Duchenne muscular dystrophy (DMD) is a clinically common X-linked recessive myopathy, which is caused by mutation of the gene encoding dystrophin on chromosome Xp21. The onset of heart injury in children with DMD is inconspicuous, and the prognosis is poor once it develops to the stage of heart failure. Cardiovascular complications remain an important cause of death in this patient population. At present, population and animal studies have suggested that Electrocardiogram (ECG) changes may be the initial manifestation of cardiac involvement in children with DMD. Relevant clinical studies have also confirmed that significant abnormal ECG changes already exist in DMD patients before cardiomegaly and/or LVEF decrease. With increases in age and decreases in cardiac function, the proportion of ECG abnormalities in DMD patients increase significantly. Some characteristic ECG changes, such as ST-segment changes, T wave inversion, Q wave at the inferolateral leads, LBBB and SDANN, have a certain correlation with the indexes of cardiac remodeling or impaired cardiac function in DMD patients, while VT and LBBB have demonstrated relatively good predictive value for the occurrence of long-term DCM and/or adverse cardiovascular events or even death in DMD patients. The present review discusses the electrocardiographic features in children with DMD. Duchenne muscular dystrophy (DMD) is a clinically common X-linked recessive myopathy, with an incidence in live male infants of approximately 1/3500–1/5000 –6. Most Early detection of cardiac involvement using diagnostic technologies, quantitative evaluation of the degree of cardiomyopathy, and initiation of therapy in the early stage(s) of the disease may delay the progression of cardiac involvement and improve the overall prognosis of children with DMD . CurrentFirstly, some ECG features are clues of specific DCM subtypes, as certain disease-causing genes are associated with characteristic ECG abnormalities that may have diagnostic value for the patients. For instance, the detection of paroxysmal supraventricular arrhythmias in young patients with DCM should prompt investigation for familial lamin A/C (LMNA) cardiomyopathy . T-wave In summary, a systematic analysis of the ECG could provide diagnostic red flags useful to orient the following phases of the diagnostic work-up, prognostic stratification criteria and information that can direct appropriate decision making in patients with cardiomyopathy. In the past decades, increasing numbers of studies have explored the characteristics of ECG in patients with DMD. Accumulating evidences have demonstrated that ECG can be used to diagnose arrhythmia and preliminarily assess the scope of myocardial damage in children with suspected DMD, thereby providing important clues for clinicians to confirm the disease and judge prognosis. More importantly, population and animal studies have suggested that ECG changes may be the initial manifestation of cardiac involvement in children with DMD. Before myocardial fibrosis appears in the heart, ECG can reveal abnormal signs. ECG may be more sensitive than echocardiography—and even CMR imaging—in detecting early manifestations of DMD-related myocardial involvement , 36. TheCross-sectional, prospective, or retrospective studies with ≥ 10 patients, published as full articles in PubMed and CNKI were included. Studies published in the form of abstracts, or with < 10 subjects were excluded.These articles were divided into three groups for retrieval: 1) study the electrocardiogram changes in DMD patients, including General electrocardiogram, dynamic electrocardiogram and vectorcardiogram; (2) study the factors influencing ECG abnormalities in DMD,such as age,genotype and cardiac function; (3) investigate the associations between ECG abnormalities and cardiac function/prognosis in DMD. Then full-text analysis of findings within eligible articles. The scope of retrieval was expanded through targeted references, and 28 articles were included after Eligibility examination. All abstracts were reviewed by Liting Tang and checked by Chuan Wang. Disagreement was resolved between the two reviewers. Full texts of eligible articles were retrieved for review. The research selection process of search criteria is shown in Fig.  study thDystrophin is a cytoskeletal protein distributed on the plasma membrane of skeletal muscle cells and cardiomyocytes. It plays the role of cell scaffold, maintains the integrity of muscle fibers, and protects against contraction-induced damage . Loss orIn 1982, Sanyal et al.  systematAnimal experiments have confirmed that abnormal ECG changes in animals with muscular dystrophy occur earlier than myocardial fibrosis   and myocardial ischemia, which are not easy to detect using conventional surface ECG examinations. Presently, a few studies have investigated DCG in patients with DMD. In 2010, Shah et al.  retrospeDCG can also be used to analyze heart rate variability (HRV), which can reflect the activity of the autonomic nervous system and quantitatively evaluate the tension and balance of cardiac sympathetic nerves and vagus nerves, and be used as a valuable predictor of adverse cardiovascular events. Presently, commonly used methods for HRV analysis include time-domain and frequency-domain analyses . Time-doThe etiology of HRV alterations in DMD patients remains speculative and several explanations were hypothesized. Firstly, previous studies have shown alteration of nitric oxide and vascular endothelial growth factor secretion in the myocardium of dystrophin deficit mice. Nitric oxide has been shown to play important vagal tone by direct and agonistic effect in preganglionic and postganglionic neurons. Therefore, nitric oxide alteration might play a role in the changes of HRV in patients with DMD , 55–57. In summary, DCG can detect ECG changes in children with DMD more comprehensively, including various types of atrial arrhythmia and ventricular arrhythmia, although the overall incidence rate varies significantly across studies. Cardiomegaly or impaired cardiac function, especially LVEF < 35%, is a predictor of abnormal performance in DCG. In addition, children with clinical symptoms are more likely to exhibit abnormal changes in DCG. Therefore, for those with clinical symptoms and/or cardiomegaly and/or decreased LVEF, DCG monitoring should be strengthened to identify abnormalities early and improve the prognosis of children with DMD. Moreover, children with DMD experience cardiac autonomic dysfunction and increased sympathetic nerve activity; as such, whether HRV-related indexes can predict the long-term adverse prognosis of children with DMD remains to be further explored.P = 0.024). ECG manifestations reflecting left ventricular electrophysiological changes, including left ventricular hypertrophy/left ventricular high voltage, deepened S wave at lead V1, and abnormal Q wave, accounted for 66.13% (41/62) of total ECG abnormalities, among which the proportion in each age group, in sequence, was 7.89%, 10.53%, 19.77%, and 31.25%, demonstrating an increasing trend with age. In addition, conduction blocks, such as CRBBB, CLBBB, cAVB, SVT, and VT, were also more common in older children, especially in children with DMD and impaired cardiac function.These findings are summarized in Table Almost all studies have confirmed that older age is an important risk factor for increased ECG abnormalities in children with DMD. In 2008, Takami et al.  retrospeThe onset of heart injury in children with DMD is inconspicuous and the prognosis is not favorable once it progresses to heart failure. Understanding relationship between the ECG characteristics and genotype in children with DMD may be useful in detecting early cardiomyopathy in children with DMD and predicting prognosis in clinical practice. Several studies have investigated the correlation between genotype and ECG abnormalities in children with DMD. In 2008, Takami et al.  retrospeP < 0.001). In their study, 45 children underwent 64 DCG examinations, 25 had DCM, and 20 had no DCM. The incidence of tachycardia in the DCM group was significantly higher than that in the non-DCM group, and only 1 child without DCM had tachycardia . In addition, a study from the United States [Impaired cardiac function is a risk factor for various types of arrhythmia among cardiomyopathies caused by various factors and DCM caused by DMD is no exception. In 2010, Shah et al.  retrosped States  includedAs explained in the above underlying mechanisms of ECG abnormalities in DMD, the absence of dystrophin in the membranes of Purkinje fiber cells may be the pathophysiological basis of early-stage ECG abnormalities in children with DMD. Moreover, abnormal electrical activity may have appeared before cardiomyocyte necrosis and fibrosis, suggesting that ECG changes may be more sensitive to early cardiac involvement in children with DMD, which has been confirmed in many clinical studies. In 2010, a study from the United States  reportedP = 0.016) and the fastest heart rate in DCG (P = 0.008) demonstrated strong correlations with the index reflecting myocardial fibrosis on CMR imaging (late gadolinium enhancement).In 2010, Shah et al.  retrospeIn 2010, Shah et al.  retrospeAlthough some progress has been achieved in understanding the pathogenesis, diagnosis, and treatment of cardiac involvement in DMD patients in recent years, cardiovascular complications remain the main cause of death in this patient population. The onset of heart injury in children with DMD is inconspicuous, and the prognosis is poor once it develops to the stage of heart failure. Research has revealed that before inflammation, necrosis, and fibrosis of cardiomyocytes in DMD patients, Purkinje fiber cells undergo changes due to dystrophin deletion, which provides important pathophysiological evidence that ECG may more sensitively reflect and/or detect early manifestations of myocardial involvement in DMD patients compared with echocardiography and even CMR imaging. Relevant clinical studies have also confirmed this inference . Due to varying sample sizes, inclusion criteria, and population backgrounds across studies, the types and incidences of ECG abnormalities in children with DMD were quite different. However, several consistent findings were observed. Pathological Q waves at leads I, II, III, avL, avF, and V4-V6, increased R wave amplitude with increased R/S ratio at lead V1, RVH, left ventricular high-voltage, and ST-segment and T wave changes were common abnormal ECG changes in children with DMD. Sinus tachycardia and short PR interval were common and characteristic ECG abnormalities in children with DMD. Conduction block, including CRBBB, CLBBB, and cAVB, was not common in children with DMD, and most occurred in older children with DMD. QT interval prolongation was rare. SVT and VT may occur; however, most occur in older children and/or DMD patients with clinical symptoms of cardiac insufficiency and/or impaired cardiac function. Patients with DMD may exhibit HRV changes in the early stage(s) of the disease, with dysfunction of cardiac autonomic regulation, decreased vagal tone activity, and increased sympathetic tone activity. With increases in age and decreases in cardiac function, the proportion of ECG abnormalities in DMD patients increase significantly. However, the correlation between dystrophin gene mutation and ECG abnormalities has not been determined and warrants further investigation. Some characteristic ECG changes, such as ST-segment changes, T wave inversion, Q wave at the inferolateral leads, LBBB and SDANN, have a certain correlation with the indexes of cardiac remodeling or impaired cardiac function in DMD patients, while VT and LBBB have demonstrated relatively good predictive value for the occurrence of long-term DCM and/or adverse cardiovascular events or even death in DMD patients.However, most current investigations are limited to retrospective descriptive studies with small sample sizes, and there is little research investigating DCG; as such, there is a lack of data regarding electrocardiovector changes in DMD patients. Therefore, further larger prospective longitudinal studies in broader age range warrant to be carried out to uncover the characteristics of general ECG, dynamic ECG and vectorcardiogram, to verify the role of ECG in detecting early cardiac injury and in predicting the worse outcomes in patients with DMD.


Patients with pulmonary hypertension (PH) are at an increased risk of perioperative morbidity and mortality when undergoing non-cardiac surgery. We present a case of a 57-year-old patient with severe PH, who developed cardiac arrest as the result of right heart failure, undergoing a revision total hip arthroplasty under combined spinal epidural anesthesia. Emergent veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) was undertaken as rescue therapy during the pulmonary hypertensive crisis and a temporizing measure to provide circulatory support in an intensive care unit (ICU). We present a narrative review on perioperative management for patients with PH undergoing non-cardiac surgery. The review goes through the updated hemodynamic definition, clinical classification of PH, perioperative morbidity, and mortality associated with PH in non-cardiac surgery. Pre-operative assessment evaluates the type of surgery, the severity of PH, and comorbidities. General anesthesia (GA) is discussed in detail for patients with PH regarding the benefits of and unsubstantiated arguments against GA in non-cardiac surgery. The literature on risks and benefits of regional anesthesia (RA) in terms of neuraxial, deep plexus, and peripheral nerve block with or without sedation in patients with PH undergoing non-cardiac surgery is reviewed. The choice of anesthesia technique depends on the type of surgery, right ventricle (RV) function, pulmonary artery (PA) pressure, and comorbidities. Given the differences in pathophysiology and mechanical circulatory support (MCS) between the RV and left ventricle (LV), the indications, goals, and contraindications of VA-ECMO as a rescue in cardiopulmonary arrest and pulmonary hypertensive crisis in patients with PH are discussed. Given the significant morbidity and mortality associated with PH, multidisciplinary teams including anesthesiologists, surgeons, cardiologists, pulmonologists, and psychological and social worker support should provide perioperative management. There is an increased risk of perioperative morbidity and mortality for patients with pulmonary hypertension (PH) undergoing non-cardiac surgery -3. RightStaphylococcus aureus (MRSA) infection. She was scheduled for left hip irrigation and debridement, removal of antibiotic cement spacer, and either stage II revision arthroplasty or placement of a repeat antibiotic spacer based on intraoperative findings and frozen sections. Her past medical history was only significant for scleroderma and PH (New York Heart Association (NYHA)/World Health Organization (WHO) Class 1). Her PH was managed by treprostinil 80 ng/kg/min subcutaneously (SC), riociguat 2.5 mg every eight hours, and torsemide 20mg every 12 hours. Preoperative transthoracic echocardiogram (TTE) showed an increased estimated pulmonary arterial systolic pressure (PASP) of 80-90 mmHg, with dilatation of right ventricle (RV) with moderately reduced systolic function of the RV  4, body mass index 19) who underwent multiple surgeries on her left hip presented with chronic methicillin-resistant V Figure . The lefShe was brought to the operating room (OR) and standard ASA monitors were placed. Oxygen was delivered via a non-rebreather facemask at 10 L/min. A pre-procedural right radial arterial line and two 18-G peripheral venous lines were placed. Baseline blood pressure (BP) was 140-150/80-90 mmHg, heart rate (HR) 80-90 beats per minute (bpm), and oxygen saturation (SpO2) 100%. Vasopressin infusion was started preemptively at 0.04 units/min.Combined spinal-epidural anesthesia was planned for surgical anesthesia. Prior to CSE placement, 250 ml of crystalloid solution and midazolam 1 mg were given. CSE was placed at the L4-L5 interspace. Bupivacaine 0.75% 1 mL was administered intrathecally, followed by incremental 2% lidocaine  via the epidural catheter to optimize an adequate anesthesia level with minimal hemodynamically changes. Two boluses of ketamine 25 mg were given intravenously (IV) and followed by dexmedetomidine 20 mcg IV when the patient was in a supine position. She was hemodynamically stable and saturated well on spontaneous ventilation . Immediately after right lateral decubitus positioning, the patient became rapidly hypotensive 60/30 mmHg and tachycardic with HR 120 bpm, then became unresponsive. She was immediately placed back in the supine position. Incremental doses of epinephrine 10 µg were immediately given to the patient through IV with minimal response in BP and HR.Advanced cardiovascular life support (ACLS) protocol was initiated. The patient was intubated with a 7.5 endotracheal tube and placed on positive pressure ventilation with 100% O2. Nitric oxide (NO) was started at 40 parts per million (ppm). ACLS was continued and three boluses of epinephrine 1 mg through IV were given with intermittent return of spontaneous circulation (ROSC). Emergent VA-ECMO was placed via left femoral artery and right femoral vein access. A transesophageal echo (TEE) probe was placed immediately and revealed severe RV dilatation, severe RV dysfunction, and no clots in the main pulmonary artery  and vasopressin (0.03 units/min) were continued. On hospital day three, the patient was brought back to the OR, intraoperative TEE revealed slight improvement in RV function. She received left hip irrigation and debridement, antibiotic cement spacer removal, and stage II revision arthroplasty under general anesthesia (GA) with no complications. She was transferred back to CTICU for post-operative care. Serial bedside TTE examinations revealed improvement in RV function. On hospital day five, vasopressin was weaned off and ECMO was successfully removed. Epinephrine 0.02 µg/kg/min was continued for inotropic support of right heart function. On hospital day six, epinephrine was weaned off. She was hemodynamically stable and discharged from the CTICU.Updated hemodynamic definitions and clinical classification of PHPH was defined as a mean pulmonary artery pressure (mPAP) >25 mmHg at rest since the first World Symposium on Pulmonary Hypertension (WSPH) in 1973 , the incPerioperative outcome and risk factors in patients with PHPatients with PH are at increased risk for perioperative morbidity and mortality when undergoing cardiac -18 and nA previous study by Ramakrishna et al. had identified independent predictors of short-term morbidity including a history of pulmonary embolism (PE), NYHA functional class ≥II, intermediate- to high-risk surgery, and duration of anesthesia ≥3 h . Right-aPre-operative assessmentGiven the significant morbidity and mortality associated with PH, perioperative management should be provided by a multidisciplinary team including anesthesiologists, surgeons, cardiologists, and pulmonologists, and psychological and social worker support . The preHigh-risk surgery is associated with increased mortality and morbidity in PH patients, especially in emergency surgery, major organ procedures, rapid blood loss, and long operation time . CurrentGiven that decreased diffusing capacity of the lung for carbon monoxide (DLCO) in patients with PH is associated with higher mortality ,31, pulmA modified NYHA/WHO functional classification system remains one of the most powerful predictors of survival and follow-up ,35. EithA basic laboratory workup should include complete blood counts and a comprehensive metabolic panel. Prothrombin time and international normalized ratio should be performed while the patient is on oral anticoagulants ,40,41. NChoice of anesthesia for non-cardiac surgeryGA and regional anesthesia (RA) have been used in patients with PH undergoing non-cardiac surgery. The general principle of anesthesia management is to maintain RV function/CO with adequate preload, contractility, and systemic vascular resistance (SVR) and avoid increases in PVR from hypoxia, hypercarbia, acidosis, agitation, pain, and hypothermia. However, there are no controlled studies or practice guidelines advising the use of GA or RA for PH patients ,45. The Induction of GA is one of the most precarious moments in the care of these patients as a sudden decrease in CO with an increase in PVR and SVR in response to sympathetic activation during tracheal intubation, which may result in a pulmonary hypertensive crisis, RV failure, and subsequent circulatory collapse. Therefore, a balanced technique with increased opioid dosing is often employed .Perioperatively, it was recommended that invasive monitoring includes pre-induction/pre-procedural arterial line in patients with severe PH . In patiGA with endotracheal intubation allows anesthesiologists to maintain a patent airway, maximize oxygenation by mechanical ventilation, precise control of the composition of inhaled oxygen, volatile anesthetics, inhaled pulmonary vasodilating agents, and perform TEE intraoperatively. Low-tidal-volume positive pressure ventilation (PPV) (5-7 ml/kg) with minimal positive end-expiratory pressure (PEEP) has been recommended to avoid overinflation of alveoli. Goals for mechanical ventilation and tracheal intubation are again targeted at maintaining an adequate level of sedation and sympathetic activation as well as preventing hypercapnia, respiratory acidosis, hypoxia, and increased PVR ,48. HoweVasodilator therapy has been used intraoperatively to reduce the PA pressure and decrease pulmonary shunt . InhaledNeuraxial anesthesia, deep plexus, or peripheral nerve blockade with or without sedation have been provided as surgical anesthesia for patients with PH in non-cardiac surgery. Maintenance of the native airway during RA with adequate oxygenation with a face mask or non-rebreather mask will avoid GA-induced atelectasis  and mechHowever, when patients are not candidates for neuraxial or deep plexus blockade due to the time and dose of systemic anticoagulation or other medical issues, peripheral nerve block has been approved as a great alternative for orthopedic, vascular, and general surgery. Seyfarth et al. reviewed 16 patients with PH undergoing major orthopedic surgery for perioperative morbidity and mortality from 2011 to 2014; combined moderate GA and femoral nerve block were used for THA, and combined GA and sciatic nerve block were used for TKA . CombinaCombination of sedation and RA has provided advantages when managing high-risk patients undergoing non-cardiac surgery, but still requires constant vigilance and dose titration for sedation to avoid attenuation of respiratory drive and hypoxia-induced pulmonary hypertensive crisis ,77. In tRight ventricular failure and ECMOThe right ventricle is triangularly shaped and is often described as a crescent in cross section. The thin free wall undergoes a longitudinal and sequential contraction. Compared to the LV, it has a lower EF, approximately 40-45%, with approximately 40% of the contractility derived from the septum ,84. TherPulmonary hypertensive crisis, as described in our patient, is the most dreaded intraoperative complication due to rapid hemodynamic deterioration. Goals include early recognition of increase in PVR and RV filling pressures with a decrease in CO, and hypotension prior to impending cardiovascular collapse. Therefore, hypotension should be aggressively treated with vasopressors to maintain right coronary perfusion and RV function. Reduction in PVR may be achieved with inhaled nitric oxide, prostacyclin, iloprost, milrinone, and or sildenafil . InotropIn patients with PH who deteriorate into cardiopulmonary arrest, resuscitation is often difficult and have had limited success ,84,87. TIn our patient, VA-ECMO as part of ECPR was indicated due to cardiogenic shock as the result of RV failure. Other indications involving specific the right ventricle include acute RV failure due to pulmonary embolism, progression of congenital heart disease, acute myocardial infarction, acute myocarditis, and septic cardiomyopathy . It is iAlthough VA-ECMO can provide effective mechanical circulatory support and allows for decompression of the RV, it is not specifically tailored towards isolated right heart failure. Specifically, systemic arterial inflow bypasses normal functioning LV or LVAD, resulting increased afterload . TherefoPatients with moderate to severe PH who are scheduled for non-cardiac surgery require complex and well-thought decision making by anesthesiologists, and perioperative planning among a multidisciplinary team to ensure a good outcome. Although there is no clear-cut data on which modality is better, GA, neuraxial anesthesia with catheter, and peripheral nerve blocks were successfully implemented. The anesthesiologist should approach these cases with an understanding of the PH pathophysiology, and possible intraoperative complications based on the modality he or she chose, such as pulmonary hypertensive crisis, which in this case required VA-ECMO rescue by sudden increases in PVR and PA pressure can be triggered by a variety of intraoperative events, such as changes in patient position, hypercapnia, hypotension, and hypoxia. A strategy of how to address these triggers should be formulated prior to the start. While ECMO availability is variable among different institutions, it is important to note that its application for cardiopulmonary arrest, in this case, secondary to right heart failure, remains a temporizing measure until there is recovery of the myocardium or another long-term plan can be instituted.


However, the response rate of BVP-CRT is variable, leaving one-third of patients not benefiting from the therapy as expected. Considering the non-physiological activation pattern of BVP-CRT, more efforts have been made to optimize resynchronization. The most extensively investigated approach is by stimulating the native conduction system, e.g., His-Purkinje conduction system pacing (CSP), including His bundle pacing (HBP) and left bundle branch area pacing (LBBAP). These emerging CRT approaches provide an alternative to traditional BVP-CRT, with multiple proof-of-concept studies indicating the safety and efficacy of its utilization in dyssynchronous heart failure. In this review, we summarize the mechanisms of dyssynchronous HF mediated by conduction disturbance, the rationale and acute effect of CSP for CRT, the recent advancement in clinical research, and possible future directions of CSP.Heart failure (HF) is a leading health burden around the world. Although pharmacological development has dramatically advanced medication therapy in the field, hemodynamic disorders or mechanical desynchrony deteriorated by intra or interventricular conduction abnormalities remains a critical target beyond the scope of pharmacotherapy. In the past 2 decades, nonpharmacologic treatment for heart failure, such as cardiac resynchronization therapy (CRT)   Heart failure (HF) is a global health burden with increasing morbidity and mortality with a 1-year mortality rate of 10–35%. . Even wivia biventricular pacing (BVP) was introduced in early 2000 and has brought remarkable benefits to HF prognosis, including a reduction of the all-cause mortality by 29%  y by 29%  and heary by 29% . Howevery by 29% . TherefoVentricular dyssynchrony can be recognized through different assessments. Both electrical and mechanical synchrony can be measured directly through ventricular endocardial mapping and catheterization. But these measurements are invasive, risky, operator-dependent, and time-consuming, which limits their use in routine clinical practice. Therefore, non-invasive methods have been the mainstream for synchrony evaluation. The most commonly used non-invasive tool to quantify electrical synchrony is the 12-lead electrocardiogram (ECG.) The QRS duration (QRSd), left ventricular activation time in lead V5 or V6 and the QRS morphology have been adopted for a long time to assess the electrical dyssynchrony prior to or after the CRT. Another simple parameter is the ECG-derived QRS area, which provided a strong association with CRT response . RecentlAdditionally, mechanical dyssynchrony can be measured using Doppler echocardiography, 2-dimensional (D) specking-tracking echocardiography, 3D echocardiography, or the cardiac magnetic resonance (CMR) strain analysis. Several qualitative markers such as septal flash and pre-systole rebound stretch, and quantitative indices like the peaking time, excursion amount, or myocardial wasted work can be calculated . The comvia the working myocardium. It has been reported that in true or complete LBBB, trans-septal conduction time takes 30–40 m and the LV free wall is activated even later, resulting in the marked prolongation of LV activation time (LVAT) and a wide-notched QRS complex  and later contraction of LVFW causes the septal flash and pre-systole septal systolic rebound stretch, leading to supranormal contraction of the latest activated LVFW . SimilarThe non-LBBB conduction disturbances such as RBBB and IVCD, which together account for about one-third of patients with QRS complex widening, represent the severity of the myocardial disease, inducing cardiac asynchrony and deteriorating cardiac function. RBBB, featuring evident delayed activation of RVFW segment , is relaIVCD, which always accompanies LBBB, holds heterogeneous delayed activation in various ventricular myocardial segments . DiffereRV pacing mimics the LBBB-type activation pattern even in patients with narrower intrinsic QRS complex. However, the LV mechanical dyssynchrony pattern in RV pacing is not identical to intrinsic LBBB. Specifically, in patients with RV-pacing-induced LBBB, the mid- and apical septal regions are activated earliest while in patients with intrinsic LBBB, the basal septum is activated earlier. Furthermore, an even higher degree of mechanical delay was reported in the lateral segments among the RV-pacing-induced LBBB pattern compared to the intrinsic LBBB . TherefoThe traditional BVP significantly normalizes the total activation time, inter-ventricular electrical coupling, and mechanical synchrony in patients with LBBB  and hencvia 252-electrode ECGi vest and computer simulations  for correcting LBBB mainly originates from the longitudinal dissociation hypothesis described by Narula in 1977, who revealed that before the separation of bundle branches, individual bundle branches also existed in a single cable within the His bundle . Therefoulations  The studulations .Additionally, HBP contains two subtypes of capture, one is by exclusive stimulation of the intrinsic His bundle, which is called selective HBP (S-HBP); the other is through activation of both the His bundle and the local myocardium, known as the non-selective HBP (NS-HBP)]. Whether one is superior to the other in terms of electrical and mechanical synchrony raises discussion. In a non-invasive epicardial electrical mapping study of 20 patients , it is found that S-HBP and NS-HBP displayed similar LV activation patterns, whereas NS-HBP displays early activation in the basal to the mid-region of RV due to the capture of local para-Hisian myocardium. However, LVAT is preserved and RVAT is not significantly prolonged in NS-HBP compared with S-HBP, implying that a minor difference in electrical depolarization may not pose a great impact on the overall activation of ventricles in either S-HBP or NS-HBP . HemodynLBBAP, compromising the left ventricular septal myocardial pacing (LVSP) and direct capture of the left bundle branch (LBBP), offers another choice of CSP with a relatively lower and stable capture threshold and capacity of bypassing the pathological lesion and capturing the nearby conduction branch to overcome Infra-Hisian “distal” LBBB that cannot be corrected by HBP with a low capture threshold. .Recent preclinical and clinical investigations have delineated the effects of each subtype of LBBAP on electrical and mechanical synchrony and further compared these characteristics with both HBP and BVP. One computer simulation study indicates that LBBP and HBP are superior to BVP-CRT with a greater reduction of LVAT. However, interventricular synchrony of LBBAP is not as ideal as HBP due to a longer RVAT, but this can be mitigated by optimizing AV delay or bilateral bundle area pacing . The samSubsequent clinical studies further confirm the beneficial hemodynamic effect of LBBAP compared with HBP or BVP in both AVB and LBBB patients. Hu and others reported similar improvement of mechanical dispersion in both LBBP and HBP groups after 3-month follow-up while LBBP had better pacing parameters and shorter procedure time . By usedNotably, the electrical and mechanical superiority among LVSP, S-LBBP and NS-LBBP have also been heatedly discussed. In a study comparing ventricular depolarization of LBBAP and HBP using UHF-ECG in bradycardia patients, both the NS-LBBP and LVSP led to longer septal and RV depolarization duration compared with HBP. Compared with NS-LBBP that preserves physiological LV depolarization but increases interventricular electrical dyssynchrony, the LVSP tended to preserve the interventricular synchrony while prolonged the depolarization time of the LV lateral wall . AnotherTaken together, HBP and LBBAP are compelling alternatives for CRT with more physiological electrical and better hemodynamical effects than BVP. Though LBBAP does not capture the right side of the conduction system, it guarantees almost equal physiological LV activation as compared with HBP and can produce a similar narrow QRS complex and mechanical synchrony by optimizing the AV delay. In both types of CSP, recruitment of at least part of the conduction system enables shorter LV activation duration and narrower QRS duration. LVSP seems to induce better interventricular electrical synchrony compared with LBBP, but whether such minor differences in electrical synchrony can translate into clinical differences remains to be evaluated.Early in 2013, Barba-Pichardo pioneered a prospective study for HBP in 16 patients with LBBB and successfully achieved permanent HBP in nine patients, with mean QRSd shortening from 166 ms to 97 ms. After a mean follow-up time of 31.3 months, they reported a significant improvement in clinical and remodeling parameters of LV function . The firFor those with chronic RV pacing or intranodal block, early observational studies also proved HBP as an applicable approach for normalizing QRS complex and T waves. Furthermore, in those with pacing-induced cardiomyopathy (PICM) and decreasing LVEF, HBP was also feasible with a highly successful implantation rate of nearly 90% and induced a significant improvement of LVEF, NYHA class, while alleviating mitral valve regurgitation and brain natriuretic peptide levels . The latin lieu of BVP  and improved clinical and echocardiographic outcomes .Given the drawbacks of a higher pacing capture threshold and a relatively long learning curve in HBP, LBBAP, with a lower capture threshold and higher success rate, sheds light on CSP for CRT. The landmark study of LBBAP for CRT was conducted by Dr. Huang in 2017 in a heart failure (LVEF of 32%) patient with typical LBBB (QRSd 180 ms). After the failure of left ventricular lead placement, HBP also failed to correct the LBBB at an output of 10 V. LBB was captured at 0.5 V at 0.5 ms, after optimization of atrioventricular (AV) delay, QRSd was reduced to 94 ms and the threshold was stable after a 1-year follow-up, with significant improvement of LVEF (32%–62%) and NYHA class (IV to I) . Since tThe latest clinical evidence also suggested LBBAP in the population of HF patients with RBBB. Though the QRSd only showed a modest reduction, LBBAP was still associated with improvement in LVEF and NYHA class, indicating that LBBAP might be a choice of alternative CRT for patients with cardiac dysfunction and RBBB .Similar to HBP, LBBAP was also proved feasible for patients with pacing-induced cardiomyopathy (PICM) and RV pacing upgrading in small sample studies . PermaneThe first multi-center comparison of LBBAP and optimized BVP was reported recently by Chen et al.  to compaIn a non-randomized treatment investigation comparing treatment outcomes of LBBAP, HBP, and BVP among patients with HFrEF and typical LBBB , similarp = 0.0196) and clinical response  than the LVSP group, indicating that capture of LBB might provide a clinical benefit over LVSP  of the cardiac conduction system with consideration of technical efficiency and pacing parameters. CSP introduces better LV electrical synchrony with a narrow QRS complex compared with traditional BVP, with HBP displaying more physiological activation similar to the normal intrinsic activation in the absence of relative RV delay observed in LBBAP. Regarding the implantation process and pacing parameters, LBBAP can be a technically more promising way due to the shorter learning curve, higher successful implantation rate and stable pacing parameters when compared to HBP. But recently reported distal HBP may overcome these drawbacks through deep septal His-bundle capture  Vijayar.Besides, the evaluation of the optimal lead position may be individualized and tailored for a different population. Current clinical evidence from small RCTs and observational studies suggest that LBBAP may bring a higher improvement of LVEF, and a similar survival rate compared with BVP in patients with NICM and LBBB as compared with patients with non-LBBB and/or ICM. However, clinical evidence of the efficacy of CSP compared with BVP among patients with non-LBBB morphology is limited. Therefore, CSP may be best suited for LBBB patients while the BVP might be more appropriate for those with non-LBBB pattern, but more clinical evidence in patients with non-LBBB morphology is required .Previous studies and guidelines suggest that in patients with reduced LVEF and narrow QRS complex, BVP provides limited benefit . CompellThe prerequisite of CSP is to place the pacing lead tip at the appropriate site of the conduction system. However, the coexisting IVCD can delay the activation of the myocardium segments, hampering the full correction of electrical disturbance. Hence, the His and LBB-optimized CRT have been introduced to further narrow the QRS complex by stimulating both the native conduction system and the later activated myocardial areas. Vijayaraman performed the His-optimized CRT (HOT-CRT) in 27 patients with LVEF≤35% and LBBB/IVCD that could not be fully corrected by HBP alone and observed a remarkable reduction in QRSd from baseline 183 m–120 m by HOT-CRT (HBP plus LV pacing) than the BVP (mean QRSd 162 m) or HBP alone (mean QRSd 151 m). They also found that HOT-CRT brought significant clinical and echocardiographic response rates of 84% and 92% respectively . By usinThe feasibility of LBB-optimized CRT (LOT-CRT) was conducted by a multicenter observational study in 112 patients with CRT indication, including 42% LBBB, 22% IVCD, 23% RV pacing, and 12% RBBB. LOT-CRT resulted in acutely improved electrical resynchronization, with the reduction of QRSd three times greater than BVP pacing and superior LVAT compared with LBBAP alone  as well as improvement of LVEF (from 28.5% to 37.2%) and NYHA class (from 2.9 to 1.9) .These findings suggest that in patients with more advanced dysfunction of the conduction system/heart muscle as evidenced by wider baseline QRSd (eg.>180 m) or myocardial scars , despiteAs described above, although LBBAP normalizes LVAT, it also creates significant right ventricular conduction delays compared with normal intrinsic rhythm or HBP. Therefore, effects have been made to diminish the RBBB during LBBP to obtain better interventricular synchrony. Despite the previously discussed optimization of AV delay for fusing intrinsic RV conduction with LBBP, in 2020, a new concept of bilateral bundle branch area pacing (BBBP) was initiated by Lin et al., which involves simultaneous stimulation of both the left branch bundle area and the right branch bundle area. With BBBP, the RBBB pattern brought by LBBP was resolved and delayed right ventricular activation was diminished with significantly shorter QRSd as compared with LBBP. . Such a via two leads with a lower capture threshold (1-2v) in a 78-year-old HF patient with LBBB, and achieved complete right and left ventricular electrical resynchronization with a QRS complex similar to that of HBP at high threshold (8 V)  .Nevertheless, bilateral bundle branch area pacing still needs further investigation. The anatomical characteristics of the RBB, which, unlike the left bundle branch, is a cord-like thin structure with a shorter intramuscular course within the septum and then distributes in sub-endocardium region of the RV . Therefovia the WISE-CRT delivery system in two swine models and eight HF patients with wide QRSd. Preclinical data suggest the possibility of electrode tines in pacing the LV septal close to Purkinje tissue. All patients had the LV septal electrode and WISE-CRT implanted successfully, and temporary LV pacing significantly reduced the QRSd from 187.1 m to 139.8 m. At an early follow-up of 82.5 days, the median LV pacing percentage was 98.5%, and 62.5% of patients had symptom improvement  and the European Society of Cardiology (ESC) had also emphasized its role as a promising approach for CRT. In the 2018 AHA guidelines, HBP is recommended as a Class II indication for patients with AV block and LVEF between 36% and 50%, with an expected RV pacing rate over 40% . In the However, whether CSP can serve as a primary CRT as BVP-CRT in routine clinical practice for patients with CRT indications needs more clinical evidence. Furthermore, for CRT response whether the previously established metrics of BVP can be used with HBP or LBBAP is unknown. The similarity and differences in characteristics of the target population appropriate for BVP and CSP remain to be addressed. Finally, novel approaches for CSP such as leadless LBBAP or bilateral bundle pacing are promising, but the safety, efficacy, and technology-specific advantages remain to be explored.CSP allows for a more physiological approach to CRT by recruitment of the native conduction system and studies in CSP demonstrate cumulative clinical evidence for its safety and efficacy in HF treatment. Although the clinical evidence from small RCT and observational studies is still insufficient to pose the CSP as a superior approach to BVP, the previous encouraging results underpin the prospect of the novel pacing modality as a primary CRT approach. The tailored candidates of CSP in CRT should be further defined by well-designed, prospective, randomized controlled studies with long-term follow-up and hard clinical outcomes including the mortality rate and HF hospitalization.


Two-dimensional (2D) strain analysis is a sensitive method for detecting myocardial dysfunction in acute cellular rejection (ACR) from post-transplant complications. This study aims to evaluate the utility of novel left (LV) and right ventricular (RV) strain parameters for prognostic risk stratification associated with ACR burden at 1-year post transplantation.128 Heart transplant patients, assessed between 2012 and 2018, underwent transthoracic echocardiography and endomyocardial biopsy. 2D strain analysis was performed and history of rejection burden was assessed and grouped according to ACR burden at 1-year post transplantation. The primary endpoint was all-cause mortality at 6-years follow up.21 patients met primary the endpoint. Multivariate analysis of 6-year all-cause mortality showed LV global longitudinal strain (LV GLS) , LV early diastolic strain rate (LV ESr) , RV GLS  and RV ESr  were significant predictors of outcome. Univariate analysis also showed LV GLS, LV ESr, RV GLS and RV ESr were significant predictors of outcome. Optimal cut-off for predicting 6-year mortality for LV GLS by receive operator characteristic was 15.5% . Significant reductions (p < 0.05) in LV GLS, RV GLS and LV and RV ESr between rejection groups were seen.Non-invasive LV and RV strain parameters are predictors of mortality in post-transplant patient with ACR. LV GLS and LV ESr are superior to other strain and conventional echo parameters. Acute cellular rejection ACR is considered one of the main causes of death in the first-year post heart transplant, along with acute graft failure and infection, but is most frequently experienced during the first 3–6 months. Primarily a histopathological diagnosis by endomyocardial biopsy, ACR can be classified according to severity based on standardised gradient from mild grade 1R) to severe (grade 3R). Although such classification allows a dichotomised decision to augment immunosuppression intensity or otherwise, a single timepoint grading fails to capture the longitudinal and cumulative nature of the immune mediated process of ACR. Furthermore, studies have highlighted the prognostic implication of recurrent mild ACR in the pathogenesis of cardiac allograft vasculopathy (CAV)[R to seveTransthoracic echocardiography is the first line non-invasive imaging modality for surveillance of allograft function post-transplant, and commonly includes 2D and Doppler assessment of bi-ventricular size and function to help determine changes associated with post-transplant complications. However, traditional 2D and Doppler parameters such as left ventricular ejection fraction (LV EF) and trans-mitral diastolic Doppler parameters are not advocated in the long-term assessment of allograft function in the setting of ACR or CAV–7.Global Longitudinal Strain (GLS) derived from 2D echocardiographic studies has been shown to be a sensitive tool for detection of subtle changes in longitudinal myocardial function, secondary to fibrosis and oedema in the sub-endocardial tissue layer in many cardiac disease states, 9. 2D sData was drawn from a pool of 322 heart transplant patients referred for transthoracic echocardiography at a tertiary hospital in Queensland, Australia between 2012 and 2018. There were 149 patients referred who had known transplant vasculopathy and were therefore excluded. Of the 173 patients remaining, 1 patient was transplanted at another institution, 18 had incomplete information of previous rejection and 26 patients were excluded because of poor image quality. The final cohort comprised of 128 transplant patients (mean age 49 ± 15 years) who were followed up during the first-year post-transplant with regular endomyocardial biopsies. Patients with LV EF < 50%, moderate or greater mitral regurgitation, moderate or greater aortic stenosis, aortic valve replacement and patients who were pacing dependent were also excluded from the study. Biopsies were performed regularly throughout the first-year post transplantation according to local hospital protocol using a standard surveillance biopsy regimen. Biopsies were performed weekly in weeks 1–6 and then during weeks 8, 12, 18, and 26 with additional biopsies performed during steroid weaning or when ACR was clinically suspected. The biopsy technique included using the internal jugular or femoral vein and specimens were examined by a cardiac pathologist. ACR was diagnosed via biopsy using the 2005 International Society of Heart and Lung Transplantation (ISHLT) grading system[A rejection score (RS) was used to classify patients into one of three groups as previously described , 19.RS group 1 (mild): <50% of biopsies with grade 1R ACR and no rejection higher than 1R.RS group 2 (moderate): One episode of ≥ 2R ACR or > 50% of biopsies with 1R.RS group 3 (severe): More than one episode of ≥ 2R ACR.The number of episodes of ACR allowed for determination of grouping with ACR episodes occurring prior to endpoints occurring. Routine transthoracic echocardiography with 2D strain analysis was performed at 1-year post-transplantation. A statewide electronic medical record was used to review patients included in the study for the primary endpoint of all-cause mortality 6-years post day of transplantation. Secondary endpoints of cardiovascular morbidity 6-years post transplantation consisting of: development of CAV determined by coronary angiography as per ISHLT guidelines, coronarFull, comprehensive transthoracic echocardiograms were performed on each patient as part of the routine clinical care at 1-year post transplantation using one of two commercially available ultrasound systems: iE33 digital ultrasound system with either an S5-1 or X5-1 transducer  or a GE Vivid E9 digital ultrasound system with a M5S 3.5 MHz transducer  with subsequent 2D strain analysis performed by R.C. M-mode, 2D imaging and Doppler imaging were performed from parasternal, apical, subcostal, and suprasternal windows. The apical images were performed in the left lateral decubitus position with images optimised to visualise the entire LV myocardium at a frame rate between 50 and 80 frames/second. Echocardiograms suitable for analysis were included when the patient was free from biopsy confirmed ACR at 1-year after transplantation.Systolic strain, diastolic strain rate and mechanical dispersion time to peak strain parameters were determined via 2D speckle tracking analysis using a vendor independent system . Strain was quantified using the 2D cardiac performance analysis package, which required manual contouring of the endocardial border in the apical 4-chamber, apical 2-chamber, apical long-axis, and focused RV view obtained from the apical window. Determination of peak LV strain was measured at the nadir of the peak negative deformation strain value from all regional LV strain curves and averaged for all 16 myocardial segments and expressed in absolute values. End systole was determined at the time of aortic valve closure (AVC). Timing of AVC was defined as the time from the onset of the R-wave on the ECG to the termination of the left ventricular outflow tract signal by pulsed wave Doppler. Determination of peak systolic RV strain was measured using peak deformation as seen on the segmental strain curve. LV GLS was calculated as an average peak strain from all 16 myocardial segments and expressed in absolute values. Systolic mechanical dispersion was calculated as the standard deviation of the time from R-wave to peak systolic strain in all 16 segments. RV GLS was calculated as an average peak strain from 3 free wall RV myocardial segments. Systolic mechanical dispersion for the RV was calculated as the standard deviation of the time from R-wave to peak systolic strain in 3 free wall myocardial segments. Strain measurements are expressed in absolute values. Diastolic speckle tracking analysis was performed from the same apical images of the LV and RV used for GLS. Longitudinal diastolic strain rate, which is defined as the rate of deformation in percent of strain per second during diastole (1/s), was calculated from an average of the 18 LV myocardial segments during early diastole. LV early diastolic strain rate was measured during the peak positive signal waveform after systole and before the P-wave on the ECG as previously described. RV earlNormal distribution for the continuous data was verified using the Shapiro-Wilk test. Continuous data is expressed as mean values ± standard deviation. Comparison of the continuous data was performed by an ANOVA with the Bonferroni correction for multiple comparisons. A univariate binary linear logistic regression model analysis was performed when comparing continuous variables with outcome data of cardiovascular morbidity and all-cause mortality whilst a multivariate Cox proportional hazard regression model was used to correct for blood pressure, CAV, de-novo regional wall motion abnormalities on stress echo, LV EF and admission with heart failure. For optimal determination of sensitivity and specificity, a value closest to the upper left corner of the receiver operator characteristic (ROC) curve was chosen to define the optimal cutoff values for Kaplan-Meier analysis. Odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) were calculated and reported and significance was set at p < 0.05.Ten patients were randomly selected and remeasured by two observers (R.C. and N.E.) who were blinded to the clinical data and each other’s results. Intra-observer variability was performed by R.C. 3 months after the original strain analysis. Inter-observer variability was performed by N.E. repeating measurements from the same images. Intra- and inter-observer variabilities were calculated by intraclass correlation coefficient (ICC) and the standard error of measurement (SEM). All statistical analysis was performed using IBM SPSS Statistics 25 .There were 128 heart transplant recipients who satisfied inclusion criteria and survived the first-year post transplantation were included in this study. No patients had evidence of CAV by coronary angiography, ACR or antibody mediated rejection from endomyocardial biopsy at the time of strain analysis performed at 1-year post-transplantation. At the 6-year post-transplantation period, 21 patients (17%) died, 47 patients (37%) developed CAV, 7 patients (6%) required percutaneous or surgical revascularisation, 14 patients (11%) experienced ≥ 2R ACR, 7 patients (6%) experienced antibody mediated rejection, 17 patients (13%) developed arrhythmia requiring treatment and 31 patients (24%) were hospitalised with treatment requiring heart failure. Table Tables There were significant relationships between echocardiographic and clinical variables for 6-year all-cause mortality Table . LV GLS,Cox proportional hazard multivariate regression analysis revealed LV GLS, LV ESr, RV GLS and RV ESr to be significant predictors of 6-year all-cause mortality Fig. . Figure Binary regression analysis for secondary endpoint data showed LV GLS, LV ESr and RV ESr to be all significant predictors of morbidity after the first-year post transplantation Table .Cox proportional hazard multivariate regression analysis revealed LV GLS, LV ESr and RV ESr were significant predictors of morbidity.The reproducibility of strain measurements was excellent as seen in Table Highlights.LV GLS is a significant predictor of both primary and secondary outcome with 15.5% being the best predictor of 6-year all-cause mortality in heart transplant patients.RV GLS is a significant predictor of 6-year all-cause mortality by multivariate and univariate analyses.Left and right ventricular diastolic strain rate are also good predictors of both all-cause mortality and complications associated post-heart transplantation.Unlike novel strain parameters of myocardial function, traditional 2D and Doppler parameters of systolic and diastolic function showed no significant differences between rejection score groups.The main finding of this study highlights repeated episodes of ACR, determined by enodomyocardial biopsy during the first-year post heart transplantation results in reduced longitudinal systolic and diastolic function as measured by 2D speckle tracking strain analysis. In contrast, traditional 2D and Doppler parameters of systolic and diastolic function showed no significant differences between RS groups. These results highlight the profound effect strain analysis can play in the assessment of cardiac allograft function.The results of this study clearly show that repeated episodes of ACR can result in significant reductions in systolic LV and RV longitudinal strain with LV GLS varying from 18.1% in RS group 1  reducing to 15.3% in those with severe burden of rejection in this cohort (RS group 3). Novel diastolic strain rate parameters for the LV and RV were also significantly reduced in line with rejection severity underscoring the importance of investigating diastolic strain rate parameters post-transplantation, 21. NorAfter adjusting for potential confounders, the present study demonstrated a significant correlation between both systolic (LV and RV GLS) and diastolic (LV ESr and RV ESr) and all-cause mortality. A cutoff value for LV GLS of 15.5% was a significant and strong predictor of mortality which is concordant with other reported work in patients post heart transplant and asymptomatic aortic stenosis, 31. IntThe prognostic importance of LV GLS as a marker of outcome has been reported in heart transplant patients during the first-year post-transplant and at aThe utility of RV strain to detect ACR has been proven to be useful, 21 but Recently, Clemmensen et al showed tInterestingly, RV ESr was also a significant predictor for both the primary and secondary endpoints in univariate and multivariate analysis with a cut of value for RV ESr of 0.80/s. This is the first study to date to investigate novel diastolic strain rate RV ESr and it can be clearly seen that RV ESr is of value determining the outcome of transplant patients.The results of the present study clearly show that a single assessment of myocardial strain performed on the LV and RV after transplantation might be a useful noninvasive tool in helping identify heart transplant patients who are subject to a poor clinical prognosis. Although echocardiography is used in the serial follow up assessment of heart transplant patients, traditional echo-based parameters may not be sufficiently sensitive in capturing the spectrum of rejection severity or provide predictive outcomes. In contrast, echocardiographic assessment using strain analysis may provide early prognostic outcomes that can be used to inform and optimise treatment strategies that will improve short and longer-term patient outcomes. Furthermore, strain assessment should not be limited to a single point in time as serial assessment of myocardial strain can provide useful insights into the patient specific changes associated with ACR and CAV, 12, 37.This study was a single center retrospective observational design from a tertiary referral center including selection bias determining a moderate sample size with a modest event rate. Radial and circumferential strain measures were not performed due to evidence of reduced reproducibility for these strain parameters. Microvascular perfusion could not be ascertained which may provide relevant information regarding impairment of long axis function in this population.Amongst heart transplant recipients, recurrent rejection burden at 1-year is associated with reduction of LV and RV strain parameters and negatively impact medium term survival. Traditional 2D and Doppler based parameters of cardiac function post-transplant are inferior compared to strain assessment of LV and RV function. LV GLS and LV ESr are the best predictors of mortality outcome at 6 years post transplantation.


Heart failure is a prominent clinical condition and a top concern as a widespread health issue. The incidence of heart failure is rising alarmingly on a global scale. Heart failure significantly strains the whole healthcare system financially, degrading the patient's quality of life and increasing the risk of morbidity and mortality. Heart failure treatment has changed over time with ongoing research and the development of new medications and equipment.Recently, the FDA and European Union (EU) approved the drug dapagliflozin, which is an inhibitor of sodium-glucose cotransporter 2 (SGLT-2i), for treating people with cardiovascular conditions and symptomatic heart failure (HF). In this review article, we will find out whether Dapagliflozin, when given at a dose of 10 mg/day in people with type 2 diabetes and in those without type 2 diabetes who have or are at risk for atherosclerotic alterations, can considerably lower the risk of cardiovascular mortality or hospitalization for HF. In the presence of concomitant HF therapies, dapagliflozin's benefits remained. Dapagliflozin's overall safety profile was comparable to its safety profile for other applications. It was often well tolerated in patients in a study group. In this review article, dapagliflozin is found to be the well-tolerated and effective novel treatment of choice for symptomatic HF. Because of the scarcity of research on dapagliflozin, it was necessary to provide data to help reduce the mortality of patients while providing further guidance on the clinical medication of dapagliflozin.  Heart failure (HF) is the most common substantial financial and medical burden in the world ,2. SinceDapagliflozin can lower blood sugar levels without being affected by peripheral tissue insulin resistance or insulin secretion. SGLT-2i inhibits the reabsorption of glucose by the renal tubules. Therefore, the excretion of glucose is increased in urine and lowers blood sugar levels by considerably reducing the functional activity of the proximal renal tubules. SGLT-2i drugs also have other effects than hypoglycaemic effects. For example, empagliflozin and canagliflozin have been proven to have additional cardiovascular protection. They can reduce the occurrence of cardiovascular events ,11. DapaMethodThe following goals are being pursued with this review: Current status of SGLT2i dapagliflozin in congestive heart failure. A search of the English-language literature was done using the electronic databases PubMed, Embase, Google Scholar, and Medline. And the search terms were Congestive heart failure or Epidemiology of HF or Dapagliflozin or SGLT-2i or type 2 diabetes. The writers' personal knowledge and experience in the field supported the archiving of relevant papers. Articles that match the following criteria are included in this review: studies in English; studies from the last ten years; and studies devoted entirely to congestive HF, dapagliflozin, and SGLT-2i. Research methodology by PRISMA  method is shown below in Figure HF and classificationHF is a complex clinical syndrome that underlines the inability of the heart to perform its circulatory function with the desired efficiency due to structural and/or functional (systolic or diastolic) alterations ,13. Not Other terms commonly used in HF are as follows ,13: StabEpidemiologyA complex syndrome of multi-morbidity and geriatric symptoms is also linked to age-related increases in the incidence and prevalence of HF ,16. In tCompared to North America and Western Europe, Asian patients are much younger. With the exception of Japan, several Asian nations have a higher adjusted risk of cardiovascular (CV) mortality. Also, Jones et al. published lasting results for 1.5 million steady chronic heart failure patients, consisting of 60 non-interventional studies. Even if five-year survival rates have increased from 29.1% to 59.7% between 1970-1979 and 2000-2009, the number of deaths is still too high and is greater than for other types of cancer -27. MakiPharmacological propertiesDapagliflozin SGLT-2i) has been approved for the treatment of patients with symptomatic HF in a number of countries, including the United States  and the i has beeClinical effectiveness of dapagliflozinA major topic discussed in this section is the current efficacy of dapagliflozin as a treatment goal in treating patients suffering from HF. In this section, these statistics are briefly addressed.a) DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) TrialKansas City Cardiomyopathy Questionnaire (KCCQ) total symptom scores (TSS) are used to divide patient populations patient population, and Cox proportional hazards models were applied to analyze how Dapagliflozin affected various clinical outcomes in each subgroup. Dapagliflozin's effects were examined on the clinical summary score and KCCQ-TSS on the overall summary score. Based on an 18-month recruitment period and a 24-month average follow-up period, it was estimated that 4,500 patients would produce the required number of primary events, with an annual event rate of 11% in the placebo treatment group . Given tb) DECLARE-TIMI  58 TrialAll patients were asked about their baseline heart failure status for the DECLARE-TIMI 58 study. Whenever available, EF was also measured. EF 45% was used to define HFrEF. Out of 17,160 patients, 671 constrained (HFrEF) heart failure with such a reduced EF, 1,316 constrained heart failure without such a documented decreased EF, and 15,173 (88.4%) had never before had heart failure. Dapagliflozin's therapeutic efficacy was similar in individuals with HF who had no known decreased EF as well as those without HF. Patients with HFrEF had against those without HFrEF reduced chance of cardiovascular mortality and HF. Dapagliflozin reduced cardiovascular death exclusively in participants constrained with HFrEF; still, no definitive effect is seen in participants without HFrEF. In contrast, it decreased the chances of HF in those participants with HFrEF and those without HFrEF. We discovered that dapagliflozin significantly reduced the incidence of heart failure in HFrEF-positive and -negative patients, cardiovascular death, and all other causes related to mortality in HFrEF-positive patients .c) DEFINE-HF  TrialThe investigator-initiated, multi-centre, randomized controlled trial known as DEFINE-HF included: a) HF patients with a left ventricular ejection fraction of less than 40%. b) An estimated glomerular filtration rate of less than 30 mL/min/1.73 m2. c) A New York Heart Association (NYHA) class of II to III. d) Elevated natriuretic peptides. Dapagliflozin 10 mg was given to 263 volunteers randomly or a placebo for a period of around 12 weeks. Two primary outcomes were considered: the percent of participants whose overall summary score somewhat on the KCCQ has improved by at least five points due to their HF condition and the mean NT-proBNP , or an NT-proBNP drop of at least twenty percent. Patients had persistent, chronic HF, a low ejection fraction, and significant usage of the best available medical care. Average adjusted NT-proBNP levels at six and twelve weeks were similar between dapagliflozin and placebo . The oved)DICTATE-AHF (Efficacy and Safety of Dapagliflozin in Acute Heart Failure) TrialThe goal is to evaluate the safety and effectiveness of initiating dapagliflozin on individuals with AHF during the first 24 hours of hospitalization versus standard therapy. A total of 240 patients are expected to participate in the prospective, multicenter, open-label, randomized DICTATE-AHF study by the United States. Hypervolemic acute heart failure (AHF) hospitalization, T2DM, and a glomerular filtration rate estimated to be about 31 mL/min/1.73m2 are all requirements for involvement. Dapagliflozin 10 mg per day or organised standard of care is randomly allocated to each patient until the end of day five or till hospital discharge. Both groups under treatment get prescribed doses of insulin and diuretics . The pri DELIVER  Triale)DELIVER is a global, parallel-group, multicenter, event-driven, double-blind trial randomized in participants with left ventricular ejection fraction > 40% and chronic heart failure when dapagliflozin 10 mg single dose daily was compared with placebo as well as standard of treatment. Patients with diabetes, without diabetes, heart failure symptoms and signs, a left ventricular ejection fraction (LVEF) of at least 40%, elevated natriuretic peptide levels, and indicators of structural heart disease are eligible . The maif) Trial Conducted by Wiviott et al.Patients with T2DM who had or were at risk for atherosclerotic cardiovascular disease were randomly allocated to either dapagliflozin or a placebo. Major adverse cardiovascular events (MACE), which include ischemic stroke, cardiovascular mortality, and myocardial infarction, were the critical safety outcome. The critical effectiveness outcomes were MACE and a composite of cardiovascular mortality or hospitalization for HF. The secondary efficacy outcomes were the renal composite and death from any cause .The study included 17,160 people, 10,186 of whom were followed for an average of 4.2 years and showed no signs of atherosclerotic cardiovascular disease. In the analysis of primary safety outcomes, dapagliflozin showed the pre-specified criteria in non-inferiority to placebo in MACE. In the two major effectiveness studies, dapagliflozin did not reduce the risk of MACE. However, it reduced the hospitalization rate for heart failure or cardiovascular mortality. A renal event occurred in 6.22 percent and 6.61 percent of the dapagliflozin groups. In comparison, it happened in 5.6 percent of the placebo group. The proportion of genital infections that resulted in drug discontinuation or were considered serious adverse events was more significant with dapagliflozin than with placebo, and diabetic ketoacidosis was more common [e) Trial Conducted by McMurray et al.Randomly assigning 4,744 patients in this phase three placebo-controlled experiment was done by McMurray et al. with New York Heart Association class 2, 3, 4 heart failure and with an ejection fraction of 40.1% or less to receive dapagliflozin at a dose of 10 mg once per day or placebo, as well as standard of treatment. Two primary outcomes were worsening heart failure or cardiovascular mortality. The main objective met in the placebo group was 502 of 2,371 patients (21.2%). Over a median of 18.2 months in the dapagliflozin group, it was 386 of 2,373 patients (16.3%). Two hundred and thirty-seven patients (10.1%) experienced worsening heart failure in the dapagliflozin group, whereas 326 patients (13.7%) experienced deteriorating heart failure in the placebo group. In the dapagliflozin group, 227 individuals (9.6%) died from cardiovascular disease, and in the placebo group it was 273 patients (11.5%); 276 patients (11.6%), and 329 patients (13.9%) suffered all other causes of death. Regardless of diabetes status, patients with low ejection fraction who received dapagliflozin had a reduced risk of worsening heart failure or dying from cardiovascular causes than those who received a placebo .DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) Trialg) The effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes were compared to the presence of T2DM and any chronic kidney disease (CKD) causes. The DAPA-CKD study participants were randomised to receive dapagliflozin 10 mg once a day or a similar placebo in addition to standard treatment. The estimated glomerular filtration rate (eGFR) of the participants was 25-75 mL/min per 1-73 m2 and the urine albumin to creatinine ratio was 200-5000 mg/g . The priThis research combines the latest information on HF, including global epidemiology, HF types, and the status of the approved drug dapagliflozin. Despite tremendous advances, cardiovascular disease (HF) remains the primary cause of poor quality of life in persons with cardiovascular illnesses or comorbidities. Since the development of innovative therapy techniques, medications in the SGLT2-i class, such as dapagliflozin, when administered at a dose of 10 mg once daily in symptomatic heart failure have decreased mortality, improved quality of life, and increased life expectancy. This review includes an overview of some of the studies that have been conducted till date, as well as a discussion of their findings. There have been certain studies which show positive reviews in terms of the use of dapagliflozin and still some experiments are currently in progress. Dapagliflozin is frequently well-tolerated and is an effective novel medication in symptomatic HF that has been added to the list of options.


Methods and Study Design: JenaMACS  is a monocenter, proof-of-concept study to determine whether treatment with an Impella CP® leads to improvement of hemodynamic parameters in patients with cardiogenic shock requiring extracorporeal, hemodynamic support. The primary outcomes of JenaMACS are changes in hemodynamic parameters measured by pulmonary artery catheterization and changes in echocardiographic parameters of left and right heart function before and after Impella® implantation at different support levels after 24 h of support. Secondary outcome measures are hemodynamic and echocardiographic changes over time as well as clinical endpoints such as mortality or time to hemodynamic stabilization. Further, laboratory and clinical safety endpoints including severe bleeding, stroke, neurological outcome, peripheral ischemic complications and occurrence of sepsis will be assessed. JenaMACS addresses essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and improve the outcome in those patients. Conclusion: The JenaMACS study will address essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® assist device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and may improve outcome in those patients. Ethics and Dissemination: The protocol was approved by the institutional review board and ethics committee of the University Hospital of Jena. Written informed consent will be obtained from all participants of the study. The results of this study will be published in a renowned international medical journal, irrespective of the outcomes of the study. Strengths and Limitations: JenaMACS is an innovative approach to characterize the effect of additional left ventricular mechanical unloading during cardiogenic shock via a minimally invasive cardiac assist system (Impella CP®) 24 h after onset and will provide valuable data for acute interventional strategies or future prospective trials. However, JenaMACS, due to its proof-of-concept design, is limited by its single center protocol, with a small sample size and without a comparison group.Introduction: Cardiogenic shock due to myocardial infarction or heart failure entails a reduction in end organ perfusion. Patients who cannot be stabilized with inotropes and who experience increasing circulatory failure are in need of an extracorporeal mechanical support system. Today, small, percutaneously implantable cardiac assist devices are available and might be a solution to reduce mortality and complications. A temporary, ventricular, continuous flow propeller pump using magnetic levitation (Impella Cardiogenic shock is characterized as a life-threatening, clinical syndrome that may present as an acute illness or an acute exacerbation of a chronic process. Acute myocardial infarction is the most common cause of this primary cardiac disorder and main cause of death ,2. AffecThe fundamental pathophysiological aspect of cardiogenic shock is a profound depression of myocardial contractility, ineffective cardiac stroke volume and failed circulatory compensation that perpetuate a vicious, downward spiral of reduced cardiac output, low blood pressure, low coronary perfusion and, eventually, further impairment of contractility .A normal heart has a trapezoidal ventricular pressure-volume loop depending on ventricular preload and afterload . CardiogClinically, this presents as hypotension refractory to volume resuscitation requiring further therapy intensification . MultiorAbout 140,000 patients develop myocardial infarction every year in Germany . Of thesAggressive treatment with inotropes and vasopressors has the potential to exacerbate the downward spiral of shock and results in higher myocardial oxygen consumption, increased afterload and impaired microcirculation .The largest randomized trial of MCS in patients with CS, IABP Shock II, did not show any advantage of mechanical cardiac support using intra-aortic balloon counter-pulsation (decrease in afterload without active unloading of the failing left ventricle) compared to a conservative medical strategy of shock treatment . Implant® is a mechanical unloading device through placement in the left ventricle with continuous blood flow from the left ventricular cavity to the ascending aorta. It has been approved for the stabilization of patients with cardiogenic shock. It facilitates unloading of the left ventricle to support contractility independently from heart function and rhythm via adjustable flow rates. A dissociation of left ventricular peak pressure from aortic pressure can be achieved with higher mean arterial pressure. The pressure-volume loop of the left ventricle is shifted leftwards resulting in a lower left ventricular end diastolic pressure, a diminished pressure-volume area, lower left atrial and pulmonary wedge pressure, decreased myocardial oxygen consumption, and a reduction in the left ventricular wall tension [® in patients with cardiogenic shock.In contrast, Impella tension . Neverth® assist device on acute and subacute hemodynamic effects after implantation in patients with cardiogenic shock in addition to standard medical therapy. JenaMACS  is a monocenter, prospective, open-labeled, proof-of-concept register study. JenaMACS will assess the impact of the Impella CPPatients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.JenaMACS includes critically ill patients with cardiogenic shock and indication for an extracorporeal, mechanical, circulatory assist device determined by corresponding PAC (pulmonary artery catheter) hemodynamics , pulmonary wedge pressure (PCPW), pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), mixed venous oxygen saturation (mvO2Sat), SV (stroke volume)). Inclusion and exclusion criteria are listed in ® implantation will be screened.All patients referred to our department with cardiac shock requiring hemodynamic support via an MCS device and that are eligible for Impella CPThe nature, aim and full extent of study participation are explained to each subject  before inclusion. Informed consent will be obtained according to the Declaration of Helsinki.There are two main modes of obtaining informed consent according to the different presentations of the patients: (1) Patients that are awake and have no cognitive impairment due to the cardiogenic shock will sign the informed consent prior to study initiation. A short and long version of the informed consent is available. (2) Patients with cognitive impairment due to the cardiogenic shock or that are sedated: two independent physicians will proof the presumed will of the patient. The patient will sign the consent form once he/she is recovered, or may not accept to be enrolled in the study and have to be excluded. Patients have the right to withdraw from study participation at any time without an explanation.® on hemodynamics and left ventricular unloading in patients with cardiogenic shock after 24 h by using a ramp test protocol (® flow support (ramp test), hemodynamic  and echocardiographic parameters (left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and grading of mitral valve regurgitation) are recorded at each level from highest (P8) to lowest (P2). Measurements take place 10 min after adjusting the console to each flow level. In theory, mechanical assistance for unloading of the left ventricle might lead to a faster decrease in LVEDD, PCWP and mitral regurgitation and faster increase in LVEF and SV that could be translated into improved left ventricular recoveryThe primary objective of the JenaMACS register is to investigate the potential benefit of the Impella CPprotocol . The ram® therapy in the time course, early from the start (10 min) to beyond 24 h, until explanation. Additionally, serial echocardiography will help to detect the effect of the Impella® support to various echocardiographic parameters such as left heart size and right ventricular function. Apart from laboratory parameters, the secondary objectives mostly include clinical surrogate measures  stay or time of mechanical ventilation) to identify or confirm potential advantages of Impella CP® during the therapy and follow-up phase. Moreover, safety data like major and minor bleedings, stroke, sepsis and acute limb ischemia requiring intervention or surgery will be evaluated. Data acquisition during hospitalization and follow-up is displayed in The secondary objectives are to gain information via serial hemodynamic measurements during Impella CP® support levels. Parameters to be measured are listed in The primary endpoint of the JenaMACS register study is the change in hemodynamic and echocardiographic parameters after 24 h during the ramp test at different Impella® implantation.The study duration is planned for 60 months: 57 months of recruitment, 3 months for final follow-up and another 3 months for data analysis and publication. ®  used for JenaMACS is an axial, non-pulsatile, continuous 14 Fr magnetic levitation propeller pump delivering a maximum flow of 3–4 L per minute. Inserted percutaneously via Seldinger technique, the Impella® is then advanced retrograde from the common femoral artery, through the aorta and across the aortic valve into the LV. An ultrasound-assisted puncture of the femoral artery can be performed to minimize access site complications. The device is using an impeller to eject blood from the left ventricle into the ascending aorta via a tube. The pump is not dependent on pulsatile flow or EKG. The impeller speed defines the flow rate of the device and therefore the blood volume to be ejected. Maximal flow rate for ImpellaCP® is 3.5 L/min. Flow rate adjustments can be set manually from an external console and are the basis of the ramp test 24 h after Impella CP® implantation , hemodynamic measurements will be obtained by pulmonary artery catheter and include pulmonary capillary wedge pressure (PCWP), mean right atrial pressure (RA) central venous oxygen saturation (cvSo2), and mixed venous oxygen saturation (mvSO2).®  will be used. This 4-lumen catheter is inserted with the cardiac catheterization lab either through the femoral or jugular vein before Impella® placement and has a caliber of 7 Fr and a length of 110 cm.The following parameters will be calculated: cardiac index (CI), stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), and cardiac output (CO). At the trial site, the pulmonary artery catheter Corodyn TD®  and the recordings are processed via dedicated software . Echocardiographic evaluation is carried out in a standardized comprehensive fashion and encompasses acquisition of features of left/right ventricular and valvular function (Transthoracic echocardiography (TTE) is performed using the ultrasound system Vivid S70function .® is a CE-approved medical device and part of routine, clinical use for cardiogenic shock and other indications. The use of a Swan-Ganz Catheter is standard practice in cardiogenic shock patients. For safety assessments, documentation of relevant events regarding Impella CP® treatment include the aspects listed in Study participation is not associated with any additional risks for patient’s safety. The Impella CPThe planning aims to obtain data on hemodynamic parameters and differences in hemodynamics in the clinical course of 20 patients.The analysis of the primary endpoint and the analysis of the secondary endpoints are carried out on the basis of the protocol. Sensitivity analysis is carried out on the basis of the Per-Protocol-Set (PPS). The analysis includes all patients, who were included, whose declaration of consent is available and who received the planned therapy. The PPS analysis population includes all patients of the ITT who did not have a serious protocol violation. For secondary analysis, all patients are included who have a complete data set for the endpoint under consideration.The primary analysis will be performed on the full analysis set which includes all patients treated. The secondary endpoint analysis is carried out descriptively using statistical test procedures. The evaluation of frequencies is done by Chi-square test/Fisher’s exact test. The evaluation of metric endpoints is carried out using an analysis of variance. Time-to-event endpoints are evaluated using Kaplan-Meier estimates and a log-rank test. In addition to the test results, effect estimates with 95% confidence intervals are given. Odds ratio will be calculated as an estimator of the effect of MCS treatment. To investigate multivariable relationships, multiple logistic regression , linear model (for quantitative endpoints) or Cox regression  are carried out. In addition, the logistic regression model will be used to evaluate the prognostic value of parameters of hemodynamics and to differentiate which might be confounders. Lists and tabular summaries are created to describe the adverse and serious adverse events. Predefined subgroup analysis is carried out for gender, age groups > 75 years, diabetes, arterial hypertension, ST-elevation myocardial infarction (STEMI) versus Non ST-elevation myocardial infarction (NSTEMI), anterior wall infarction versus infarction in other locations, previous infarction. According to the data distribution, two-sided independent samples t test or Mann-Whitney-U test will be applied for continuous endpoints. Safety analyses will be run in the safety population to be defined in the protocol; these analyses will summarize and tabulate all observed safety events including a measure of uncertainty . The confirmatory analysis will be performed at a significance level of 5%.Patients with cardiogenic shock are screened and transferred to the cardiac catheterization laboratory as soon as possible after admission or after being transferred from another hospital. After checking the inclusion/exclusion criteria and receiving consent, the patient will be included in the study. Left heart and right heart catheter examinations are performed and the coronary vessel responsible for the infarct is recanalized using percutaneous coronary intervention (PCI) as soon as possible. In case of an indication for immediate bypass surgery, the study is not discontinued, but further evaluation according to the intention-to-treat principle will apply. Further medicinal measures for the treatment of acute myocardial infarction, circulatory-support therapy with catecholamines, assisted or volume-controlled ventilation, etc., are carried out according to the decision of the physician in charge according to recognized therapy guidelines.®. Pulmonary artery catheter examination will measure the various pressures , pulmonary capillary wedge pressure (PCWP)) and resistances . This is repeated at defined intervals together with an arterial and mixed venous blood gas analysis for determination of pH, serum lactate and standard base excess.Hemodynamic parameters such as arterial systolic and diastolic blood pressure, mean blood pressure and heart rate are documented in the cardiac catheterization laboratory prior to the implantation of Impella CP® implantation as well as on a daily basis until the Impella CP® is explanted. Parameters of the left and right ventricular size and function as well as the documentation of possible valve abnormalities are standard and will be stored within the internal Picture Archiving and Communication System (PACS). Parameters are listed in Echocardiography is performed before and after Impella CP®. Furthermore, a new arterial and mixed venous blood gas analysis is performed with additional determination of pH, serum lactate and standard base excess. Echocardiographic parameters are recorded according to the protocol.At the end of the examination in the catheterization laboratory, the hemodynamic parameters from pulmonary artery catheterization are documented again about 30 min after implantation of the Impella CPThe patients are monitored until they are transferred to the intensive care unit. The flow of the device should be optimized according to clinical goals (MAP ≥ 65 mmHg).Further intensive medical therapy is carried out according to generally recognized guidelines. Systemic anticoagulation with unfractionated heparin will be used for the duration of left ventricular support (target activated clotting time around 180 s).Drug therapy with catecholamines  according to current recommendations is possible. The use of calcium sensitizers  or other hemodynamically relevant drugs  are also possible according to an individual intensive care medicine assessment . The aimAs part of the recording of the intensive medical treatment, the SAPS (Simplified acute physiology score) II score is recorded serially every day in the intensive care unit. To determine inflammatory parameters, as well as liver and kidney functions, a full blood work-up is recorded daily including C-reactive protein (CRP) and procalcitonin (PCT). All other laboratory parameters are determined at least once a day according to the documentation sheets in the routine laboratory program. Ethylenediaminetetraacetic acid (EDTA), blood, serum and plasma are stored at all times  for later molecular biological analysis.2Sat), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR)).At least three times a day the measuring of selected hemodynamic parameters takes place and includes: arterial systolic/diastolic blood pressure, mean arterial pressure, heart, arterial blood gas analysis with additional determination of pH, base excess, serum lactate and parameters from invasive monitoring via PAC (pulmonary capillary wedge pressure (PCPW), pulmonary artery pressure (PAP), cardiac output (CO), central venous pressure (CVP), mixed venous oxygen saturation The duration of therapy is determined by the need for supportive therapy with catecholamines. In previous studies, the mean duration of mechanical circulatory support was 3–4 days . The maiA new echocardiographic assessment is carried out before discharge from the hospital. After 30 days, the patient’s vital status is again ascertained through contact. All clinical events are verified by obtaining the original documentation. In addition, dyspnea according to the New York Heart Association (NYHA)-classification, angina pectoris according to the Canadian Cardiovascular Society (CCS)-classification and quality of life according to the EuroQol (EQ)-5D questionnaire are recorded.Further treatment of the patients after the end of the clinical trial is carried out by the general practitioners/resident and/or cardiologists. In the event of undesirable side effects, patients are instructed to contact the study director or one of his representatives in accordance with Section 7, Paragraph 2, Item 13 of the Good Clinical Practice (GCP)-ordinance.® that are embedded in a quality management system. Investigators are trained in good clinical practice (GCP). All medical professionals involved are qualified and hold the appropriate national diploma or at least operate under surveillance of a senior staff member.Blinding is not possible because of the intervention used. Methods used against bias are standardized examination protocols to even out systematic differences due to differing expertise at all levels, and an independent clinical endpoint committee to evaluate adverse events other than death; high clinical standards are maintained with regard to the number of PCIs performed/year (about 1000) of patients treated in cardiogenic shock and participation in clinical studies. Furthermore, our study center has a certified, cardiac ICU specialized in the treatment of cardiac shock and application of Impella CP® system. Finally, monitoring  will be carried out during the trial by staff of the Department of Cardiology and of the Center for Clinical Studies, Jena University Hospital.At each visit, the measured parameters are documented in the case report forms (CRFs). In addition, all patients will be followed-up after screening and implantation of the Impella CPTreatment compliance is not influenced by the patient as the patient is normally unconscious and in a critical clinical condition. As a result, 100% treatment compliance is assumed. Loss of follow-up is estimated to be less than (<4%) based on other clinical studies in cardiogenic shock ,11,12.Paper CRF and a web application for study management software are used for data documentation (Redcap Database). The data will be stored online in REDCap ). REDCap is a secure web application for building and managing online surveys and databases. The software meets the regulatory requirements . The data will be entered via encrypted connection (HTTPS) in web browser input masks. Each subject will be given an unambiguous patient identification number to ensure pseudonymized data analysis. The data are verified by range, validity and consistency checks. The data manager will demand clarification of missing or implausible data from the study teams. Each change in data, e.g., due to resolved queries, will be documented in the data base by an automated audit trail. Unauthorized data access is prohibited by a hierarchical concept of access based on users and roles.The study was approved by the institutional review board and ethics committee of the Friedrich Schiller University (registration number: 4939-10/16).All data/information obtained during the study are subject to appropriate use and protection and will be treated in accordance with the comprehensive regulations of the national data protection law in strictest confidence. During the study, subjects will be identified exclusively by an individual identification code (subject number). For protection of these data, organizational procedures are implemented to prevent distribution of data to unauthorized parties. The appropriate regulations of local data legislation will be fulfilled in their entirety.All findings of this study will be published in a renowned international medical journal, regardless of the outcomes. We used the SPIRIT reporting guidelines for reporting .® is an option in cardiogenic shock, data published assessing the use of Impella® and its impact are too small to draw definite conclusions with regard to clinical endpoints such as unloading characteristics, hemodynamics or mortality. The only currently recruiting larger randomized clinical trial powered for clinical endpoints—DanGer-Shock—will still need several additional years until finalization [® in patients with cardiogenic shock offers rapid improvement from circulatory failure and increases in end-organ tissue perfusion in a less invasive rescue strategy. This could be the optimal device for patients with cardiogenic shock, reducing the rate of severe bleeding events, systemic inflammatory response syndrome, or limb ischemic events. Furthermore, left ventricular performance might also be positively influenced as a result of direct cardiac unloading an antegrade, more physiological outflow into the acceding aorta. However, the Impella CP® has a flow limitation of maximally 3.5 L/min (under laboratory model conditions using water) and is limited to compensation for left ventricular failure. By contrast, this technology is not able to support profound, critical states of shock with coexisting condition that need combined respiratory and (biventricular) circulatory therapy. Prospective clinical studies such as the JenaMACS trial are therefore warranted.Although MCS-treatment with Impella CPlization . The imp