We aimed to validate CPO as a marker of LV SW min− 1 under various inotropic states.Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min− 1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVPmax) and maximal rate of rise of LVP (LV dP/dtmax).We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68 ± 1 kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0 °C, 38.0 °C and 40.5 °C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min− 1  while LV EF did not correlate at all . Further parameters correlated moderately with LV SW min− 1 . LV dP/dtmax correlated worst with LV SW min− 1 (r2 = 0.28).CPO showed the best correlation with LV SW minCPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU. Benefits of acquiring hemodynamic information by pulmonary artery catheterization (PAC) in conditions of critical illness are controversial. Following several neutral studies arguing against the survival benefit of hemodynamic monitoring by PAC in different populations of critically ill patients –9, the u− 1 measured via the invasive gold-standard (conductance method) has never been tested so far. The aim of the study was therefore to validate CPO as a marker of the actual LV SW min− 1 over a wide range of inotropic states. We therefore conducted a retrospective data analysis of previous animal studies from our group, in which we investigated the hemodynamic impact of mild hypothermia  and hyperthermia  by pressure-volume analysis in several porcine models of acute heart failure representative for patients in the ICU  and triple product (TP = RPP x LV dP/dtmax).The most comprehensive way to describe ventricular performance is pressure-volume analysis. Over the last decades, it became the gold standard to quantify cardiac function in vivo by providing measures that are reasonably load-independent, such as the end-systolic and end-diastolic pressure-volume relationships –17. Pres the ICU –24. LV SThe experimental protocols were approved by the local bioethics committee of Vienna, Austria , and conform to the “European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes” . Landrace pigs were ordered from Heinz Stelzl, Großklein, Austria, and were delivered to the Institute for Biomedical Research of the Medical University of Graz . The experiments were performed either at the Section for Surgical Research, Department of Experimental Surgery  or at the abovementioned Institute for Biomedical Research of the Medical University of Graz.n = 59, 68 ± 1 kg) were fasted overnight with free access to water and sedated with 0.25–0.5 mg kg− 1 midazolam  and 10–20 mg kg− 1 ketamine . The animals were intubated and anaesthesia was continued with 1.0–2.0 Vol% sevoflurane , 30–35 μg kg− 1 h− 1 fentanyl , 1–1.25 mg kg− 1 h− 1 midazolam, 3 mg kg− 1 h− 1 ketamine and 0.2 mg kg− 1 h− 1 pancuronium . Pigs were ventilated  with an FiO2 (Fraction of inspired oxygen) of 0.5, an I: E-ratio of 1:1.5, the positive end-expiratory pressure was set at 5 mmHg and a tidal volume (VT) of 10 ml kg− 1. The respiratory rate was adjusted constantly to maintain an end-expiratory carbon dioxide partial pressure between 35 and 45 mmHg. Under fluoroscopic guidance, all animals were instrumented with a Swan-Ganz catheter , and an LV conductance catheter . A 14-F sheath was introduced into the left femoral vein, and an intravascular cooling catheter connected to a cooling unit  was positioned with the tip at the level of the diaphragm in the inferior caval vein. The body core temperature was measured at the tip of the Swan-Ganz-catheter. After instrumentation, the animals were allowed to stabilize for 30–60 min.The experimental setup has been described before . BrieflyThe experimental protocols are summarized in Fig. Steady-state hemodynamics were obtained and averaged over three respiratory cycles. At each time point, volumetric conductance data were calibrated by measuring cardiac output (slope factor a) and hypertonic (10%) saline infusion  as described earlier , 27. At − 1, a single bolus of 15 mg kg− 1 adrenaline and biphasic defibrillation . Pigs  were assigned in a sequential 1:1 fashion to either normothermia  or MH  as shown in Fig. − 1 crystalloid solution and 8 ml kg− 1 hydroxyethyl starch  due to a substantial intravasal fluid loss. No further inotropes were given after ROSC  × 0.000133322LV SW minLV EF (%) = Stroke volume (SV)/End-diastolic volume (EDV)− 1) = HR x LVPmaxRPP (mmHg min2 min− 1 s− 1) = RPP x LV dP/dtmaxTP . A one-way ANOVA for repeated measurements was used to compare data within one group (group 4). Steady state data at different temperatures, before and during dobutamine infusion, were compared by two-way ANOVA for repeated measurements (group 5). Post-hoc testing was performed by Tukey’s test. Normality was demonstrated by the Shapiro-Wilks test or by visual inspection of normal probability plots. Nonnormally distributed variables were examined either by Kruskal-Wallis- or Friedman-Test. A p-value < 0.05 was considered significant. For statistical calculations, we used the software Sigmastat  and SPSS .All data are presented as mean ± standard deviation (SD). The correlations between LV SW and LV SW min− 1 and CPO spanned over a wide range of values, with the following means (ranges): CO 5.7 L min− 1 (8.2 L min− 1), CPO 0.94 W (1.75 W) and LV SW min− 1 0.99 W (1.88 W).Systemic hemodynamics from the experimental protocols are summarized in Table p < 0.05) in all animals and was significantly lower at MH than during normothermia or hyperthermia after each intervention. Dobutamine infusion increased heart rate at each temperature step.During mild hypothermia, heart rate decreased (p < 0.05).Mean aortic pressure decreased with all interventions and was more preserved during MH after myocardial infarction (In group 5 (DOB), CO and CPO decreased with cooling from hyperthermia to normothermia to MH and were increased by dobutamine at each temperature step Table . In grouSystemic vascular resistance increased with cooling from hyperthermia to MH and was decreased by dobutamine at each temperature step. Except for sevoflurane-induced myocardial depression, SVR was significantly higher during MH after each intervention.− 1 . LV EF did not correlate at all, neither with LV SW  nor with LV SW min− 1 . Other common parameters of cardiac function showed a statistically significant but moderate correlation. RPP  did correlate better than TP  with LV SW min− 1. LVPmax showed a similar correlation with LV SW , but correlated worse with LV SW min− 1 . LV dP/dtmax showed the worst correlation with both LV SW  and LV SW min− 1 . An additional file shows the correlations between CPO and LV SW min− 1 of each individual experimental group  resuscitation after ventricular fibrillation, 2) coronary no-reflow infarction, 3) endotoxemia by LPS-infusion, 4) sevoflurane-induced myocardial depression and 5) beta-adrenergic stimulation via dobutamine infusion at different core-body temperatures. We therefore investigated conditions ranging from hypo- to hypercontractile LV function. CPO showed a high positive correlation over the whole range of inotropic states with LV SW min− 1 measured via the invasive gold-standard (conductance method) has never been tested so far. Since pressure-volume analysis remains a time-consuming, complex and highly invasive measurement requiring additional equipment and expertise, the concept of deriving similar information by assessing CPO instead of LV SW is therefore quite attractive for the clinical practice. Being assessed as the product of cardiac output and mean aortic pressure and therefore combining the heart’s ability to create both pressure and flow, CPO describes the function of the heart as a hydraulic pump [− 1 under various inotropic states during acute heart failure. Of note, none of the experiments included LV output tract (LVOT) obstruction or aortic valve obstruction as well as severe stiffness of the aorta, which in turn would have increased LV SW min− 1 without changing CPO.The correlation between CPO, as measured by pulmonary artery catheterization (PAC) and invasive arterial pressure, and LV SW minlic pump . More prlic pump . Hence, lic pump –36. In tlic pump , 37. Thelic pump . AlthougAs abovementioned, CPO was shown to be the best predictor of intrahospital mortality in patients with cardiogenic shock . FurtherWe could clearly show that LV EF does not reflect external cardiac work over a wide range of experimental inotropic states representative for patients during acute heart failure. In clinical practice, LV EF plays a major role in the diagnosis and treatment of heart failure, as a surrogate marker of cardiac remodelling  and reve− 1. In our findings, we confirm a correlation between both RPP and TP with LV SW min− 1, with RPP having a better correlation than TP. The worse correlation of TP with LV SW min− 1 could be explained by integrating LV dP/dtmax into the calculation which is known to be a preload, afterload and heart rate dependent measure of cardiac contractility [max itself correlated worst with LV SW and LV SW min− 1.The rate pressure product and the triple product are both clinical indices of myocardial oxygen consumption and therefore regarded as indirect measures of cardiac work –52. Thusactility , 53–55. max alone correlated as good as the TP with LV SW, emphasizing the potential role of estimating LV pressure as a measure of the actual work done by the left ventricle in specific subpopulations of cardiogenic shock patients, i.e. under left ventricular assistance.Interestingly, LVPThe main limitation is the retrospective design of the study, meaning that the analysed data were not always part of the major outcome of the original studies. However, the quality of the original tracings has been reviewed by 2 independent investigators. Specific limitations related to the experimental setup from which these data were derived have been described earlier –24. AnotCPO is an excellent parameter of external cardiac work over a wide range of inotropic states, while clinically established indices to describe cardiac function, such as LV ejection fraction, rate-pressure product and triple product perform poorly.These data further support the use of CPO to monitor cardiac workload as well as the effect of inotropic interventions in critically ill patients in the ICU setting. Clinical studies will address the impact of CPO on improving patients’ survival.Additional file 1. Individual correlations of CPO (W) vs. LVSW min− 1 (W). Cardiac Power Output (CPO) significantly reflects Left ventricular stroke work per minute (LV SW min-1) over a wide range of inotropic states in each experimental group (Group 1–5). Groups are described as follows: a) group 1: resuscitation after ventricular fibrillation (RES); b) group 2: myocardial infarction by coronary microembolisation (CME); c) group 3: endotoxemia by LPS-infusion (LPS); d) group 4: sevoflurane-induced myocardial depression (SEVO); e) group 5: Temperature modulation from hyperthermia to mild hypothermia vs dobutamine (DOB). Any rise or fall of LV SW min-1 corresponds to an equivalent change of CPO.


Continuous-flow left ventricular assist devices (LVADs) improve survival and morbidity in patients with stage D heart failure. Management of LVADs for longer durations is necessary in some clinical settings, and a better understanding of the hemodynamics of patients using LVADs is warranted. Arrhythmia, including atrial (AA) and ventricular (VAs) arrhythmias, is a modifying factor of hemodynamics that is highly prevalent among patients with LVADs. However, the clinical impact of arrhythmias in various clinical settings in patients with LVAD, in which the hemodynamic load is likely to present as worsening of right heart failure, remains to be completely elucidated.We describe the case of a patient under sustained ventricular fibrillation for extraordinarily long duration who was stabilized using LVAD support and in whom newly developed atrial fibrillation led to a significant worsening of right heart failure while using an LVAD.This case demonstrates the substantial clinical impact of AAs in the management of right heart failure using an LVAD.The online version of this article (10.1186/s12872-019-1132-1) contains supplementary material, which is available to authorized users. In patients with medically intractable heart failure, continuous-flow left ventricular assist devices (LVADs) improve quality of life as well as survival and morbidity rates compared with conventional medical therapy . Althoug® Viva XT CRT-D; AAI 60) was implanted due to VF 7 years ago, and as a bridge to transplantation, a HeartMate II® LVAD was implanted 4 years ago. No arrhythmia developed immediately after LVAD implantation; thus, his CRT-D shock therapy was turned off immediately after LVAD implantation. At the time of LVAD implantation, his transthoracic echocardiographic study showed a significant decrease in the left ventricular (LV) contractility , dilation of left ventricle (51 mm in diastole) and trivial aortic regurgitation (AR) without opening of aortic valve but right ventricular (RV) contraction had maintained well relatively .A 47-year-old male developed heart failure due to dilated cardiomyopathy 12 years ago. A cardiac resynchronization therapy-defibrillator . These interventions reduced organ dysfunction, suggesting that minimum-required perfusion to vital organs was maintained even under sustained VF. The patient was followed up on an outpatient basis thereafter.Approximately 2 years after the development of sustained VF, paroxysmal AF was detected on the monitoring records of CRT-D, with a gradually increasing frequency. After 3 years of sustained VF, the patient was readmitted to our hospital due to worsening of symptoms associated with right heart failure and liver congestion . Although his electrocardiogram remained sustained VF Fig. , the CRTAdditional file 1 (MOV 108 kb)Additional file 2 (MOV 87 kb)Additional file 3 (MOV 148 kb)Additional file 4 (MOV 147 kb)Additional file 5 (MOV 133 kb)Additional file 6 (MOV 128 kb)Both AAs and VAs are common in patients with severe heart failure under LVAD support; furthermore, VAs have been reported in about 20% of LVADs patients , with soWe have reported the case of a patient who developed VAs 8 months after LVAD implantation and sustained VF for the following 4 years. To date, there have been several case reports revealing the tolerability of sustained VF under LVADs; furthermore, we have also experienced some cases of sustained VF without progressive organ dysfunction . However2 during a cardiopulmonary exercise test between patients with and without AF under LVAD support . In the sinus rhythm, LV and LA contracted regularly in turn (1) and rhythmic blood flow in the tricuspid valve was observed (2). There was no significant tricuspid valve regurgitation. In the sinus + VF rhythm, LA contracted regularly, whereas no visible contractions were observed by fibrillating LV . The regular mitral and tricuspid valve movements were also observed. In the AF + VF rhythm, no regular contractions of LV and LA were observed (5) and blood flow to and from the tricuspid valve was detected (6). The regular mitral and tricuspid valve movements could not be observed.


Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias. Underpinning these actions are complex but increasingly understood cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the vasculature. In clinical trials, PDE5 inhibitors improve symptoms and ventricular function in systolic HF, and accumulating epidemiological data indicate a reduction in cardiovascular events and mortality in PDE5 inhibitor users at high cardiovascular risk. Here, we focus on the translation of underpinning basic science to clinical studies and report that PDE5 inhibitors act through a number of cardioprotective mechanisms, including a direct myocardial action independent of the vasculature. We conclude that future clinical trials should be designed with these mechanisms in mind to identify patient subsets that derive greatest treatment benefit from these novel cardioprotective agents. Progression of heart failure (HF) is driven in part by maladaptive responses of cardiac muscle to pathological stress.PDE5is have proven safety profiles with low incidence of adverse cardiovascular events.PDE5is have consistently improved patient exercise capacity and ventricular function in trials of HFrEFAlthough there is additional interest in PDE5is in treatment of congenital heart disease, chemotherapy cardiotoxicity and hypertension, here we outline evidence behind PDE5i cardioprotection in HFrEF, HFpEF and MI. In particular, we highlight the direct myocardial actions of these novel cardioprotective agents, with a focus on translation of cellular mechanisms to clinical actions.2+ into the cell (ICa-L). This triggers a larger release of Ca from its intracellular store, the sarcoplasmic reticulum (SR), giving rise to an increase in cytosolic Ca termed the ‘Ca transient’, which activates myofilament proteins and elicits contraction. Ca transient amplitude is a major determinant of cardiac inotropy and can be modified by (1) changing the size of triggering ICa-L or (2) changing SR Ca content. The latter is determined largely by rate of Ca uptake via the sarcoplasmic-endoplasmic reticulum Ca ATPase pump (SERCA). While cellular Ca is tightly controlled in healthy myocytes via elegant feedback mechanisms,To understand the effects of PDE5is on cardiac function, we must first address the processes linking excitation of the surface membrane  to mechanical contraction of the cardiac myocyte, termed ‘excitation–contraction coupling’ .20 BriefICa-L.cGMP is an intracellular second messenger generated by guanyl cyclase in response to NO stimulation . cGMP acICa-L and SR Ca content via increased SERCA function. These effects increase Ca transient amplitude, and, when SR content reaches threshold, cause Ca waves leading to triggered arrhythmias. Under basal conditions, the majority of cAMP deactivation is achieved by phosphodiesterase-3 (PDE3). The PDE3 binding site also has affinity for cGMP, allowing cGMP to inhibit cAMP hydrolysis,Cyclic-AMP (cAMP) has broadly opposing effects to cGMP. It is generated in response to epinephrine and elicits inotropic and hypertrophic responses by activating protein kinase A (PKA). As such, cAMP increases Vascular effects of PDE5is likely contribute to its cardioprotective actions, although full appraisal is beyond the scope of this review. Vascular tone is largely determined by availability of endothelial NO, which diffuses to adjacent smooth muscle and stimulates cGMP production leading to relaxation and vasodilatation. PDE5is increase cGMP, inducing vasodilatation. While PDE5 is particularly highly expressed in penile vasculature, it is additionally expressed in pulmonary vasculature and at lower levels in peripheral vasculature including coronary.IKr prolonging repolarisation at highly supratherapeutic concentrationsIKr or IKs components of repolarisationClinical safety and epidemiological studies have established proven safety profiles for PDE5is which are now among the top 75 dispensed drugs in the USA.2).In small scale, randomised, double-blinded, placebo-controlled trials in patients with HFrEF predominantly on optimal medical therapy, treatment with PDE5is improved quality of life and exercise capacity . This was borne out in a pilot study by Lewis Improved contractile function, reduced chamber dilatation and reduced LVH are observed in a wide range of animal models of LV systolic dysfunction treated with PDE5is. These include mouse angiotensin II-induced HF,There is strong evidence that PDE5i remodelling is due to a direct myocardial action of the drug class. While peripheral vasodilatation could contribute via reduced LV afterload, systemic blood pressure (BP) reduction by PDE5is is small in HF and may indeed be negligible making this mechanism unlikely.without significant pulmonary hypertension, PDE5i improved LVEF at 6 and 12 months treatment with little or no effect observed during acute treatment.Clinically, in randomised placebo-controlled trials of patients PDE5is improve diastolic function both in animal models of systolic HF and clinical studies of HFrEF, although catheter-based assessments of diastolic dysfunction are lacking. In murine angiotension II-induced HF, sildenafil increased diastolic performance in addition to systolic, and reduced LVH.In a double-blinded, randomised, placebo-controlled trial of symptomatic HFrEF with echo features of diastolic dysfunction (45 patients), sildenafil improved diastolic mitral Doppler velocities and reduced ratio of early transmitral flow velocity to annular velocity (E/E′).et al found sildenafil improved cardiac function, associated with reduction in transforming growth factor beta markers.Evidence links cardiac dysfunction with inflammatory mediators in HF. A recent study demonstrated that sildenafil reduces levels of chemokine CXCL10 in T2DM and reduced CXCL10 protein and expression in cardiac myocytes.2 delivery, are largely unexplored but may pose a therapeutic target given that HF is accompanied by impaired coronary endothelial function, and PDE5is improve peripheral endothelial function in systolic HF patients.Finally, effects of PDE5is on HF coronary microcirculation, and thus OHFpEF, defined as clinical syndrome of HF with LVEF >50%, is characterised by concentric remodelling, fibrosis and stiffness of both myocyte and extracellular matrix components of ventricular muscle. Recently proposed HFpEF paradigms implicate multiple comorbidities including T2DM, obesity, hypertension and vasculopathy, causing a systemic proinflammatory state, coronary microvascular inflammation and compromised NO availability.et al.Early promise of PDE5is was suggested by a randomised trial of 44 patients with HFpEF by Guazzi et al used patients with confirmed pulmonary hypertension (PAP >40 mm Hg) and RV systolic dysfunction showed marked improvements in right-sided pressures, improved RV function and reduced dilatation. Improvement in LV diastolic function was more modest. In contrast, Redfield et al included patients with multiple comorbidity, most of whom had no significant pulmonary hypertension or RV systolic dysfunction. Thus, overall positive effects of PDE5is noted by Guazzi et al suggest efficacy on pulmonary vasculature and RV systolic function/remodelling, with smaller effect on LV function, and in the larger study by Redfield et al, with no RV systolic impairment or pulmonary hypertension, no benefit was observed. Taken together, PDE5is in HFpEF have shown marginal efficacy on LV performance, with any slight improvement in diastolic function offset by small but significantly reduced contractility. Some potential could exist in a select HFpEF subset with elevated PAP and RV systolic dysfunction, perhaps via a similar remodelling action to that seen in LV systolic dysfunction, although this requires clarity in larger-scale randomised trials. It is unclear why PDE5is induce remodelling in HFrEF but not HFpEF, possibly reflective of distinct signalling pathways. It is noteworthy that cGMP production in HFpEF is substantially reduced secondary to low NO bioavailabilitySeveral factors may reconcile differing outcomes between the Guazzi and Redfield clinical trials. First, Guazzi While sildenafil was initially trialled as an antianginal, discovery of its ‘side effect’ lead investigators to focus on safety rather than benefit in patients with cardiovascular disease. PDE5is are again being evaluated in MI and ischaemia–reperfusion.Several factors are implicated in the PDE5i cardioprotection in MI.PDE5is activate signalling pathways involved in preventing apoptosis  pulmonary vasodilatation in HFrEF-PHT, (2) LV remodelling through direct myocardial actions independent of afterload and (3) improved diastolic function. LV remodelling effects do not appear to be significant in HFpEF, and PDE5i use here may only benefit select patients with reversible pulmonary hypertension and RV systolic impairment. Second, PDE5is have acute negative inotropic effects in naive cardiac myocytes and in vivo which may limit utility in HFpEF. Finally, PDE5is compellingly reduce infarct size and have antiarrhythmic properties which, given the context of markedly decreased mortality in PDE5i users at high cardiovascular risk, requires clinical correlation in randomised trials. We propose this could be progressed further in a blinded, placebo-controlled trial of PDE5is in patients with LV impairment following acute MI, examining LV dilatation and remodelling.


LVOTO is defined as a peak instantaneous Doppler LV outflow tract gradient ≥30 mmHg, but the threshold for invasive treatment is usually considered to be ≥50 mm Hg3.About one-third of patients with hypertrophic cardiomyopathy (HCM) have resting left ventricular outflow tract obstruction (LVOTO). The presence of LVOTO in HCM facilitates the progression of heart failure and increases the risk of death3. There are different strategies of invasive treatment of LVOTO: 1) septal myectomy; 2) septal alcohol ablation (SAA) and 3) sequential DDD-AV pacing  improves symptoms in the majority of patients. However, a percentage of patients do not improve with medical therapy and need an invasive treatment. Invasive treatment to reduce LVOTO should be considered in patients with an LVOTO gradient ≥50 mmHg, NYHA class III-IV and/or recurrent exertional syncope in spite of maximally tolerated drug therapyV pacing . In this4.In medically refractory symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM) who are suboptimal candidates for septal reduction therapy, DDD pacing with a short AV delay is an alternative strategy. The mechanism of action of AV sequential pacing is not completely elucidated. Hypotheses to explain the beneficial effects include: 1) negative inotropic effect and reduced hypercontractility of the LV; 2) asynchronous septal activation and delayed septal thickening; 3) limitation of abnormal mitral valve motion; 4) interactions with LV filling, and 5) ventricular remodelling5–7. A European multicentre double-blind cross-over trial (the PIC study) in 83 patients of active vs. inactive short AV delay pacing demonstrated that active pacing was associated with a significantly lower outflow gradient, reduction in symptoms, and improved NYHA class and quality of life, with effect persisting at 1 year. Surprisingly, even pacemaker implantation without activation of AV sequential pacing lowered the LVOTO but subsequent activation of pacing in the same patients showed further reductions. Exercise tolerance was only improved in those with severe baseline impairment5.Three small, randomized, placebo-controlled studies of dual chamber pacing and several long-term observational studies have reported reductions in LV outflow tract gradients but a variable improvement in symptoms and quality of life6.Another randomized, double-blind cross-over study (the MPATHY study) with 48 patients confirmed significant benefit of pacing therapy on outflow gradient and quality of life score but without improved exercise capacity. There were some responders, but they were significantly older (69 ± 4 years) than non-responders (51 ± 16 years) and had a lower baseline exercise time and peak VO2 than non-responders. The authors concluded that DDD pacing might be an option for patients >65 years if they reject other therapeutic options7.Finally, in a Spanish study with 82 patients, sequential pacing in selected patients with HOCM improved functional class and reduced dynamic gradient and mitral regurgitation immediately after pacemaker implantation and at final follow-up. Prolonged ventricular pacing appeared not to have negative effects on systolic or diastolic function2 consumption8. Furthermore, one study has directly compared SAA with pacing and demonstrated superior gradient reduction with ablation9.These studies do not provide sufficient data to compare results on all-cause mortality, cost effectiveness, exercise capacity, quality of life, and peak O3.The conflicting data on both gradient reduction and functional capacity improvement mean that current clinical practice guidelines recommended sequential DDD pacing only for symptomatic patients who have contraindications for SAA or myectomy or are at high risk of developing heart block following SAA or myectomy. Sequential DDD pacing may also be an option for patients with resting or provocable LVOTO ≥50 mmHg, sinus rhythm and drug refractory symptoms, in whom there is an indication for an ICD or pacing for bradyarrhythmia10.Several studies have suggested that the effectiveness of pacing can greatly improved by individual optimization of pacemaker settings. Pacing parameters should be optimized to achieve maximum pre-excitation of the RV apex with minimal compromise of LV filling . Atrioventricular nodal ablation or modification has been advocated as a method for achieving optimal AV programming in some patients with a very short P-R interval11–16  or biventricular (BiV) pacing might further reduce the LVOT pressure gradient and improve symptoms in patients with HOCM and LVOT obstruction11–16 . Data ob11–16 15, in a pilot study, demonstrated that BiV or LV pacing were superior to RV pacing and was the best configuration for acute LVOT gradient reduction in selected patients with HOCM and sinus rhythm. Moreover, the best possible configuration obtained with BiV or LV pacing was associated with a progressive reduction of LV mass (reverse remodelling) and a significant improvement of symptoms, functional capacity, and quality of life. The magnitude of improvement in NYHA class, quality of life and functional capacity were superior to other long-term observational or randomized studies on DDD RV pacing in HOCM5,6,10,17.Berruezo et al.14–16 that have shown the beneficial effects of BiV pacing in HOCM optimized the A-V and the V-V intervals by echo after the implant. The optimal A-V interval was considered as the shortest AV interval that did not truncate the A wave on pulsed Doppler of the mitral inflow18.All studies15.With the optimum AV interval set, LVOTG reduction was tested consecutively during right ventricle (RV) pacing, LV pacing, or biventricular pacing . The optimal VV interval was selected on the basis of maximum reduction of LVOTG after a 5-minute equilibrium phase for each set up19.Unlike cardiac resynchronization therapy in dilated cardiomyopathies, the objective of BiV-pacing in patients with HOCM is to dyssynchronize the ventricular contraction and change the pattern of LV activation. LV/BiV pacing might be able to induce a supplementary reduction in LVOT gradient by an alteration in the contraction of a larger area of the LV. The reversed LV depolarization sequence [caused by pre-excitation of the LV posterolateral/lateral wall during LV/BiV pacing] may activate the longitudinally oriented epicardial fibers earlier, advancing the lateral wall longitudinal displacement with regard to interventricular septal longitudinal displacement20 analysed by echo the LV mechanical displacement of the patients with HOCM who were consider responders to BiV pacing. A responder was defined as one who had a follow-up gradient <50 mmHg and had a reduction in LVOT pressure gradient of at least 50% from baseline. Patients with HOCM who obtained a better response to BiV pacing had an inversion of the wall motion timing with an earlier displacement of the lateral wall and a delay of the septal wall. In patients who did not respond to the therapy this phenomenon was not observed. Therefore, the mechanical dyssynchrony induced by LV or BiV pacing which inverted the timing of LV wall activation plays an important role in the reduction of LVOT obstruction.Giraldeu G et al.By changing the timing of LV activation and inverting the LV wall displacement, BiV pacing might create changes in the diameter of the LVOT and geometry of the mitral valve apparatus resulting in the reduction of LVOT obstruction observed at short time. At long term follow-up, the LV reverse remodelling observed in these patients may play an additional role by the reduction of the septal and posterior wall thickness.21The optimal AV delay is defined as the shortest interval able to produce full ventricular capture by pacing (without fusion with intrinsic QRS) with no impairment of diastolic filling. Programming an optimal AV delay in practice, may be difficult since the AV-delay must be short enough to fully capture the LV and exclude fusion, but on the other hand, long enough in order to allow complete LV filling. Atrioventricular node ablation (AVNA) could be necessary to obtain complete ventricular pre-excitation without impairment of diastolic filling in these patients.BiV pacing changes the timing of LV activation, which delays contraction of the basal interventricular septum and therefore increases the systolic dimension of the LVOT, with secondary reduction in systolic anterior motion of the mitral valve. However, to be effective, pacing must induce a full ventricular capture (depolarization only caused by pacing) of the LV, because the septum is the first part of the myocardium to be depolarized by intrinsic conduction. AVN ablation ensures this mechanism, because it prevents the intrinsic depolarization of the interventricular septum.22.In the series of Berruezo et al. the mean LVOT gradient decreased from 80 ± 25 to 10 ± 17 mmHg at end follow-up in patients without fusion while there were no significant changes (from 81 ± 25 to 58 ± 32 mmHg) in patients with fusion. Patients with fusion also did not improve in symptoms. The observations of the present study confirm that the presence of fusion minimizes the benefit of pacing on LVOTG reduction, as well as on clinical improvementAfter echocardiographic AV optimization, ECG fusion is present in approximately 60% of patients with AS-BiVP and nullifies the benefit of pacing. In patients with ECG fusion, AVNA further reduces LVOTG. Atrial synchronous biventricular pacing (AS-BiVP), which ensures no ECG fusion by means of AVNA when needed, appears to be the optimal pacing mode for gradient reduction in HOCM patients and significantly improves functional capacity and quality of life .A basal 12-lead ECG is obtained to record the intrinsic PR interval and QRS morphology. After CRT implant, the device is programmed to VVI, BiV pacing with optimal VV interval defined by echocardiography, and pacing rate 10 bpm higher than the intrinsic heart rate. Then, a 12-lead ECG is obtained to record the morphology of the paced QRS without fusion. Finally, the device is programmed to optimized DDD, BiV pacing, with the optimal sensed AV and VV intervals defined by echocardiography. Then, a 12-lead ECG is obtained. Fusion between intrinsic LV depolarization and paced QRS will be considered when changes in duration, morphology or axis are detected in any of the 12 leads surface ECG of VVI paced QRS and QRS obtained after programming the device according echo optimization .23.A prospective, randomized, single-blinded, multicenter study named TRICHAMPION is designed to investigate the benefit of optimized atrial synchronous biventricular pacing in absence of QRS fusion in highly symptomatic HOCM patients with severe LVOT obstruction who are not candidates for ablative therapies. The results of this trial may answer several questions about the role and the optimization of A-V biventricular sequential pacing in these patientsIn selected patients with HOCM, and non-candidates for myectomy or SAA, sequential A-V BiV pacing is feasible and usually the best configuration for LVOT gradient reduction. Overall, BiV pacing in patients with HOCM significantly and progressively improves functional capacity, quality of life and may also induce LV reverse remodeling.It should be highlighted that the benefits of sequential DDD-BiV pacing in HOCM appear when fusion between intrinsic and paced rhythm does not exist after the device programming optimization, therefore a high percentage of these patients will required AVN ablation.


In pulmonary hypertension (PH), hypoxia represents both an outcome and a cause of exacerbation. We addressed the question whether hypoxia adaptation might affect the mechanisms underlying PH alleviation through phosphodiesterase-5 (PDE5) inhibition.2) for 0 , 2  or 4  weeks. The rats were treated (0.3 mL i.p.) with either saline or sildenafil (1.4 mg/Kg per day).Eight-week-old male Sprague-Dawley rats were divided into two groups depending on treatment  and were exposed to hypoxia (10% OP = NS), blood hemoglobin  and nitrates+nitrites , right ventricle fibrosis , right ventricle hypertrophy  and systolic pressure , pulmonary vessel density , and the frequency of small  vessels . Most of these changes were maintained for 4-week hypoxia, except blood hemoglobin and right ventricle hypertrophy that continued increasing . To further assess these observations, small vessel frequency was found to be linearly related with the right ventricle-developed pressure independent of hypoxia duration.Two-week hypoxia changed the body weight (− 31% vs. − 27%, respectively, Thus, although hypoxia adaptation is not yet accomplished after 4 weeks, PH alleviation by PDE5 inhibition might nevertheless provide an efficient strategy for the management of this disease. The pathophysiology of pulmonary hypertension (PH) includes progressive rising of the pulmonary artery pressure, with subsequent straining of the right ventricle (RV) thereby causing hypertrophy and leading to potential right heart failure and/or ventricular arrhythmias. In addition to the fact that PH contributes to the impairment of the pulmonary function with subsequent deterioration of the gas exchange, thereby causing systemic hypoxia, hypoxia per se also represents one of the main complications of PH, establishing an irreversible vicious circle, whereby PH causes hypoxia, which in turn exacerbates PH . HealthyThe design of the present study was focused on assessing if some of the mechanisms known to underlie alleviation of hypoxia-induced PH by PDE5 inhibition  are time2) as described previously  at both t2 (P < 0.05 vs. t = 0) and t4 (P < 0.05 vs. t = 2 weeks). A slight borderline effect of sildenafil was observed at t4 (P = 0.052).All the animals used in this study survived the protocols. Hypoxia markedly decreased the body weight at t2, the heart/body weight ratio increased by 60% in controls (P < 0.05 vs. t0) and did not change further at t4 (P = NS vs. t = 2 weeks), indicating no increase in myocardial hypertrophy after 2-week hypoxia. Sildenafil halved the progression of myocardial hypertrophy at both times . To follow up the effect on RV hypertrophy, we used the RV/(LV + S) ratio. This index increased markedly at t2 (P < 0.05 vs. t0 for both control and sildenafil), but the increase was less marked in sildenafil than controls (P = 0.007). At t4, the RV/(LV + S) ratio did not change appreciably in control hearts (P = NS vs. t2) but increased significantly in sildenafil hearts (P < 0.05 vs t2). Consequently, the difference between control and sildenafil decreased but remained significant (P = 0.046).At P < 0.05 vs. t0). Only a borderline (P = 0.058) effect of sildenafil was observed. At t4, the vessel density did not change appreciably vs. t2, but the anti-angiogenic effect of sildenafil became very clear (P < 0.0001).Two-week hypoxia augmented the vessel density in both the right and left lungs  and sildenafil (P = NS). By contrast, the RV systolic pressure nearly doubled at t2 in controls (P < 0.05 vs. t0), indicative of PH, with no change at t4. In sildenafil rats at t2, the raise in RV systolic pressure was markedly less  and was maintained at t4 . The end-diastolic pressure did not change appreciably at t2, but it increased significantly at t4. The increase was + 377% (P < 0.0001) and + 147% (P = 0.02) in control and sildenafil rats, respectively, with a highly significant difference between the two groups (P = 0.007). By contrast, + dP/dtmax and − dP/dtmax were significantly increased + 50–70% at t2 in both groups with no significant difference. At t4, sildenafil blunted the increase in + dP/dtmax vs. no significant effects in − dP/dtmax.Figure P < 0.0001 vs. control) and virtually zero for larger vessels. In no case, however, was there a difference between t2 and t4, indicating a stable situation.Figure P < 0.0001), the increase was markedly more pronounced in control vs. sildenafil rats , indicating that sildenafil has a strong anti-fibrotic effect in this model.Figure P < 0.05), as opposite to constant and increased p-eNOS/eNOS ratio in sildenafil-treated hearts (P = 0.01) and lungs (P < 0.0001), respectively. At t4, the situation remained stable, highlighting a protective effect of sildenafil in both tissues independent of hypoxia duration.Figure P < 0.05 vs. t0), but in sildenafil-treated rats, this effect was higher (P = 0.007). The situation did not change appreciably at t4.Plasma NOx concentration marks the blood NO storage level. Two-week hypoxia increased this marker in both control and sildenafil rats (P = NS). However, the best-fit slope increased markedly to + 2.352 ± 0.2563 (P < 0.0001 vs. zero) in the RV. Of interest, the relationship between the RV systolic pressure and the small vessels frequency was independent of hypoxia duration, indicating that the treatment with sildenafil could reduce the RV systolic pressure for both time durations.To further assess the effects observed above, Fig. In our observations, 2- and 4-week duration of hypoxia induced relevant non-lethal cell and molecular alterations. As expected, hypoxia impaired the homeostasis and increased blood [Hb] and NOx, and increased the degree of RV hypertrophy, the extent of pulmonary angiogenesis, the total number of small vessels in the lungs, and the values of RV systolic pressures, without any direct or secondary influence on LV pressures. Most, but not all of these changes, occur within 2 weeks and are essentially maintained unchanged at the 4-week interval. However, some of the variables investigated, including blood [Hb] and RV hypertrophy, continue to change with the extension of the duration of hypoxia from 2 to 4 weeks. Whereas augmenting [Hb] reflects a situation of ongoing hypoxia without complete adaptation, increased RV hypertrophy reflects the long-term morphological effects of pro-angiogenic and proliferative factors engaged during the first 2 weeks of hypoxia. Thus, although adaptation seems to be a process not yet completely accomplished after 4-week hypoxia, most of the myocardial and pulmonary responses to hypoxia are independent from the total process of adaptation.NO handling is of critical relevance because NO controls myriads of cell/molecular pathways relevant for heart and lung viability. For example, RV hypertrophy without lung hypertrophy, as well as the raise of RV pressure, without effects on LV pressure, has been associated with increased e-NOS phosphorylation in both hearts and lungs, and increased plasma NOx levels . RemarkaThe entity of the distribution of the vessels within the lungs is markedly depending on the diameter of the vessels. While the size of the small pulmonary vessels is affected by the degree of hypoxia and by sildenafil administration, the effects of both hypoxia and sildenafil are progressively diminishing in correlation with the size of the vessels. If we accept that the size of the vessel is associated with their degree of maturation, then this effect may be attributed to their maturation process. Although there is still disagreement about the molecular trigger of such process, the degree of phosphorylation of eNOS is most probably an important mediator; its persistent increase after 2 and 4 weeks of hypoxia in both the myocardial and pulmonary tissues of the sildenafil-treated rats reflects the angiogenic stimulus caused by hypoxia and the persistent correction of this stimulus by sildenafil.t2 and t4.The response to sildenafil, evident at both t2 and t4, can be considered to be due to the combination of the indirect effects on the RV function as a consequence of reduced afterload secondary to reduced pulmonary vascular resistance, as well as of the direct effect on the RV diastolic function. Whereas the effect of the afterload reduction was already well established , the capWith regard to the correlation between RV function and fibrosis, topic of controversies in the recent literature, it is important to evaluate presence, degree and distribution of fibrosis in the RV, as well as the duration of fibrosis. All these can influence not only RV systolic function, as generally studied and reported, but also diastolic function. Our observations, for instance, have proven the positive effects of sildenafil on RV diastolic function, regardless of the associated effects of the pulmonary vascular resistance, because the degree and distribution of RV fibrosis remained unchanged after 2 and 4 weeks. Masson staining is a reliable procedure to evaluate RV fibrosis . The resAs a consequence of the design of our study, the treatment with sildenafil was started simultaneously with the induction of chronic hypoxia, and we are fully aware of the potential criticism of missing the evaluation of the potential effects of sildenafil after establishing chronic hypoxia. On the other hand, the effects of sildenafil on pulmonary hypertension per se are well acknowledged. Moreover, the RV diastolic pressures, which could provide useful information in order to correlate the values of RV end-diastolic pressure with the degree of RV hypertrophy and/or of PH, were not recorded in this study because of logistic reasons.In this study, sildenafil was not compared with other pulmonary vasodilator drugs which recently have appeared on the market, because our aim was to specifically evaluate the effects of sildenafil, without adding other confounding factors.Sildenafil provides an efficient strategy for the management of RV hypertrophy, PH, and pulmonary remodeling, thanks to its effects on the pulmonary vasculature, facilitating improvement of the RV function, irrespectively of hypoxia adaptation. This finding suggests that sildefanil potentially could be used in the management of clinical settings characterized by pulmonary hypertension complicated by subsequent chronic hypoxia, as in PH secondary to congenital heart defects or acquired lung issues with chronic obstructive disease. Prospective randomized clinical trials are required to verify the applicability of this therapeutic strategy in patients.


Reliability of left ventricular function measurements depends on actual biological conditions, repeated registrations and their analyses.To investigate test–retest reliability of speckle-tracking-derived strain measurements and its determinants compared to the conventional parameters, such as ejection fraction (EF), LV volumes and mitral annular plane systolic excursion (MAPSE).In 30 patients with a wide range of left ventricular function , standard echo views were acquired independently in a blinded fashion by two different echocardiographers in immediate sequence and analyzed off-line by two independent readers, creating 4 data sets per patient. Test–retest reliability of studied parameters was calculated using the smallest detectable change (SDC) and a total, inter-acquisition and inter-reader intra-class correlation coefficient (ICC).p = 0.03) only for EF, while no significant difference was observed for any other LV function parameter. Mean intra-subject standard deviations were significantly correlated to the mean values for CS and LV volumes, but not for the other studied parameters.The smallest detectable change normalized to the mean absolute value of the measured parameter (SDCrel) was lowest for MAPSE (10.7%). SDCrel for EF was similar to GLS , while SDCrel for CS was much higher (35.6%). The intra-class correlation coefficient was excellent (> 0.9) for all measures of the left ventricular function. Intra-patient inter-acquisition reliability (ICCacq) was significantly better than inter-reader reliability (ICCread) , but was much higher for CS (35%). Surprisingly, reliability of GLS was not superior to that of EF. Acquisition and reader to a similar extent influenced the reliability of measurements of all left ventricular function measures except for ejection fraction, where the reliability was more dependent on the reader than on the acquisition. Evaluation of left ventricular (LV) function remains a crucial issue in clinical decision-making and risk stratification across different cardiac disorders. Recently introduced speckle-tracking-derived measures of myocardial deformation, mainly the global peak systolic longitudinal strain (GLS), have emerged as a new standard in the assessment of LV function, with the potential of complementing or even replacing ejection fraction (EF) due to the well-recognized examiner-dependency of the latter –4. GLS hEvaluation of the test–retest reliability in a real-life clinical setting is crucial to distinguish the effects of the disease  from the variability of the measurement. The variability of the measurement depends both on acquisition and reading variability and therefore is more complex, but also more realistic than inter-observer or intra-observer variability, which focus on repeated analyses of the same not-repeated registrations. Much more limited data exist on the test–retest reliability of functional left ventricular parameters than on their observer variability.The purpose of this study was to investigate test–retest reliability of speckle-tracking-derived LV strain measurements  and circumferential strain (CS)) and its determinants in relation to the conventional parameters, such as ejection fraction (EF) calculated from end-diastolic (EDV) and end-systolic volumes (ESV), and mitral annular plane systolic excursion (MAPSE), in a prospective study of patients with a wide range of left ventricular function.A total of 30 patients in sinus rhythm with different degrees of LV function impairment were prospectively recruited in the study. All the patients were referred from the Department of Cardiology or outpatient clinic, Uppsala University Hospital, for a routine transthoracic echocardiography for different indications and had acceptable acoustic windows. The rate of recruitment was determined by whether two of the three echo examiners  could acquire the data at the scheduled time in a patient fulfilling the above criteria. No other selection criteria were applied. The study was approved by the Regional Ethical Review Board at Uppsala University (Reference number: 2013/487).Standard two-dimensional apical four-, three- and two-chamber views, as well as a parasternal mid-papillary short axis view, were acquired independently and in a blinded fashion by two different, experienced echocardiographers in immediate sequence during the same examination, according to the study protocol. Both image sets (acquisition 1 and 2) were analyzed off-line by two independent readers blinded to each other´s results, creating 4 data sets per patient . In total, 60 acquisitions and 120 analyses were performed; see Fig. All views were obtained at a frame rate of at least 40 frames/s, recording three sequential sinus beats. After choice of the best beat, the endocardial borders were manually traced in the end-diastolic frame for automatic calculation of peak systolic global longitudinal strain (GLS) and circumferential strain (CS), and the resulting region of interest was visually checked for accurate tracking. For GLS calculation, the apical four-, three- and two-chamber views were used, while for CS the mid-ventricular short axis view was traced. We accepted automatic definition of aortic valve closure (AVC) by the software, on the basis of ECG-trigging. Echocardiographic images were acquired with a GE Vivid E9 Ultrasound system. According to recommendations from the American Society of Echocardiography and the European Association of Cardiovascular Imaging we excluded images with suboptimal tracking of the endocardium in more than two segments in one single view or if frame rate was below 40 Hz. Figure For sample size calculation, we assumed that intra-class correlation coefficients (ICC) would be 0.9 and required that the margin of error of a 95% confidence interval (CI) for ICC should be 0.07, i.e., the CI should be the estimated ICC ± 0.07. These conditions indicated a sample size of 30 patients.Categorical variables were presented as the number of patients and percentages. Continuous variables were presented as mean ± standard deviation (SD). From 2 acquisitions (acquisition 1 and 2) and 2 readings (reading 1 and 2) a total of 4 data values per patient were obtained.Reliability of measurements was measured in two ways see Fig. :Smallest detectable change (SDC) The square root of the intra-subject variability, which is the standard deviation of the four measurements within patients , was calculated. The SDC was then calculated as 1.96 × SEM, representing the minimal difference between the measurements that must be overcome to ascertain a true change or difference with a less than 5% chance of error. To enable comparison between parameters, the relative smallest detectable change (SDCrel) was defined as the ratio of the SDC to the mean value of the measured parameter.Intra-class correlation coefficient (ICC) for single measures. The ICC is defined as the ratio of the variance between subjects to the total variability which is the sum of between-subject and intra-subject variability. These variance components were estimated in a one-way analysis of variance model with patient as factor. We used Cicchetti’s guidelines for interpretation of ICC values [C values .acq) and two different readers analyzing the same acquisition ; see Fig. acq and ICCread for all the analyzed parameters was calculated and presented with 95% confidence interval and p value, assessed with jackknife technique.In order to separate and quantify the impact of acquisition and reading on the reproducibility of measurements, the ICC was calculated separately for two different acquisitions analyzed by the same reader  and IBM SPSS version 24 .For all analyses, two-sided n = 19) of the patients were males. For baseline characteristics see Table n = 18) of the patients. For mean values of the studied parameters in total and in separate data sets see Table Mean age of the study population was 60.6 ± 18.9 years and 63.3% (rel observed for volume-derived EF (14.2%). The intra-class correlation coefficient was excellent for all measures of the left ventricular function. For ICCs, their 95% CI, intra-subject SDs and smallest detectable changes, see Table The relative smallest detectable change among the conventional echo parameters was lowest for MAPSE (10.7%). Among strain parameters, the relative smallest detectable change was much smaller for GLS than for CS , but similar to the SDCacq) was significantly better than inter-reader reliability (ICCread) only for EF, while no significant difference between those components of test–retest reliability was observed for any other LV function parameter, see Table Intra-patient inter-acquisition reliability (ICCMean intra-subject relative difference (expressed as percent of the mean within the subject) between acquisition 1 and 2 after averaging of reading 1 and 2 for each acquisition (acquisition-effect) and the mean difference between reading 1 and 2 after averaging of acquisition 1 and 2 for each reading (reading-effect) for strain parameters, volume-derived LV function measurements and MAPSE in relation to the mean value of respective parameter within the patient are presented in Fig. With the exception of LV volumes, mean intra-subject standard deviations of EF, MAPSE and GLS did not correlate with their absolute values, indicating that the calculated smallest detectable changes could be shown to be independent (homoscedastic) of LV function impairment level; see Fig. In the present study, systematically evaluating components of test–retest reliability in a wide range of left ventricular functions and in a true test–retest clinical setting, we found a reasonable reproducibility for both GLS and conventional measures of left ventricular function. The smallest detectable change of GLS, EF and MAPSE ranged between 11–15% and was not dependent on the grade of LV function impairment. Importantly, GLS measurement did not show higher test–retest reliability than EF. Circumferential strain showed much poorer reproducibility. Repeated recordings had an equal impact on reliability of measurements as repeated readings for all the parameters except for ejection fraction, for which the variability was more dependent on the reader than on the acquisition.Reproducibility of measurements is pivotal for the clinical application of cardiac imaging, but has received much less attention than accuracy. Measurement data from cardiac imaging, including echocardiography, no matter how accurate, are only meaningful when we can be confident that they are reproducible in other examiners’ hands. However, such measurements inherently and inevitably have considerable measurement variability, which stems from differences in acquisition, in data processing, and in data interpretation, besides the possibility of biological variability of the “true” data, e.g., due to changes in heart rate, blood pressure, or cardiac function itself.An important component of measurement variability is test–retest reliability , which describes variability of separately acquired and interpreted echocardiographic measurements of the same patient, independent of “true” underlying biological variability. This is the typical clinical scenario for example for follow-up examinations or re-examinations of referred patients. The amount of test–retest reliability must be known in order to decide, with confidence, whether a recorded difference in functional parameters represents a “true” change in cardiac function or just reflects measurement variability.Echocardiographic measurements of left ventricular function, in particular left ventricular ejection fraction, have been known to involve substantial measurement variability. However, the vast majority of reported “inter-observer” and “intra-observer” variabilities reflect only the variability between different observers reading the same dataset, or of one observer reading the same dataset repeatedly. True test–retest reliability is clinically more meaningful, because it reflects more closely the reality of healthcare, but such data are comparatively scarce.Variability of conventional echo parameters in a test–retest setting was studied by Otterstad et al. , who ideSimilar test–retest reliability data from early 2D echocardiography were reported by Gordon et al. , who shoThavendiranathan et al. studied 56 females undergoing chemotherapy at 2 different time points assuming unchanged LV function between measurements evaluated by GLS. The authors reported the smallest detectable change  of absolute 13% for EF, 59 ml for EDV and 29 ml for ESV , which iLess reproducibility data than for volume-based measurements are available for longitudinal strain measurements including GLS. Although intra-observer and inter-observer variability of measurements performed on the same dataset has been assessed in many studies, few data on a true test–retest reliability exist, and these data are largely from patients with normal or near normal left ventricular function –18.rel) reported in our study, and the results are similar in case of GLS , while the variability of EF is lower (SDCrel 14.2%) in our study, equivalent to “relative mean error” of 7.1% for our study vs. 10.1% in Farsalinos’ study.Farsalinos et al. in the largest to date study designed for head-to-head comparison of GLS measurements among seven different vendors, examined a group of 62 volunteers with normal/near normal LV systolic function (average EF 60%) . During Kleijn et al. studied test–retest reliability of both volumetric parameters of LV function and 3 different global strain components, using three-dimensional speckle-tracking echocardiography. In a group of 50 patients with normal or mildly impaired EF, ICC for volume-based parameters was good (0.85 for EF), but only moderate for global strain parameters, however poorer for GLS than for GCS  . CalculaBarbier et al. reported test–retest reliability of strain and volume-based LV function parameters, when the same operator in random order read two image sets recorded during the same examination  in 40 patients with normal/near normal EF (average EF 52%). The variability of global longitudinal strain was slightly lower for GLS than for EF , which is in the range of our results . Interestingly, the measurement variability was higher in the lower range of EF, which is in contrast to our study showing no association between grade of measurement variability and LV impairment .Thorstensen et al., in a group of 10 healthy individuals, evaluated impact of repeated recordings (within 30 min) (inter-observer reproducibility) and analyses  on variability of LV function parameters . ReporteFirstly, variability of left ventricular function parameters is strongly influenced by the image quality. In the current study, we included patients with satisfactory quality of the images and with sinus rhythm, therefore the study population is selected. Secondly, the current study was performed using one manufacturer and software. Although only minor, significant inter-manufacturer differences have been described , 19, whiIn a test–retest setting, both with normal and impaired left ventricular function, the smallest relative detectable change of EF, GLS and MAPSE was similar (11–15%), but was much higher for CS (35%). Surprisingly, reliability of GLS was not superior to that of EF. Acquisition and reader to a similar extent influenced the variability of measurements of all left ventricular function measures except for ejection fraction, where variability was more dependent on the reader than on the acquisition.


Welcome to this special supplement devoted to the proceedings of the 3rd Annual Acute Cardiac Unloading and REcovery (A-CURE) Working Group meeting, which was held on November 9, 2018, in Chicago, USA. The A-CURE Working Group is comprised of leading academic experts in clinical and basic cardiac research who are dedicated to advancing the science and clinical application of acute cardiac unloading. This meeting brought together experts from multiple disciplines, including interventional cardiologists, heart failure specialists, cardiac surgeons, molecular biologists, and biomedical engineers. The 2018 Symposium featured talks and posters that highlighted cutting-edge advances in the field of acute cardiac unloading that have taken place since the conclusion of the 2017 A-CURE Symposium in Barcelona, Spain.Cardiac disease states such as myocardial infarction (MI), myocarditis, cardiomyopathy, and cardiogenic shock impair the ability of the heart to pump blood, resulting in end organ failure and, ultimately, death. Pharmacological therapies for these disease states aim to maintain cardiac output but, in the process, impose further stress on the heart. Additional treatment strategies are needed. The A-CURE Symposium focused on the basic science and clinical application of new technologies. Acute cardiac unloading decreases myocardial oxygen consumption and maximizes the ability of the heart to rest and recover after damage. Mechanical unloading employs percutaneous ventricular assist devices such as the FDA-approved Impella family of devices, to decrease the physical workload of the heart.This supplement features a number of presentations covering a broad range of subjects related to cardiac unloading. The first session of the symposium was devoted to the advances in basic and preclinical science of acute unloading and myocardial salvage. Topics discussed during the presentations ranged from influence of acute unloading on intercellular and inter-organ communication through exosome-based signaling to preservation of mitochondrial structure and function post-myocardial infarction (MI). New models of cardiogenic shock and investigations demonstrating enhanced collateral blood flow with acute unloading to reduce infarct size were also discussed.In the keynote lecture, James Udelson focused on the physiologic and pathologic basis of left ventricular remodeling and the lessons learned from clinical trials in the field of chronic heart failure.The second session of the symposium focused on clinical research programs of cardiac unloading. Wide spectrum of clinical studies presented included cardio-renal system interaction with effect of hemodynamic support on acute kidney injury, outcomes associated with adoption of standardized protocol for treatment in cardiogenic shock, and the first-in-man experience with the new Impella 5.5 heart pump.The afternoon’s presentations had a stronger focus on the clinical translation of left ventricular (LV) unloading. The temporal trends and patterns of the incidence of new heart failure (HF) post-MI and the potential of cardiac cell transplantation to fashion an external auxiliary circulatory pump were presented. The meeting concluded with two talks focused on the first exploratory study testing the safety and feasibility of LV unloading and delayed reperfusion, the door to unload (DTU) in ST-elevation in myocardial infarction (STEMI) pilot trial. The rationale, challenges, and learnings from the DTU in STEMI pilot trial were discussed.The presentations highlighted the exciting new developments and represent substantial advances in the field of acute myocardial unloading and recovery that have developed in the last year. The A-CURE Working Group meeting is unique in involving a diverse group of experts from multiple disciplines within an open, constructive, and intimate public setting.We hope that you find this supplement informative and interesting.Dr. Burkhoff commenced the meeting by stating the mission of the A-CURE symposium, which is to advance the science and mechanistic understanding of acute cardiac unloading and support the translation of basic and clinical research into therapies aimed at heart muscle recovery. He noted that since the inception of the A-CURE Working Group 4 years ago, the mission and application of the science has rapidly progressed into the clinical setting, particularly in reference to the recent completion of the Door To Unload in STEMI clinical trial, an idea initially proposed at the first annual A-CURE Symposium in 2016.Dr. Burkhoff presented a brief history of the A-CURE symposium, which began with the first faculty meeting in Paris in 2015. This was followed by the 1st Annual A-CURE Symposium in Rome (2016) and the 2nd Annual Symposium in Barcelona (2017). He added that following this year’s meeting in Chicago (2018), the next meeting will be held in Paris in 2019. He highlighted the steady year-over-year growth in attendees of the Annual Symposia.He guided the audience through a brief discussion of the proposed formal definition of left ventricular (LV) unloading. He put forth that LV unloading is defined as the reduction of total mechanical power expenditure of the ventricle which correlates with a reduction in myocardial oxygen consumption and hemodynamic forces that lead to ventricular remodeling . He emphWhile the concept of unloading has been discussed for decades, he highlighted that the scientific investigation and application of unloading emerged from the seminal work by E. Braunwald and M. Pfeffer in 1985. This team first demonstrated the benefits of LV unloading using captopril, an angiotensin-converting enzyme inhibitor, in a rat model of myocardial infarction (MI) . This prHowever, there are inherent limitations to myocardial unloading using pharmacological therapies. Importantly, more unloading of LV pharmacologically to leads to more compromise in aortic pressure and cardiac output. Hence, the use of pharmacological therapies has been limited as a route to LV unloading. On the other hand, use of a percutaneous ventricular assist device (pVAD) like Impella can simultaneously unload the ventricle, reduce the workload of the heart, and increase the end-organ perfusion while maintaining cardiac output. As early as 1992, Smalling et al. showed improved regional myocardial blood flow, LV unloading, and infarct salvage using the Hemopump in a dog-model of MI . Meyns e2) in the context of pressure-volume loops. MVO2 is linearly related to pressure-volume area (PVA). PVA is the sum of the stroke work and the potential energy, i.e. the energy that is stored in the myocardial filaments after contraction rather than being released as external work. It is also important to note that even when the heart is producing no external work, it still consumes energy, largely due to calcium cycling, but also due to basal metabolism. As drugs increase contractility, they increase the mechanical work of the heart resulting in increased MVO2, which is detrimental in the setting of MI where energy supply is limited. In addition, heart rate is another determinant of MVO2. Recent work by Sunagawa et al. demonstrated that the combination of mechanical unloading and ivabradine (a bradycardic agent), synergistically reduces MVO2 and significantly reduces infarct size in a dog-model of ischemia-reperfusion  or placebo . SubsequGiven the high rate of adverse events associated with ventricular remodeling post-MI, research efforts have focused on assessing the effect of drugs and devices in attenuating ventricular remodeling. Early work by Pfeffer et al. in a rat model showed that captopril therapy for 3 months post-MI attenuated LV remodeling and the deterioration of cardiac performance in chronic MI . FurtherResults from additional trials with ACE inhibitors and beta-blocker therapy post-MI and in HF, including the SOLVD and CAPRICORN trials, suggested a pattern of reduced LV volume and concomitant decrease in mortality. Along the same lines, the PRIME-II trial that investigated the use of the dopaminergic receptor agonist, ibopamine, in patients with chronic HF also showed increased LV volumes to be associated with increased mortality. These findings led to the attractive supposition that LV remodeling was a fundamental feature of the post-MI or CHF disease process and progression, and the effect of the intervention on remodeling may act as a “surrogate” for its potential impact on outcome . HoweverDr. Udelson discussed the use of biomarkers as potential surrogates for patient outcomes. Fleming and DeMets define a biomarker as a strong surrogate if: 1) it is in the causal path between an intervention and the outcome; 2) all intervention effects pass through the marker in the causal pathway; and most importantly 3), the effect of the intervention on the surrogate reliably predicts the overall effect on the clinical outcome . Of noteHowever, results from the CAST and ILLUMINATE trial have demonstrated that biomarkers that are prognostic are not necessarily good surrogates. Premature ventricular contractions (PVCs) are known to associated with unfavorable prognosis post-MI; however, in CAST trial suppression of PVCs was associated with increased mortality. Similarly, ILLUMINATE demonstrated that increased HDL was associated with increased mortality, counter to prevailing thought. Dr. Udelson cautioned that this danger was not just limited to biomarker use. Even successful outcomes in a phase 2 trial don’t necessarily predict successful outcomes in phase 3 trials. This was demonstrated by the opposite effect of vesnarinone on mortality in the phase 3 VEST trial compared to the preceding phase 2 trial. Since heterogenous pathways contribute to the progression of HF and resulting mortality, it is unlikely that any individual marker will be able to predict the clinical outcome of interest with precision. However, the magnitude of correlation of an intervention on a biomarker, and the effect of that intervention on longer-term outcomes should be quantifiable. Therefore, Dr. Udelson suggested that the change in a biomarker following an intervention should be viewed as a ‘probability signal’ of outcome effects, rather than as a precise surrogate. He highlighted the study by Kramer et al. that demonstrated a positive correlation between an intervention’s short-term effect on LV remodeling and long-term mortality in HF. This study concluded that the effect of interventions on LV remodeling can serve as a probability signal of the likelihood of a favorable, neutral, or adverse effect on long-term mortality .Dr. Udelson discussed strategies used by contemporary clinical trials to overcome the challenges such as huge sample size and contribution of only 10–15% of patients enrolled in the trial to the endpoint. He mentioned the use of hierarchical composites such as such as the Finkelstein-Schoenfeld method, and other analytic approaches including adaptive design and expedited access pathway to assess the outcome of an intervention using a reasonable sample size.In conclusion, LV remodeling is a stereotypical response to injury underlying pathology. Remodeling is associated with adverse outcomes and is a fundamental driver of HF progression. The remodeling response to an intervention provides a probability signal of the intervention’s response to the clinical outcome, and this concept can be leveraged into novel trial designs to enhance the likelihood of outcome response with smaller sample sizes.Dr. Westenfeld began by referring to the recent PRESERVE trial showing a lack of benefit of bicarbonate and acetylcysteine for prevention of contrast-induced acute kidney injury (CI-AKI) . This hiThe pathophysiology of CI-AKI is related to the decline in glomerular filtration rate (GFR) caused by renal vasoconstriction, oxidative stress due to reduced renal blood flow, and renal tubular cell damage. Many interventions aimed at preventing CI-AKI have been tested but the protective effect has been observed only in studies of low quality, and no effect of the intervention was observed in high quality studies. According to a recent publication by Vanmassenhove et al., only volume loading for prevention of CI-AKI has proven to be of value . Dr. Wesp < 0.05)  . This leDr. Westenfeld concluded by proposing a prospective “Protect Kidney Trial” to investigate the role of Impella in preventing CI-AKI in patients undergoing HRPCI.Cardiorenal syndrome type 1 refers to the condition of acutely decompensated heart failure (ADHF) leading to kidney dysfunction. During heart failure (HF) the presence of venous congestion can increase renal vein pressure and interstitial pressure which compresses Bowman’s capsule leading to a reduced glomerular filtration rate (GFR). A recent study from Ichiki et al. showed significant upregulation of several inflammatory cytokines, particularly in the renal cortex, in a canine model of HF, providing insights into the pathophysiology of kidney dysfunction in HF .Since several hemodynamic parameters influence kidney function, Dr. Kapur’s research team is investigating the effect of acute mechanical circulatory support devices on renal blood flow and function. Previously, Møller-Helgestad et al. compared the hemodynamics and blood flow to the kidneys with intraaortic balloon pump (IABP) versus Impella 2.5. They found higher renal blood flow (RBF) with Impella 2.5 and no change with IABP support . Studiesn = 4/group). Renal injury biomarkers, kidney injury molecular 1 (KIM1) and NGAL, were measured. Results showed that the urinary KIM1 levels were elevated in the IRI and VA-ECMO groups, but not the Impella group. No changes in plasma KIM-1 levels were observed in any group. Compared to baseline values, VA-ECMO increased urinary NGAL levels but Impella did not. Compared to IRI, Impella reduced plasma NGAL levels after reperfusion. Further, Impella reduced urinary Cystatin-C (Cys-C) levels from the baseline but VA-ECMO did not. No change in plasma Cys-C levels was observed between groups.Based on these findings, Dr. Qiao hypothesized that compared to Impella, VA-ECMO would increase levels of renal injury biomarkers in acute myocardial infarction. To test this hypothesis, adult male swine were subjected to left anterior descending artery (LAD) occlusion for 90 min followed by either immediate reperfusion (IRI), ventricular unloading with Impella for 30 min prior to reperfusion while on support, VA-ECMO support for 30 min prior reperfusion while on support, or sham-operated controls .Dr. Wiora presented results from his investigation into the effect of Impella support on contrast-induced acute kidney injury (CI-AKI) in patients undergoing high-risk percutaneous coronary intervention (HR-PCI). He reminded the audience that approximately 7% of all patients undergoing PCI experience AKI regardless of comorbidities , and theA recent study by Flaherty et al. was the first to demonstrate protection against CI-AKI by Impella 2.5 compared to no support in high-risk PCI patients. Interestingly, Impella 2.5 support was independently associated with a significant reduction in the risk of developing AKI during high-risk PCI . Dr. WioPatients in the non-Impella support group were older and had less compromised left ventricular ejection fraction (LVEF) than patients in the Impella support group. In the Impella group, the procedure time was longer with more number of lesions treated and stents implanted than the non-Impella group. Based on the Mehran risk score, CIN rates were predicted to be 25% with Impella support and 22% without Impella support. Interestingly, CIN was observed in only 11% of patients undergoing Impella-protected PCI compared to 31% in the non-Impella supported group Fig. . In addiIn conclusion, Impella use during HR-PCI was associated with a lower incidence of CIN compared to a propensity-matched unprotected control group. Use of Impella during HR-PCI is safe and feasible based on the low complications rates. Future studies will focus on the use of Impella during HR-PCI in patients with moderately reduced LVEF.Dr. Schäfer began by stating that acute myocardial infarction complicated by cardiogenic shock (AMICS) is a growing clinical challenge in clinical practice. Conventional therapeutic approaches using inotropic support with or without intra-aortic balloon pump have not improved outcomes. Retrospective studies have associated early identification and standardized treatment including early initiation of hemodynamic support with Impella followed by weaning of inotropes and complete revascularization with reduced mortality. Given the challenges of conducting randomized trials in CS and the lack of evidence on the efficacy of Impella from prospective trials thereof, Dr. Schäfer presented results from a retrospective analysis conducted by his research team in a contemporary cohort.First, he highlighted the recently published Hannover Cardiac Resuscitation Algorithm (HaCRA) for patients presenting with Out-of-hospital cardiac arrest (OHCA) and/or cardiogenic shock . The algn = 25) fulfilling the inclusion/exclusion criteria of the former IABP-Shock II trial was observed , highlighting the importance of a standardized algorithm for treatment of CS incorporating early use of active hemodynamic support using Impella.He then referred to a recent publication of 61 patients with cardiogenic shock (CS) supported using Impella CP for isolated left ventricular (LV) failure in the HAnnover Cardiac Unloading REgistry (HACURE) . CompariHe then presented the retrospective analysis of > 160 patients with AMICS treated at four dedicated European shock centers, fulfilling the inclusion criteria of the IABP-Shock II trial, mostly treated with Impella CP. Risk of mortality was calculated based on IABP-Shock II, CardShock, and SAVE scores. Cardiac arrest prior to Impella implantation was relatively common. Impella was implanted prior to percutaneous coronary intervention (PCI) due to the operator’s discretion. While overall, 30-day mortality for the entire cohort was still slightly above 40%, mortality was higher among patients undergoing resuscitation and among those receiving Impella post-PCI. The predicted in-hospital mortality was 69% by SAVE score, 40% by CardShock score, and 49% by IABP-Shock II score, respectively. The observed 30-day mortality with use of Impella devices was lower than the predicted mortality. Furthermore, the observed mortality was lower than predicted mortality even among patients in the high-risk subgroup.In conclusion, the results from these retrospective analyses encourage the use of active MCS by Impella devices in critically-ill patients with AMICS undergoing PCI and support the concept of early initiation of support prior to PCI.Dr. Bernhardt began by reminding the audience of the features of the Impella 5.0. This device is an established transaortic axial flow ventricular assist device capable of providing forward blood flow of up to 5 L/min. It was originally designed for femoral access but axillary access is increasingly used as it allows for mobilization of the patient. Recently, a published meta-analysis of Impella 5.0 reported favorable survival outcomes and high rates of myocardial recovery in patients with cardiogenic shock . ImpellaImpella 5.5 was developed to address the need for a longer duration of support with a low rate of complications. It is designed to provide hemodynamic support for up to 30 days. Like the the Impella 5.0, the Impella 5.5 device is an axial flow transaortic cardiac support device mounted on a 9 Fr steering catheter with a 21 Fr pump cannula Fig. . The pumDr. Bernhardt presented the first-in-man experience with the new Impella 5.5 in two critically ill patients . The firThe second patient was a 52-year-old male patient with ischemic cardiomyopathy and a history of coronary artery bypass grafting and mitral valve repair. Three weeks prior, the patient suffered an acute decompensation that was treated with Impella CP support for five days. After that episode the patient needed dialysis. He suffered a second decompensation due to ventricular arrhythmia, was resuscitated and placed on a veno-arterial extra corporeal life support (ECLS) through femoral vessel cannulation. The Impella 5.5 was implanted during the same operation. The arrhythmias were treated using catheter ablation under ECLS and Impella 5.5 support, and the patient was extubated. The ECLS cannulas were explanted under local anesthesia the day after the ablation procedure. During Impella 5.5 support, renal function improved and the patient was mobilized. Impella 5.5 support was continued uneventful for 21 days. A durable LVAD (HeartMate 3) was implanted and Impella 5.5 was explanted. The patient is ambulatory at 7 months post-Impella 5.5 implantation with improved creatinine levels and off-dialysis. Two additional patients have been treated using Impella 5.5 since. No pump-related adverse events has been observed.In conclusion, the Impella 5.5 expands the spectrum of available short-term mechanical circulatory support devices. New technical design features such as the absence of pig-tail helps minimize risk, and the optical pressure sensor aids in easy pump placement and monitoring. Early experience with Impella 5.5 in patients with no occurrence of pump-related adverse events indicate feasibility and safety of the new device.Dr. Kochar began by presenting the background of heart failure (HF) post-myocardial infarction (MI). Over half of contemporary MI patients are ≥65 years old. Despite decline in MI-related mortality in the past 2 decades, there has been an increase in the incidence of post-MI HF with significant long-term implications. The objective of Dr. Kochar’s research study was to identify the temporal trends and patterns of the incidence of new HF among older MI patients and evaluate the association of post-MI HF with long-term mortality and major adverse cardiac events (MACE).Dr. Kochar evaluated patients in the Medicare database between 2000 and 2013 who survived their first MI (based on ICD9 coding). Post-MI HF was defined as HF during index MI admission or a HF hospitalization within 1 year post-index MI admission. Outcomes assessed were HF hospitalization and all-cause death at 1 year and all-cause death and MACE  at 5 years. The incidence of post-MI HF was calculated at 1 year based on estimates from the cumulative incidence function. The 5-year implications of HF post-MI was evaluated by comparing patients with HF post-MI with patients without any HF within 1 year post-MI.The study population included 1,531,628 patients from 5948 hospitals. The mean age was 78 years, 49.7% were women, 64.6% had NSTEMI and 35.4% had STEMI. Among these patients, 36% had HF post-MI: 32.8% had HF during index MI and 10.4% had HF hospitalization post-MI within 1 year. The median time to first HF hospitalization was 66 days. The temporal trend from 2000 to 2012 suggests mild reduction in the incidence of HF during index hospitalization (34.7% in 2000 to 31.2% in 2012), HF hospitalization within 1 year (11.3% in 2000 to 8.7% in 2012), and 1-year mortality (22.5% in 2000 to 18.8% in 2012). Five-year mortality was 38.4% for patients without any HF, 66.2% for patients with HF during index admission only, 68.2% for patients with a HF hospitalization within 1 year only, and 79.7% for patients with HF at index admission and at least one HF hospitalization within 1 year  or 5 × 106 neonatal cardiomyocytes each (n = 22). The aorta was exposed through a retroperitoneal approach, and cardiomyocytes isolated from 2 day old neonatal Fischer rats of both sexes were implanted at the outer wall of the abdominal aorta at a site 3 mm above the renal arteries. Histological analysis showed viable graft formation in the outer wall of the aorta at 2 weeks in 9 of 10 rats and at 6 weeks in 9 of 9 rats in the cell-treated group. In comparison, none of the rats in the medium-treated group showed viable graft formation in the outer wall of the aorta. In addition, neonatal cardiomyocytes in the graft formed compact, longitudinally oriented cardiac muscle bundles, and were differentiated with cross-striations and a high degree of vascularization. At 2 weeks after transplantation, spontaneous rhythmic beating was observed at the grafted site following excision of the native heart in 7 out of 10 rats in the cell-treated group versus none in the medium-treated group. Further, pacing in a cell-grafted aorta increased aortic pressure by 5-fold from the baseline.Female Fischer rats received either medium only (n = 6) or 5 × 106 neonatal cardiomyocytes each (n = 6). The vena cava was exposed through a midline incision of the abdominal wall and cardiomyocytes isolated from 2 days old neonatal Fischer rats of both sexes were implanted around the vena cava below the renal vein.These results suggest that grafted neonatal cardiomyocytes can survive, differentiate, and develop blood supply with the ability to spontaneously contract within the outer walls of the aorta in the rats. Encouraged by these results, his research team investigated whether it is feasible to develop a vein that rhythmically beats by implanting immature cardiomyocytes in the wall in aorta near the vena cava . Female Histological analysis showed viable graft formation and maturation around the vena cava with cross striations at 3 weeks after transplantation. In addition, following aortic clamping and excision of the native heart, spontaneous rhythmic beating was observed at the grafted site at a rate different than the aortic rate in 100% of the cell-treated group versus none of the medium-treated group. The spontaneous beating rate of vena cava was 101 ± 7 beats at 1–3 min after excision of the native heart. Also, the diameter of the vena cava was reduced by 17.5 ± 5.4% when the grafted cardiac cells contracted. These results show that the grafted neonatal cardiomyocytes around the vena cava can survive, mature, and contract spontaneously.In conclusion, Dr. Kloner suggested that the potential of cardiac cell transplantation to fashion an external auxiliary circulatory pump should be further investigated.Dr. Kapur presented the purpose and learnings from the Door-To-Unload (DTU) in ST-elevation in myocardial infarction (STEMI) pilot trial using Impella CP as the mechanical left ventricular unloading platform. He began by providing the background for this trial. By the year 2030, 1 out of every 33 individuals in the United States will have heart failure (HF), and the associated total costs will reach $70 billion per year . For eveMaroko and Braunwald in 1971 suggested “that measures designed for reduction of myocardial oxygen demands and improvement of coronary perfusion, when effected promptly might reduce the ultimate size of  infarction” . Since 1Several studies spanning 4 decades have tested mechanical unloading using mechanical devices and demonstrated that unloading before not after reperfusion is required to reduce infarct size . Since 2In this phase 1, multi-center, safety and feasibility pilot trial, 50 patients with anterior STEMI were randomized (1:1) to LV unloading using the Impella CP followed by immediate reperfusion (U-IR) or delayed reperfusion after 30 min of unloading (U-DR) Fig. . ImpellaDr. Kapur highlighted that the DTU STEMI Pilot trial is the first step towards developing a physiologically integrated approach to acute AMI therapy. He further stated that the success of the DTU STEMI pilot and pivotal trials may pave way for testing additional investigations in conjunction with primary unloading, targeting both the ischemic as well as reperfusion injury to further reduce infarct size such as intravenous beta-blockade  and intrDr. Faraz presented a clinical case from the Door-To-Unload (DTU) in STEMI pilot trial. In this phase 1, multi-center, safety and feasibility pilot trial, 50 patients with anterior STEMI were randomized (1:1) to LV unloading using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 min of unloading (U-DR). Impella CP was explanted after a minimum of 3 h of support.The patient was a 62-year-old morbidly obese male with a history of smoking who presented with chest pains that started about an hour prior to presentation. The patient had experienced a vague epigastric discomfort two days prior that spontaneously resolved, but recurred with greater intensity and was associated with shortness of breath and diaphoresis. Baseline LV ejection fraction (LVEF) was 43%. This patient was enrolled in the U-DR arm of the trial. Following successful LV unloading and percutaneous coronary intervention, the patient was discharged home on day 3. At 30 day follow-up, the patient’s LVEF had improved to 55%. Dr. Faraz noted that immediately after initiating LV unloading with the Impella CP ST-elevation began to resolve and the intensity of chest pain experienced by the patient had reduced, which reassured him of the benefits of LV unloading.Dr. Faraz highlighted the challenges with enrolling and obtaining informed consent from patients experiencing anterior wall myocardial infarction (MI) for participation in the first exploratory study in humans testing the safety and feasibility of left ventricular (LV) unloading and delayed reperfusion as a method to reduce infarct size. He emphasized that choice of words regarding the purpose of the trial and positive reinforcement from the emergency department staff regarding the interventional cardiologist’s experience was vital in enrolling patients in the trial. He suggested a strategy of active 24/7 enrollment for the future pivotal trial and a dedicated champion at each clinical trial site to ensure coordination of multiple systems and processes needed for the successful completion of the trial.