, with the aid of image intensification, and confirmed by injection of radiographic contrast media  , 22. Then = 15) by occluding the LCx through the same closed-chest preparation procedure described for the LAD. Volume overload was then induced by infusing iv a large volume of crystalloids  over 1 h, and an arterial hypertensive peak (pressure overload) was concurrently induced by iv infusion of phenylephrine .Two weeks after the first AMI, a second AMI was induced in the survived animals  a sustained left ventricular ejection fraction (LVEF) < 30%, (2) a 3-fold increase in PWCP, and (3) an increase of thoracic fluid content (TFC) of more than 25% from the baseline value.n = 9) or saline (n = 6) for the following 48 h. The pump was surgically positioned and secured with sutures between the right sternocleidomastoid muscle bands; the polyethylene catheter was inserted into the right external jugular vein and advanced for 8 cm  was implanted for a continuous iv infusion of either serelaxin  given by intramuscular injection. Animals underwent daily clinical examination by veterinarian doctors to identify and eventually alleviate signs of severe pain, severe distress, or suffering, i.e., poor physical appearance, severe respiratory distress, neurological signs, rapidly progressive weight loss, and impending death. Under judgment of the responsible veterinary doctor, termination of the experiment could be considered by humanely euthanizing the animal . At the end of the 48-h treatment, animals were re-anesthetized for hemodynamic measurements as described above , echocardiographic examination, TFC quantification, and blood sample withdrawal. The pigs were then euthanized painlessly with an intravenous injection of 150 mg/kg sodium thiopental, and the heart and lung were harvested , 22.2 were recorded continuously on a personal computer–based acquisition system . CO was measured by using the thermodilution technique  [Hemodynamics, heart rate (HR), and EtCOeld, IL) , 22.To quantify lung congestion, TFC was continuously measured by non-invasive chest bioimpedance. Chest bioimpedance was assessed through four skin sensors placed on the neck and left side of the thorax to allow for the continuous measurement of the changes of electrical conductivity within the thorax with the aid of an ICON electrical cardiometer .E) and the early diastolic mitral annular tissue velocity (e′) ratio (E/e′) from the four apical chamber views. Echocardiographic recordings and measurements were followed at 5-min intervals from baseline  function was echocardiographically evaluated during the different experimental timepoints. Transthoracic echocardiography was performed using a phased-array multifrequency 2.5- to 5-MHz probe . LV volumes and ejection fraction calculations (LVEF) were performed on two-dimensional (2D) images obtained from two and four apical views using the modified Simpson’s method of discs. LV diastolic function was evaluated by combined pulse wave and tissue Doppler calculating the early diastolic trans-mitral flow velocity (Chest computed tomography (CT) was executed with a 16-slice scanner  only in one representative animal to visualize the presence of lung congestion.Myocardial infarct size was assessed by triphenyltetrazolium chloride (TTC) staining. The ventricles were sliced into 5-mm-thick transverse sections, which were incubated 20 min) in a solution of TTC and then transferred to 10% neutral buffered formalin overnight before image analysis. Infarct size (deriving from the occlusion of both LAD and LCx) was reported as a percentage of TTC-negative area relative to LV plus septum area, as presented in Fig. 0 min in After separating a portion of the caudal left lung lobe of each animal, it was weighed and placed in the oven at 80 °C for ≥ 72 h. After removal from the oven, it was reweighed for calculation of the wet/dry weight ratio, an indicator of lung congestion.Arterial blood samples were withdrawn at baseline prior to inducing ADHF, at ADHF occurrence, and after 1 h and 48 h of treatment. Arterial blood gasses were assessed with the i-STAT System . Plasma high-sensitivity cardiac troponin T (hs-cTnT) was measured with an electrochemiluminescence assay . N-terminal proatrial natriuretic peptide (NT-proANP) was assayed with a validated ELISA kit (Biomedica BI-20892). Circulating levels of bio-adrenomedullin  were quantified as marker of pulmonary congestion. In order to further investigate renal and liver function, serum levels of creatinine and alanine transferase (ALT) were measured . Finally, plasmatic levels of relaxin-2 were measured with an ELISA kit .Z test was used to confirm the normal distribution of the data. For comparison of time-based variables, two-way analysis of variance (ANOVA) with Sidak multiple comparison test was performed. A logarithmic (Log10) transformation was executed prior to analyzing variables that were not normally distributed. For comparisons of variables with only a timepoint, one-way analysis of variance was used. When the dependent variable was categorical, a Fisher exact test was used. All data are reported as mean ± SEM. A p value ≤ 0.05 was regarded as statistically significant. GraphPad Prism 7.5  was used for statistical analyses.A one-sample Kolmogorov–Smirnov p = 0.43). Criteria for ADHF were achieved in all animals, with a reduction in LVEF < 30% and increases in TFC > 25% from baseline and in PCWP to values of 28 ± 2 mmHg .Two animals died due to the first AMI. Thus, ADHF was induced in 15 pigs. The total amount of crystalloids infused was 5.7 ± 0.5 L in the control group and 5.2 ± 0.3 L in the serelaxin one p = 0.3. Criterp = 0.25, Table With approximately 50% of animals surviving up to 48 h, no difference in mortality was observed between the two groups, although a trend towards earlier death was observed in the serelaxin group compared to the control one .TFC increased 40% in the control group and 35% in the serelaxin one compared to baseline at onset of ADHF . PCWP markedly increased in both groups after the onset of ADHF . Forty-eight hours later, HR increased in animals that received serelaxin, while it remained low in controls . Similarly, LVEDV and LVESV significantly increased compared to baseline in both groups  and started to decrease at 48 h  selected articles to be discussed, giving priority to those with higher clinical relevance. The ischemia-induced HF is the most commonly used approach [AHF is a highly prevalent and morbid syndrome, with different etiologic causes, but common pathophysiologic features, including changes in LV structure and function, and neurohormonal activation. Different large animal models of AHF are available, all valuables but with limitations. Thus, an unrestricted literature search was performed on approach , 25. Howapproach . Microemapproach . Pressurapproach . Volume approach . Artery approach , 28. Tacapproach , 29, 30.approach . More moE/e′). Finally, the pressure overload, induced by phenylephrine infusion, contributed to the final decompensation, i.e., through excessive vasoconstriction and consequent increase in afterload [The new ADHF described in this study may represent, instead, a valid model since it encompasses all the several pathophysiological events occurring during AHF in humans. Thus, an initial MI by occlusion of the LAD caused a chronic HF, represented by the already impaired LVEF at baseline prior to induce the AHF, i.e., < 45%. An AMI additionally induced concurred to a further depress myocardial systolic function with a subsequent decrease in EF, down below 30%. Indeed, a history of ischemic heart disease is present in up to 45–60% of patients with AHF, and nearly 40% of patients with AHF have experienced a prior MI , 31–33. fterload . The modThe clinical diagnosis of ADHF is supported by circulating biomarkers levels. High LV filling pressure leads to increased ventricular wall stress. Thus, B-type natriuretic peptide (BNP) is secreted from cardiac myocytes in response to atrial or ventricular wall stretch, and its increased levels correlated well with LV function impairment . Thirty Treatment of acute HF remains a major challenge. Diuretics are guideline-recommended first-line therapy in “wet and warm” patients in whom congestion is predominantly attributable to fluid accumulation and volume overload , 42, 47.The Pre-RELAX-AHF trial initially demonstrated a clear vasodilatory effect of serelaxin with trends towards greater resolution of congestion and improved morbidity and mortality in patients admitted for AHF . SubsequSerelaxin, through its effects in ameliorating dyspnea and congestion in AHF, represented a valid tool in order to test the accuracy of the proposed new animal model. Indeed, results observed in our model were similar to those obtained in the clinical trials. A beneficial effect represented by a more rapid decrease in lung congestion was observed, i.e., significantly lower TFC, together with a reduction in LV filling pressure and function, with no effects on mortality. In addition, in our model, a more rapid decrease in PAP in serelaxin-treated animals was observed, as in 71 AHF patients receiving serelaxin in whom hemodynamics were invasively investigated . The hemSome limitations deserve to be mentioned. The studies were conducted in healthy anesthetized animals and therefore in the absence of underlying diseases or injuries that are causative of AHF and with potential anesthesia-related effects, i.e., cardio-depressant action of propofol and mechanical ventilation-related hemodynamic impact. Second, no data on baseline prior to first AMI were reported. However, hemodynamics, echocardiographic, and biomarker data from healthy pigs from the same breeder, with same age and weight and with the same anesthesia and mechanical ventilation setting, have been previously published by our group , 22, 52.Several animal models of AHF have been developed and employed over the years, all valuables but with limitations in reproducing disease mechanisms and pathophysiology. A new model of ADHF, resulting from a combination of chronic and acute MI, and volume and pressure overload, appeared able to replicate all the clinical features of the disease. The proposed model may represent a reproducible and valid approach to test new treatments for AHF prior to being clinically translated.ESM 1(DOCX 526 kb)ESM 2(DOCX 14 kb)ESM 3(AVI 33753 kb)ESM 4(AVI 32346 kb)ESM 5(AVI 42190 kb)ESM 6(AVI 40784 kb)


Trypanosoma cruzi infection. Our goal was to test in CCC the associations of the myocardial tissue phenotype with cardiac dysfunction, and heart failure (HF) severity, using cardiac magnetic resonance (CMR).Chronic Chagas cardiomyopathy (CCC) constitutes the most life-threatening consequence of the ic, a measure of cardiomyocyte diameter, were compared to CCC disease progression, including Rassi score and New York Heart Association (NYHA) class. An exploratory prognostic analysis was performed to investigate the association of both ECV and τic with CV death.We performed a prospective observational cohort of patients with consecutive CCC with a CMR protocol, including ventricular function, myocardial T1, and late gadolinium enhancement (LGE). Extracellular volume (ECV), and intracellular water lifetime, τP = 0.009), higher NYHA class, and LV EF . τic decreased linearly with NYHA class (P = 0.007 for non-parametric test of linear trend) and showed a positive association with LV EF . Over a median follow-up of 734 days , CV death or cardiac transplantation occurred in 10 patients. The Rassi score  and ECV  were simultaneously associated with CV death.A total of 37 patients with intermediate-to-high-risk CCC were enrolled  ejection fraction (EF) 32 ± 16%). Myocardial ECV (0.40 ± 0.07) was correlated with Rassi score (r = 0.43; In patients with intermediate-to-high-risk CCC, an expanded ECV and regression of cardiomyocyte diameter were associated with worsening systolic function and HF severity, respectively. The exploratory analysis indicates that ECV may have a prognostic value to identify patients with CCC at a higher risk for cardiovascular events. The Centers for Disease Control and Prevention (CDC) declared that Chagas disease is one of the major neglected parasitic infections in the United States and other developed countries. Chagas disease has been reported to affect up to 6 million patients in South America  and migrTrypanosoma cruzi protozoan and it may lead to heart failure (HF), stroke, arrhythmias, and even sudden cardiac death. Between 20 and 40% of those infected with the protozoan will develop CCC . The criteria for CCC diagnosis were the presence of any of the following: (1) atrioventricular block , left or right bundle branch block, left anterior fascicular block, premature ventricular beats, or abnormal Q waves; (2) cardiomegaly on chest radiography; (3) abnormal LV systolic function (LV ejection fraction <50%), or any wall motion abnormality; and (4) ventricular tachycardia on ECG monitoring. The Rassi score for death in CCC was obtained in all patients . Brieflyic) were performed with an inversion-recovery cine Look-Locker sequence with segmented gradient-echo acquisition , covering approximately 2 cardiac cycles . The T1 imaging was repeated in the same mid-LV short-axis slice, before and 5–7 times after the injection of gadolinium. Clinical, anthropometric, and hemodynamic data were obtained at the same CMR exam. Only euvolemic ambulatory patients, judged to be likely to tolerate a 50-min CMR in a supine position and not receiving IV therapy , were recruited for imaging.All patients underwent CMR imaging in a 3 Tesla system  with a 6-element phased-array surface coil. The CMR sequences were ECG-gated and followed our routine protocol for LV function, viability assessment, and tissue characterization in patients with CCC. Cine imaging with steady-state free precession was performed in short-axis and long-axis-views to assess LV mass and volumes . LGE images were obtained in slices matching those for cine imaging with a segmented, phase-sensitive inversion-recovery-prepared (PSIR) gradient-echo acquisition, triggered every other heartbeat at approximately 10 min after a cumulative gadolinium dose of 0.2 mmol/kg . The presence of LGE in the LV in the PSIR images was quantified as a percentage of total LV mass using 5SD criteria. T1 measurements for ECV and intracellular water lifetime  was used for the analysis of images from T1 images. The LV wall was divided into 6 standard segments, and inversion recovery curves were generated for each segment. The segmental T1escribed . The modt-test was used for the comparison of normally distributed values and, otherwise, the Mann–Whitney test for continuous variables. Associations between variables were assessed by the linear regression analysis and the Pearson correlation coefficient. Differences in correlation strength for two correlations sharing one common variable were tested using Steiger's method. Specifically, we were interested in comparing the correlation strengths of tissue markers with systolic function and ventricular remodeling, respectively. To test for a linear trend of a continuous CMR variable with ordered levels of NYHA class, we used the non-parametric Jonckheere–Terpstra (J-T) test. The primary outcome of interest for the exploratory survival analysis was CV death, and heart transplantation was considered a competing risk. We defined follow-up time as days from the date of CMR (entry time) to the date for the last follow-up or the date of death or cardiac transplantation. Cumulative incidence functions (CIFs) were calculated for each CV death and heart transplantation, and stratified by the median ECV, intracellular water lifetime, native T1 and Rassi score, respectively, to determine the effect of these on outcomes. The subdistributions for a competing risk were compared across strata using Gray's test implemented in the R-package “cmprsk”. Data are presented as mean ± standard deviation if normally distributed, as median with interquartile range (IQR) if not normally distributed, or as count (percentage) for categorical variables. A  “cmprsk”. Univari2, and 40.5% were female) with intermediate-to-high-risk CCC as determined by the Rassi score (n = 23) or angiotensin receptor blocker , and >80% being treated with beta blocker , as summarized in n = 2), significant coronary artery disease by coronary angiography (CA), defined as ≥70% narrowing of luminal diameter of any of the three major epicardial arteries, and assessed by invasive CA (ICA) in the majority of patients with CCC , was observed in only one patient. In the remaining 4 patients without ICA, CAD was ruled out by functional tests. Among the 35 (91%) patients of our CCC cohort with positive scar detected for LGE, none had typical findings for ischemic heart disease, excluding the possibility of overlapping ischemic heart disease  index: 107 ± 66 ml/m2, LA volume index: 56 ± 35 ml/m2] compared to published normal ranges  index: 147 ± 69 ml/ml ranges . While Ln = 18) of cases, epicardial in association with the mesocardial pattern in 24% (n = 8), and epicardial in association with mesocardial and transmural patterns in 3% (n = 1) of the cases . CCC patients with ECV above the median had more severe HF symptoms  and had a lower blood hematocrit , but did not differ otherwise in patient characteristics, as shown in A total of 34 92%) patients had LGE in the LV. The percentage of LGE in the LV had a median of 12% (interquartile range: 6–19%) applying the 5SD criterion. The most commonly seen LGE pattern was epicardial, occurring exclusively in 53% . The ECV increased significantly with the Rassi score  and Rassi score .The ECV increased overall linearly with NYHA classes . Myocardial ECV showed a moderate negative correlation with LV EF . The difference in the correlations between LV EF and ECV, and LV EF and LGE, was significant (P = 0.0032 from Steiger's test for the comparison of correlations). Similarly, the difference in the correlations between LV mass-to-EDV and τic, and LV mass-to-EDV and LGE, was significant (P = 0.009 from Steiger's test for the comparison of correlations).An increasing burden of LV interstitial fibrosis, assessed by ECV, was associated with a decreasing LV mass-to-EDV ratio  or CV deaths (n = 6). The cumulative incidence of CV death trended higher with above-median ECV , shorter intracellular water lifetime , longer native than median T1 , Rassi score ≥ median   in the group with the Rassi score above its median value of 10 and in patients with NYHA III or IV (P = 0.031). Univariate Cox models with cardiac transplant as a competing risk identified the following significant predictors of CV death: Rassi score , ECV  and higher HR . LV EF , native T1, and the extent of LGE were not associated with CV death in the respective univariate Cox proportional hazard models. To ascertain the incremental value of ECV, a multi-variable Cox model was created with the addition of ECV as a predictor to the Rassi score. An elevated ECV provided an incremental prognostic value to the Rassi score , 10 (27%) subjects experienced HF transplantation ( = 0.07) , and in si score .T. cruzi infection, this study shows for the first time that in patients with CCC and HF symptoms, the cardiomyocyte diameter regresses. Furthermore, the expansion of extracellular space by ECV was significantly associated with the Rassi score, a validated and recognized risk score, for cardiovascular events in patients with CCC. LV remodeling contributes to the development and progression of CCC, ultimately leading to moderate to severe HF symptoms. This study identifies cellular and tissue factors associated with adverse ventricular remodeling in CCC.The main findings of this study are that ECV and intracellular water lifetime, or cardiomyocyte diameter regression, correlate with adverse ventricular remodeling and NYHA HF classification. While cardiomyocytes undergo hypertrophy as an early response to T. cruzi infection and the associated inflammation  covering multiple slices in the LV (the MOLLI software only became available after most patients had been recruited for this study). Although MOLLI and Look-Locker T1 measurements demonstrated acceptable agreement , direct The present results suggest that an increase in interstitial fibrosis measured by ECV, and reduced cardiomyocyte diameter, assessed by the intracellular water lifetime, has potential implications for the cardiomyopathy severity and prognosis of patients with CCC. This exploratory study indicates that ECV and intracellular water lifetime identify a tissue phenotype in patients with Chagas cardiomyopathy at a risk for adverse ventricular remodeling, HF, and cardiovascular events.Trypanosoma cruzi infection. CCC is characterized by an increase in myocardial fibrosis, and the extent of myocardial fibrosis in CCC has been associated with cardiovascular events and mortality. Cardiac magnetic resonance (CMR) imaging is a well-validated modality for myocardial tissue phenotyping with promising prognostic findings in patients with CCC. However, most studies of patients with CCC used late gadolinium enhancement (LGE) to assess focal fibrosis which underestimates diffuse fibrosis. Furthermore, other characteristics of the tissue phenotype, such as cardiomyocyte size, have not been assessed to-date. This study investigated the association between novel myocardial tissue markers with HF status and cardiovascular outcomes in CCC. A novel finding is that diffuse interstitial fibrosis is more strongly correlated with systolic dysfunction than LGE. Similarly, the marker of cardiomyocyte diameter is more strongly correlated with eccentric remodeling than LGE. In survival analysis, ECV was associated with CV death. These findings indicate that in patients with CCC novel, CMR-based tissue phenotype markers are related to HF status and clinical outcomes.Chronic Chagas cardiomyopathy (CCC) constitutes the most life-threatening consequence of the The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by CAAE: 2647481920005404. The patients/participants provided their written informed consent to participate in this study.CN, TS, LM, LS, LP, AS, WN, FF, SS, JS, EA, KM, TN, MJ-H, and ORCF made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, drafted the article or reviewed it critically for important intellectual content, and given final approval of the version to be published. All authors contributed to the article and approved the submitted version.ORCF was supported by grant in research productivity (303366/2015-0) from the National Council for Scientific and Technological Development (CNPq) and by grants from the São Paulo Research Foundation . TN was supported by a gift from A. Curt Greer and Pamela Kohlberg, and grants from the National Institutes of Health/National Heart, Lung, and Blood Institute under grants R01HL130539, R01HL137562, K24HL150238, and the National Institutes of Health/Harvard Center for AIDS Research under grant P30 AI060354.TN has received support from Astra Zeneca, Bristol Myer Squibb, AbbVie, Amgen, and H3 Biomedicine. ORCF has received research grants and/or speaking honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Novartis, Takeda, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cardiomyopathy is segregated into primary and secondary categories, leading to different phenotypes, including dilated, hypertrophic, and restrictive patterns. Dilated cardiomyopathy (DCM) is a mixed bag of heart diseases with the unique features of cardiac dilatation and subnormal to poor myocardial contractility. Dilated cardiomyopathy in the pediatric age group is generally characterized by unobstructed, dilated, and contracting left ventricular chamber defects and is associated with heart failure. Other causes include genetic juvenile-onset cardiomyopathy, drug-induced cardiomyopathy, stress-induced cardiomyopathy, hemochromatosis, endocrine causes (thyroid disorder and pheochromocytoma), autoimmune diseases, and nutritional deficiencies (selenium and thiamine). It is characterized by thinning of the left ventricle, a dilated left ventricle or biventricular dilatation, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, global hypokinesia, and cardiomegaly (seen on a chest X-ray). Decreased cardiac output leads to fatigue, cachexia, narrow pulse pressure, dicrotic pulse/hypokinetic pulse, dyspnea, cool extremities, decreased blood supply to the brain (cognitive dysfunction), and reduced blood supply to the kidney . Left ventricular diastolic dysfunction can result in dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. Cardiomyopathy can also occur with or without left ventricular dysfunction, as in left ventricular non-compaction cardiomyopathy (LVNC), which is a rare heart disease occurring due to two (likely) pathogenic nonsense mutations: DSG2-p.S363X and TBX20-p.D278X. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Right ventricular chamber failure can be identified on the electrocardiogram as sinus tachycardia and non-specific ST/T changes. The complications include arrhythmia  and thromboembolism . It is of utmost importance in the field of heart transplantation as the definitive treatment of the disease. Heart transplantation is now an acceptable treatment option for patients with dilated cardiomyopathy. This short review highlights different methods for the detection and diagnosis of dilated cardiomyopathy and the treatment modalities available for the same. Cardiomyopathies are diseases of the heart that affect the systole, diastole, or both phases of the cardiac cycle. Cardiomyopathy can be divided into primary  and secondary categories, which has ultimately led to varied phenotypes that include dilated, hypertrophic, and restrictive patterns. Based on specific morphological and functional phenotypes, cardiomyopathies can be clinically classified into dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular dysplasia, as shown in Table Most patients have been found to have "pure" forms of the above, which completely adhere to the diagnostic criteria. However, some patients have an overlap of symptoms with mixed conditions of cardiomyopathies . In hypeDCM, a myocardial disorder, is recognized as a left ventricle that is dilated and is a frequently occurring type of cardiomyopathy. It is one of the critical diseases treated by cardiac transplantation in both the pediatric and adult age groups. It is of utmost importance in the field of heart transplantation as the definitive treatment of the disease. The utilization of heart transplantation has led to improved survival after the diagnosis of pediatric DCM. Most of the deaths occur within one year of presentation, which suggests that most of the patients are not diagnosed until they have an end-stage disease that is not effectively palliated with the medical therapies used to treat them . If not This review article highlights the various methods for the detection and treatment of dilated cardiomyopathy in children.EpidemiologyDCM is usually due to left ventricular (LV) dilatation. The patient might additionally have right ventricular dilatation, but it is of no great importance in diagnosing the condition as it can be present in several conditions, including pulmonary valve stenosis. pulmonary arterial hypertension (PAH) or an atrial septal defect (ASD). The prevalence of the disease (DCM) is seen in all age groups, races, and ethnicities. In children, the incidence is around 0.57 per 100,000 population and is usually seen more frequently in boys than girls, with incidences of 0.66 per 100,000 population and 0.47 per 100,000 population, respectively . Arola eEtiologyCardiomyopathy can be primary or secondary, depending on the etiology. Primary cardiomyopathies can have a genetic cause, or they can also be acquired. Secondary cardiomyopathies are secondary to systemic or multiorgan disease causing myocardial damage. At times, it is diagnosed as an incidental finding during the evaluation of some other associated cardiac disease, usually by two-dimensional echocardiography. Cardiomyopathies are a frequent cause of inpatient admission in hospitals and are the most typical cause of the need for heart transplantation procedures in patients of all age groups -17. DCM  On pathologic examinationGrossly dilating all four chambers of the heart can be identified as a flabby, hypocontracting heart. On histopathology, a) hypertrophied muscle fibers can be identified, and b) ninja star nuclei (irregular and hyperchromatic), are seen due to a titin gene mutation. c) box-car nuclei are seen in hypertensive and atherosclerotic disease; d) Tokotsubo cardiomyopathy; and e) arrhythmogenic cardiomyopathy. Tokotsubo cardiomyopathy, a type of DCM found in situations of extreme emotional stress (broken heart syndrome), is characterized by selective left ventricle ballooning in which the neck of the left ventricle becomes narrow with a round bottom, resembling the Japanese octopus trap (Takotsubo). This cardiomyopathy is more commonly found (mostly) in elderly females than in males. Troponin-one is elevated, and ST-segment elevation can be identified on the electrocardiograph (ECG). Arrhythmogenic cardiomyopathy, an autosomal dominant disorder, is generally characterized by right ventricular dysfunction caused by mutations of plakoglobin or desmin. Naxos syndrome is arrhythmogenic cardiomyopathy characterized by hyperkeratosis of the palms and soles.Clinical featuresPatients can present with symptoms of overt heart failure, including sweating, breathlessness, orthopnea, and decreased exercise tolerance, to name a few. Young children usually show a reduced appetite and cachexia. Sinus tachycardia, jugular venous pressure distension, pallor, and hepatomegaly are some of the clinical signs that can be seen. The late signs include peripheral edema and abdominal distension. At times, a murmur of mitral regurgitation can be heard. Despite this, clinical signs and symptoms observed in most children with heart disease include discomfort, weakness, breathlessness after activity, and pain in the chest. Other commonly found signs and symptoms common to most children with cardiomyopathies include arrhythmias (which can be an increased or decreased heart rate), inflammation of the innermost layer of the heart wall known as endocarditis, and congestive heart failure or abrupt death due to cardiac failure. The hallmarks of the disease include a dilated left ventricle, biventricular dilatation, left ventricular (LV) systolic dysfunction or thinning of the LV, LV diastolic dysfunction, global hypokinesia, and cardiomegaly. Decreased cardiac output leads to fatigue, cachexia, narrow pulse pressure, dicrotic pulse/hypokinetic pulse, dyspnea, cool extremities, reduced blood supply to the brain (cognitive dysfunction), and decreased blood supply to the kidney . LV diastolic dysfunction leads to dyspnea and orthopnea. Right ventricular failure can be identified on the ECG as sinus tachycardia and non-specific ST/T changes. The complications of which include arrhythmias  and thromboembolism , which can eventually lead to sudden cardiac failure and death. Cardiomyopathy can therefore be considered a differential diagnosis for sudden cardiac failure and death in children in the pediatric age group.DiagnosisThe diagnosis of the condition is made through a multifold approach that includes asking about the family history to take into consideration the genetic predisposition and environmental factors, the clinical history, the physical examination findings, blood investigations, and various modalities of radiography and echocardiography (ECG).The genetic basis of dilated cardiomyopathy highlights the importance of screening at-risk family members. The basic evaluation of a family in which DCM is present should include a detailed family history with a minimum of three generations and an initial clinical screening of first-degree relatives ,23. A stThe chest X-ray usually shows hypertrophy of the heart chambers and signs of pulmonary venous congestion. More commonly, notching at the ribs can be seen in Takaya's arteritis than in coarctation in an elder child suspected of heart disease. The electrocardiogram most commonly shows atrial fibrillation or sinus tachycardia, arrhythmias , hypertrophy of the left atrium, and sometimes intraventricular conduction defects and low current. In cases of dilated or congestive cardiomyopathy, the left bundle-branch block (LBBB) is also seen with a deviation toward the right axis, which is not a common finding together. Electrocardiography can be used to see the presence of sinus tachycardia, conduction blocks, and left ventricular enlargement changes.Echocardiographic evaluation of the presence of dysfunction in the ventricles is considered the best method for the assessment and diagnosis of various types of heart diseases in pediatric age groups and adolescents. Even though two-dimensional morphological echo and ejection fraction are the critical elements for phenotype characterization, in echo, morphologically, we can identify biventricular dilatation as an increase in left ventricular end-diastolic dimension (LVDD) and left ventricular end-systolic size (LSVD), enlargement of the atrium in relation to the ventricular enlargement, decreased LV contractility, and an apical thrombus. It also shows a reduced ejection fraction along with dilatation of the left ventricle with regular or thin walls.Cardiac magnetic resonance imaging (MRI) can be done to understand the extent of the dilatation of the ventricular chambers, the morphology, the fibrosis, the pumping capacity of the heart, and where irregular heartbeats originate, which is essential in determining the type and severity of cardiomyopathy and to rule out arrhythmogenic right ventricular cardiomyopathy (ARVC). On cardiac MRI, the left ventricular dimensions and functions, including strain measurements, can be appropriately measured. Gadolinium, which is used as a contrast agent, is helpful in evaluating fibrosis and is used to provide information about the quality of the myocardial tissue. In dilated cardiomyopathy, the amount of fibrosis and delay in the enhancement of gadolinium contrast are predictors of mortality and also predict the necessity of future hospitalization.A few blood investigations can be used as biomarkers for diagnosing genomic mutations, which is helpful in the management and also as a prognostic indicator. They include ventricular natriuretic peptide and N-terminal pro-brain natriuretic peptide (NT-BNP). The levels of BNP have markedly increased . EndomyoThe assessment of cardiac anomalies in systolic function (excitability and ability to contract), diastolic function (relaxation and compliance), and myocardial growth (hypertrophy and atrophy) is the hallmark of the differential diagnosis of pediatric cardiomyopathies. Anomalous origin of the left coronary artery from the pulmonary trunk (ALCAPA) must be ruled out as it is a rare cause of left ventricular dysfunction in infants. Its recognition is important because of the superior results of surgery as opposed to medical management. Its recognition can be done using cross-sectional echocardiography followed by confirmatory contrast cine arteriography, which remains the definitive investigation in these patients .Treatment The goals of medical management are to reduce the symptoms of CHF and thereby stop the progression of the disease. Although medical therapy remains a mainstay in treating patients, it is not the definitive management. The primary aim is to control symptoms and prevent disease progression and complications, and it also improves the quality of life of symptomatic DCM patients . The druDopamine and dobutamine should be administered intravenously to partially reverse chronic congestive heart failure and additionally improve heart function temporarily; these are the sympathomimetics belonging to the ionotropic group of drugs. Still, excessive use can lead to arrhythmia and myocardial irritability. Milrinone is the preferred agent in the pediatric population. It has been observed that in patients with poor myocardial excitation and contraction along with symptomatic arrhythmias, amiodarone can be used, a class III agent widening the action potential belonging to the antiarrhythmic group of drugs. There are many nutrients benefiting patients with cardiovascular disease that might reverse myocardial dysfunction, including L-arginine, propionyl-L-carnitine, and coenzyme Q10 ,33. RecoPrognosisMost infants with DCM die within the first year of their lives as soon as they are diagnosed, with survival rates at one and five years of 79% and 61%, respectively -45. MostDilated cardiomyopathy remains an enigma. Despite the intensive search for etiology, the underlying cause of most cases remains unknown. Despite the extensive quest for an etiology, most cases have an unknown reason. Multiple causes are probably present, with many of them leading to clinically identical cardiac myopathies. Because patients' outcomes range from complete recovery to sudden death, characteristics that predict results should be identified so that treatment solutions for a single patient can be selected appropriately. Furthermore, recognizing patients with the worst outcomes should aid in determining the best time for a heart transplant. Despite recent developments in medicine and surgical procedures, various novel investigations and treatment approaches have been offered with little success. In treating the condition, stem cell therapy has shown some promise. Although they were not so successful, palliative surgical techniques were also tried as a bridge to heart transplantation. The future of disease therapy remains an intriguing topic of study, but for the time being, traditional treatment methods continue to be prioritized. Early detection and treatment of the condition may be aided by screening echocardiography.


Obesity exerts multiple deleterious effects on the heart that may ultimately lead to cardiac failure. This study sought to characterize myocardial microstructure and function in an experimental model of obesity-related cardiac dysfunction.n = 12) or standard control diet  for 15 weeks. At the end of the study period, cardiac function was assessed by ultra-high frequency echocardiography, and hearts were processed for further analyses. The three-dimensional myocardial microstructure was examined ex vivo at a spatial resolution of 100 × 100 × 100 μm3 by diffusion tensor magnetic resonance imaging (DT-MRI) at 7T. Myocardial deformation, diffusion metrics and fiber tract geometry were analyzed with respect to the different myocardial layers (subendocardium/subepicardium) and segments (base/mid-cavity/apex). Results were correlated with blood sample analyses, histopathology, and gene expression data.Male C57BL/6N mice were fed either a high-fat diet . Obese mice showed signs of diastolic dysfunction, whereas left-ventricular ejection fraction and fractional shortening remained unchanged . Additionally, global longitudinal strain was reduced in the HFD group , which was mainly driven by an impairment in basal segments. However, histopathology and gene expression analyses revealed no myocardial fibrosis or differences in cardiomyocyte morphology. Mean diffusivity and eigenvalues of the diffusion tensor were lower in the basal subepicardium of obese mice as assessed by DT-MRI (P < 0.05). The three-dimensional fiber tract arrangement of the left ventricle (LV) remained preserved.HFD feeding induced significantly increased body weight combined with a pronounced accumulation of visceral fat (body weight 42.3 ± 5.7 vs. 31.5 ± 2.2 g, body weight change 73.7 ± 14.8 vs. 31.1 ± 6.6%, both Fifteen weeks of high-fat diet induced alterations in myocardial diffusion properties in mice, whereas no remodeling of the three-dimensional myofiber arrangement of the LV was observed. Obese mice showed reduced longitudinal strain and lower mean diffusivity predominantly in the left-ventricular base, and further investigation into the significance of this regional pattern is required. Obesity is a major risk factor for heart failure (HF) with rising prevalence worldwide during the past ∼50 years , 2. It iExcessive adiposity causes structural and functional cardiac alterations that ultimately may lead to HF , 7. ObesCardiac diffusion tensor magnetic resonance imaging (DT-MRI) is a unique method to quantify structure, organization and integrity of the myocardium at the microscopic scale . NeverthIn the present study, the cardiac phenotype of a mouse model of diet-induced obesity was comprehensively characterized by DT-MRI, ultra-high frequency echocardiography, and histopathology regarding myocardial microstructure and function. We hypothesized that (1) high-fat diet (HFD) feeding in mice induces obesity-related cardiac dysfunction; and (2) diet-induced obesity is accompanied by altered cardiac diffusion properties as well as remodeling of the three-dimensional myofiber arrangement of the left ventricle (LV).in vivo experiments were carried out in accordance with the German Law and directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes. The study protocol was prospectively prepared and approved by local authorities . Results are reported according to the ARRIVE guidelines.All n = 12) or standard control diet  for 15 weeks. Weight development and food consumption were monitored twice a week. After 14 weeks of dietary intervention, blood pressure measurements were performed. Cardiac function was assessed by transthoracic echocardiography before the animals were sacrificed after 15 weeks of dietary intervention via cervical dislocation under inhalational anesthesia with isoflurane. Organs and visceral fat depots were excised and weighed. The right superior lung lobe was weighed immediately after removal (wet weight) and again after being dried to a constant weight (dry weight) for calculation of the wet-to-dry lung weight ratio. The mean tibia length was used to normalize organ weights.The study protocol is illustrated in Systolic blood pressure was measured non-invasively in conscious animals using a mouse tail cuff method blood pressure system . Briefly, animals were restrained and placed in a dedicated chamber with temperature being maintained at 37°C. After ∼5 min of acclimatization, a minimum of three different measurements were obtained and averaged per animal. To reduce stress during final measurements, animals were trained by exposing them to the procedure several times before.Mice were anesthetized by isoflurane inhalation and placed in supine position on a heated examination table with integrated ECG electrodes (37°C). The chest was depilated and prewarmed ultrasound gel was applied. Transthoracic echocardiography was performed using an ultra-high frequency linear transducer  coupled to a Vevo 3100 Imaging System  as described before . AcquireLeft-ventricular ejection fraction was derived from the parasternal long axis view using a modified Simpson’s method of disks. End-diastolic wall thickness and fractional shortening of the LV were measured in M-Mode at mid-papillary level in the parasternal short axis view. Mitral flow velocities were assessed with pulsed-wave Doppler above the mitral leaflets; tissue velocities were obtained with tissue Doppler at the medial mitral annulus.sys). Analysis of longitudinal deformation also included assessment of peak diastolic strain rate .B-Mode images were processed with a dedicated software algorithm for myocardial strain analyses . Longitudinal strain and strain rate were derived from the parasternal long axis view, whereas radial and circumferential parameters were generated from the parasternal short axis view. Three different tracings of the endocardial and epicardial border were performed, and all parameters were averaged over three consecutive cardiac cycles. Longitudinal deformation was assessed along both the endocardial and epicardial border; circumferential parameters were acquired from endocardial tracings only. Radial parameters were derived by analysis of the deformation of endocardial points and corresponding ones along the epicardial border. In addition, longitudinal layer-specific strain and -strain rate were assessed along the endocardial and epicardial border. The myocardium was divided into six segments, and segmental strain curves were averaged for calculation of global strain and strain rate parameters. Segmental longitudinal strain values were calculated as the mean of the two apical, mid-cavity and basal segments, respectively. Strain was indicated as peak systolic strain; longitudinal, radial and circumferential strain rates were given as peak systolic strain rate . Subsequently, samples were centrifuged, and serum aliquots were stored at −80°C until further measurements. Circulating levels of TIMP-1  were quantified by an enzyme-linked immunosorbent assay according to the manufacturer’s instructions . All other parameters were determined by colorimetry using an AU480 clinical chemistry analyzer .n = 5 per group), whereas the remaining samples were processed for further tissue analyses. Preparation for DT-MRI was performed as previously described  in order to prevent distortions at tissue-medium interfaces and to adjust the receive chain of the MR system to signal from heart tissue. Prior to sealing the syringe, a dull needle was used to carefully compress both ventricles in order to remove any remaining saline solution or trapped air. Syringes were fixed on a dedicated 3D-printed sledge that enabled consistent placement with respect to the scanner isocenter and the radiofrequency coil. Hearts remained in Fomblin™ for the duration of the measurement (∼12 h) and were placed in phosphate-buffered saline afterward.1H-cryoprobe . Axial, coronal, and sagittal gradient echo acquisitions with 50 μm in-plane resolution and a slice thickness of 0.4 mm were used to determine the short axis orientation. Echo times of 3.3 ms allowed to detect image distortions caused by trapped air. DT-MRI data were acquired for 90 slices with 100 μm isotropic resolution using a spin echo sequence with standard readout and monopolar diffusion encoding (2.5 ms gradient duration and 8.4 ms gradient separation). Two reference images (b = 0 s/mm2) were acquired, while the signal attenuation induced by the diffusion process was measured in 12 directions (bmax = 933 s/mm2). Further measurement parameters were TE/TR: 17.5/4000 ms, bandwidth: 447 Hz/Pixel, field of view: 10 mm × 10 mm, matrix size: 100 × 100 resulting in an in-plane spatial resolution of 0.1 mm × 0.1 mm. Total scan time for 10 averages of the DT-MRI protocol amounted to 11 h and 40 min.All MRI measurements were performed using a PharmaScan™ (70/16) 7T MRI system and a two-channel 1 (15 November 2018 build). All images depicting tractography of cardiomyocyte bundles were generated using fiber tracking algorithms and visualization tools of DSI Studio. Adjustments to interface scripts connecting MATLAB and DSI studio enabled the introduction of helix and sheetlet angle values into the DSI data format. In order to assess fiber bundle coherence on smaller scales, we performed tractography in the LV using a minimal fiber bundle length of 0.1 and 1 mm as termination criteria. Seed points  were placed within LV segmentation, and a fractional anisotropy of 0.075 as well as angular coherence was required along tracts.DT-MRI images were denoised using over complete local partial component analysis  and thenCardiac cross sections derived from the cardiac base, mid-cavity and apex were fixed with 4% formalin and paraffin-embedded for staining with hematoxylin/eosin  and Picrosirius Red . A blinded expert in veterinary pathology (RK) was asked to grade cellular damage in slides stained with hematoxylin/eosin using a semiquantitative scale ranging from 0 (no damage) to 3 (severe damage). Similarly, cardiomyocyte hypertrophy was graded on a semiquantitative scale as follows: 0 , 1 (few cardiomyocytes with increased size in transverse sections), 2 (some cardiomyocytes with increased size in transverse sections), and 3 (majority of cardiomyocytes with increased size in transverse sections). For collagen quantification, histological slides were digitized using an Aperio CS2 image capture device , and the relative proportion of red-stained collagen from total tissue area was determined by a software algorithm . Total collagen in the LV was calculated as the mean of apical, mid-cavity and basal values.CT–ΔΔ method.Total RNA was isolated from frozen cardiac tissue using QIAzol lysis reagent and the RNeasy Micro kit according to the manufacturer’s protocol . RNA was transcribed into cDNA by reverse transcriptase in combination with ribonuclease inhibitor and deoxynucleotide triphosphates . Primer sequences are depicted in t-test or two-tailed Mann-Whitney U test, as appropriate. Body weight development was analyzed by two-way repeated measures ANOVA. A value of P < 0.05 was considered statistically significant. Statistical analyses were performed using GraphPad PRISM 7 . DT-MRI, echocardiography and histopathology were performed in a blinded manner regarding the experimental group.Data are reported as mean ± SD or median [95% confidence interval]. Normality was assessed by Q-Q plots and Shapiro-Wilk test. Differences between the two diet groups were compared by two-tailed unpaired Student’s All animals completed the study protocol without mortality or any adverse events. One animal in the HFD group exhibited insufficient body weight gain (< 30%) and was therefore excluded from further analyses (proportion of non-responders: 8.4%).Mice in the HFD group began to weigh significantly more than control animals after 4 weeks of dietary intervention . OverallThe HFD group showed an excessive accumulation of visceral fat indicated by significantly increased perirenal and epididymal fat depots . Gross pNormalized heart weights did not differ between both groups . The wetHistopathology showed unremarkable cardiomyocyte morphology without evidence of relevant cellular damage or hypertrophy . MoreoveEchocardiography data acquired at the end of the study period is depicted in sys along the endocardium did not differ significantly  and globally as an average of the different segments . Represeficantly . Global ficantly . Global ese mice . Similarice  and segments  . MyocardSimilar to MD, the magnitude of the main eigenvalue of the diffusion tensor (lambda 1) was lower in the entire myocardium, where significant differences were predominantly located in the basal and apical subepicardium . ReductiDerived microstructure metrics were analyzed in the same fashion as diffusion metrics. The concept of myofiber tract geometry is illustrated in In this experimental study we demonstrated that (1) diet-induced obesity led to diastolic dysfunction and impaired longitudinal deformation; and (2) obesity-related cardiac dysfunction was association with altered cardiac diffusion properties in certain regions of the LV, whereas the three-dimensional myofiber arrangement remained preserved. In summary, the model of diet-induced obesity resembled several characteristics of obese patients at pre-heart failure states (corresponding to ACCF/AHA stages A and B), and myocardial microstructure was characterized by DT-MRI for the first time in this context.Cardiovascular diseases are major determinants of the high morbidity and mortality of obesity, a condition whose global prevalence nearly tripled during the past ∼50 years, now reaching pandemic proportions , 3. ObesThere is no uniform definition of obesity-related cardiac dysfunction, and cardiac changes in response to excessive body fat accumulation are quite heterogeneous . Here, wThe present findings suggest that obesity is associated with alterations of cardiac diffusion properties, whose assessment may serve as a diagnostic marker in the future. Notably, these changes were detectable even in the absence of relevant cardiac hypertrophy, signs of overt HF, or histopathological evidence of myocardial damage. This implies that myocardial remodeling in response to excessive body fat accumulation may be present even in early disease stages, and that DT-MRI is capable of assessing these. We did not observe any changes of the three-dimensional myofiber- and sheetlet arrangement in the LV, which are major determinants of its mechanical and electrophysiological function. Future clinical studies evaluating DT-MRI in obese patients are warranted for the translation of our results.Comprehensive image segmentation allowed the investigation of DT-MRI and myocardial strain parameters with respect to myocardial layers and segments. Diffusion in the myocardium is modulated by its multiple components such as cells, permeable membranes, and extracellular space . We obseThere is mounting evidence that longitudinal deformation is impaired in obese individuals –9. ComplEpicardial adipose tissue is located between the myocardium and the epicardium  without fascial separation, which is why it can be found directly within the subepicardial layer of the myocardium . The dis2 is the average body mass index reported in current HFpEF trials (The vast majority of patients suffering from HFpEF are overweight or obese, and approximately 30 kg/mF trials , 29. IndF trials , 30. IntF trials , 32. GivF trials , we antiThis study has several limitations that should be acknowledged. First, only a relatively small sample size was studied by DT-MRI due to long acquisition times and the complex post-processing. As the focus of this work was on myocardial microstructure, epicardial adipose tissue was removed during sample preparation, and its impact on cardiac diffusion properties remains to be examined. The small size of the murine heart limits layer-specific strain analysis to the endocardial and epicardial borders, which differs from clinical approaches for the assessment of myocardial layer-specific strain. In addition, the present study lacks a validated structural correlate for the observed decrease in diffusivity. Therefore, our results should be considered hypothesis-generating, and may serve as a pilot for future investigations. Fixation with formalin affects diffusion properties, which should be considered when comparing absolute diffusion metrics. Although diet-induced obesity generally does not induce type 2 diabetes in mice, the cardiac phenotype may be confounded by a mild glucose intolerance as shown before for BL/6 mice .Mice with diet-induced obesity displayed several features of patients with obesity-related cardiac dysfunction. DT-MRI revealed altered myocardial diffusion properties in this model, whereas the three-dimensional myofiber arrangement of the LV remained preserved. A regional pattern of reduced longitudinal strain and lower mean diffusivity in basal segments of the LV was newly identified. These findings indicate that DT-MRI may serve as a novel diagnostic tool in obesity-related cardiac dysfunction, and future studies are warranted for the translation of our results.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Landesamt für Gesundheit und Soziales Berlin, Germany.DL: DT-MRI analyses, data acquisition, preparation and analysis, and writing. AT: animal study, echocardiography, data acquisition, preparation and analysis, and review and editing. MS: blood pressure measurements and echocardiographic analyses. VB: quantitative PCR, histopathology, review, and editing. ES: animal study. JS: review and editing. SB: data analysis, review, and editing. RK: histopathology. AF-L: conceptualization, project administration, and supervision. LS and UK: conceptualization, project administration, supervision, and funding acquisition. NB: blood pressure measurements, echocardiographic analyses, data acquisition, preparation and analysis, writing, conceptualization, project administration, and supervision. All authors read and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Due to its low incidence, isolated cardiac sarcoidosis (ICS) is often missed or misdiagnosed. Herein, we describe a case of ICS in a 52-year-old male patient. Advanced imaging, including cardiac magnetic resonance (CMR) and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), could not only screen high-risk patients for establishing diagnosis, but also guide endomyocardial biopsy (EMB) for improving cardiac disease detection rate. This case highlights the importance of multimodal imaging for screening and necessity of EMB for diagnosis. Sarcoidosis is a systemic disease that can occur in various organs. Although the most common clinical manifestation in > 90% of patients with sarcoidosis is enlargement of the hilar and mediastinal lymph nodes, circular erythema of the skin is the main symptom in some patients. However, some patients (approximately 5%) also have heart involvement called cardiac sarcoidosis (CS) that can develop in any part of the heart. The three most common clinical manifestations of CS are atrioventricular block, ventricular arrhythmia, and heart failure. Some studies reported that a small number of primary lesions in patients with sarcoidosis originate from the heart: isolated cardiac sarcoidosis (ICS). The definition of ICS was first established in the CS guidelines proposed by the Japanese Circulation Society –3. This A 52-year-old man presented to our hospital with palpitations and dizziness. Physical examination on admission did not show any skin or mucosal damage or superficial lymph node enlargement. Laboratory test results showed only a slight increase in troponin levels (0.032 ng/ml). In addition, electrocardiography (ECG) showed ventricular premature contractions and complete right bundle branch block [left ventricular ejection fraction (LVEF) % = 65%].Eleven months prior, the patient experienced unexplained intermittent palpitations, with dizziness, fatigue, chest tightness, and shortness of breath. He was admitted to a local hospital. Twenty-four hour Holter monitoring in the patient showed frequent ventricular extrasystoles, paroxysmal ventricular tachycardia, and right bundle branch block. Echocardiography revealed LVEF of 60% with no obvious abnormalities in cardiac structure or function. Cardiac magnetic resonance (CMR) imaging revealed abnormal signals in the right ventricular surface of the ventricular septum, and late gadolinium enhancement (LGE) . Based oSurgery and medication did not improve the patient’s symptoms within the following 7 months. In local hospital repeat CMR imaging showed that LGE was aggravated . FluorinAfter admission, based on the patient’s imaging findings and symptoms, we considered a possible diagnosis of: CS, myocarditis, hypertrophic cardiomyopathy, or myocardial amyloidosis. CS can invade any part of the myocardium. However, transmural involvement of the left and right ventricular walls is the most common. The inflammatory phase of CS is characterized by myocardial granulomatous infiltration, inflammation, and edema. This can lead to local thickening and abnormal movement of the heart muscle. Although both CS and myocarditis manifest cardiac inflammation, myocarditis mostly involves the lateral wall of the heart, whereas CS mostly involves the septum . In patiTo further clarify the cause of arrhythmia, we performed an EMB. To accurately locate the lesion and improve the success rate of the EMB, the patient underwent the last CMR . Using CDuring 2 months after discharge, the patient had no symptoms of palpitations. The 24-h Holter monitoring showed frequent premature ventricular contractions without further ventricular tachycardia. FDG-PET showed that the area of increased glucose metabolism in the original lesion was reduced, indicating the effectiveness of immunosuppressive therapy .Due to the low incidence and inconsistent diagnostic methods of ICS, it is often missed or misdiagnosed. However, multimodal imaging evaluation is of great significance to guide diagnosis of CS. A Japanese study indicated that approximately 26.8% of patients with CS could be diagnosed with ICS . Some stAlthough some researchers advocate CS diagnosis through clinical manifestations and imaging examination, EMB is the gold standard for CS diagnosis. Owing to the uneven distribution of non-caseous granulomas in the myocardial endocardium, the positive predictive accuracy of EMB is low. In our case, to accurately obtain tissue from the lesion, we used CMR to locate the lesions and thus, obtained positive results. Some studies have reported that the positive predictive value of EMB could reach 89% (Corticosteroid immunosuppressants are currently the first-line treatment of sarcoidosis as they improve cardiac remodeling and effectively relieve symptoms when used as early as possible after CS diagnosis. Of note, CMR and FDG-PET scans can also be used for evaluating the efficacy of immunosuppressive therapy in patients with CS.Based on the findings of our case, due to lack of specific biomarkers for detecting CS and ICS, diagnosis is still very difficult. Multimodal imaging examination should be used more frequently in patients with suspected CS or having high-risk factors for CS. Timely and accurate diagnosis has important clinical significance for better follow-up, treatment, and prognosis of patients.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Clinical Research Ethics Committee, First Hospital of Lanzhou University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained by the patients/participants for the publication of this case study.YW and XN contributed to manuscript writing. JX, GJ, SH, and MB contributed to concept design, manuscript editing, and revision. All authors contributed to the article and approved the submitted version.


To investigate the prognostic value of pulmonary transit time (pTT) determined by cardiac magnetic resonance (CMR) after acute ST-segment-elevation myocardial infarction (STEMI).Comprehensive CMR examinations were performed in 207 patients 3 days and 4 months after reperfused STEMI. Functional parameters and infarct characteristics were assessed. PTT was defined as the interval between peaks of gadolinium contrast time-intensity curves in the right and left ventricles in first-pass perfusion imaging. Cox regression models were calculated to assess the association between pTT and the occurrence of major adverse cardiac events (MACE), defined as a composite of death, re-infarction, and congestive heart failure.p = 0.009) remained significantly associated with MACE occurrence after adjustment for left ventricular ejection fraction (LVEF) and cardiac index. The association of pTT and MACE remained significant also after adjusting for infarct size and microvascular obstruction size. In Kaplan-Meier analysis, pTT ≥ 9.6 s was associated with MACE (p < 0.001). Addition of pTT to LVEF resulted in a categorical net reclassification improvement of 0.73  and integrated discrimination improvement of 0.07 .PTT was 8.6 s at baseline and 7.8 s at the 4-month CMR. In Cox regression, baseline pTT (hazard ratio [HR]: 1.58; 95% CI: 1.12 to 2.22; After reperfused STEMI, CMR-derived pTT was associated with hard clinical events with prognostic information independent of and incremental to infarct size and LV systolic function.• Pulmonary transit time is the duration it takes the heart to pump blood from the right chambers across lung vessels to the left chambers.• This prospective single-centre study showed inferior outcome in patients with prolonged pulmonary transit time after myocardial infarction.• Pulmonary transit time assessed by magnetic resonance imaging added incremental information to established prognostic markers. The evaluation of surrogate markers of cardiopulmonary status may provide risk stratification and prognostication in patients with acute myocardial infarction , 2. WhilWe therefore aimed to investigate (1) the dynamics of pTT with progressive infarct healing within the first 4 months after STEMI and (2) the prognostic value of pTT in terms of predicting hard clinical events after STEMI.2, age < 18 years, any history of coronary artery disease or previous myocardial infarction and general contraindications to perform magnetic resonance imaging.In this prospective observational study at the Heart Center of the University Clinic of Innsbruck, consecutive STEMI patients who met the following inclusion criteria were enrolled: first-time STEMI according to the ESC/ACC/AHA committee criteria , revascuThe primary endpoint of the study was the occurrence of MACE, consisting of all-cause death, myocardial re-infarction and re-hospitalisation for new congestive heart failure. Re-infarction was defined in accordance with the redefined ESC/ACC committee criteria . New conAll patients gave written informed consent before inclusion. This study was designed and conducted in compliance with the Declaration of Helsinki and approved by the local research ethics committee of the Medical University of Innsbruck.fit; Siemens Healthineers) within the first week and 4 months after reperfused STEMI, respectively. Patients were positioned head first in supine position on a multi-channel spine phased-array radiofrequency coil with 24 elements integrated into the patient table. An 18-channel body coil was additionally placed in craniocaudal alignment on the chest of the study subjects.All examinations were performed on a 1.5-T clinical MR imaging unit ; typical imaging parameters were as follows: repetition time/echo time: 2.2 ms/0.97 ms, saturation recovery time: 90 ms, flip angle: 50°, acquisition matrix: 128 × 82, field of view: 400 × 300 mm, bandwidth: 1370 Hz/pixel, slice thickness: 8 mm, parallel imaging mode: GRAPPA, and acceleration factor: 2. Image acquisition was started simultaneously with contrast media injection; a total of 60 images in one 4-chamber long-axis view as well as two short-axis views were acquired.LV and RV volumes and LV mass were assessed on short-axis cine stacks (10–12 slices) using standard software . Papillary muscles were included to the blood pool . CardiacPTT time-intensity curves were created on syngo.via imaging software , as used in clinical routine. Circular regions of interest (ROI) were placed within the basal RV and LV blood pool on the first-pass perfusion 4-chamber long-axis view. Care was taken to avoid partial volume effects at the papillary muscles or myocardial wall Fig. . ROIs weAll CMR images were analysed by experienced observers blinded to clinical information and previous examinations in the case of follow-up examinations. A subset of 20 patients was randomly selected for determination of inter- and intra-observer variability.U test; differences in proportions were compared by chi-squared test or Fisher’s exact test, as appropriate. Intra-class correlation coefficients (ICC) by a two-way mixed model for single measures were used to evaluate inter- and intra-observer reliability; differences were tested with Wilcoxon rank test. Univariable and multivariable Cox regression analysis was used for evaluation of significant and independent predictors of MACE. Variables with a p value < 0.10 in univariable analysis were included in multivariable models. To ensure statistical robustness with respect to our sample size and event rate, two different models were defined a priori. Apart from pTT, model 1 included dynamic parameters  and R 4.1.2  were used for statistical analysis. Continuous variables were expressed as median with interquartile range (IQR), categorical variables as absolute number and corresponding percentage. Differences in continuous variables between two groups were evaluated by Mann-Whitney art rate ) and wasf values . MACE-frculation . A two-tIn total, 207 STEMI patients were included in the final analysis. A detailed study flow chart is depicted by Fig. p < 0.001).CMR scans were performed at a median of 3 (IQR: 2 to 4) days and 18 (IQR: 17 to 20) weeks after STEMI. In the overall population, pTT was 8.6 seconds (s) (IQR: 7.5 to 9.7 s) at baseline and decreased to 7.8 s (IQR: 7.1 to 8.7 s) within the first 4 months after STEMI (p = 0.032), but not at follow-up  and lower LVEF at baseline  and at 4-month follow-up  as well as a larger extent of microvascular obstruction . PBVI was comparable in patients with and without MACE .During a median follow-up time of 25 (IQR: 24 to 25) months, 12 patients (6%) suffered from MACE . Patients with MACE had significantly longer baseline pTT  significantly predicted MACE. As demonstrated by a multivariable “tissue model”, pTT  and microvascular obstruction size  remained significant predictors of MACE after adjustment for infarct size (Table p = 0.091).In a multivariable model  including pTT, LVEF and cardiac index only pTT (hazard ratio (HR): 1.58; 95% confidence interval (CI): 1.12 to 2.22; J statistic was 9.6 s. According to the Kaplan-Meier analysis, patients with baseline pTT ≥ 9.6 s showed significantly lower MACE-free survival (p < 0.001) than patients with pTT < 9.6 s , continuous net reclassification improvement of 1.03  and integrated discrimination improvement of 0.07 . The addition of prolonged pTT to a risk model based on infarct size  resulted in a categorical net reclassification improvement  of 1.03 , continuous net reclassification improvement of 1.03  and integrated discrimination improvement of 0.08 .The best pTT cut-off value for MACE prediction according to Youden’s 6 s Fig. . Additiop < 0.001). There was no relevant intra-observer variability (mean difference of 0.0 (IQR: − 0.1 to 0.1) s with an ICC of 0.96 ).The inter-observer difference of pTT was 0.1 (IQR: − 0.1 to 0.2) s with an ICC of 0.96  at the time of CMR and first-time STEMI were included; hence, our findings may not be transferable to haemodynamically less stable patients or to patients with previous myocardial infarction. Notably, the vast majority of STEMI patients present with Killip class < 3 .The lack of a validation cohort and the relatively small number of events in our cohort represent an important limitation of the study. Our cohort comprised patients with relatively high LVEF; a subgroup analysis of patients with impaired LVEF was not feasible due to the small number of adverse events. However, pTT was still predictive of patient outcome, highlighting its value for risk stratification even in preserved LV function.According to current guidelines, echocardiography is the recommended imaging modality during the hospital stay after STEMI, while CMR is considered as an alternative in inconclusive cases, thus hampering the broad applicability of pTT measurement via CMR . HoweverTo conclude, pTT assessed by first-pass perfusion CMR imaging emerged as an independent predictor of MACE with incremental prognostic value to established prognostic parameters and could be used as an alternative for risk stratification after STEMI.