Endothelial dysfunction is an early abnormality in the process of atherosclerosis and cardiovascular disease and has been associated with worse clinical outcome. Cardiac rehabilitation (CR) has been reported to be helpful to reduce cardiovascular events in various types of cardiac disease, but the mechanisms of its beneficial effects remain only partially known. In this article, we review the studies that assessed the effect of CR on endothelial function in patients with various cardiac conditions. Available data show that CR significantly improves impaired endothelial function in these patients, which may contribute to the beneficial effects of CR on clinical outcome. Cardiac rehabilitation (CR) is a program of physical and respiratory exercises, handled by an interdisciplinary team, aimed to improve cardiovascular function and physical capacity mainly after an acute cardiac event or intervention. CR programs have been reported to decrease morbidity and improve quality of life in these patients; furthermore, they have also been suggested to improve survival. These beneficial effects are likely mainly achieved through a tighter control of cardiovascular risk factors (CVRFs) as well as adherence to optimal medical therapy, which prevent the progression of atherosclerosis and reduce complications of atherosclerotic lesions ,2,3,4,5.Based on the evidence of their beneficial cardiovascular effects, CR has a Class I indication in several American and European guidelines for patients with various heart conditions, including heart surgery, acute myocardial infarction, stable angina, heart failure (HF) with reduced left ventricular function, as well as peripheral artery disease ,12,13,14This article is mainly focused on briefly reviewing the evidence of a favorable effect of CR programs on endothelial function in cardiac patients. An impairment of endothelial function is indeed considered a major cause of susceptibility to vascular complications and an improvement in endothelial function may therefore constitute a major mechanism through which CR may improve vascular function and, consequently, clinical outcome. We will precede the review of the available data on the effects of CR on endothelial function by a comment on the function of the normal endothelium and the implications of its dysfunction and by a short review of the main methods applied to assess endothelial function in clinical studies.2) and endothelium-derived hyperpolarizing factor (EDHF), in response to various chemical substances , but also physical stimuli . Furthermore, the normal endothelium also exerts anti-platelet, anti-coagulant, fibrinolytic, anti-inflammatory and antiproliferative actions [The vascular endothelium has an outstanding role in maintaining vascular homeostasis and regulating blood vessel function. Thus, in normal people, the endothelium is a major regulator of blood flow through its vasodilator properties. These are mainly exerted by the release of nitric oxide (NO), but also of prostacyclin  and HF. Of note, the prognostic implications of endothelial dysfunction have been reported for both coronary and peripheral, as well as macrovascular and microvascular, circulation ,27,28,292 and EDHF may contribute to the improved physiologic effects of the endothelium by exercise [Importantly, the control of cardiovascular risk factors with some drugs, such as statins and antihypertensive drugs, improves endothelial function ,31, whicexercise ,35. The exercise ,34,35.Several methods have been described and are used to assess the functional state of the endothelium. Most of these methods are devoted at exploring systemic endothelial function through the assessment of endothelium-mediated dilator function both in large peripheral arteries and microcirculation and include flow-mediated dilatation (FMD), venous occlusion plethysmography, peripheral arterial tonometry (PAT) and laser Doppler flowmetry. Furthermore, indications on the functional state of the vascular endothelium can be obtained from in vivo or in vitro measurements of markers of endothelial activity.Importantly, methods have also been developed to specifically assess endothelial function in the coronary circulation, although their application in clinical practice is challenged by the need of invasive investigation. Yet, in cardiac diseases it would be important to specifically assess coronary, rather peripheral, endothelial function, as the relation between the presence and severity of endothelial dysfunction in peripheral and coronary circulation has been shown to be less than optimal ,37.A detailed review of the methods applied to assess endothelial function can be found elsewhere ,39,40. IFMD has become one of the most used techniques to assess systemic endothelial function non-invasively. It consists in measuring by ultrasound the diameter change of a peripheral artery in response to a maximal increase of blood flow consequent to reactive hyperemia. The increase in blood flow velocity, indeed, leads to stimulation of endothelial cells to release NO by the increased shear stress, which results in the dilatation of the vessel.In clinical practice, FMD is usually assessed in a brachial artery . To thisFMD values obtained manually by operators are subject to some variability of the measurements, which affects the comparability of the data and has until now limited a wide applicability in the clinical setting and precluded a recommendation of its use in clinical guidelines . The useFMD has been reported to be impaired in several clinical conditions, including subjects with various CVRFs, patients with stable CAD or HF, as well as in acute settings of CAD ,44. FurtMeasurement of forearm blood flow velocity at baseline and during reactive hyperemia may also give some insight in the status of peripheral microcirculation. A limited decrease of peripheral resistances during hyperemia, indeed, may indicate an impairment of the microvascular dilatation function, which may also involve the endothelium. Accordingly, an impairment of FMD may, in fact, depend on a reduced microvascular dilatation, which limits forearm blood flow increase, rather than an impaired NO-mediated dilatation of the brachial artery.This technique investigates peripheral microcirculatory dilatation by measuring pulsatile arterial volume changes by finger plethysmography (EndoPAT) . PracticRHI is considered to reflect microvascular endothelial function  However,The functional state of the endothelium can also be derived by measuring blood concentrations of substances that are typically or mainly, released by endothelial cells following endothelial activation and dysfunction, as previously described. An increase in the blood of a large number of biomarkers reflecting endothelial activation, in particular in CAD populations, has been described , but thoMore sophisticated laboratory methods to assess functional endothelial state include the measurement of endothelial progenitor cells (EPCs) concentrations, which are crucial for repairing endothelial lesions , and theIn coronary circulation, endothelial function can adequately be assessed only by invasive methods. Although other stimuli may be used , at present it is usually assessed by intracoronary administration of low to medium doses of acetylcholine, which in normal subjects dilate coronary vessels by inducing NO release from endothelial cells . The endAn alternative stimulus to assess endothelial function in coronary circulation is cold pressor test (CPT), which is performed by putting a hand in ice for 90–120 s. In normal subjects, CPT induces a mild adrenergic activation which results in NO release through alpha–receptor stimulation on endothelial cells . In dysfCR programs mainly focus on exercise training, but they involve a careful implementation of integrative measures, including appropriate treatment of CVRFs, optimization of medical therapy, psychosocial interventions and patients’ education ,6,7,8,9.Several studies have investigated the effects of CR programs on endothelial function, mainly in those recovering from an acute myocardial infarction (AMI), but also in those with stable CAD or HF. A summary of the main characteristics and results of these studies is shown in p < 0.01). Of note, CPT caused a constriction of the brachial artery at baseline in both groups; at follow-up, however, no changes in brachial artery diameter was observed in the CR group, whereas vasoconstriction still occurred in controls. The improvement of endothelial function was associated with a significant increase in exercise tolerance. Importantly, these benefits of CR disappeared in the treated group after detraining, suggesting that continuous exercise training may be necessary to maintain the improvement of endothelial function.Several studies investigated the effects of CR programs on endothelial function in patients recovering from AMI. Vona et al. , randomip < 0.001), together with a significant reduction of plasma levels of vWF. No changes in FMD and plasma markers of endothelial function were observed in 20 matched control patients who did not undergo CR. No significant differences in endothelial function improvement were found between home-based and hospital-based cardiac rehabilitation programs.Lee et al.  randomizp = 0.14). However, in the subgroup of patients with endothelial dysfunction at baseline (n = 16 or 55.2%), as diagnosed by an lnRHI lower than 0.51, lnRHI improved significantly at follow-up from 0.37 (0.27–0.42) to 0.53 (0.43–0.66) (p = 0.002), thus suggesting that CR may have beneficial effects on endothelial function only when it is significantly depressed at baseline. However, patients training for 24 sessions (n = 16) had similar lnRHI changes to those of patients training for 12 sessions .Peller et al.  assessedFinally, Oliveira et al.  randomizp < 0.001), whereas no significant change was observed in RHI .In patients with clinically stable CAD, the effects of CR programs on endothelial function were investigated by a few studies. Cornelissen et al.  assessedp < 0.05) in the CR group but showed no change in the control group (8.5% ± 2.3% at baseline and 8.2% + 2.3% at follow-up). In addition, an increase in plasma nitrite and nitrate levels was observed in the CR group, confirming the improvement of endothelial function. Moreover, an increase of superoxide dismutase levels, an antioxidant enzyme, was found in the CR group, but not in controls, suggesting that the favorable effects of endurance exercise training as part of a CR program on endothelial function may be related to decreased oxidative stress.Edwards et al.  assignedp < 0.05). No significant difference in the changes of FMD was observed between the two groups in the brachial artery (p = 0.23), thus suggesting that exercise may improve endothelial function only in peripheral arteries of the exercised limbs. However, FMD in the brachial artery improved by 1.9 points in CR patients (6.4% ± 3.4% vs. 8.3% ± 3.4%), but only by 0.3 points in controls (7% ± 3.5% vs. 7.3% ± 3.5%), suggesting that the lack of statistical difference in brachial FMD between the two groups could be related to a limited statistical power of the study.Gokce et al.  assessedGagliardi et al.  randomiz2, FMD, CVRFs and quality of life in patients with stable CAD [2, CVRFs and quality of life. The improvement of FMD showed a significant correlation with the peak VO2 . No effects of both types of ET programs were observed on the blood levels of EPCs, angiogenic T cells and endothelial microparticles [The multicenter SAINTEX study compared the effects of aerobic interval training (AIT) and aerobic continuous training (ACT) on peak VOable CAD . In thisarticles .p for change vs controls < 0.05). Mean peak flow velocity in response to Ach in the exercise group showed a significant improvement . Thus, this study showed that exercise training improves endothelial function both in epicardial and resistance coronary vessels in patients with coronary artery disease.While the previous studies investigated peripheral endothelial function, in a study Hambrecht et al. assessed coronary endothelial function . They raSeveral studies have shown that an abnormal endothelial function is present in patients with HF ,82, likeTwo studies investigated the effects of CR on endothelial function of patients with HF. Tanaka et al.  retrospep = 0.04) and after CPT  compared to basal values. Furthermore, after CR, MBF increased significantly in response to CPT, whereas no significant change had been observed at the baseline test .Legallois et al.  assessedIn conclusion, although with some variable results, the complex of available data supports the notion that, in cardiac patients, CR programs improve endothelial function, particularly when it is significantly impaired. This beneficial effect is likely mediated by a combination of factors, including exercise training programs, lifestyle changes and a tighter control of CVRFs through a better adherence to medical therapy.The improvement of endothelial function found in the published studies seems largely independent of the type of aerobic exercise training programs, including walking on treadmill vs. bicycle, as well as continuous vs. interval training. Thus, rather than recommending for specific exercise programs, what seems important to achieve beneficial effects on the cardiovascular system and endothelial function, is that the supervised exercise training allows to reach an adequate exercise intensity  and that sessions are performed on a regular basis  and for an adequate period . The beneficial effects of CR in cardiovascular patients, indeed, strongly depend on the volume and intensity of exercise program delivery . ImportaAccording to available data, the assessment of endothelial function could, therefore, be useful to assess whether CR programs result in benefits on vascular function in individual patients. To this scope, FMD (with forearm blood flow assessment) seems the most simple and comprehensive method, but it still suffers from center and operator variability; efforts should be done, therefore, to achieve a standardization of this (as well as other) method for endothelial function assessment that may allow a large application in clinical practice.Importantly, while an improvement of endothelial function by CR programs in cardiac patients has been suggested by several studies and is expected to portend beneficial effects on cardiovascular complications, whether it actually translates into improved clinical outcome remains to be demonstrated. To this scope, adequately designed and sized randomized multicenter clinical trials should be planned, using both standardized CR exercise training programs and methods for the assessment of endothelial function.


To evaluate diagnostic performance and time saved by LV-METRIC, a novel automated algorithm for LV quantification, among a broad unselected clinical patient population undergoing CMR.Cardiac magnetic resonance (CMR) is an imaging standard for quantification of LV ejection fraction (EF) and volume. CMR typically relies on manual tracing (MT). MT can be time consuming and operator-dependent. Automated segmentation holds potential for rapid LV quantification. Established automated algorithms often fail or require extensive user interface, possibly due to the fact that they employ assumptions regarding cavity shape or regional propagation. We developed an automated segmentation algorithm (LV-METRIC) that involves no geometric assumptions and instead quantifies LV EF and volume based on local per-pixel signal intensity while accounting for partial voxel effects. The purpose of the current study was three-fold; (1) to evaluate LV-METRIC performance vs. MT among a broad unselected patient population; (2) to compare processing time by LV-METRIC to MT, and (3) to compare LV-METRIC and MT to an independent standard of LV flow quantification.LV-METRIC and MT were independently applied for quantification of LV EF and volumes on consecutive patients that underwent CMR (1.5 T) between June-November, 2007. Processing times were recorded. Quantification was based on endocardial border delineation of consecutive short axis SSFP images throughout the LV . Through-plane aortic valve phase contrast imaging was performed on a subset (n = 65) of patients for independent confirmation of LV stroke volume. No patients were excluded based on clinical characteristics; the only exclusion criteria were cardiac arrhythmias or image artifacts that prohibited MT (6.7% patients).2 > .95). Both LV-METRIC and MT similarly agreed with phase contrast ; Although volumetric stroke volume by MT was, on average, similar to PC (Δ5.9 mL), there was substantial variance between the two techniques (SD ± 13.4 mL). Similar differences were evident when comparing PC and LV-METRIC with (6.2 ± 14.2 ml) or without (-3.9 ± 14.7 ml) partial voxel interpolation.The study population was comprised of 151 patients . LV-METRIC was successful in all patients; average processing time was 22 seconds for LV-METRIC and 4 minutes 59 seconds for MT (p < 0.001). An example segmentation is shown in Figure Among a broad population of consecutive patients, LV-METRIC, a novel automated CMR segmentation algorithm, provides highly accurate quantification of LV ejection fraction and volumes with a marked reduction in processing time vs. MT. Both LV-METRIC and MT provide similar agreement with an independent standard of phase contrast imaging.


Exercise training induces morphological and functional cardiovascular adaptation known as the “athlete’s heart” with changes including dilatation, hypertrophy, and increased stroke volume. These changes may overlap with pathological appearances. Distinguishing athletic cardiac remodelling from cardiomyopathy is important and is a frequent medical dilemma. Cardiac magnetic resonance (CMR) has a role in clinical care as it can refine discrimination of health from a disease where ECG and echocardiography alone have left or generated uncertainty. CMR can more precisely assess cardiac structure and function as well as characterise the myocardium detecting key changes including myocardial scar and diffuse fibrosis. In this review, we will review the role of CMR in sports cardiology. Prolonged and intense exercise training induces morphological and functional cardiovascular adaptation known as the “athlete’s heart.” Changes include left ventricular hypertrophy (LVH), left ventricular (LV) and right ventricular (RV) cavity dilatation and increased stroke volume. Intense prolonged training can induce changes that overlap with cardiomyopathy . DistingCombined with non-imaging data , transthoracic echocardiography (TTE) is the first line test due to low cost and wide availability. Cardiac magnetic resonance (CMR) is increasingly used as it can refine discrimination of health from a disease where echocardiography alone has left or generated uncertainty , 3. CMR CMR is the gold standard for heart chamber morphology and wall motion assessment, for size and mass calculation and for biventricular systolic function quantification, which are performed with fewer geometrical assumptions compared to echocardiography and with no blind spots  Fig. . MultipaNative (precontrast) T1 is increased weakly by the presence of fibrosis and strongly by amyloid and oedema. T1 falls with fatty infiltration and iron overload –8. In thFinally, late gadolinium enhancement (LGE) imaging post contrast administration is used to identify focal myocardial fibrosis (MF). Broadly, MF can be divided into ischaemic  and non-ischaemic . The pattern of LGE provides information on aetiology, whilst the extent may indicate risk—risk of heart failure and risk of sudden death. With high resolution imaging, some LGE can be physiological  . In athlThe human heart senses demand and adapts both short and long term . The lonCMR is helpful because measurement precision is superior. Relative features can be helpful, for example disproportionate RV or LV dilatation can point to ARVC or DCM, whilst disproportionate hypertrophy, especially if focal can point to HCM Fig. . MorpholOne of the most common and challenging differential diagnoses is distinguishing between physiological left ventricular hypertrophy (LVH) induced by sporting activity and mild phenotypic expression of hypertrophic cardiomyopathy (HCM). In athletes, LVH can reach 15 mm; however, this was described in male rowers and is always associated with increased LV volumes , 20. EchTTN, 20–25% of all familiar DCM cases) and lamin A/C . The latter, along with cardiac sodium channel NAv1.5 (SCN5A), filamin C (FLNC) and desmoplakin (DSP) mutations, is associated with a more aggressive disease and an arrhythmogenic phenotype [Dilated cardiomyopathy is a heterogeneous disease characterised by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment –33. Sevehenotype . This ‘ahenotype .DCM has a long preclinical stage, in which patients are mostly asymptomatic and present with minor cardiac abnormalities, followed by an overt phase, characterised by systolic heart failure-like manifestations . VentricThe athlete’s heart shares features with DCM. Dose-dependent exercise-induced cardiac chamber enlargement and mildly reduced ejection fraction (EF) at rest are common in competitive athletes, especially in endurance sports. However, in athletes, this is associated with bradycardia and high stroke volume with balanced RV dilatation . In unclArrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically inherited heart muscle disease, predominantly associated with mutations in the genes encoding desmosomal proteins and with an estimated prevalence of 1 in 2000–5000 people . It is cA correct and timely diagnose of ARVC in athletes can be critical and challenging. Physical exercise can promote disease expression and progression, triggering malignant arrhythmias . EnduranHowever, many conditions can resemble ARVC, posing a diagnostic dilemma . Heart dIn asymptomatic athletes with a negative family history, balanced biventricular dilatation is likely to be benign but a RV ejection fraction < 45% on CMR, RV end-diastolic volume/LV end-diastolic volume > 1.3:1, regional wall motion abnormalities in the RV and the presence of typical LV/RV LGE are highly indicative of ARVC . PerhapsOriginally considered rare, left ventricular non-compaction (LVNC) is increasingly identified by imaging. It is an inherited cardiomyopathy characterised by a thin, compacted epicardial layer and an extensive, non-compacted endocardial layer with increased LV trabeculation and trabecular recesses . The proTrue LVNC has a variable clinical presentation, and non-compaction may be a component of other cardiomyopathies. Symptoms include palpitations, chest pain, heart failure and rarely aborted/sudden cardiac death or thromboembolism . AthleteThe electrocardiogram (ECG) in LVNC is abnormal in up to 87% of cases but variable, with no definitive criteria. The most common ECG finding in athletes with LVNC is LVH by voltage criteria , with otIncreased LV trabeculation is found in up to 30% of patients with LV systolic dysfunction of any cause . CardiacVentricular arrhythmias can be a warning sign of an underlying cardiac condition. CMR can reveal abnormal myocardial tissue usually missed by echocardiography; however, there are no definitive studies exploring the role of LGE as a prognostic tool in athletes. The data are limited to a small study where 72 athletes presenting with complex ventricular arrhythmias and non-ischemic LGE had a worse prognosis .It is indisputable that regular aerobic exercise is beneficial for primary and secondary prevention of cardiovascular disease; however, the impact of lifelong endurance exercise on the heart has only recently been explored. In the minority of susceptible veteran athletes, exercise can precipitate adverse events like sudden cardiac death (SCD), which in two thirds of cases, is attributable to silent coronary artery disease (CAD) . SeveralThere is an ongoing debate on the possible negative effect of lifelong sporting activity on the heart. CMR plays an important role in assessing the veteran athlete’s heart. Physiological adaptation includes a lack of LGE and lower myocardial native T1 and ECV than controls. When comparing veteran athletes with controls, LGE CMR imaging showed a significantly higher scar burden; overt myocardial scar was detected in 11.4% vs 0% controls, mainly in males (15.2 vs 2.2%) . AssociaIt appears that the impact of long-term athleticism on the veteran athlete’s heart exhibits significant gender variation and more work is required to understand why male athletes demonstrate more pathological findings than women . Also, tCMR requests in the sports cardiology field are growing. CMR provides substantial certainty in many ‘grey area’ cases. It can integrate anatomy, function and tissue characterisation in a single imaging test and has particular utility when athletes present with an abnormal electrocardiogram or ventricular arrhythmias and either apparently normal echocardiography or echocardiographic changes that may or may not relate to athletic adaptation. Particular findings of utility are the presence of hypertrophy, RV involvement and significant scar. CMR needs however to be performed appropriately  with app


Atrial fibrillation and heart failure are common coexisting conditions requiring hospitalisation for heart failure and death. Pulmonary vein isolation is a well-established option for symptomatic atrial fibrillation and for atrial fibrillation concomitant with heart failure with reduced left ventricular ejection fraction. Recently, pulmonary vein isolation using cryoballoon showed non-inferiority to radiofrequency ablation with respect to the treatment of patients with drug-refractory paroxysmal atrial fibrillation. However, the effectiveness of acute-phase rhythm control by semi-urgent pulmonary vein isolation using cryoballoon in patients with haemodynamically unstable atrial fibrillation storm accompanied with low cardiac output syndrome is unclear. Herein, we present a case in which semi-urgent pulmonary vein isolation using cryoballoon was effective for acute-phase rhythm control against drug-resistant and haemodynamically unstable repetitive atrial fibrillation tachycardia accompanied with low cardiac output syndrome.A 57-year-old man was hospitalised for New York Heart Association functional class 4 heart failure with atrial fibrillation tachycardia and reduced left ventricular ejection fraction of 20% accompanied with low cardiac output syndrome-induced liver damage. The haemodynamics collapsed during atrial fibrillation tachycardia, which had become resistant to intravenous amiodarone and repeated electrical cardioversions. In addition to atrial fibrillation, atrial tachycardia and common-type atrial flutter appeared on day 3. Multiple organ failure progressed gradually due to haemodynamically unstable atrial fibrillation tachycardia storm accompanied with low cardiac output syndrome. On day 4, to focus on treatment of heart failure and multiple organ failure, semi-urgent rescue pulmonary vein isolation using cryoballoon to atrial fibrillation and cavotricuspid isthmus ablation to common-type atrial flutter were performed for acute-phase rhythm control. Soon after the ablation procedure, atrial fibrillation and common-type atrial flutter were lessened, and sinus rhythm was restored. A stable haemodynamics was successfully achieved with the improvement of hepatorenal function. The patient was discharged on day 77 without complications.This case demonstrates that acute-phase rhythm control by semi-urgent pulmonary vein isolation using cryoballoon could be a treatment option in patients with haemodynamically unstable atrial fibrillation tachycardia storm accompanied with low cardiac output syndrome, which is refractory to cardioversion and drug therapy. Atrial fibrillation (AF) and heart failure (HF) are common coexisting conditions with hospitalisation for HF and death . PulmonaA 57-year-old man was referred to our hospital for New York Heart Association functional class 4 HF and extremely elevated liver enzymes. He had palpitation from 2 weeks ago which was accompanied with orthopnoea and serious fatigue on admission, despite being healthy without any history of AF. The electrocardiography showed AF tachycardia of approximately 180 beats per minute, and the bedside echocardiography showed low LVEF of 20%. In addition to fatigue, coexisting hypotension and elevated lactate of 13 mmol/L indicated LOS. Electrical cardioversion was conducted, barely terminated AF successfully on day 1, and restored blood pressure and urinalysis response to intravenous furosemide. Intravenous landiolol hydrochloride was administered for AF tachycardia. HF and LOS were treated with intravenous dobutamine, intravenous furosemide and oral tolvaptan, and non-invasive positive pressure ventilation under mild sedation using intravenous dexmedetomidine hydrochloride. On day 2, torsade de pointes suddenly occurred subsequent to a premature atrial beat in a long-short manner of coupling interval with QT prolongation. Cardiopulmonary resuscitation with electric cardioversions, intratracheal intubation, and establishment of mechanical ventilation were carried out, which achieved return of spontaneous circulation. Temporary atrium-atrium inhibited pacing was emergently established to shorten prolonged QT and maintain regular heart rate. However, AF tachycardia recurred repetitively. Repeated electrical cardioversions failed to terminate AF. Hypotension continued along with oliguria. The liver dysfunction was further exacerbated with aspartate aminotransferase of 11,708 U/L. The intravenous amiodarone was started. On day 3, AF tachycardia with hypotension still occurred despite intravenous amiodarone and gradually became resistant to electrical cardioversions. The atrial tachycardia (AT) and common-type atrial flutter (AFL) appeared in addition to AF. On day 4, disseminated intravascular coagulation (DIC) was diagnosed according to the Japanese Society on Thrombosis and Hemostasis criteria, with DIC score of 6 points . Acute kThe patient’s family agreed with our treatment policy and signed informed consent for the semi-urgent rescue ablation procedure.On the same day, prior to the procedure, trans-oesophageal echocardiography was performed and found no detectable thrombus in the left atrium (LA). PVI to the AF and cavotricuspid isthmus ablation to common-type AFL were planned. Fortunately, the patient’s haemodynamics did not collapse at the time of ablation, we performed our institutional standard procedure including 3-D mapping. The cryoballoon was chosen as a PVI catheter because cryoballoon ablation was expected to have a shorter procedure time and lesser thrombogenic effect than other catheter types , 12. A 2Thereafter, AF and other atrial arrhythmias seldom occurred and was terminated by single electrical cardioversion Fig. . Normal To our knowledge, this is the first report of semi-urgent rescue PVI using cryoballoon for acute-phase rhythm control against amiodarone-resistant AF tachycardia storm causing LOS and LOS-induced MOF with DIC in a tachycardia-induced cardiomyopathy.AF may cause adverse haemodynamic effects and lead to decrease in cardiac output through the loss of atrial contraction, reduction of left ventricular filling due to rapid ventricular rates and irregular RR interval, increase maximal oxygen consumption, and exacerbate mitral and tricuspid regurgitation . TherefoWe chose the cryoballoon ablation for semi-urgent rescue PVI in the present case. Cryoballoon ablation is a balloon-based ablation system using cryoenergy. In recent years, cryoballoon ablation has become the most effective alternative approach to radiofrequency catheter ablation showing non-inferiority to radiofrequency catheter ablation in freedom from AF/AT recurrence and overall safety –9. SeverIn conclusion, acute-phase rhythm control by semi-urgent PVI using cryoballoon might be a considerable treatment option in patients with haemodynamically unstable AF tachycardia which is refractory to cardioversion and drug therapy and accompanied with LOS and LOS-induced MOF with DIC.


SCN10A/voltage-gated sodium channel 1.8 (NaV1.8) and cardiac conduction has been demonstrated; however, the exact role of SCN10A/NaV1.8 in the heart rate response to atropine remains unclear. To identify the role of SCN10A variants that influence the heart rate responses to atropine, we carried out a retrospective study in 1,005 Han Chinese subjects. Our results showed that rs6795970 was associated with the heart rate response to atropine. The heart rate responses to atropine and methoctramine in NaV1.8 knockout mice were lower, whereas the heart rate response to isoproterenol was like those in wild type mice. Furthermore, we observed that the NaV1.8 blocker A-803467 alleviated the heart rate response to atropine in wild type mice. The retrospective study revealed a previously unknown role of NaV1.8 in controlling the heart rate response to atropine, as shown by the animal study, a speculative mechanism that may involve the cardiac muscarinic acetylcholine receptor M2.Atropine is commonly used to counter the effects of the parasympathetic neurotransmitter acetylcholine on heart rate in clinical practice, such as in the perioperative period; however, individual differences in the response to atropine are huge. The association between  Atropine is a competitive antagonist of acetylcholine muscarinic receptors because of its similar structure with acetylcholine, a parasympathetic neurotransmitter . An incrSCN10A, which is locus on chromosome 3 and encodes voltage-gated sodium channel 1.8 (NaV1.8), is involved in cardiac conduction and dysrhythmia   . Moreove in dogs . These oV1.8 in the effects of atropine on heart rate. Additionally, a drug experiment, based on an animal model using NaV1.8 knockout mice, was performed to validate the clinical results.This study used retrospective analysis to investigate the roles of variants of NaSCN10A variants in the effects of atropine on heart rate. Second, to explore the mechanism underlying the role of NaV1.8 in heart rate, an animal experiment was designed to investigate the effects of atropine, methoctramine, and isoproterenol on heart rate using NaV1.8 knock-out mice and wild type mice. All patient data and all experimental data of this study can be acquired from the corresponding author on a reasonable request via e-mail.This study had two parts. First, a retrospective study was performed to explore the role of The study was a retrospective study and the protocol was approved by the Institutional Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The cohort was obtained from our previous study  and, becSCN10A SNPs were included in the analysis. The SNP rs6795970 (nucleotide level: NM_006514.2:c.3218 G>A), whose minor allele causes a non-synonymous substitution , is the most frequently reported non-synonymous SCN10A SNP to be associated with cardiac conduction , rs57326399 , and rs74717885 , were selected based on a minor allele frequency ≥5% and their locations in exons, which can cause amino acid substitutions.A total of 5 nduction  and was V1.8 knockout mice, generated as described previously (ad libitum) in the animal center of Tongji Hospital. Polymerase chain reaction genotyping was performed as described previously  was dissolved in sterile isotonic saline and was administered by intraperitoneal injection at a dose of 3 mg/kg . Isoproteriments .After intraperitoneal anesthesia with chloral hydrate at a dose of 400 mg/kg, the mice were laid on the back with the right thigh shaved . A heatiThe data of the retrospective study are presented as mean ± standard deviation or number (percentage). The SPSS Statistics Version 22.0 statistical package  was used to analyze the data. For the gene association analysis, the sample was tested for each SNP to determine whether the null hypothesis of the Hardy-Weinberg equilibrium (HWE) could be rejected by applying the chi-square method. As the included population was considered as an exploratory cohort, we did not calculate the required sample size before the study. Independent-sample t-test and one-way analysis of variance (ANOVA) test were used to compare the quantitative data between different genotype groups and a chi-square test was performed for qualitative data. A two-way repeated ANOVA with post-hoc paired-samples t-test was used to compare the difference in heart rate before and after atropine use between different genotype groups. In addition, a propensity score-matched analysis was performed to further compare the heart rate after atropine use. The basal characteristics, including age, BMI, MAP, time period, basal heart rate, and electrocardiographic data , were considered as matched factors and matching using a 1:1 nearest neighbor method without re-placement under a logit model was performed.The data of the animal experiment are presented as mean ± standard error of the mean. The Prism 7.0 Software  was used to analyze the data. A two-way repeated ANOVA with a post-hoc paired-samples t-test was used to compare the difference in heart rate between groups. A p-value of <0.05 was considered statistically significant.rs7630989, rs57326399, rs74717885, and rs12632942. Furthermore, for all patients with these genotypes, the heart rate after atropine use was significantly increased compared to the basal value . For rs6795970, the HWE value was P = 0.852. No significant difference was observed in basal characteristics or other electrophysiological data from patients with different SCN10A rs6795970 alleles  and GA . In patients with GG (P < 0.001) and GA, the heart rate after atropine use was significantly increased compared to the basal value . After propensity score matching, patients with AA had a lower heart rate after atropine use than patients with other rs6795970 genotypes  was intraperitoneally injected as the vehicle. After 15 min of recording, atropine was intraperitoneally injected at the dose of 3 mg/kg. After the injection, the heart rate was monitored continuously and the average heart rate was recorded every 5 min. The details of the experimental timeline are shown in supplementary material    was intraperitoneally injected. After the injection, the heart rate was monitored continuously and the average heart rate was recorded every 5 min . The hearts rate response to atropine in the A-803467+atropine group was obviously decreased compared to the vehicle+atropine group . . The allele (AA), which induces the loss-of-function of NaV1.8 . Our results revealed the correlation between SCN10A variant rs6795970 and heart rate response to atropine. Several studies have demonstrated that rs6795970 accelerates inactivation and decreases persistent currents of NaV1.8 .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.


To determine if axial slices or short-axis slices should be the method of choice for routine clinical measurement of right (RV) and left (LV) ventricle volumes of patients with congenital heart disease (CHD) by cardiac magnetic resonance (CMR).RV and LV volumes and function need to be measured reliably by CMR in the long-term follow-up of patients with CHD. However, no standard protocol to measure RV volumes by CMR exists. A standard protocol, LV short-axis slices, exists only for the LV. However, the basal boundary of the RV is difficult to trace using LV short-axis slices. Axial slices through the patient's chest have been suggested as an alternative. Axial slices are potentially beneficial compared to short-axis slices. Firstly, axial slices are very easy to plan. This is especially true in complex anatomy, as is often the case in CHD. Secondly, by using axial slices valuable morphologic information about the large vessels and atria is obtained without need of further scans. It is known that in normal individuals, RV volume measurements made from axial slices are feasible and have a superior reproducibility to conventional short-axis slices. However, using axial slices measuring RV volumes in patients with RV morphology and pathology has not been tested. Additionally, the reproducibility of measuring LV volumes from axial slices has never been studied, neither in normal individuals nor in patients with CHD. Therefore, taken together, to date the best slice orientation for the routine clinical measurement of RV and LV volumes in patients with CHD remains unknown.Therefore, the aim of this study was to determine if short-axis or axial slices should be the method of choice for the routine clinical measurement of RV and LV volumes in patients with CHD.We studied two homogenous patient groups with RV pathology  in which both axial slices and short-axis slices can easily be obtained by CMR. By using the f-test the inter- and intra-observer variances of both methods were compared for four volumes (enddiastolic and endsystolic RV and LV volumes) in both groups.Eight variances were significantly smaller in the axial data sets compared to the short-axis data sets. The remaining eight variances were not significantly different from another.Routine clinical measurements of RV and LV volumes by CMR in patients with corrected Tetralogy of Fallot and Ebstein's anomaly should be aquired from axial slices and not short-axis slices. We furthermore suggest that axial slices should also be the method of choice for the routine clinical measurement of RV and LV volumes in all other forms of CHD.


Percutaneous coronary intervention (PCI) is sometimes considered as an alternative therapeutic strategy to surgical revascularization in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). However, the types or conditions of patients that receive the clinical benefit of left ventricular reverse remodelling (LVRR) remain unknown. The purpose of this study was to investigate the determinants of LVRR following PCI in CAD patients with reduced LVEF. From 4394 consecutive patients who underwent PCI, a total of 286 patients with reduced LV systolic function  were included in the analysis. LVRR was defined as LV end-systolic volume reduction ≥ 15% and improvement of LVEF ≥ 10% at 6 months follow-up left ventriculography. Patients were divided into LVRR (n = 63) and non-LVRR (n = 223) groups. Multivariate logistic regression analysis revealed that unprotected left main coronary artery (LMCA) intervention was significantly associated with LVRR , while prior PCI , presence of in-stent restenosis , and presence of de-novo stenosis  were negatively associated with LVRR. These data suggest the potential prognostic benefit of unprotected LMCA intervention for LVRR and importance of angiographic follow-up in patients with CAD and LV systolic dysfunction. Given LV systolic function is a powerful prognostic predictor in patients with CAD1, whether the revascularization therapy benefits patients by improving LV systolic function or not is an important clinical question to be answered when the therapy is considered.The increasing number of coronary artery disease (CAD) patients with reduced left ventricular (LV) systolic function is a major clinical problem3. Although PCI could improve LV function in some cases, it is not always effective and the types or conditions of patients that receive the benefits of LV functional improvement from revascularization by PCI remain unknown. LV functional improvement is typically associated with reduction in LV end-systolic volume, which is defined as LV reverse remodelling (LVRR). LVRR has been established as a prognostic factor in patients with ischemic or non-ischemic LV systolic dysfunction6. In the present study, we aim to examine the determinants of LVRR following PCI in CAD patients with reduced ejection fraction (EF).While coronary artery bypass grafting (CABG) is thought to be a preferred therapy to treat CAD patients with reduced systolic function, percutaneous coronary intervention (PCI) has also become a strategy of choice in CAD patients with reduced systolic function7. Subacute myocardial infarction (≤ 1 week from onset) was also considered as acute myocardial infarction, whereas recent myocardial infarction (> 1 week from onset or unknown onset) were considered as old myocardial infarction, and were included in the present study. In addition, one patient who underwent CABG (n = 1) after PCI and one patient who newly developed acute myocardial infarction (n = 1) during the follow-up period were also excluded. A patient without pressure data during the LVG study (n = 1) and patients who received LVG by contrast medium injection from the pulmonary artery because of left ventricular thrombus (n = 5) were excluded. A patient who received cardiac resynchronization therapy during the follow-up period was excluded from the analysis, which may itself affect LVRR (n = 1). There were no patients included who newly received implantable cardioverter defibrillators or cardiac resynchronization therapy during the study. Finally, a total of 286 patients with CAD and LV dysfunction  who underwent PCI and received follow-up LVG were included in the present study  was routinely performed together with diagnostic coronary angiography (CAG) unless contraindicated . Follow-up CAG and LVG were also routinely performed approximately 6 months after each PCI. LVG performed together with the initial diagnostic CAG before PCI was defined as “initial LVG”, and LVG performed together with follow-up CAG after a series of PCI as “follow-up LVG”. At first, patients who did not have initial LVG (n = 1290) were excluded. Then, patients who did not have follow-up LVG (n = 257) were excluded. Next, patients with an LVEF ≥ 50% at initial LVG (n = 2388) were also excluded. Duplicated counting of patient number due to multiple procedures during one LVG follow-up period was corrected (n = 139). Furthermore, we excluded patients diagnosed as acute myocardial infarction (n = 22) and stress cardiomyopathy (n = 3). Acute myocardial infarction was defined as a rise in cardiac enzyme concentrations  with at least one value above the 99th percentile upper reference limit in the first 24 h and with at least one of the following: (1) symptoms of myocardial ischemia, (2) new or presumed new significant ST-segment-T wave changes or left bundle branch block, (3) development of pathological Q waves in electrocardiogram, (4) imaging evidence of new loss of viable myocardium or a new regional wall motion abnormality, and (5) identification of an intracoronary thrombus by angiography8. End-diastolic and end-systolic endocardial contours were traced in the frames with maximal and minimum volume, respectively. Left ventricular volume was calculated by the area-length method. LVEF% was calculated from end-diastolic and end-systolic left ventricular volumes  as (LVEDV − LVESV) × 100/LVEDV9. Because the aim of our study was to investigate the determinants of LVRR, it was important to compare LVG findings before and after PCI. LVRR was defined as LV end-systolic volume reduction ≥ 15% and improvement of LVEF ≥ 10%10.All LVG data analysis was performed by skilled radiology technicians in our catheterization laboratory at the time of LVG, and was approved by experienced cardiologists. LVG was performed during retrograde left heart catheterization with the patient in the 30° right anterior oblique position3. Revascularization by PCI was considered for stable angina patients who have angiographically significant stenosis  or functionally significant stenosis . Coronary in-stent restenosis was defined as the angiographic detection of a recurrent stenosis with a diameter > 50% at the stent segment or its 5 mm adjacent segments13. Unprotected left main coronary artery (LMCA) disease was defined as angiographically significant stenosis of the LMCA without patent surgical grafts to the left coronary artery system14.We typically followed the current guidelines when patients were referred for revascularization15. Dyslipidaemia was defined as a low-density lipoprotein cholesterol level > 140 mg/dl or treatment for dyslipidaemia. Chronic kidney disease was defined as glomerular filtration rate < 60 mL/min/1.73 m2. Hyperuricemia was defined as serum uric acid > 7.0 mg/dL or treatment for hyperuricemia. The LMCA was defined as segment from the ostium of the left coronary artery through the bifurcation into the left anterior descending and left circumflex branches. The proximal left anterior descending artery (LAD) was defined as a segment of the LAD proximal to and including the first major septal branch. The proximal left circumflex artery (LCx) was defined as the main stem of the circumflex from its origin of the left main and including the origin of the first obtuse marginal branch. The proximal right coronary artery (RCA) was defined as the segment from the ostium to half the distance to the acute margin of the heart16. A chronic total occlusion was defined as a complete coronary arterial obstruction with thrombolysis in myocardial infarction flow grade of 0 for > 3 months (estimated)17. The present study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the institutional research ethics committee of the University of Tokyo . The informed consent was waived due to the retrospective nature of the study according to the ethics committee approval.Hypertension was defined as systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg, or medical treatment for hypertension on admission. Diabetes mellitus was defined as a haemoglobin A1c level in National Glycohemoglobin Standardization Program (NGSP) units > 6.5% or medical treatment for diabetes mellitus. If the haemoglobin A1c level in Japan Diabetes Society (JDS) units was only available, a conversion from HbA1c (JDS) to HbA1c (NGSP) units was performed as follows: NGSP (%) = 1.02 × JDS (%) + 0.25%t test. Otherwise, continuous variables were compared using the Mann–Whitney U-test. Univariate and multivariate logistic regression analyses were applied to investigate the determinants of LVRR. In these logistic regression models, the dependent variable was LVRR. Variables that showed a marginal association with LVRR (P < 0.10) in the univariate logistic regression analyses, use of angiotensin converting enzyme inhibitor (ACE-I)19 and/or angiotensin II receptor blocker (ARB)20, and use of beta-blocker23 were adopted as independent variables. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. A value of P < 0.05 was considered statistically significant. All analyses were performed using statistical software .All study patients were divided into LVRR and non-LVRR groups. We compared patient characteristics, LVG findings, types of intervention, and medications at discharge after PCI between the groups. Categorical variables are presented as numbers (percentages), and were compared using the chi-squared test. Continuous variables are expressed as the mean ± standard deviation or median [interquartile range], depending on their distribution as assessed by visual inspection and the Shapiro–Wilk test. Normally distributed continuous variables were compared using the Student’s A total of 286 patients were divided into the LVRR (n = 63) and the non-LVRR (n = 223) groups. The baseline characteristics of the study patients are shown in Table LVG findings of the study patients are shown in Table At follow-up LVG, LVEF was significantly higher in the LVRR group (59.5 ± 6.4%) compared with the non-LVRR group . LVEDV, LVESV, LVEDVI, and LVESVI were significantly lower in the LVRR group . B-type natriuretic peptide level at follow-up LVG was significantly lower in the LVRR group (41.6 [23.5–112.8] pg/mL) compared with the non-LVRR group , which may reflect the reverse remodelling of left ventricle. LV systolic pressure showed a trend towards being higher in the LVRR group (123.6 ± 22.0 mmHg) compared with the non-LVRR group . Aortic systolic pressure was significantly higher in the LVRR group (125.8 ± 22.7 mmHg) compared with the non-LVRR group . LVED pressure, aortic diastolic pressure, heart rate, mitral regurgitation grade, Canadian Cardiovascular Society grading of angina pectoris, and haemoglobin level were similar between the LVRR group and the non-LVRR group at follow-up LVG.Details of the PCIs are shown in Table Details of medications at discharge after PCI are shown in Table The results of the univariate and multivariate logistic regression analyses are shown in Table From 4394 consecutive patients who underwent PCI, we extracted 286 patients with LV dysfunction , and examined the determinants of LVRR. Multivariate logistic regression analysis revealed that unprotected LMCA intervention, prior PCI, presence of in-stent restenosis at follow-up, and presence of de novo stenosis at follow-up were significant determinants of LVRR after adjusting for confounding factors. Of these factors, unprotected LMCA intervention was the only positive predictor for LVRR. To the best of our knowledge, this is the first study that demonstrated the impact of LMCA intervention on LVRR.19, ARB20, and beta-blockers23 on LVRR. There are several confounding factors that may explain these contradictions in optimal medical therapies on LVRR in the present study. The most significant confounding factor was the selection bias for medication, and it is possible that patients with more severe LV dysfunction tended to receive ACE-I/ARB and/or beta-blockers, which may mask the efficacy on LVRR. Furthermore, our study included relatively mild LV dysfunction patients, such as patients with an LVEF near 50% and without symptoms of heart failure, which may weaken the effects of ACE-I/ARB and/or beta-blockers.In the present study, the prescription rate of optimal medical therapy including ACE-I/ARB and beta-blockers was similar between patients in the LVRR group and the non-LVRR group. Previous studies have confirmed the efficacy of ACE-I4. In that study, LVRR was significantly associated with prevention of sudden death and major ventricular arrhythmia, and a higher baseline systolic blood pressure was a predictor of LVRR . Furthermore, the authors suggested that patients with higher baseline systolic blood pressure may have more chances of tailoring treatment and modulating the afterload, which may result in LVRR4.Although there was no relationship between aortic systolic pressure and LVRR in multivariate logistic regression analysis in the present study, the univariate logistic regression analysis showed a trend towards a relationship between high aortic systolic pressure and LVRR. Merlo and colleagues previously examined the prognostic role of LVRR and baseline predictors of LVRR in idiopathic dilated cardiomyopathy24. Current European and United States guidelines recommend that most patients with unprotected LMCA disease undergo CABG3. However, randomized trials suggested that PCI with drug-eluting stents (DES), such as sirolimus-eluting stent25 or paclitaxel-eluting stent26, may be an acceptable alternative strategy for selected patients with unprotected LMCA disease. Several meta-analyses have reported similar findings29. In 2019, the Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization trial revealed that PCI with an everolimus-eluting stent was similar to CABG with respect to the rate of the composite end point of death, stroke, or myocardial infarction at 5 years follow-up in patients with unprotected LMCA disease of low or intermediate anatomical complexity30. Nevertheless, the majority of patients in that study had a preserved EF. Accordingly, the association of unprotected LMCA intervention with LVRR remains poorly understood in patients with a reduced EF. The present study focused on the population with LV systolic dysfunction, and found a potential benefit of unprotected LMCA intervention for LVRR. Because LVRR is a significant predictor of long-term outcomes in patients with LV dysfunction4, LVRR following PCI may improve long-term clinical outcomes in patients with LV dysfunction if performed together with optimal medical therapy. Currently, there are no randomized trials comparing the effects of PCI and medical therapy with those of medical therapy alone in patients with CAD and LV systolic dysfunction. However, an ongoing trial, REVascularisation for Ischaemic VEntricular Dysfunction (NCT01920048), is comparing the effects of PCI with those of medical therapy alone in patients with CAD and LV systolic dysfunction, and the findings, particularly on the effects of LMCA intervention, are eagerly awaited.Unprotected LMCA disease is associated with high morbidity and mortality because of the large volume of myocardium at risk31. The present study included left main intervention using a bare-metal stent or 1st generation DES. However, the use of 2nd generation DES may provide a greater improvement in outcomes after unprotected LMCA intervention32. Thus, in the future, a larger number of patients with unprotected LMCA disease and LV dysfunction may be treated with PCI, together with improved devices, implantation techniques, and medications33.Although the operator’s proficiency such as the left main stent implantation technique may be associated with patient outcomes including LVRR, improvements of DES, anti-platelet therapy, imaging guidance, and physiological lesion assessment have markedly improved PCI outcomes, and the indications of PCI have been expanded to more complex lesionsAs this was a single-centre, retrospective, and observational study, there is a possibility of patient selection bias. LVEF and LV volume were measured using the single plane area-length method by LVG, which is less accurate than biplane ventriculography or cardiac magnetic resonance imaging. Echocardiographic parameters were not included in the analysis because not all patients underwent echocardiography before and after PCI in the echocardiographic laboratory. Patients with an elevated end-diastolic pressure did not receive the LVG examination itself because of an increased risk of acute pulmonary oedema, thereby they were not included into the present study. Although no patients in this study were diagnosed as having severe valvular disease or idiopathic cardiomyopathy, we might not have fully excluded possible pre-existing chronic reduction of LV function, due to other conditions than CAD. It would be better to evaluate myocardial viability using stress scintigraphy before revascularization, however, we did not routinely evaluate myocardial viability by scintigraphy in all cases. Patients with complex CAD were treated with PCI or CABG after the Heart Team discussion, in which anatomical complexity and clinical characteristics were considered, and patients who had LMCA disease and treated with PCI were few in our study population, which might weaken the strength of our findings. Finally, the patients who did not receive PCI were excluded from this study in advance. As the clinical application of PCI basically varies depending upon the lesion type and patient status, this exclusion criteria itself might have caused the patient selection bias.Unprotected LMCA intervention was significantly associated with LVRR, while prior PCI, presence of in-stent restenosis, and presence of de novo stenosis were negatively associated with LVRR. These findings suggest a potential benefit of unprotected LMCA intervention for LVRR and importance of angiographic follow-up in patients with CAD and LV systolic dysfunction.Supplementary Table S1.


Peripartum cardiomyopathy (PPCM) can be classified as a variant of dilated cardiomyopathy identified usually within the first five months of delivery or during the last month of pregnancy. This condition presents as systolic heart failure. PPCM affects thousands of women in the United States each year. Even though it was first noticed in the 1800s, its etiology remains unknown. This study aims to review the pathophysiology and management of PPCM and explore the possible outcomes of peripartum cardiomyopathy. PPCM can lead to maternal death if diagnosis or treatment is delayed. Diagnosing PPCM has been challenging because it can be misdiagnosed or perceived as a sign of pregnancy since most of the symptoms of PPCM strongly match those within the typical pregnancy continuum and postpartum cycle. Patients' implications are fatal and carry a high mortality rate when PPCM is misdiagnosed or treatment is delayed. To accurately identify PPCM, using echocardiography, the left ventricular end-diastolic size and the ejection fraction should be measured to determine the severity of PPCM. Managing peripartum cardiomyopathy involves using traditional treatments for heart failure. Therapeutic recommendations are made depending on the patient's status  while considering the drug-safety profiles before administration. Some other treatments have also been used to control PPCM depending on how severe it has become; for example, antiarrhythmics have been used to treat cardiac arrhythmias when they ensue. In extreme cases, mechanical assistance and transplantation could be required. Based on the proposed pathophysiology involving the 16kDA anti-angiogenic sub-fragment, bromocriptine may be used even though it still needs more assessment due to limited evidence.Using PubMed as a major search resource, a thorough analysis of publications was carried out after incorporating this review's inclusion and exclusion criteria. A total of 455,141 publications were found using keywords and keyword combinations. With a careful selection of articles, 31 publications provided relevant information on our primary endpoint. All articles in this examination were chosen without limitation to the type of study, including clinical trials, review articles, meta-analyses, and so on. Our review suggests that, based on factors such as early detection and management, disease severity, ethnicity, and quality of patient care, patients with PPCM presented different outcomes and prognosis. However, despite PPCM's high mortality rate and its risk of recurrence, most patients tend to recover within six months of disease onset. In the United States, it can be estimated as one in 4000 live births affecting women each year while in African countries like Nigeria, there is a higher incidence, estimated as one in 100 live births per year . PeriparPeripartum cardiomyopathy is heart disease with multiple manifestations and unexplored pathogenesis; however, it shares the most similarities with dilated cardiomyopathy, which presents as a systolic dysfunction due to ventricular dilation. While it is believed that both heart diseases share similar pathological paths like impaired cardiac microvasculature and high oxidative stress, these deleterious effects in postpartum cardiomyopathy usually reverse within one year after delivery as compared to dilated cardiomyopathy .The outcomes of PPCM has been proved to be strongly associated with ethnicity and race. Women from Africa have presented with more severe systolic dysfunctions and lesser cardiac ejection fraction. This scrutiny is believed to have caused less recovery as compared to non-African ethnicities . The feaIn this evaluation, we aim to explore the possible outcomes and management of peripartum cardiomyopathy. We will also summarize the epidemiology and pathophysiology of PPCM.Methods This review study was conducted using preferred reporting items for the literature review. All studies included in the review were selected without the restriction of study type, including investigation of clinical trials, systematic reviews, and meta-analyses. Studies were selected based on gender  and clinical preference. There was no geographical restriction in this search. The search was performed with articles related to postpartum or peripartum cardiomyopathy, heart failure, and pregnancy. This search yielded many articles like case reports, meta-analyses, editorials, and review articles.The inclusion criteria included (1) English language publications, (2) studies published within the last 10 years, and (3) studies strictly related to PPCM, pregnancy, and heart failure.The exclusion criteria included (1) non-English language publications and (2) articles published more than 10 years ago.Using parallel strategies to identify original research and review of articles from PubMed, data were collected using keywords. Table After applying the inclusion and exclusion criteria using the keywords as a searching tool, 31 publications from PubMed were used for this review article.DiscussionEpidemiology of DiseasePeripartum cardiomyopathy occurrence in the United States varies from one in 1000 to 4000 live births . The occPathophysiology of Peripartum CardiomyopathyHemodynamic improvements in maternal circulation also begin in the first trimester, with a significant decrease in systemic vascular resistance and a subsequent rise in cardiac output . Renin-aThe etiology of PPCM is still a pending puzzle yet to be accurately solved. A hybrid 'two-hit' paradigm involving systemic angiogenic dysfunction and patients' vulnerability (predisposition) is thought to be critical in PPCM pathophysiology. Potential factors contributing to PPCM involve genetic predisposition, low levels of selenium, viral infections, stress-activated cytokines, inflammation, autoimmune reaction, inflammatory response to hemodynamic changes, oxidation, as well as the effects exerted by anti-angiogenic factors -16. In pGenetics may also play a role in PPCM prevalence; genetically mediated dilated cardiomyopathy (DCM) may evolve during early adulthood and is often hard to distinguish from PPCM. Recent findings also support the notion that about 15%-20% of peripartum heart failure patients have cardiomyopathy-induced mutations, i.e., in genes such as titin, beta-myosin, myosin-binding protein C, lamin A/C, or sodium voltage-gated channel alpha subunit 5 (SCN5A). One hypothesis is that in gene-positive, phenotype-negative female patients with no clinical symptoms before pregnancy, the physiological stress encountered during pregnancy and delivery can uncover concealed DCM .The incidence of mutations in patients with peripartum cardiomyopathy correlated with familial dilated cardiomyopathy genes indicates that these two diseases' clinical range may overlap. Van Spaendonck-Zwarts and colleagues reported five peripartum cardiomyopathy cases within 90 familial dilated cardiomyopathy cases. They also reported three peripartum cardiomyopathy patients with partial rehabilitation and first-degree dilated cardiomyopathy in their families, including one patient with c.149A > G, p. Gln50Arg.e. Other researchers reported familial mutations in the MYH7, SCN5A, and PSEN2 genes and spontaneous mutations in peripartum cardiomyopathy patients with the MYH6 and TNNT2 DCM genes. If indeed, these findings are accurate, the above results reflect an actual correlation between cardiac gene mutations and peripartum cardiomyopathy ,25-26.No particular potential causes have yet been established for peripartum cardiomyopathy. Nevertheless, black race, multiparity, maternal age > 30 years, twin gestations, a history of hypertension, preeclampsia, and eclampsia have also correlated with a more significant occurrence of peripartum cardiomyopathy, although no causal relationship has been established . HoweverSymptoms of Peripartum CardiomyopathyShortly after delivery or when PPCM ensues, most likely in the first week post-delivery, common signs like orthopnea and paroxysmal nocturnal dyspnea are suggestive of heart failure. Usually, these symptoms are attributed to normal pregnancy, and this explains why the diagnosis of PPCM is usually missed in the early stages of the disease. The physical examination results include tachycardia, elevated jugular venous pressure, bilateral pulmonary crackles caused by pulmonary edema, a third heart sound (S3), and a displaced apical pulse. Severe cases may occur, which may warrant admission into the intensive care unit, presenting as acute respiratory failure or cardiogenic shock needing close monitoring .Table Evaluation of Peripartum CardiomyopathyThe first steps in evaluating PPCM include general blood workup to evaluate signs such as anemia, electrolyte irregularities, endocrine disorders such as thyroid diseases, and renal or liver failure. Even though there are no specific diagnostic tests for PPCM, it remains a diagnosis of exclusion, which requires detailed investigation. Table Treatment and Management of Peripartum CardiomyopathyPPCM is currently being treated in order to comply with the guidelines for heart failure in pregnancy. In the later phases of pregnancy, treatment modalities need to consider the patient's health and that of her fetus. Beta-blockers, thiazide diuretics, or loop diuretics can be initiated before delivery in certain PPCM patients, but this is done carefully and caution should be taken, as diuretic therapy can impair the blood supply to the placenta with possible fetal harm. Therefore, to prevent such cases, the lowest possible doses of diuretic therapy should be used. During the postpartum period, the standard heart failure therapy in PPCM, including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBS), mineralocorticoid receptor antagonists, and diuretics are recommended following delivery. Since there are no data on the use of inotropes like dobutamine in PPCM, knowing that catecholamines in such patients can provoke myocardial damage, intravenous infusion should be initiated in cases of profound hypotension in patients with PPCM. When the blood pressure and volume return to normal, inotropes can be slowly tapered and the standard guidelines used for patients with heart failure in pregnancy should be followed afterward. Even in patients with a severely depressed ejection fraction, early beta-blocker therapy has shown to be protective at very low doses .Ivabradine, a selective If (funny channel) channel blocker, slows the heart rate by decreasing the sinus node's automaticity. It has been suggested that ivabradine decreases heart rate without further increasing the deleterious effects of congestive failure (CHF) in patients who already have CHF and an altered left ventricular function or have contraindications to beta-blockers. Ivabradine is beneficial in treating patients with left ventricular dysfunction and decompensated heart failure when comparing it to beta-blockers .Atrial fibrillation, so far, has been the most common arrhythmia in peripartum cardiomyopathy patients. Some antiarrhythmic therapies have been used to salvage arrhythmias in PPCM patients, and amongst this list, quinidine and procainamide are reasonably safe to use in the puerperium, and for this reason, they have been used as the first-line medication for PPCM patients. Digoxin, a cardiac glycoside, can also be used as first-line therapy, as it has a positive inotropic effect and a negative chronotropic effect. In some refractory cases of atrial fibrillation, a permanent pacemaker and an implantable cardioverter-defibrillator will be required. As we discuss possible treatments, we should also remember that heart failure and PPCM predispose patients to thromboembolism. Anticoagulants like low molecular weight heparin should be added during pregnancy, and when the left ventricular ejection fraction is less than 0.30 in the postpartum period, warfarin can be initiated .Bromocriptine, an agonist of the dopamine receptor with prolactin-blocking properties, was also found to be effective in PPCM patients. According to a study by Hakata et al., bromocriptine was reportedly useful in treating cardiomyopathy. It was speculated that prolactin over-secretion increased the amount of a 16-kDa antiangiogenic prolactin fragment, which, as mentioned above, has played a vital role as a pathological mediator of PPCM by adversely affecting myocardial micro-vascularization ,27. As aOutcomes of the DiseasePatients with peripartum cardiomyopathy have a strong tendency to recover. At the time of diagnosis, the left ventricular ejection (LVEF) fraction correlates with improved survival rates and higher rates of complete recovery . DecidinLong-term results vary amongst patients. With routine medical care, up to 50% of patients with PPCM show improvements; however, 25% of patients end up developing chronic heart failure while the remaining dies during the disease course. If the ejection fraction remains low, pregnancy should be avoided because survival rates appear to be low in such circumstances. Patients who desire to get pregnant in the future should wait for at least five years after the initial ejection fraction has normalized .Limitations While we were compiling pieces of information for this review, some limitations were encountered. PPCM is a rare condition and we were unable to find literature that explained its etiology accurately. A way to reduce this limitation would be the establishment of further research studies to identify the cause(s) of PPCM. Another limitation encountered was that of finding literature that had specific diagnostic tests for PPCM. PPCM is ideally a diagnosis of exclusion and the subsequent limitation can be reduced by further researching specific diagnostic parameters. PPCM is an important condition that affects both mother and child and investigating these limitations will lead to improved fetal and maternal outcomes.Peripartum cardiomyopathy is an uncommon yet highly fatal condition with unexplained etiology. The diagnosis of peripartum cardiomyopathy requires early recognition of signs and symptoms, including the early initiation of medical therapy to prevent further complications and preserve life. Peripartum cardiomyopathy treatment can mainly strive to manage heart failure signs by therapeutic approaches used in treating heart failure. In some cases, specific targeted therapies like bromocriptine can be considered; however, further clinical evaluation is needed before they can be implemented fully. The outcome and prognosis are best if PPCM is diagnosed and managed early. It is also crucial that clinicians are adequately acquainted with PPCM, and in doing so, they should always have it in mind as a potential diagnosis when treating dyspneic patients within the PPCM timeframe, as this can be a lethal condition. Further research is required to understand the complexity of PPCM in the near future.


The CML involvement in myocardial ischemia has been reported. We studied the immunohistochemical localization of CML in the hearts from forensic autopsies in relation to the age, serum N-terminal-pro basic natriuretic peptide (NT-proBNP), heart weights, and the degree of peri-myocardial fibrous tissues reflecting coronary microvascular infarction and myocardial remodeling.Advanced glycation end products (AGEs) are known to play important roles in the development of diabetes mellitus and atherosclerosis.　NThe CML immunoreactivity in the endothelial cells and intima of arterial walls in the interstitium of ventricular muscles was significantly stronger in the aged group, compatible with the progression of atherosclerosis. The blood level of NT-proBNP, a known useful marker for heart failure, had the positive correlation with the CML immunoreactivity. The degree of fibrosis, heart weights and the histories of hypertension and hyperlipidemia showed positive correlations with the CML immunoreactivity. Our results show the novel positive correlation between the CML immunohistochemistry in the heart vessels and heart conditions, and its future usefulness in the cardiovascular evaluation in histopathology. It is shown that the major AGE, Npatients . CML is patients . The totpatients . CML waspatients . Previoupatients , 5.Myocardial ischemia is caused by a significant coronary stenosis or by coronary microvascular dysfunction. The former involves the whole myocardial ischemia, whereas the latter causes myocardial ischemia localized in small, patchy diffuse areas of myocardium . The difIn this study, we hypothesized that CML accumulation in the cardiovascular system plays an important role in the development of cardiac ischemia, cardiac failure and fibrosis. Therefore, we evaluated the immunohistochemical presence of CML in hearts of forensic autopsy cases, in relation to the proportions of the interstitial fibrous tissues in the myocardium resulting from microvascular ischemia and myocardial remodeling. Other factors such as heart weights, the age, the clinical presence of hypertension, hyperlipidemia, diabetes mellitus were also studied for the CML immunoreactivity. Since N-terminal-pro basic natriuretic peptide (NT-proBNP) is known to be correlated with heart failure  and myocThe sample collections and analyses were performed as our routine autopsies, approved by Teikyo University Review Board (Approve number 17-069-2) pursuant to the guidelines by the Ministry of Welfare and Labor of the Japanese Government.Totally, 113 consecutive cases without postmortem degradation  were studied. The causes of deaths (COD) were: 12 heart diseases, 17 other diseases, 28 traumata, 7 asphyxiations, 18 drowning, 4 burning, 10 carbon monoxide intoxications, 5 drug intoxications, one heat shock, one other external cause, and 10 unknown causes. The 12 heart diseases consisted of ischemic heart disease, congestive cardiomyopathy, arrhythmia, and cardiomegaly.The hearts were fixed in 16% formalin for 1 week, and horizontal sections of the ventricles were embedded in paraffin, and sectioned in 3 μm thickness. Images from sections stained with Masson Trichrome were captured using Olympus microscope attached to DP73 camera, and processed by cellSense Dimension software . The percentage of the area of the blue-stained interstitial fibrous tissue in the middle of the myocardium of the left anterior ventricle  was calculated. The massive fibrous tissues from the old myocardial infarction due to the proximal coronary artery occlusion were excluded, since the study focused on the microvascular ischemia and myocardial remodeling. The measurement was carried out by one person who had no knowledge of the case data.Frozen sections (6 μm) from the left ventricular muscles from anterior, lateral, posterior, and septal areas were made, and stained with the anti-CML antibody  by the BOND RX automated immunostainer  using BOND polymer refine detection system .The immunohistochemistry of CML in the endothelial cells and intima of the small arteries in the interstitium of the ventricular muscle tissue were classified into three grades: 2 (strong immunostaining), 1 (weak to middle immunostaining), and 0 (negative immunostaining). The representative figures for the CML grades are shown in Fig. In order to demonstrate the relevance of the CML, its receptor of AGE (RAGE) was immunohistochemically stained on the sequential frozen sections with the antibody against RAGE , and with the anti-CML antibody, using the BOND RX automated immunostainer as above.Serum hemoglobin A1c (HbA1c) and NT-proBNP levels were measured consecutively where serum samples were available in cases within postmortem intervals of 3 days , in which 5 heart disease cases were included. Serum HbA1c was measured by Latex agglutination method using Rapidia Auto kit , and serum NT-proBNP was measured by ECLIA (electro chemiluminescence immunoassay) using Eclusis NT-proBNP II .p value less than 0.05 was considered statistically significant. For NT-proBNP and the percentage of cardiac fibrosis, the ROUT (Q = 0.1%) test in Prism software was used to exclude only definite outliers.The data were expressed as mean ± SEM, and analyzed using ANOVA and Holm-Sidak’s multiple comparisons test in Prism v7.0 software . For the correlation between the history of diseases and the CML immunohistochemistry, Chi square test was used using Prism software. The The CML was immunohistochemically positive in the endothelial cells and intima of the small coronary arteries in the interstitium of ventricular muscles Fig. . AnterioThe relevance of CML is supported by the immunohistochemical colocalization of RAGE in the endothelial cells and intima of the interstitial arteries Fig. d, e.We studied the correlation between the age and the immunohistochemical CML-positivity in the small arteries in the interstitium of the ventricular muscles. The means of ages of the CML-positive cases were statistically significantly higher than of the CML-negative cases  had a statistically significantly higher NT-proBNP values in autopsy blood samples than grade 0 and 1  as COD showed the positive CML immunoreactivity, no statistically significant correlation was detected between the heart disease as COD and the CML immunoreactivity (Chi square test, Fig. The history of hyperlipidemia showed the statistically significant correlation with the CML immunoreactivity (Chi square test, Fig. Our results clearly indicate that the CML is immunohistochemically positive in the endothelial cells and intima of the small coronary arteries in the interstitium of ventricular muscles Fig. . BaidoshThere was the statistically significant difference in the degree of fibrosis in the cardiac tissue between CML 0 and 1, and CML 1 and 2 (Fig. Our results failed to show the statistically significant difference in the degree of the CML immunoreactivity in the coronary microvasculature between cases with heart diseases as COD and other cases Fig. . This maThe histories of hyperlipidemia and hypertension show the statistically significant correlation with the positive CML immunoreactivity, whereas diabetes mellitus did not Fig. . This inOur results show the CML immunoreactivity in the endothelial cells and the intima of the small arteries in the interstitium of the human heart muscles. The CML immunoreactivity increased in intensity with the age. The CML immunoreactivity also shows the positive correlation with the presence of high serum NT-proBNP, which is a novel indication of the CML involvement in heart failure.　Interstitial fibrosis in the cardiac tissue showed the significant increase in the group with the high CML immunoreactivity. Heart weights, the histories of hypertension, and hyperlipidemia also show the positive correlation with the CML immunoreactivity.　Our results warrant the further study for the role of CML deposition in the cardiac microvasculature for the evaluation of ischemic heart disease.Correlations between CML immunoreactivity and various factors do not directly prove that CML is the cause for the disease states.


The primary aim was to examine the association between rSO2 values (both baseline rSO2 and intraoperative decrease in rSO2) with the composite of morbidity endpoints. We retrospectively analyzed 356 cardiac surgical patients having continuously recorded data of intraoperative rSO2 values. Per institutional guidelines, patients received interventions to restore the rSO2 value to ≥80% of the baseline value. Analyzed rSO2 variables included baseline value, and area under the threshold below an absolute value of 50% (AUT50). Their association with outcome was analyzed with multivariable logistic regression. AUT50  was shown to be an independent risk factor  of adverse outcomes. In cardiac surgical patients who received interventions to correct decreases in rSO2, increased severity of intraoperative decrease in rSO2 as reflected by AUT below an absolute value of 50% was associated with a composite of adverse outcomes, implicating the importance of cerebral oximetry to monitor the brain as an index organ.While both baseline regional cerebral oxygen saturation (rSO If the average value of the last two consecutive values [(rSO2TN + rSO2TN-1)/2] was below zero, the average was excluded from the SUM. Therefore, AUT should reflect the severity of decrease in rSO2 as it has both the magnitude and time components. Minimal and maximal rSO2 values and maximal degree of desaturation were also determined.The rSO2 values (both baseline rSO2 and intraoperative decrease in rSO2) with a composite of morbidity endpoints. The composite of morbidity endpoints included in-hospital mortality combined with postoperative morbidity endpoints as defined by the Society of Thoracic Surgery (STS) database registry , cerebrovascular disease, chronic obstructive lung disease), medications, European System for Cardiac Operative Risk Evaluation (EuroSCORE), left ventricular ejection fraction (LVEF), and Hb and Cr levels.Preoperative data assessment included demographic data, comorbidities , central venous pressure (CVP), mean pulmonary arterial pressure (mPAP), PaO2, PaCO2, and Hb concentrations were recorded at predetermined time points . Postoperative data assessment included fluid balance, transfusion requirement, chest tube drainage for 24 h, as well as the use of norepinephrine, vasopressin, milrinone, and dobutamine.Intraoperative data assessment included the duration of cardiopulmonary bypass (CPB) and aortic cross clamp, fluid balance, packed erythrocytes (pRBCs) transfusion, urine output, and the use of norepinephrine, vasopressin, milrinone, and dobutamine. Hemodynamic and blood gas variables including mean arterial pressure (MAP), cardiac index (CI), mixed venous oxygen saturation , rSO2, pulmonary artery catheter, and transesophageal echocardiography. Anesthesia was provided using sufentanil and sevoflurane and BIS was maintained at 40–60. MAP was maintained at 60–80 mmHg using norepinephrine first, and if the target MAP could not be maintained with escalating doses of norepinephrine (maximum of 0.3 μg/kg/min), vasopressin was added (2.4–4 unit/h). Milrinone was used in cases of LVEF <30%, right ventricular dysfunction, or pulmonary hypertension. During CPB, non-pulsatile perfusion was utilized at 2.0–2.5 L/min/m2 using a tepid temperature (32–34 °C) and alpha-stat management. pRBCs were transfused when Hb was <7.0 g/dL during CPB or <8.0 g/dL otherwise.All patients were managed according to standardized institutional anesthetic and CPB practice guidelines. Briefly, standard monitoring included bispectral index , which were as follows: checking neck and cannulae position, increasing end-tidal CO2 to approx. 40 mmHg (in the absence of pulmonary hypertension), increasing the dose of norepinephrine or addition of vasopressin to increase the MAP above 65 mmHg up to 80 mmHg, if necessary. In addition, milrinone and/or dobutamine to maintain a SvO2 of ≥60% and CI > 2.0 L/min/m2 (increase of flow rate to 2.5 L/min/m2 during CPB) was administered, while efforts to optimize preload was done using mini-fluid boluses in 100 mL aliquots. Lastly, when all interventions failed to restore the rSO2 value above 80% of the baseline, pRBCs transfusion was considered at Hb of 8–9 g/dL.All patients received interventions according to a modified institutional guideline based on the algorithm of Denault et al.  when sighttp://www.R-project.org). Results were shown as mean (standard deviation [SD]) or number of patients (%). Sample size was not determined a priori.Statistical analyses were performed using SPSS version 17  and SAS  and R package  curve. Then, rSO2 variables with the highest AUROC were introduced to the regression analysis, which were baseline and AUT 50. An ROC curve was constructed for the identified rSO2 variables with prognostic importance.For analysis of the primary endpoint, to confirm independent risk factors of the composite of morbidity endpoints, multivariable logistic regression analysis was performed. First, well known risk factors were chosen a priori to minimize the introduction selection bias, which included age, CKD, congestive heart failure, and CPB duration in order to abide the rule of ten ,14,15. I2 values  and rSO2. The Pearson’s correlation coefficient (r) was demonstrated. In addition, intergroup analysis of the hemodynamic and arterial-blood gas analysis variables was performed between patients who exhibited AUT50 greater than 113.2 min·% or not. A p < 0.05 was deemed as statistically significant.For analysis of the secondary outcome, Pearson’s correlation analysis was used to verify the correlation between the factors influencing rSOThe composite of morbidity endpoints occurred in 47 of the 356 (13.2%) patients that were analyzed. In those patients, permanent stroke occurred in 5 patients (1.4%), reoperation in 7 patients (1.9%), renal failure in 8 patients (2.2%), mechanical ventilation >24 h in 29 patients (8.1%), deep sternal wound infection in 4 patients (1.1%), and mortality in 1 patient (0.3%).Patients who exhibited a composite of morbidity endpoints had a higher incidence of preoperative CKD, higher incidence of heart failure, higher EuroSCORE, lower LVEF, lower Hb and albumin levels, higher Cr levels, longer CPB time, higher incidences of intraoperative pRBCs transfusion, and milrinone and vasopressin requirements compared to those without morbidities .2 values are shown in 2 values including the baseline, AUT < 80% of baseline rSO2, and AUT < absolute value of 50% were significantly lower in the group with morbidity compared with the non-morbidity group, except for the percentage of maximal decrease from baseline rSO2 recovery to more than 80% of the baseline value at the end of the surgery (which occurred in 67% of patients). Subgroup analysis between patients whose rSO2 value was recovered to more than 80% of the baseline value at the end of the surgery and those who did not revealed no significant differences in the composite of postoperative morbidity endpoints (data not shown).Representative rSO2 below an absolute value of 50%, and duration of CPB were identified as independent risk factors, whereas baseline rSO2 and AUT below 80% of the baseline rSO2 were not (p < 0.001) with 80.9% sensitivity and 40.8% specificity.In the multivariable logistic regression analysis for finding risk factors of the composite of morbidity endpoints, age, preoperative CKD, AUT of rSOwere not . The cutp < 0.001), Hb , CI , and CVP  were statistically significantly, but weakly correlated with changes in rSO2. In further analyses to find variables related to decrease in rSO2, there were no significant differences in MAP, CI, PaO2, CVP, and body temperature between patients who exhibited AUT of greater than 113.2 min·% below an absolute value of 50% (high AUT 50) or not (low AUT 50), while Hb levels were significantly lower and PaCO2 levels were significantly higher in the high AUT50 group throughout surgery (p < 0.001) and had higher vasopressin requirements  than patients in the low AUT 50 group.In Pearson correlation analysis, changes in MAP , AUT of 80% of the baseline, and AUT below an absolute value of 50%, were all significantly different between the morbid and non-morbid groups, indicating the prognostic importance of cerebral oximetry monitoring. However, the prognostic value of low baseline rSO2 was not present after adjusting for potential confounders of adverse outcome. In contrast, the severity of intraoperative decrease in rSO2 below an absolute value of 50%, expressed as AUT 50, was revealed to be an independent risk factor of adverse outcome together with advanced age, preoperative CKD, and prolonged CPB time. The assessed major STS morbidity endpoints are well validated surrogate measures of overall outcome [As our findings show, various assessed rSO outcome . In the  outcome . In addi2 values for a hard, clinical endpoint, mortality, when compared to those of intraoperative decrease in rSO2. This evidence includes a prospective, observational study involving more than 1100 cardiac surgical patients, showing a close correlation between baseline rSO2 value and mortality, which was even more predictive than the EuroSCORE in high-risk patients [2 value was a simple and useful predictor of mortality [2 values were actively treated without any specific information regarding the cut-off value upon which treatment was initiated [2 value below a specific point (20% reduction from baseline) in the current study. Also, it may be related to the low mean baseline rSO2 values of the current study (58% versus >62%) when compared to other studies or to the suggested normal range of approximately 70% [In previous studies, evidence was more solid in terms of the prognostic importance of low baseline rSOpatients . Anotherortality . It is dortality , while tnitiated . Yet, thtely 70% ,20,21. T2 below an absolute value of 50% was a meaningful predictor of outcome, whereas desaturation to 80% of the baseline value was not. The currently used cerebral oximetry device  uses 2 wavelengths to detect rSO2 and accordingly, the U.S. Food and Drug Administration recommends its use only as a trend monitor. Thus, a decrease to 80% of the baseline rSO2 value was a commonly adopted threshold for interventions in many previous studies [2 values in whom a 20% decrease from baseline would be even lower.Likewise, the low baseline values may have affected the results that showed only an intraoperative decrease in rSO studies ,22. Yet, studies . As our 2 and that are commonly targeted for cerebral oximetry-based interventions such as MAP, CI, CVP, and Hb, all showed significant correlation, reaffirming the importance of the brain as an index organ for overall hemodynamic status. In addition, patients in the high AUT 50 group received more pRBCs transfusion and vasopressin, and had higher PaCO2 levels and lower Hb levels compared to the low AUT 50 group, indicating that they apparently received more interventions to increase rSO2. Still, only 67% of the patients showed restoration of rSO2 value above 80% of the baseline value and considerable numbers of patients with AUT 50 were present in the morbid group despite corrective interventions. Studies have shown the lower limit of cerebral autoregulation to be higher than 90 mmHg in some cardiac surgical patients [2 would result in improved outcomes considering the inherent technical limitations related to cerebral oximetry and its well-known high sensitivity but low specificity in detecting adverse outcome [Variables that are associated with changes in intraoperative rSOpatients . Additiopatients , while cpatients . Nonethe2 values were guided by our given institutional protocol, we were unable to check the rate of non-adherence to the protocol. Third, composite of morbidity endpoints could only be observed in 47 patients, which have limited comprehensive introduction of variables known to affect outcome and thus, limiting the statistical power of the study.The current study is linked to limitations intrinsic to its retrospective nature and the technical aspects of the cerebral oximetry  including the approximate depth of measurement of 2 cm , while t2 as well as intraoperative rSO2 desaturation on overall outcome in cardiac surgical patients who received interventions to correct intraoperative decrease in rSO2 using a comprehensive rSO2 data set collected at 30-s intervals.Still, the strength of the current study lies in that it provides primary evidence regarding the prognostic value of baseline rSO2 as reflected by AUT below an absolute value of 50% was found to be an independent risk factor of dismal prognosis, implicating an important ancillary role of cerebral oximetry to monitor the brain as an index organ.In conclusion, in cardiac surgical patients who received interventions according to cerebral oximetry monitoring, increased severity of intraoperative decrease in rSO