Left ventricular dysfunction is a common reason for patients’ referral to cardiology departments for examination. Cardiac involvement is one of the possible yet rare presentations of malignant mesothelioma. We present a case of a patient in whom a routine cardiac examination and imaging revealed malignant mesothelioma. We discuss a possible association between a malignant tumor and myocardial scarring and how the oncologic treatment is influenced by concomitant heart failure. This article aims to raise awareness of the importance of multidisciplinary cooperation and thinking beyond the daily routine of our specialty to ensure the quality care of our patients. It also forced us to think about the possible causes of the association between malignant mesothelioma and myocardial fibrosis.The online version contains supplementary material available at 10.1186/s12872-021-02079-2. A 45-year-old man was referred to our cardiology department with pleuritic chest pain without any symptoms of heart failure. Transthoracic echocardiography (TTE) revealed moderate systolic dysfunction of the left ventricle (LV) due to wall motion abnormalities of lateral and posterobasal segments of the LV associated with localized pericardial effusion which was first suspected to be a pseudoaneurysm. Ejection fraction of the LV was approximately 35%. The systolic function of the right ventricle was normal and both the atria were not dilated. Ventriculography revealed dyskinesia of the basal segments of the lateral and posterior walls and no signs of extravasation of the contrast agent. Surprisingly, there was no significant coronary artery disease on coronary angiography explaining the findings above.We performed cardiac magnetic resonance (CMR) imaging which confirmed moderate systolic dysfunction of the LV and nonischemic pattern of non-homogenous late contrast agent enhancement of the thin lateral and posterior walls without myocardial edema  imaging Fig.  and confWhile medical therapy for heart failure with telmisartan, bisoprolol, and spironolactone was initiated, dysfunction of the LV persisted and the patient remained asymptomatic. After 4 cycles of lower-dose less-toxic neoadjuvant chemotherapy with carboplatin and pemetrexed, the patient underwent extrapleural pneumonectomy with resection of the diaphragm and pericardium and subsequent hyperthermic intrathoracic chemotherapy with cisplatin. There was a need for inotropic support and blood transfusion shortly after the surgery, uncomplicated weaning led to extubation the fourth post-operative day. The chest drain had to be reinserted due to development of tension fluidothorax. The patient developed signs of heart failure which was managed with diuretics shortly thereafter. He was discharged the twentieth post-operative day and was recommended for active surveillance as he did not qualify for adjuvant chemotherapy or radiotherapy due to LV dysfunction. Histopathology revealed tumor free margins of the resected material, therefore, no direct invasion of the tumor into the myocardium was expected, leaving the localized fibrosis of the LV unexplained.After the surgery, systolic function of the LV deteriorated and the patient tolerated only very low doses of medical therapy for heart failure due to symptomatic hypotension. LV dysfunction thus led to reducing the dose of neoadjuvant chemotherapy; moreover, it made our patient ineligible to receive any adjuvant treatment. Follow-up PET revealed FDG avid tissue in the site of the resected tumor. It could not be determined whether it represents just postoperative fibrosis or is a sign of recurrence of the tumor. One year after the surgical treatment, echocardiography revealed severe LV systolic dysfunction, ejection fraction was approximately 20–25%, and dysfunction of the right ventricle which was not associated with any significant increase in pulmonary arterial pressure. The patient is in functional class NYHA (New York Heart Association) III and was able to return to his job despite significant exertion intolerance. Given the worsening systolic dysfunction of the LV, dysfunction of the right ventricle and symptoms of heart failure, the patient will be referred to assess his eligibility for a biventricular assist device.Malignant mesothelioma is a rare malignant disease affecting the pleura, less commonly the pericardium and other serous membranes. The most common presenting symptoms are dyspnea, cough, and chest pain. Concerning cardiac involvement, malignant mesothelioma of the pericardium is known to cause constrictive pericarditis and pericardial effusion . InvasioWe searched medical databases for keywords “mesothelioma left ventricular dysfunction”/scarring”/aneurysm”, “mesothelioma heart failure”, and reviewed available case reports. To our knowledge, a case of malignant mesothelioma causing localized LV dysfunction has not yet been described apart from cases in which malignant mesothelioma invaded the myocardium . Since aIn general, tumors and other masses can cause LV dysfunction by external compression of the coronary artery , 5. In oMalignant mesothelioma is known to be resistant to cytostatic therapy and the immune suppressive microenvironment is likely contributing to this therapy resistance. Therefore, it was studied in an attempt to target the cytokines and their receptors deemed responsible for the progression of the tumor with the biological therapy. Malignant mesothelioma was found to attract cancer-associated fibroblasts and fibrocytes and macrophages with their collagenolytic activity responsible for tissue remodeling . In our While we cannot omit the possibility that the correlation of localization of mesothelioma and the myocardial scar is coincidental, such a perfect correlation of the site of the tumor and myocardial fibrosis is striking. Apart from that, localized myocarditis is likewise improbable in this case as CMR did not reveal any myocardial edema. Both malignancy and myocarditis could be caused by radiation, however, our patient did not have any history of radiation exposure.This case taught us to think beyond the daily routine of treating patients with localized dysfunction of the LV. In the era of superspecialization in medicine, multidisciplinary cooperation is more important than ever for the quality of patient care. In cases like this, the therapeutic interests of one specialty may influence the intentions of others' which we need to bear in mind treating patients with similarly complex diagnoses. It also forced us to think about the possible causes of the association between malignant mesothelioma and myocardial fibrosis.Additional file 1: Movie File 1. This movie file demonstrates the cardiac motion in a short-axis cine loop. It re-veals akinesia of the posterolateral wall of the left ventricle.


It has been estimated that 33% of these patients suffer from ventricular arrhythmias, which are associated with an increased mortality.A 66-year-old man with familial dilated cardiomyopathy and a CRT-D device  visited our outpatient clinic owing to transient faintness and palpitations. He had been diagnosed with juvenile sick sinus syndrome and was implanted with a permanent pacemaker at the age of 25. Furthermore, his son had been diagnosed with juvenile dilated cardiomyopathy and died at the age of 15. The pulse rate was 90 beats per minute and systolic blood pressure 102 mm Hg. The 12-lead electrocardiogram (ECG) revealed a regular wide QRS rhythm with a QRS duration of 200 ms and right bundle branch block configuration with a marked left axis deviation in the absence of obvious P waves A. The deAt the beginning of the procedure, a 10-polar catheter and a 20-polar catheter were placed into the coronary vein (CV) and on the RA free wall, respectively. A 4-polar catheter was also placed in the right ventricular apex. The intracardiac electrograms revealed different A-A intervals between the right atrium (970 ms) and CV (350 ms) with a V-V interval of 700 ms A. OverdrWe had made a false diagnosis of AIVR from the CRT-D telemetry data  at the beginning because our case represented extremely rare electrophysiological findings: (1) interatrial dissociation; (2) a sustained left AT, which was not detected by the telemetry ECG tracing or 12-lead ECG; and (3) 2:1 LA-to-V conduction without RA-to-V conduction.6 lead,There are numerous algorithms and criteria for discriminating wide QRS rhythms based on the 12-lead ECG findings.,However, once the information of the LA was obtained from the coronary sinus catheter, we could reach a correct diagnosis; that is, the wide QRS rhythm we had believed to be AIVR was actually a left AT with interatrial conduction block from the LA to RA with 2:1 LA-to-V conduction. According to the previous reports, the interatrial connections are made up of the Bachmann bundle, the coronary sinus musculature, and transseptal connectionsAtrial remodeling is common in patients with advanced structural heart disease.•The discrimination of wide QRS arrhythmias is sometimes hard to achieve based on the existing criterion of the 12-lead electrocardiogram or intracardiac electrogram findings, especially in heart failure patients.•Interatrial conduction disturbances possibly make the left atrial electrical activity indeterminable in patients with cardiac resynchronization therapy.•The right atrium-to-ventricle conduction could also dissociate from the left atrium-to-ventricle conduction, possibly based on advanced myocardial degeneration.We experienced a case with a unique mechanism of a wide QRS arrhythmia: a left AT with an interatrial conduction disturbance and 2:1 LA-to-V conduction in a patient with a CRT-D. We should note that the current algorithms for a differential diagnosis of wide QRS arrhythmias cannot always provide a correct diagnosis, especially in patients with advanced myocardial degeneration. Abnormal electrical activations in both the RA and left atrium should be taken into account to understand the true mechanism.


Cross-sectional.It is known that left ventricular mass (LVM) and cardiorespiratory fitness (CRF) are associated to fat-free mass (FFM).  It is unknown if these factors associated with left ventricular (LV) structure and function outcomes in individuals with spinal cord injury (SCI).University-based laboratory.Vancouver, BC, Canada.r) and Spearman’s rank (Rs)] tests were used for normal and non-normal distributed variables, respectively.Thirty-two individuals (aged 40 ± 11 years) with chronic, motor-complete SCI between the fourth cervical and sixth thoracic levels were recruited. Echocardiographic LV parameters and body composition were assessed at rest, as per the recommended guidelines for each technique. CRF was assessed during an incremental arm-cycle exercise test until volitional fatigue. The appropriate bivariate correlation coefficients  . The association between peak oxygen pulse and the resting echocardiographic-obtained SV was medium sized . The LVM associations with FFM and fat mass (FM) were large and small . Associations of absolute V̇O2peak were medium- positive with FFM  but negative with FM .LV structure and function parameters were not associated with the indexed peak oxygen consumption (V̇O2peak in individuals with cervical and upper-thoracic SCI. Given the observed associations between LVM and V̇O2peak with FFM, future studies may consider utilizing FFM for indexing cardiovascular measures following SCI.LV parameters measured at rest are not associated with V̇O It is well-established in non-injured individuals that higher levels of cardiorespiratory fitness (CRF) are associated with a reduced risk of cardiovascular disease (CVD), all-cause mortality, and other inactivity-related chronic diseases . Individ2peak)]. CVD events are elevated in individuals with SCI  , 20. Whi2peak would have more favorable resting LV parameters. Due to the observed association between LVM and body composition in the non-injured population, we also explored this association in our cohort .The purpose of this study was to investigate the associations between LV structure and function with CRF. We hypothesized that those with a higher V̇OClinicalTrial.gov, November 1, 2012, the study protocol of which has been previously published  conducted at the University of British Columbia, with the registration number (NCT01718977) on ublished . All parublished . All parublished . ExclusiAll participants underwent non-invasive trans-thoracic echocardiography  in the left lateral decubitus position, as per the recommendations of the American Society for Echocardiography . Images 2peak was normalized to body mass and FFM. Peak oxygen pulse (O2pulse) was calculated as a ratio between V̇O2peak and HRpeak.An incremental arm-crank exercise test on an electrically braked arm-crank ergometer , done until volitional exhaustion was performed to determine the peak parameters. HR was recorded continuously using a chest-strap HR monitor . Respiratory gases were collected using a metabolic cart  calibrated immediately before each test. Participants performed the test while sitting in their wheelchair and were asked to empty their bladder prior to the test to avoid the possible development of autonomic dysreflexia. After two minutes of resting, the test protocol began with a warm-up with no resistance for two minutes and then continued with one-minute stages, where resistance was increased by 5–10 Watts per stage for participants with cervical and upper-thoracic NLI, respectively . The parBody composition was measured using Dual-energy X-ray absorptiometry (DXA) . Outcomes were reported as per the International Society for Clinical Densitometry guidelines and as detailed previously in the study protocol . The stur) or Spearman’s rank (Rs)] tests were used for normal and non-normal distributed variables, respectively. We also ran partial correlation coefficients controlling for pre-determined covariates . The NLI was converted into a continuous variable, where C4 = 1, and C5 = 2, and so on until T6 = 11. The magnitude of each correlation was interpreted using the following: small (r > 0.1), medium (r > 0.3), large (r > 0.5), and very large (r > 0.7). Univariate (simple) regression (R2) was used where appropriate .All statistical analyses were performed using the Statistical Package for the Social Sciences  and GraphPad Prism (version 6). All data were visually inspected and analyzed for normality using a Q–Q plot and Shapiro–Wilk test, respectively. To investigate the association between CRF, LV parameters, and body composition, bivariate correlation coefficient [i.e., Pearson’s  (Table 2pulse), a surrogate of exercise SV that was obtained at peak CRF testing, was medium with resting echocardiographic-obtained SV . Associations between absolute V̇O2peak with FFM were medium- positive  but negative with FM . LVM associations with FFM and FM were large and small  .A total of 32 participants were included. Participants’ demographics, injury characteristics, peak CRF, body composition parameters and level of leisure time PA are presented in Table 2peak (relative to body mass or FFM). There is a medium association between CRF test-obtained peak O2pulse, a surrogate of exercise SV, and resting echocardiographic-obtained SV. Although LV parameters have been shown to be altered following SCI compared to non-injured individuals [The present study examined the associations between resting echocardiographic LV structure and function parameters and CRF, as well as exploring the associations between LVM and DXA-obtained body composition  in individuals with cervical and upper-thoracic SCI. The results of this study show that none of the resting LV parameters  are associated with V̇Oividuals , these r2max and cardiac function at rest, except for an inverse association with LV filling pressure (pulmonary capillary wedge pressure as a surrogate).Two large cross-sectional studies that recruited individuals referred for an echocardiogram, with no overt cardiac disease, showed that CRF measured in metabolic equivalents was strongly and inversely associated with LV diastolic dysfunction , 14. No 2peak and resting LV parameters in the SCI population. In this study, 17 males with paraplegia  were compared against non-injured individuals. In individuals with SCI, and independent of training status, they found that relative V̇O2peak was positively associated (r = 0.36 and P < 0.05) with aortic flow velocity (a surrogate of SV). This association was documented when trained and untrained participants were combined and was reflected by a higher relative V̇O2peak compared to our cohort (~17.6 mL/kg/min vs. 11.2 mL/kg/min). We used O2pulse, a surrogate of exercise SV, and this demonstrated a medium-sized association with the resting echocardiographic-obtained SV. Participants in our study were motor-complete and had a higher NLI (C4–T6). The disparity in V̇O2peak between our results and theirs may be related the inclusion of different cohorts characterized by AIS and NLI or the different modalities used for peak exercise testing (wheelchair ergometer vs. arm ergometer). Besides the participants in the Maggioni et al. study having a greater degree of sympathetic innervation to splanchnic beds, wheelchair propulsion may increase venous return and eventually improve SV. This could be due to the movement mechanics possibly mimicking an abdominal binder [To the best of our knowledge, Maggioni et al.  was the l binder . FurtherThe lack of associations between resting LV parameters and peak CRF in this study is perhaps, unsurprising. During exercise, there are marked changes resulting from the interactions between different body systems, and the interplay of all of these systems cannot be explained simply by their resting state. The sympathetic arm of the autonomic nervous system plays a crucial role in bodily system adjustment in response to physiological stimuli . In non-injured individuals, the sympathetically induced vasoconstriction of peripheral vascular beds (splanchnic circulatory bed and lower limbs) and the action of skeletal muscle pumps serve to achieve appropriate venous return and increased end-diastolic ventricular volume (pre-load). As a result, in accordance with the Frank–Starling mechanism, SV is maintained. It might be interesting to speculate that these physiological responses apply to individuals with SCI. However, individuals with injuries ≥T6 experience drastic alterations to these normal physiological mechanisms, along with potentially reduced circulating catecholamines , which iThe cardiovascular system has mainly evolved for the efficient distribution of food/nutrients  to metabolically active tissues, such as muscles, during an exercise stressor rather than to less metabolically active tissue  . CompareThis study is limited by its cross-sectional design. Thus, further studies are needed to investigate longitudinal changes in CRF and LV parameters. Exercise itself produces marked changes in LV performance; thus, future studies may want to investigate the association between exercise parameters and stress echocardiographic-obtained LV dynamic measures, preferably with the position in which the exercise was performed . DXA, among other techniques, is the current “gold standard” in determining body composition; however, it is less available in daily clinical practice. Devices such as a bioelectrical impedance analysis may offer a portable and alternative way of measuring body composition . Due to In conclusion, resting LV parameters in individuals with cervical and upper-thoracic SCI are not associated with peak CRF. Nevertheless, assessing CRF is crucial to quantify the responses to exercise training, irrespective of LV parameters and likely provides an indication of peripheral adaptations and functional improvements. The nature of the associations between LVM and FFM needs further studies to investigate the possibility of using this measure to index LV parameters in the SCI population. Likewise, the association between parameters of CRF and body dimensions needs further investigation to determine the appropriate indexing approaches relative to active musculature .


In this article, we describe the modulation of pathophysiology by SSO2, review the existing trial data and present our first impressions with the technique in real clinical practice.Optimal medical therapy for secondary prevention following acute myocardial infarction reduces non-fatal ischaemic events. Intensive antithrombotic or lipid-lowering approaches have failed to significantly lower mortality. In the past, reduction of infarct size in patients undergoing primary percutaneous revascularisation for acute myocardial infarction had been considered as a surrogate outcome marker. However, infarct size measured by magnetic resonance imaging or SPECT is strongly associated with all-cause mortality and hospitalization for heart failure within the first year after an acute myocardial infarction. Intracoronary administration of super-saturated oxygen (SSO Acute myocardial infarction (MI) is one of the major contributors to cardiovascular morbidity and mortality. In the acute phase of ST-elevation MI (STEMI), ventricular arrhythmias and cardiogenic shock are the main drivers of mortality contributing to in-hospital mortality of approximately 10% and time from first medical contact to primary percutaneous coronary intervention (PCI) is a strong predictor of an adverse outcome ,5,6,7,8.A meta-analysis of 10 randomized primary PCI trials including more than 2500 STEMI patients showed that infarct size measured within 1 month by cardiac magnetic resonance (CMR) imaging or technetium-99m sestamibi single-photon emission computed tomography (SPECT) was strongly associated with all-cause mortality and hospitalization for heart failure within 1 year . A centrOne of the approaches to reduce reperfusion injury was infusion of the mitochondria-targeted peptide, Bendavia, to reduce mitochondria-produced reactive oxygen species, which are believed to be centrally involved in reperfusion injury. While this approach seemed to reduce infarct size in animal models , no effe2 at 4 atmospheres [As local hypoxia was considered as a driving force for free-radical generation and mitochondrial dysfunction, the first experimental step to counteract this was hyperbaric oxygen therapy (HBO). In the 1950s, initial experiments of coronary sinus occlusion leading to higher coronary sinus pressure resulted in reduced mortality in animal models of coronary arterial occlusion . Hence, ospheres . Similarospheres . These eospheres . In 1973In 1993 Sterling et al. started to investigate in a rabbit model whether HBO affects infarct size. They surgically occluded one branch of the left coronary artery for 30 min prior to reperfusion. In their experimental setup they observed significant infarct size reduction from 42 to 10% when both ischaemia as well as reperfusion occurred during hyperbaric conditions and to 15% when only reperfusion was hyperbaric . At the Placing patients with acute STEMI into HBO chambers might pose several logistical problems including poor accessibility, difficulties for monitoring, claustrophobia and necessary decompression phases when performing the treatment for multiple hours. Blood hyperoxygenation might be possible using conventional extracorporeal membrane oxygenation (ECMO). However, this approach is limited by invasiveness, activation of coagulation and inflammation and the need for specialized personal for monitoring. It would counteract the minimal-invasive approach using radial access for prevention of bleeding when performing primary PCI nowadays. A solution for all those problems would enable easy hyper-oxygenation of blood components able to reach the peripheral myocardium. Aqueous oxygen has an oxygen-carrying capacity which is approximately 10-fold greater than those of blood. The advantage of aqueous oxygen is that it can be infused into other aqueous media at normal pressure without formation of gas bubbles . Followi® system  produces aqueous oxygen from bottled oxygen for medical use and sterile sodium-chloride solution. It requires arterial blood either from a singular femoral 4F-sheath in case of trans-radial catheterization or escalation of femoral access to a 7F-sheath which can host both arterial drainage as well as the guiding 5F-catheter for coronary reinfusion of hyperoxaemic blood. For easy handling in the cath-lab, a single-use sterile cartridge is placed in the TherOx® system and connected with a saline infusion as well as one line for drawing arterial normoxic blood and one line to connect with the coronary guiding catheter placed in the left-main coronary artery. Within the cartridge, aqueous oxygen solution was produced and injected into the circulating blood. The guiding catheter then delivers hyperoxaemic blood to the coronary system [The TherOxy system .2 appears to be controversial at first sight. However, animal experiments suggest that aqueous oxygen does not result in an increased formation of reactive oxygen species but rather reduces them in an animal setting [The proof of principal for aqueous oxygen therapy was provided by Spears et al. in an animal model using dogs subjected to coronary hypoxaemia. In that model, intra-arterial aqueous oxygen preserved left-ventricular ejection fraction . In a pi setting .2 provides hyperoxemic levels of oxygen, which are up to 10 times higher than normal, of dissolved oxygen when it is infused in the infarct-related artery. This allows for high oxygen diffusion before flow is restored downstream. Increased oxygen delivery via the plasma to endothelial cells can prevent severe cell edema, allow better perfusion and correct persistent myocardial ischemia, particularly in regions where erythrocyte flow is impaired by compromise of the microvascular luminal integrity [2 in contrast to LV unloading or hypothermia either requires or benefits from revascularisation prior to application. On the other hand, this provides the clinical advantage of not delaying primary PCI compared to the other methods [Experimental data support the pathophysiological hypothesis that microvascular ischemia caused by microvascular obstruction contributes to myocardial tissue injury over a prolonged time during reperfusion. It is believed that SSOntegrity . As the  methods ,22.2 concept and preclinical studies to clinical studies finally leading to FDA approval [After the encouraging results from animal experiments, first smaller pilot trials were started in humans with acute MI. A recent review extensively describes the evolvement from hypothesis generation over introduction of the SSOapproval .® device was reported in 2002 by an American–Italian multicentre investigation. In this pilot trial, 29 patients with acute MI undergoing primary PCI received hyperoxaemic blood infusion into the infarct-related artery for 60–90 min after successful revascularisation. Hyperoxemic reperfusion was well tolerated by all patients and neither clinical, electrical nor hemodynamic instability was observed during the aqueous oxygen infusion. The primary purpose of the study was to evaluate the feasibility and safety of performing hyperoxemic reperfusion in patients undergoing primary PCI for acute MI. While safety could be demonstrated, it remained unclear whether there was a potential benefit regarding reduction of infarct size or improvement in left-ventricular function [Initial experience with aqueous oxygen in humans using the TherOxfunction .An Italian study reported 27 patients with acute anterior AMI treated with primary PCI within 12 h after symptom onset receiving selective hyperoxemic perfusion into the left anterior descending coronary artery for 90 min. They were compared to 24 anterior STEMI patients matched in clinical and angiographic characteristics and treated with conventional primary PCI. Recanalization and hyperoxemic perfusion were successfully performed in all patients. After hyperoxemic perfusion patients showed shorter time-to-peak creatine kinase release and a higher rate of complete ST-segment resolution. A significant improvement of mean LV ejection fraction from 44 to 55% was observed after 3 months in hyperoxemic perfusion patients only. Therefore, the authors concluded that hyperoxemic perfusion using the aqueous oxygen technique is associated with LV function recovery .The first prospective, randomized trial of intracoronary hyperoxemic reperfusion after primary PCI was the Acute Myocardial Infarction With Hyperoxemic Therapy (AMIHOT I) trial published in 2007 . In AMIH2 and 79 were controls. The analysis was planned to include all patients from both groups in AMIHOT I meeting the AMIHOT II inclusion criteria for a pooled analysis, which finally included 124 control and 258 SSO2 therapy patients. There was no significant difference in MACE rate, neither in AMIHOT II alone nor in the pooled group. Regarding non-MACE adverse events, the rate of hemorrhagic adverse events was higher with SSO2 than in controls  predominantly attributable to access site related bleeding. However, at that time 9F sheaths were used in 53%, 8F sheaths in 22%, and 7F sheaths in 25% of patients. During the trial, the type of catheter used for SSO2 therapy did change accompanied by preferring a single unilateral instead of dual bilateral femoral artery access. This resulted in less access site bleeding complications on SSO2 during the later phase of the trial compared to the initial phase. On the ischemic site of events, the rate of stent thrombosis trended to be higher in the SSO2 group , but it has to be acknowledged that in AMIHOT II patients received early-generation drug-eluting stents  and the P2Y12 inhibitor used had been clopidogrel [2 therapy reduced infarct size determined after 14 days by 99mTc-sestamibi SPECT from 26.5–20.0% (adjusted p = 0.03). In the pre-planned pooled analysis form both AMIHOT-trials, infarct size was reduced from 25.0–18.5% (p = 0.02). Among 154 patients with a baseline LV-EF below 40%, SSO2 therapy reduced infarct size from 33.5–23.5%. Therefore, the overall conclusion from both AMIHOT trials was that intracoronary SSO2 infusion into the infarct-related artery following successful primary PCI is feasible and safe and reduces myocardial infarct size in patients with acute anterior AMI presenting within 6 h of symptom onset [2 therapy, this trial indicates that patients with apparent ventricular compromise (LV-EF < 40%) suggestive for larger infarct zone are the ones profiting most from the intervention.Based on the positive findings in the anterior AMI group treated within 6 h in AMIHOT I, a second prospective, multicentre trial (AMIHOT II) was conducted only randomizing patients with anterior AMI and symptom onset < 6 h prior to primary PCI and reported in 2009. Of 301 patients randomized in the intention-to-treat analysis, 222 received SSOpidogrel . In AMIHom onset . In addi2 directly via a guiding catheter in the left-main coronary artery evolved. Therefore, the IntraCoronary Hyperoxemic Oxygen Therapy (IC-HOT) trials was conducted. IC-HOT, published in 2019, was a single-arm, safety trial including 100 patients with anterior STEMI presenting within 6 h of symptom onset [2 delivery was successful in 98% of patients. NACE rate at 30 days was 7.1%. Infarct size was 24% at 4 days and 19% at 30 days. Therefore, the conclusion was that infusion of SSO2 via the left-main coronary artery was feasible and safe [To overcome the limitation of selective infusion catheters placed within the proximal segment of the infarct-related coronary artery, the idea of applying SSOom onset . The priand safe .The clinical findings observed in the three studies are summarized in ® system for application of SSO2 therapy in everyday clinical routine. In terms of practicability during acute STEMI treatment in the cath-lab, the SSO2 technique has one major advantage over other approaches aiming for infarct size reduction in large anterior MIs such as LV-unloading by Impella [2 therapy. While the assigned operator performed routine primary PCI, the core team set up the TherOx® system. After initial training, it was easily possible to exchange the femoral sheath in case of primary femoral access or to place the additional femoral 4F-sheath in case of a primary radial approach. The perfusion catheter, which is a 5Fr coronary diagnostic catheter, is rapidly placed in the left main coronary artery, while the TherOx® system is primed with blood, and SSO2 therapy can start within 4 min after the last angiography at the end of primary PCI. The patients tolerated the 60 min of SSO2 administration well. The downside in a busy cath-lab might be that the patients stay on the cath-lab table for one hour of SSO2 therapy.At Hannover Medical School, in March 2021 we had the opportunity to be the first in Europe to gain experience with the commercially available TherOx Impella  or thera Impella : the add2 in anterior AMI patients, all our patients undergo distinct imaging for LV function and detection of myocardial inflammation and necrosis using transthoracic echocardiography, cardiac magnetic resonance imaging and 99mTc- tetrofosmin perfusion SPECT [2 therapy. In the meantime, German authorities have demanded that prior to reimbursement a large randomized controlled trial with patient-relevant outcome measures has to be conducted to prove the additive benefit suggested by the previous smaller clinical trials.To evaluate further the potentially beneficial effect of SSOon SPECT ,48. Once2 therapy is easy to set up and applicable during standard clinical treatment of acute AMI patients by primary PCI. The application does not delay standard procedures prior to revascularization and can start within minutes after PCI.Overall, SSO2 therapy using aqueous oxygen demonstrated proof of principle in animals and showed feasibility and safety in humans undergoing primary PCI for treatment of acute anterior STEMI. While larger clinical trials powered to demonstrate reduction of major adverse cardiovascular events directly are still lacking, evidence from almost 360 patients indicates a potential to reduce infarct size at least in anterior STEMI receiving treatment within 6 h of symptom onset. Aggregate data from AMIHOT I, AMIHOT II, and IC-HOT suggest that SSO2 therapy might reduce infarct size in those patients from approximately 25 to 27% of the LV to about 19% of the LV [2 therapy, would reflect an approximate 17% reduction in all-cause mortality and heart failure hospitalization within 1 year. Considering 1-year mortality or heart failure hospitalization rates in these patients of 2–3% each, an adequately powered randomized controlled outcome trial would have to be unfeasibly large and, therefore, difficult or even impossible to conduct. Using infarct size in early presenting anterior STEMI based on the effects of the older trials, an adequately powered, randomized-controlled trial is feasible with approximately 200 patients per group.SSOf the LV ,45,46. N2 therapy. The earlier trials showed some development from trial to trial. AMIHOT I identified the anterior MI presenting within 6 h of symptom onset as the subgroup profiting most from the procedure [2 therapy had larger infarct size (33.5% vs. 16.5% of LV) than those with preserved LV-EF and SSO2 reduced infarct size by an absolute 10% [2 could translate into a clinical benefit of almost 36% regarding reduction of mortality and heart failure hospitalization within 1 year [2 therapy while avoiding selective catheterization of the left-anterior descending coronary artery by simply reperfusing hyperoxemic blood through a guiding catheter into the left-main coronary artery, making the procedure extremely easy and rapid to conduct [It will be important to identify patients who are ideally suited to profit from SSOrocedure . AMIHOT lute 10% . Identifn 1 year . Finally conduct .2 therapy is the least invasive one. Using Impella devices for LV unloading starting prior to and delaying revascularization requires a femoral 14F access [In comparison to other approaches aiming for infarct size reduction in AMI, which almost all focus on large anterior STEMI within 6 h of symptom onset, SSOF access . PerformF access . FurtherF access .2 through cooled blood providing additive intracoronary hypothermia [In the future, it might be interesting to see whether a combination of different approaches reducing infarct size in addition to primary PCI will provide additive benefit to the patient. However, this will require that the individual interventions provide a benefit on their own. Respective clinical trials are either on their way or in the stage of planning. Theoretically, it is appealing to think about combining these strategies, for example, by infusing SSOothermia  or applyothermia .2 therapy in acute STEMI is feasible and safe. It does not delay state-of-the art revascularization and can start within 5 min after the end of primary PCI. Earlier studies demonstrated an approximate absolute 6–7% reduction of infarct size in anterior STEMI, which translates into almost 20% reduction of 1-year all-cause mortality and heart failure hospitalization. However, an adequately powered clinical trial under contemporary PCI conditions is needed.In summary, intracoronary application of SSO


Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its influence on cardiomyocyte structure, function, and hormonal receptors when associated with heart failure is still unreported. Methods: Twenty-six consecutive patients with heart failure (LVEF < 40%) and normal coronaries and valves underwent left ventricular endomyocardial biopsy (EMB) for evaluation of myocardial substrate. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western blot analysis of myocardial aldosterone receptor and aquaporin-1 correlated with plasma aldosterone (AD) and renin activity (PRA). Eight patients with virus-negative inflammatory cardiomyopathy (ICM) had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy CM (6), alcohol CM (2), and diabetic CM (3) showed vacuolar degeneration and cloudy swelling of cardiomyocytes corresponding at electron microscopy to ions and water accumulation into cytosol, membrane-bound vesicles, nucleus, and other organelles, and was associated with an increased AD, PRA, and myocardial expression of aldosterone receptor (2.6 fold) and aquaporin 1 (2.7 fold). In the 8 patients recovered from ICM, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles and normalization of cytosol, nucleus, and cell organelles’ electron-density, along with down-regulation of aldosterone receptor and aquaporin-1. Conclusion: Human heart failure is associated with overexpression of myocardial aldosterone receptor and aquaporin-1. These molecular changes are paralleled by intracellular water overloading and cardiomyocyte swelling and dysfunction. Cardiac recovery is accompanied by down-regulation of hormonal receptors and normalization of cell structure and composition. The role of excessive aldosterone signaling in mediating cardiovascular damage is increasingly recognized by clinical and experimental evidence.Convincing data come from Rales , EmphasiThe aim of the present study was to evaluate the myocardial AR and AQ1 expression in human failing heart and after recovery and their influence on cell composition and function.Twenty-six consecutive patients with dilated cardiomyopathy and left ventricular dysfunction (LVEF < 40%) who from January 2019 to December 2019 underwent a left ventricular endomyocardial biopsy study for morpho-molecular characterization of myocardial substrate represented our patient population . At the The patient population (group A) was compared with a control group of 30 patients with mitral stenosis and normal LV size and function undergoing surgical repair (group B). A total of 8 of 26 patients with an amenable disease (virus-negative active myocarditis) had a control biopsy after cardiac recovery, obtained following 6-months of immunosuppressive therapy according to the TIMIC protocol .The study was approved by the ethical committee of our institution and all patients signed informed consent (patient population and controls).Fasting blood samples for plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were obtained in all patients. Patients were comfortably laying in a clinostatic position for at least half an hour. The assay for aldosterone (PAC) was performed with diagnostic kits . Normal ranges were 10–150 pg/mL supine and 30–320 pg/mL upright on a normal Na diet; intraassay and interassay coefficients of variation were both less than 5.6%, and the cross-reactivity of the antibody for aldosterone for other adrenal steroids was less than 0.001%. PRA was measured by radioimmunoassay (RIA) using commercial kits . The normal range sitting at rest and on a normal sodium diet was 0.2–2.8 ng/mL per h; intraassay and interassay coefficients of variation were within 8% and 10%, respectively. A cutoff upright PAC/PRA ratio (ARR) of less than 30 in the presence of aldosterone greater than 15 ng/dl and suppressed PRA was used as a screening test to exclude primary aldosteronism.Cardiac StudiesAll patients were evaluated with 2D-echocardiography, cardiac magnetic resonance (CMR), and invasive cardiac studies including coronary angiography and left ventricular EMB to clarify the etiology of cardiomyopathy. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western blot analysis of myocardial aldosterone receptor and aquaporin 1.Cardiac Magnetic ResonanceIn all patients, a standard CMR examination was performed with a 1.5T system  using a body and phased array coils. Scanning protocol consisted of the acquisition of TSE T2w-STIR, cine SSFP (steady-state free precession), and delayed enhancement (DE) sequences 12–18 min after gadolinium administration; on short-axis images, the left ventricle was completely encompassed from the base to the apex, acquiring a total of 10–12 images. T1 mapping imaging was also performed in all cases before and after contrast, using a modified look-locker (MOLLI) sequence acquired in short axis at basal, mid, and apical segments before and after contrast. All CMR studies were analyzed to consensus by two experienced observers blinded to the EMB results and using a workstation with dedicated cardiac software .Histology, electron microscopy and molecular studiesA total of 5 to 8 endomyocardial biopsy samples from each patient were cut and processed for routine histological analysis and for transmission electron microscopy (TEM). In those patients with inflammatory cardiomyopathy at histology, two frozen samples were processed for PCR for the most common cardiotropic viruses, including adenovirus, enterovirus, influenza A/B, parvovirus B19, cytomegalovirus, HHV6, HSV1, HSV2, EBV, and HCV. In addition, two myocardial fragments from each patient were processed for assessment of aldosterone receptor and aquaporin channels. For histological analysis, the endomyocardial samples were fixed in 10% buffered formalin and paraffin embedded. Five micron-thick sections were stained with hematoxylin & eosin, Masson trichrome, and Miller’s Elastic Van Gieson. For TEM, samples were fixed in 2% glutaraldehyde in a 0.1 M phosphate buffer at pH 7.3, post fixed in osmium tetroxide, and processed following a standard schedule for embedding in Epon resin. Ultrathin sections were stained with uranyl-acetate replacement stain  and lead hydroxide. A Jeol-1400-plusTEM was used for observation and photographic analysis. Assessment of myocardial aldosterone receptors and aquaporin channelsImmunohistochemistryThe expression of aldosterone receptor (AR) and aquaporins (AQP) was evaluated by immunoperoxidase using mineralocorticoid receptor monoclonal antibody  and Aquaporin 1 (AQP1) mouse monoclonal antibody  as primary antibodies. Intensity of immunostaining was semi quantitatively evaluated as absent (grade 0), weak (grade 1), mild (grade 2), moderate (grade 3), or strong (grade 4). For each patient, the grading was calculated on 10 different histological sections, and the average value was computed.Protein isolation and western blotHeart tissue samples were treated as described . The expStatistical analysis t-test, x2 test, and Fisher exact test were used for comparisons. Differences between variables with no normal distribution were tested with the Mann-Whitney U test. For all tests, a p value less than 0.05 was considered statistically significant.Normal distribution of variables was assessed with the Kolmogorov-Smirnov test. For continuous variables, descriptive statistics were provided , while median (interquartile range) was used for non-normal data. Categorical data were described as number (percentage). Baseline demographic and clinical characteristics are presented in table format. The Student Changes observed before and after immunosuppressive treatment were examined by paired t-test and McNemar test.To normalize target protein expression, the band intensity of each sample was determined by densitometry with ImageJ software. Next, the intensity of the target protein was divided by the intensity of the loading control protein. This calculation adjusted the expression of the protein of interest to a common scale and reduced the impact of sample-to-sample variation. Relative target protein expression could then be compared across all lanes to assess changes in target protein expression across samples. The change of AR and AQ1 expression in human failing heart and after therapy was calculated using the Wilcoxon matched-pairs signed-rank test.The statistical analysis was performed using SPSS version 25.0 for Windows .Twenty-six patients were included in the study; 20 were males (77%), median age was 58.4 ± 11.4 years. Comparison of baseline biochemical, clinical, and endomyocardial biopsy data among patient population (Group A) and normal controls (Group B) are shown in Cardiac studiesTwo-dimensional echocardiography showed a dilated left ventricle (LVEDD 61.5 ± 7.4 mm) with severely reduced ejection fraction (LVEF % 27.8 ± 5.8). Cardiac magnetic resonance (CMR) confirmed LV dilation (LVEDV 226.8 ± 69.6 mm) and dysfunction (LVEF % 26.3 ± 7.1)  [Histological diagnosis was virus-negative inflammatory cardiomyopathy in 15 patients (57.7%), idiopathic non-familiar dilated cardiomyopathy in 6 patients (23.1%), and in the remaining cases (19.2%), the etiology of heart failure was alcoholic cardiomyopathy (n = 2) and diabetic cardiomyopathy (n = 3) .In all patient population, regardless of the etiology of heart failure, histology showed an increased volume of cardiomyocytes, containing large intracellular vacuoles (vacuolar or hydropic degeneration) and a typical cell swelling (or cloudy swelling), as described by Virchow  Figure .At TEM, a number of subcellular changes were constantly present, all directly or indirectly related to the cell volume changes and water and ion accumulation. The size varied greatly, suggesting an abnormal dynamic in the fusion/fission process. Moreover, the distribution of mitochondria along the cell was highly irregular, being mostly grouped in large clusters, in contrast with the columnar arrangement seen in a normal myocardium , digitalis, diuretics in case of congestion, nitrates, mineralocorticoid/aldosterone receptor antagonists (spironolactone 25 mg daily), and if needed, antiarrhythmic drugs  In partiAll patients were clinically followed up at 6 months with ECG, echocardiogram, and CMR. As a consequence of optimized heart failure treatment, all patients showed an improvement in clinical status and better exercise tolerance. No patient died. In particular, LVEF in patients with dilated CM, alcoholic CM, and diabetic CM raised from 23.4 ± 4.2% to 30.1 ± 5.9%. Better metabolic control in diabetic patients and withdrawal from alcohol in diabetic patients contributed to clinical recovery.Patients with virus-negative inflammatory cardiomyopathy showed a more pronounced clinical benefit after the immunosuppressive therapy, with an increase in LVEF . CardiacA detailed description of the recovery of each cell compartment is shown in the Additionally, aldosterone receptor and aquaporin channels that were both equally overexpressed in heart failure were normalized after cardiac recovery  is activated, producing AQP1 expression and increasing water movements along the osmotic gradient .Role of Aquaporin-1 In the myocardium are present three AQPs: AQP1 is the most expressed, and AQ3 and AQP7 are expressed to a lesser extent ,24. AQP1Role of water and ion movements in damage production and its reversal+ channels , producing an intracellular Na+ (and anions) inflow with increased cell osmolarity that activates AQ1 channels with consequent water mobilization  and water overloading might negatively influence myocyte relaxation and contraction contributing to an impairment of diastolic and systolic cardiac function.In support of this interpretation, endomyocardial biopsies obtained after recovery of cardiac contractility show reduction in size as well as normalization of cardiomyocyte composition in parallel with the down-regulation of cell receptors. Noteworthy, myocardial edema was at least in part independent of the cause of heart failure. Indeed, patients with myocarditis as well as subjects with various types of dilated cardiomyopathy manifested the same histologic and ultrastructural findings correlated with cardiomyocyte water accumulation. This also suggests that the effect of AR signaling activation may also affect mesenchymal components of the myocardium, including vessels and fibroblasts, the swelling of which may contribute to the accumulation of water and ions in the extracellular space (edema). The Finally, our data confirm the negative impact of aldosterone pathway activation in the failing heart and the potential benefit from administration of aldosterone inhibitors.Limitations of the Study Our study, through sequential analysis of endomyocardial biopsies suggests that heart failure, independent of etiology, is associated with overexpression of AR and AQP1. A major limitation of the present study is that there is no definite proof of a cause-and-effect relationship between the molecular and the histological changes. Nevertheless, a previous report on endomyocardial findings associated with primary aldosteronism cardiomyopathy  showed sTo avoid a confounding effect on myocardial expression of AR, patient enrolment was limited to those subjects not taking aldosterone inhibitors. They started spironolactone only after histological and ultrastructural diagnosis and study.While the present study shows for the first time the ultrastructural myocardial changes associated with secondary aldosteronism, it is unable to quantify its impact in terms of impairment of cardiomyocyte relaxation and contraction, as well as its potential role in the generation of cardiac electrical instability.Further unanswered points are the quantification of structural and functional recovery inducible by aldosterone-inhibitors and the determination of their most appropriate dosage.Finally, novel experimental studies in human myocardial organoid or in animal models  are neceHuman heart failure is associated with a reversible up-regulation of myocardial AR and AQP1. These molecular changes are paralleled by intracellular ion/water overloading, (cell swelling and large vacuole formation and a number of changes in other subcellular components) and by a likely compromise of contractile function. For a cause/effect demonstration and a quantification of morpho-molecular effects of aldosterone inhibitors and their ideal dosage, further studies are needed.


Patients with end-stage kidney disease (ESKD) are often sedentary and decreased functional capacity associates with mortality. The relationship between cardiovascular disease (CVD) and physical function has not been fully explored. Understanding the relationships between prognostically relevant measures of CVD and physical function may offer insight into how exercise interventions might target specific elements of CVD. 130 patients on haemodialysis , recruited to the CYCLE-HD trial (ISRCTN11299707), underwent cardiovascular phenotyping with cardiac MRI (left ventricular (LV) structure and function, pulse wave velocity (PWV) and native T1 mapping) and cardiac biomarker assessment. Participants completed the incremental shuttle walk test (ISWT) and sit-to-stand 60 (STS60) as field-tests of physical function. Linear regression models identified CV determinants of physical function measures, adjusted for age, gender, BMI, diabetes, ethnicity and systolic blood pressure. Troponin I, PWV and global native T1 were univariate determinants of ISWT and STS60 performance. NT pro-BNP was a univariate determinant of ISWT performance. In multivariate models, NT pro-BNP and global native T1 were independent determinants of ISWT and STS60 performance. LV ejection fraction was an independent determinant of ISWT distance. However, age and diabetes had the strongest relationships with physical function. In conclusion, NT pro-BNP, global native T1 and LV ejection fraction were independent CV determinants of physical function. However, age and diabetes had the greatest independent influence. Targeting diabetic care may ameliorate deconditioning in these patients and a multimorbidity approach should be considered when developing exercise interventions.The online version of this article (10.1007/s10554-020-02112-z) contains supplementary material, which is available to authorized users.  Chronic kidney disease (CKD) is associated with progressive decline in exercise capacity and ability to perform activities of daily living, with patients on haemodialysis amongst the most sedentary of all patient groups . The reaIt is well documented that patients with end-stage kidney disease (ESKD) have significantly elevated CV risk . This exThe relationships between prognostically significant measures of CV disease (CVD) and physical function in patients with ESKD have not been fully explored. Establishing the CV determinants of physical functioning would offer insight into how exercise interventions may improve CV outcomes for these patients. This could guide development of studies seeking to mitigate CV risk through lifestyle interventions.This study investigated the relationship between prognostically relevant measures of CV structure and function, assessed with CMR and cardiac biomarkers, and objective measures of physical function in patients on haemodialysis. These data will offer valuable insight into the relationships between core outcome measures for haemodialysis patients, as identified by the SONG-HD initiative .The data from this study is taken from the baseline CMR scans and associated clinical, biochemical and physical functioning data of the 130 patients on haemodialysis recruited to the CYCLE-HD trial ISRCTN11299707). This was a randomised controlled trial investigating the impact of six months of intradialytic cycling on CV structure and function, assessed by CMR, in patients on maintenance haemodialysis. Inclusion and exclusion criteria were as previously described [299707. T2 peak, which is the gold-standard measure of aerobic capacity and associated with mortality in the haemodialysis population [The incremental shuttle walk test (ISWT) is highly correlated with V̇Opulation . The ISWpulation . The sitpulation , and haspulation .Field-tests of physical function were completed on non-dialysis days and not after the long-break. Trained research staff performed all assessments following standard operating procedures. For the ISWT, participants walked between two cones placed nine metres apart and walking speed was guided by a recorded bleep sound . The STSAll subjects underwent comprehensive cardiovascular phenotyping with a CMR scan and blood tests for circulating markers of cardiovascular disease. Left ventricular mass index (LVMi); LV ejection fraction ; LV massComplete LV and aortic functional analysis was undertaken on a 3T CMR platform  with an 18-channel phased-array receiver coil. To standardise participants’ volume status at time of assessment, scans were conducted on a non-dialysis day, but not after the long-break. The CMR protocols for acquiring LV cine imaging, native T1 maps, and PWV conformed to internationally recognized standards , 16. Sho42 , as previously described [Scans were analysed offline by a single blinded observer (MGB). LV structural and functional analysis, native T1 maps and GLS were analysed using the software package CMRescribed , 18. PWVescribed .LV volumes and mass were quantified with epicardial and endocardial short axis cines at end-diastole and end-systole. LV mass was indexed to body surface area. For T1 mapping, endocardial and epicardial borders were drawn on basal and mid-ventricular T1 parametric maps. The anterior right ventricular insertion point was defined to automatically divide the basal-ventricular and mid-ventricular slices. After removal of segments affected by artefact, an average T1 time for the whole of the myocardium was calculated from the mean of remaining segments. The average native T1 time for healthy control subjects on this scanner and analysed in this way is 1204 ± 38 ms. Tissue tracking analysis was used to define strain parameters. Global longitudinal strain was assessed by drawing endo- and epicardial contours on LV long-axis cines in end-diastole and defining the LV base and apex.Every ninth slice of the ascending and descending aorta was manually contoured and propagated using a gradient echo cine. Contours were mapped onto the phase-contrast cine, allowing the temporal shift to be determined. The cut made to define the axial slice for the phase-contrast sequences was superimposed on the sagittal–oblique cine and the average distance measured around the aortic arch. aPWV was calculated as described in Fig. 3 Serum-Gel treated tubes  to be centrifugated at 2500 × g for 15 min 20 °C. The serum was pipetted into 2 ml polypropylene micro tubes  before being stored at – 80 °C for later analysis. Analysis of hsTnI and NT-proBNP were completed in triplicate as per the manufacturer’s instructions .Blood samples were collected from the arterial needle before dialysis (but not following the long-break); 9.8 ml of blood was collected into two S-Monovette KRoutine clinical information was extracted from medical records. Routine biochemical and haematological data were collected prospectively as well as full past medical history.Statistical analysis was undertaken using R version 3.4.1 to fit both the univariate and multi-variable linear regression models. Normally distributed data are expressed as mean ± standard deviation and non-normally distributed data are expressed as median (interquartile range), with a log-transformation being applied for subsequent inclusion as an outcome in analysis. Comparisons between subgroups were made using independent t-tests for normally distributed data and Mann U Whitney tests for non-normally distributed data. Pearson correlations were used for correlations of normally distributed data and Spearman correlation coefficients for non-normally distributed data.Sixteen separate multivariate linear regression models were tested with each physical function test (ISWT and STS60) as the dependent variable and each biomarker of CV health as the independent variable. Models were adjusted for the following pre-determined variables known to influence performance in physical function tests: age , 20, bodBaseline patient demographics, CMR variables, circulating markers of CVD and completeness of datasets are shown in Table Results of the univariate analyses between biomarkers of CV health and the ISWT and STS60 are shown in Table On univariate analyses, troponin, NT pro-BNP, PWV and global native T1 were each associated with performance in the ISWT . There was some evidence of an association between left ventricular ejection fraction and ISWT, though not to the defined level of statistical significance (p = 0.06).Troponin, PWV and global native T1 were significant univariate associations with STS60 performance . There was some evidence of an association between NT-pro-BNP and the STS60, though not to the defined level of statistical significance (p = 0.06).The results of the regressions, adjusted for predetermined variables, between physical function tests and biomarkers of CV health are shown in Table NT pro-BNP, LV ejection fraction, and global native T1 were independent CV determinants of ISWT performance, when adjusted for age, diabetes, gender, BMI, ethnicity and SBP Table . For eveIncreasing age, female gender and having diabetes were consistently, significantly associated with worse performance in the ISWT (Appendix 3). Participants with diabetes walked 74–95 m less than those without diabetes.NT pro-BNP and global native T1 remained independent determinants of STS60 performance after adjustment in the multivariate models Table . For eveOf the adjusting variables, age and diabetes were significantly associated with STS60 performance (Appendix 3). Presence of diabetes was associated with four to six fewer stands in 60 s than those without diabetes.This is the first study to describe the relationships between prognostically relevant measures of CVD and physical function a in a well-phenotyped cohort of patients with ESKD receiving maintenance haemodialysis. Multiple CV biomarkers were significant univariate determinants of physical function. After adjustment, reduced global native T1, reduced NT pro-BNP and increased LV ejection fraction independently associated with better performance in physical function tests. Age and presence of diabetes had the strongest influence in the multivariate regression models. Consistent with previous literature, female gender was independently associated with worse ISWT performance .Limited exercise tolerance, as measured by the ISWT in this study, is a cardinal manifestation of CVD. On average, our cohort walked 220 m in the ISWT; this is considerably less than reference values for this age group in a healthy population (810 m) , but sim2 peak have been shown to be insignificant [In our population, higher LV ejection fraction independently associated with distance walked, despite the average LV ejection fraction being only at the lower end of normal. This could be attributed to the spread of values and could explain why the relationship is not particularly influential. If our population included more people with very low ejection fractions, the relationship may have been stronger. There have been no previous studies exploring the association between LV ejection fraction and ISWT performance in this population. The relationship between LV ejection fraction at rest and V̇Onificant , with chnificant . However2 peak across populations of people with cardiovascular disease and can reduce following programmes of exercise [NT pro-BNP is released in relation to atrial and ventricular dilatation and myocardial wall stress. It is an established prognostic marker in heart failure. Few studies have explored the relationship between BNP and the ISWT, with mixed results , 26. Howexercise . Our fin2 peak in patients with cardiovascular disease [2 peak found no significant association [Our study showed a statistically significant independent association between native T1 times, a measure of myocardial fibrosis, and metres walked in the ISWT . This is disease . The onlociation , althougociation . NeverthA large population-based study found healthy participants aged 55–59 years could do 36  to 41  repetitions of the STS60, a measure of lower extremity strength and endurance . Our cohThere have been no previous studies which have investigated the association between NT-pro-BNP and the STS60 test. An inverse relationship between BNP and muscle mass has been demonstrated in haemodialysis patients . It is pWe found that native T1 values decreased with increasing numbers of sit-to-stands in our ESKD population. There are no previous studies investigating global native T1 and STS60 or with other measures such as leg strength. However, in line with our findings, T1 values in the myocardium of endurance athletes are lower than in controls . The abi2 peak compared to similarly obese and sedentary individuals without diabetes [Participant age and presence of diabetes consistently had the greatest impact on the multivariate regression models. Those with diabetes performed significantly worse in physical function tests, in line with previous evidence . Cardiovdiabetes . The phediabetes . Unsurprdiabetes . Limitatdiabetes . Furtherdiabetes .It is unclear whether the pathophysiological dysfunction leading to poor physical functioning in diabetes is reversible. Interventions such as exercise training and improved glycaemic control can ameliorate subclinical cardiac dysfunction and may be a potential intervention in improving aerobic fitness in this population , 42. The2 peak). However, field-based tests can give more information about ability to perform activities of daily living and therefore may be more important to the patient. Some studies have found variables such as leg strength and lung function to be associated with physical performance, but such variables were not collected in the original cohort and therefore could not be included.Our study aimed to capture a holistic view of physical performance, by including tests measuring aerobic capacity and lower-extremity strength. In addition, the use of CMR and other biomarkers offers extensive CV phenotyping in this population. Our cohort are representative of a maintenance haemodialysis patient population in the United Kingdom, although females are relatively underrepresented. Field-based physical performance measures are considered a surrogate for ‘gold-standard’ laboratory-based measurements of physiological impairment Below is the link to the electronic supplementary material.


In a multivariate analysis, a delta of HRV5 > 23 ms was an independent predictor for LVEF improvement of ≥10% between prescription and 3-month follow-up. Patients with newly diagnosed HFrEF showed significant changes in heart rate, step count, and HRV5 between the beginning and end of WCD prescription time. HRV5 was an independent predictor for LVEF improvement and could serve as an early indicator of treatment response.The wearable cardioverter–defibrillator (WCD) is used in patients with newly diagnosed heart failure and reduced ejection fraction (HFrEF). In addition to arrhythmic events, the WCD provides near-continuous telemetric heart failure monitoring. The purpose of this study was to evaluate the clinical relevance of additionally recorded parameters, such as heart rate or step count. We included patients with newly diagnosed HFrEF prescribed with a WCD. Via the WCD, step count and heart rate were acquired, and an approximate for heart rate variability (HRV5) was calculated. Multivariate analysis was performed to analyze predictors for an improvement in left ventricular ejection fraction (LVEF). Two hundred and seventy-six patients  were included. Mean LVEF was 25.3 ± 8.5%. Between the first and last seven days of usage, median heart rate fell significantly ( Patients with heart failure with reduced ejection fraction (HFrEF) secondary to ischemic or non-ischemic cardiomyopathy may be at high risk for malignant arrhythmias and sudden cardiac death ,2,3 withIn clinical practice, patients with newly diagnosed HFrEF are typically discharged on starting doses of guideline-directed medical therapy and are scheduled for a follow-up visit after three months. However, in a significant fraction of patients, medication is not up-titrated to adequate target doses after the first three months . An earlThe aim of this study was to evaluate the clinical relevance of the additional telemetric parameters recorded and provided by the WCD and to identify potential early predictors of LVEF improvement at 3-month follow-up.The PROLONG-II study enrolled patients who received a WCD  at Hannover Medical School . The aimBaseline characteristics were taken at the date of WCD prescription, at the 3-month follow-up, and date of the latest follow-up, as available. Characteristics included medical history, clinical status, LVEF, and 12-lead ECG. LVEF was routinely assessed by echocardiography using Simpson’s method. All measurements were made in the same center by trained physicians, according to current recommendations for echocardiographic measurements ,20. All patients gave informed consent. The present study was conducted in compliance with the Declaration of Helsinki and was approved by the Ethics Committee of Hannover Medical School, Germany.WCD data were collected via remote monitoring, using an internet platform provided by the manufacturer  .Heart failure parameters included in the analysis were heart rate and step count, recorded in five-minute intervals. Data were monitored during the period of heart failure therapy optimization. Five-minute heart rate variability approximate (HRV5), a surrogate for beat-to-beat heart rate variability, was calculated as the cycle length standard deviation over all data points per 24-h period. HRV5 is closely related to the standard deviation of the average normal–normal intervals (SDANN), an established measurement of heart rate variability . When comparing the first and last seven days of usage, only patients with at least 14 days of wear time were included to avoid data overlap. Using the term “wear time”, following the specific criteria chosen by the WCD manufacturer, the first and last day of wear, as well as days with usage below fifteen minutes per day, were excluded. Regarding LVEF response, patients with an absolute improvement of at least 10 percentage points between prescription and 3-month follow-up were classified as LVEF improvers.Data extraction and merging were performed using R  and Python . Heart rate was calculated as the mean of a day, and step count was given as the sum of the day before further analysis. For heart rate and HRV5, data provided as value “zero” from the WCD were excluded from further analyses. Categorical variables are presented as numbers and percentages. Continuous data are presented as median and interquartile rate (IQR) or mean and standard deviation (SD) where appropriate. Heart rate (bpm) was converted to cycle length (ms) for further analysis. The Wilcoxon test was used for between-group comparisons. For correlation analysis, Spearman’s correlation coefficient was calculated. In order to illustrate the diagnostic ability of parameters, receiver operating characteristic analysis was performed.p-values < 0.05 were considered statistically significant.Three-day rolling averages of WCD-derived parameters were compared between baseline (day 3) and day 45. Optimum cut-off values for the change in HRV5, daily step count, and daily mean heart rate were identified through receiver operating curves (ROC) and YOUDEN’s J statistic. These parameters, along with other candidate predictors for LVEF improvement, were used as predictors in univariate logistic regression models. Significant predictors from the univariates models were then used as covariates in a multivariate logistic regression model. Statistical data analysis was performed using SPSS , R, and the pROC package for R . p-valueTwo hundred and seventy-six patients between April 2013 and December 2017 met the inclusion criteria for further heart failure parameter evaluation and were included in this analysis. n = 127), myocarditis (n = 22), peripartum cardiomyopathy (n = 21), or other origin (n = 4). Fifty-eight point seven percent (n = 162) of examined patients suffered from arterial hypertension, 22.5% (n = 62) from diabetes mellitus, 33.0% (n = 91) from dyslipidemia, and 21.7% (n = 60) from renal failure. Forty-three patients (15.6%) had a family history of cardiovascular disease. Mean NYHA functional class at prescription was 2.6 ± 0.8. Mean LVEF at prescription was 25.3 ± 8.5%. Eighty-eight (31.9%) of the patients were female. Mean age was 57.4 ± 15.3 years. Etiology was non-ischemic in 174 patients (63.0%) and ischemic in 102 patients (37.0%). Non-ischemic etiology majorly included patients with dilated cardiomyopathy  had a wear time of at least 14 days. One hundred and thirty-two patients wore the WCD for at least 90 days .n = 268) met ICD indication criteria after WCD-prescription time.Sixty-nine patients (25.0%) had a prolonged WCD prescription time after 3-month follow-up. Eleven patients (4.0%) received WCD shocks during the prescription period; all were appropriate shocks for ventricular tachyarrhythmias. There was a total number of 12 delivered WCD shocks. No inappropriate shocks were delivered by the WCD during follow-up. The heart failure etiology was non-ischemic cardiomyopathy in six patients (54.5%) and ischemic cardiomyopathy in five patients (45.5%). Two patients (0.1%) died during the prescription period. One hundred and thirty-three patients , while median step count per day (p < 0.001) and HRV5 significantly increased (p < 0.001)  .The results were independent of whether patients did or did not meet the criteria of ICD indication after the prescription time .Comparing the first and last seven days of usage, the median difference for the heart failure parameter heart rate was 2.8 (IQR −1.7–7.8) bpm. The median difference for HRV5 was 15.6 (−5.4–42.0) ms. The median difference for step count between the first and last seven days of usage was 712.6 (IQR −676.7–2763.6) steps per day. Executed analyses showed a significance in correlation analysis for several parameters, all associated with correlation coefficients < 0.5 points .As shown in In univariate logistic regression models, an increase in HRV5 of more than 23 ms, an increase in the daily average cycle length of more than 112 ms, and an increase in the daily step count of more than 1163 steps at day 45 were all significant predictors of ≥10% absolute LVEF improvement by three months. Other significant predictors of improvement were female sex, younger age, non-ischemic cardiomyopathy, and a lower baseline LVEF. When using the significant covariates in a multivariate regression, non-ischemic cardiomyopathy, lower baseline LVEF, and HRV5 increase were still significant predictors .Patients with newly diagnosed HFrEF show a decrease in heart rate, as well as an increase in heart rate variability approximate and step count during the first three months of heart failure treatment.A higher delta of heart rate or step count between the first and last seven days of usage correlates with a higher delta of the heart rate variability approximate.A delta of heart rate variability approximately >23 ms within the first 45 days of WCD wear time was an independent predictor of LVEF improvement.The present study evaluated for the first-time heart failure parameters recorded via the WCD in patients with newly diagnosed heart failure. The main findings are:This study is the first to analyze the parameters heart rate and step count, as provided and continuously monitored by the WCD additionally to SCD prevention. Patients with newly diagnosed HFrEF without meeting ICD implantation criteria were included in this analysis, representing a well-established indication for WCD prescription ,17,23. PSeveral population-based cohort studies have shown an association between a higher resting heart rate and cardiovascular mortality ,28,29,30In this study, patients showed a significant decrease in heart rate, most likely attributed to an early start of heart failure therapy. There is a further increase in heart rate during WCD-wear time after recompensation and during further heart failure therapy optimization. Data showed a positive correlation between the delta of heart rate and HRV5. Nevertheless, there was no significant correlation between the delta of heart rate and step counts per day. Furthermore, there was no significant correlation between heart rate and LVEF.Heart rate variability is a noninvasive method to assess the automatic nervous system function and the automatic activity in patients suffering from cardiovascular diseases . A higheIn this study, we calculated an approximate for the heart rate variability using the standard deviation of the cycle lengths of the given five-minute heart rate data, based on the heart rate variability component SDANN.We found a significant positive correlation between the delta of HRV5 and the delta of step counts per day between the first and last seven days of usage. A higher number of step counts per day suggests a higher amount of exercise per day. Results of this study are in line with previous studies, which have shown a correlation between exercise and heart rate variability ,41,42. TStep count monitoring is popular in the general population, using wearable devices such as smartphones, smartwatches, or wearable pedometers . Just asThe present study showed an increase in step count per day over time, which reflected an improvement in heart failure symptoms after initiation and up-titrating of heart failure medication. Moreover, a higher delta of step count per day between the first and last seven days of usage correlated with a higher delta of the LVEF, when measured at prescription and 3-month follow-up.In the present study, ischemic cardiomyopathy and a higher LVEF at baseline were shown to be independent predictors for an LVEF improvement of less than 10 points at the 3-month follow-up. In comparison, a delta of HRV5 >23 ms within the first 45 days of wear-time was shown to be an independent predictor for LVEF improvement >10% between prescription and 3-month follow-up. An improvement in LVEF with more than 10 percentage points between the beginning of prescription and three-month follow-up was used as the cut-off for LVEF improvement. The cut-off is comparable to the used cut-off in other studies for identifying responders to heart failure therapy . FurtherVia remote monitoring, it may be possible to closely monitor analyzed heart failure parameters in patients prescribed with a WCD. Analyzed parameters, especially heart rate variability, can be used for clinical decision-making during heart failure therapy. This process may improve heart failure management using the WCD.Patients with a significant change in HRV5 until day 45 may be more likely to be LVEF-improvers at the 3-month follow-up. Furthermore, LVEF improvers without reaching a LVEF > 35% at the 3-month follow-up may benefit especially from prolonged WCD-prescription time. Further, prospective studies are needed to confirm this result. On the other hand, patients without an adequate change regarding heart failure parameters, especially the improvement in HRV5, can be selected early. Lack of HRV5 improvement at 45 days could trigger additional interventions, such as additional in-office visits and more aggressive optimization of medical treatment for HFrEF to increase the possibility of LVEF-improvement and avoid ICD-implantation. In contrast to other remote heart failure monitoring systems ,49,50, nManagement of heart failure therapy and, therefore, LVEF at the 3-month follow-up may be improved, and the number of patients without a need of an ICD device may increase due to the possibility of closer monitoring of additional heart failure parameters.This study represents a real-world collective with the known limitations of retrospective analyses. In order to aim for robust and complete datasets, only patients with a wear time of at least 20 h per day were included in this study, resulting in a selection bias. Furthermore, heart rate variability data were only provided in 5-min intervals. Thus, we derived HRV5 as an approximate metric of heart rate variability.The WCD provides heart failure monitoring using additional parameters. Patients with newly diagnosed HFrEF showed significant changes in heart rate, step count per day, and heart rate variability during WCD prescription. Heart rate variability was an independent predictor for LVEF improvement and could serve as an early indicator of treatment response. Remote monitoring for heart failure parameters might be helpful for close monitoring and further HFrEF therapy optimization during WCD wearing.


As a medical student in a government medical school in Mumbai, I cared for patients with heart failure. I particularly remember a 63-year old man with ischemic cardiomyopathy. After instituting the guideline-directed management of heart failure, I planned for a defibrillator for primary prevention of sudden cardiac death. But the chasm between theory and practice was vast: he declined the defibrillator because the cost  was more than his annual income and he could not understand the value of an intervention that made no difference in how he felt. I don't know what happened to this gentleman after our brief connection years ago, but with the gaps between best medical practice and his care, I doubt he did well.,Much has changed in India over the 8 years since I came to the United States to pursue advanced training. The number of heart transplants has risen exponentially in India in the recent years, from 53 heart transplants in 2014 to 241 transplants in 2018 and 187 in 2019 .1 In facIn November 2019, a local Indian newspaper described how a donor heart was transported 200 miles to a Mumbai hospital in record 80 min, a distance that would take 5 hours by road. The feat required the coordination of multiple air-traffic control units as the helicopter with the donor heart traversed dense air-transport routes. The heart was successfully transplanted in an LVAD patient. This feat exemplifies India's enthusiasm, momentum, and untapped potential of heart failure innovation. Some of the challenges  may be insurmountable in short term, but others such as lack of health literacy, technology, infrastructure and advanced training among cardiologists can be corrected.The early history of heart transplantation is well-known: Dr. Christiaan Barnard performed the first heart transplantation in Capetown, South Africa on December 3, 1967. It is less well-known that the fourth surgeon to attempt heart transplant was Dr. Prafulla Sen in Mumbai, India on February 17, 1968.Recognizing the importance of transplant infrastructure, a 2011 amendment to the Transplantation of Human Organs Act defined the role of transplant coordinators and advisory committees.The National Organ and Tissue Transplant Organization (NOTTO) was established in 2014 to oversee the organ procurement and distribution. Prior to NOTTO's inception, organ transplantation in India lacked coordination, standardization and national oversight. Illegal organ trade was rife, resulting in multimillion-dollar scandals. Heart transplants were being performed sporadically at certain centers without national dissemination. Among its various functions, NOTTO is entrusted with maintaining the waiting list and post-transplant outcome data, bringing significant organization, legislation and transparency to the organ procurements nationwide. Since its commencement, NOTTO has instituted several policy guidelines and protocols that every transplanting center is expected to follow. The establishment of the Indian Network for Organ Sharing (INOS) in the state of Tamil Nadu improved the organ procurement rates and set a precedence for other states to follow. This has been further coordinated by NOTTO at the national level.Like any other country, the rate-limiting step in heart transplantation is the scarce supply of donor hearts. But in India, other barriers also exist. Rates of voluntary organ donation are low and approaching grieving relatives remains the major mode of donor identification. This is often fraught with poor awareness, religious misinterpretation or even taboo. Moreover, there is a lack of awareness among treating physicians regarding the availability of advanced heart failure therapies, reducing the referral of eligible patients to appropriate centers. Another highlight is the geographical disparity in donor availability and transplant rates, with transplants predominantly performed in southern India, largely due to religious beliefs and lack of health literacy in North India which preclude organ donation.In addition to mistrust and taboo, financial barriers are significant. Various hospital websites quote a starting cost from Rs. 20,00,000 , not including the expensive post-transplant care. In a country where the averageper-capita annual national income is estimated at Rs. 1,30,000 (USD 1800),https://www.mohanfoundation.org). Such campaigns strive to erase the religious stigma associated with organ donation. In addition, an India's Heart Failure Society was inaugurated in 2006 which evolved into the Indian Society of Heart and Lung Transplantation (inshlt.org.in). The society aims to create an awareness among medical professionals and the public regarding the developments in advanced heart failure therapies in India. In accordance to this goal, the society holds annual and midterm meetings with several hundred attendees. The Indian Heart Journal and the Indian Journal of Thoracic and Cardiovascular Surgery are at the forefront of recognizing the current and the ongoing advances in heart transplantation in India.However, India is working to overcome these barriers. In August 2018, India created a world record of over 24,000 organ donation pledges in one day, and then surpassed its own record in November 2019 with more than 54,000 pledges. This is enormous when one considers the previous record, held by United States, was 3200 pledges in one day. The feats were accomplished through awareness campaigns conducted in collaboration with NOTTO and non-governmental organizations (NGO) like the MOHAN foundation  option. Durable ventricular assist device implantation started in India in 2012 but further growth has been hampered by the paucity of financial, infrastructure and political backing.To sustain the current momentum of organ transplantation in India, further infrastructure is necessary, including recruitment of experienced cardiologists, surgeons, coordinators and infectious disease providers. Despite the rising transplant numbers, the enthusiasm has not been shared by cardiologists in training in India.When I began training in the United States, I would not have predicted the enormous advances in India in less than a decade. I recently cared for a 58-year old man in the United States with cardiogenic shock complicated by refractory VT. He required a percutaneous left ventricular assist device and later extracorporeal membrane oxygenation support to stabilize him to successful heart transplantation. The barriers I had experienced when caring for my heart failure patient in India did not exist: there was no concern for expense for this insured patient and he had full faith in the medical system. As he presents for routine clinic appointments, one would never guess that weeks earlier he was near death. I see him in clinic, but I think of my patient, years earlier in India. When I cared for him then, I was sure he would die of end-stage heart failure, not due to lack of effective therapies, but due to his inability to receive them. But thanks to improvements in infrastructure and awareness, I look forward to a future in India where a patient could present with end-stage heart failure and experience an outcome as joyous and miraculous.


Long-segment pulmonary atresia (PA), non-confluent branch pulmonary arteries, ventricular septal defect, tricuspid valve atresia (type 1A), and single ventricle physiology is a relatively rare and extremely heterogeneous form of congenital heart disease. This subset of patients having pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries (MAPCAs) have to undergo multiple unifocalization staging operations before a complete repair is attempted. Most of the patients were deemed inoperable. We report a rare case of a concomitant single-stage unifocalization and cavopulmonary anastomosis  in an adolescent cyanotic girl with tricuspid valve atresia (type 1 A), long-segment pulmonary atresia, non-confluent branch pulmonary arteries, bilateral patent ductus arteriosus, MAPCAs, and single-ventricle physiology. Reconstruction of the absent central pulmonary artery and non-confluent branch pulmonary arteries was achieved by dividing the bilateral patent ductus arteriosus feeding the bilateral pulmonary arteries. Functional single ventricle and major aortopulmonary collateral arteries (MAPCAs) still remain a surgical challenge in low-resource settings . While sWe report a case of a 10-year-old girl weighing 20.7 kg at the time of surgery who presented with complex cyanotic congenital heart diseases (late presentation) - tricuspid valve atresia (type 1-A), restricted atrial septal defect (ASD), large ventricular septal defect, long segment pulmonary atresia (PA), non-confluent branch pulmonary arteries, hypoplastic right ventricle, dominant left ventricle, MAPCAs, and single-ventricle physiology - was referred to our cardiac center. She complained of breathlessness and fatiguability gradually increased over time and which were aggravated by physical activity and relieved by rest. On examination, she had poor weight gain since birth and dyspnea on exertion (NYHA Grade 3) for five years. The patient had central as well as peripheral cyanosis and clubbing.She underwent detailed cardiological evaluation with 2D echocardiography, cardiac computed tomography dynamic study. Cardiac CT dynamic study revealed that the branch pulmonary arteries were non-confluent and had feeders from the aortic arch through short bilateral patent ductus arteriosus Figures -2. To plan further palliation, it was necessary to record pressure in the individual pulmonary arteries and it was attempted by pre-operative angiography/catheterization studies. Selective cannulation of collateral arteries/bilateral ductus was tried multiple times to enter pulmonary arteries but was not successful, and hence, the procedure was abandoned. With written informed high-risk consent and Covid-19 (RT-PCR) reports negative, the patient underwent complete single-stage unifocalization and concomitant bi-directional Glenn procedure with division and suturing of bilateral patent ductus arteriosus and atrial septectomy Figures -4. The e2 is 72-79% on discharge. Regular follow-up 2D echocardiography revealed well flowing right bi-directional Glenn shunt without any turbulence; good flow in the RPA and LPA: RPA 12 mm and LPA 9.4 mm with saturations ranging between 72% and 79%. Post-operative X-ray revealed no abnormalities  2 for better surgical results and to overcome myocardial edema. She had a stormy postoperative period with hemodynamic instability needing cardiopulmonary resuscitative (CPR) measures twice and hiking up of inotropic supports. She was extubated on a POD 6 after 168 hours. Oral feeds were started gradually and she was discharged in a stable condition and healthy wound. Her hemoglobin is 11.6 g/dl, total leucocyte count is 16.6 × 1000/µl, and SPOs Figure . Functionally single-ventricle physiology and MAPCAs highlight a significantly heterogeneous subset of patients. Though the mortality and morbidity remain high most of them can benefit from elective palliative surgery by eventually completing the Fontan circulation ,2. ComplPulmonary atresia with MAPCAs and single-ventricle physiology still remains a rare subset. MAPCAs, as an abnormality, are rather infrequent in practice. Rarely, case studies and series of patients with single ventricle and MAPCAs have been reported in the past. Three percent of all patients with right isomerism present with MAPCAs . HoweverConcomitant cavopulmonary anastomosis was performed owing to the fact that complete unifocalization was achieved in a very young patient with good perfusion in peripheral pulmonary arteries. Superior vena cava pressure was 15 mmHg after surgery and remained constant on follow-up. Stent implantation in highly stenotic MAPCAs to ensure adequate perfusion to the lung is an alternative in dealing with highly stenotic MAPCAs; in younger patients can be managed by stent implantation as an alternative where the pulmonary artery development cannot be bargained. What makes it technically challenging is the rare absence of central pulmonary arteries and it is very essential to provide adequate growth potential to the newly reconstructed pulmonary artery . Our patThe combination of pulmonary atresia, tricuspid atresia, MAPCAs with single-ventricle physiology is found to be an extremely rare presentation accounting for only a small percentage of all patients with MAPCAs. Most of these patients have been considered inoperable and the mortality is significant, which confirms that this group is a very high-risk group. On the other hand, we achieved a good pulmonary vascular bed by recruiting branch pulmonary arteries and achieved a low pulmonary vascular resistance in our patient to perform bidirectional Glenn shunt at this stage. Adequate counseling for the parents needs to be sought at every step in the process and the significant risk of death owing to coronary problems needs to be explained clearly. As per the literature, concomitant single-stage unifocalization and cavopulmonary anastomosis (Glenn shunt) should be contemplated in patients with univentricular physiology and tricuspid atresia and the pulmonary vascular bed can be achieved by unifocalization.