In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin–angiotensin–aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems  and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated. In patients with heart failure (HF), various neuroendocrine systems may be activated and produce the often-noted tachycardia and concomitant increased systemic vascular resistance ,2. FurthAmong the three neurohumoral systems, more consistently one observes the elevation of catecholamines and SNS activation that are responsible for the excessive vasoconstriction, the persistent tachycardia and attendant cardiac arrhythmias  Figure . The excStudies propose that increased SNS neurostimulation with resultant elevated plasma catecholamines may account for a reduction in the density of the beta adrenergic receptors or downregulation of these receptors, within the failing myocardium . This maAn ostensible clinical picture that reflects the myocardial toxicity of excess of catecholamines, albeit reversible, is best illustrated in the case of pheochromocytoma . Similarchronotropic incompetence (CI), exercise intolerance and compromised exercise capacity in these patients that are associated with both central and peripheral autonomic derangements [Another important caveat in HF patients with heightened sympathetic activity concerns the development of ngements . CI is tTakotsubo syndrome (TTS) or stress cardiomyopathy or apical ballooning [Yet another prominent manifestation of catecholamine toxicity relates to the development of the llooning ,19,20. Tllooning . The annllooning ,22. A mallooning ,24. Its llooning ,22.Beta Blockers. In the animal model, denervation-induced depletion of catecholamines causes an elevation in the density of beta adrenergic receptors and restoration of physiologic responsiveness [siveness . In analsiveness ,27,28.The question whether beta blockers may furnish extra advantage in patients already taking aldosterone antagonists was addressed in the COPERNICUS trial of 2289 patients with severe HF treated with the beta1-beta2/alpha1 blocker carvedilol compared with placebo ,30. A poLimitations/Practical Issues. One limitation of beta blocking therapy in HF relates to the mode of initiation of such therapy, as one needs to start with low dosing in order to avoid HF worsening and acute decompensation [ensation .Another limitation relates to chronotropic incompetence (CI), the inability to adequately raise the heart rate (HR) from rest to exercise, frequently noted in HF patients, especially when receiving beta blocker therapy. CI may occur because of the downregulation of β-adrenergic receptors, β-blocker use, high baseline HR or a combination of such etiologies. Elevated norepinephrine levels in these patients contribute to altered chronotropic responses in HF patients and consequently result in compromised exercise capacity. One potential countermeasure to deal with CI in this group of patients could be rate-adaptive pacing, employing a sensor to track physical activity, without causing neurohormonal activation of the sympathetic system with its attendant consequences .Plasma arginine vasopressin (AVP) concentrations are high in patients with congestive HF and may participate in the disease progression via excess signaling at the V1a or V2 receptors ,33,34. IThere are three receptor subtypes that effectuate the actions of AVP  . The actVasopressin Antagonists/Vaptans. Many non-peptide AVP antagonists or “vaptans” have been produced and are being evaluated mainly for managing hyponatremia and fluid overload. Conivaptan is a combined V1-A/V2-receptor antagonist that induces diuresis and leads to hemodynamic improvement. In clinical trials, this agent has been found to restore euvolemic and hypervolemic hyponatremia and has been granted approval by the US FDA for the management of euvolemic hyponatremia as an intravenous infusion. Tolvaptan, a selective V2-receptor antagonist, has been successful as tested clinically in treating hyponatremia in volume overloaded patients with HF. The results are pending of a large CV outcome trial (n = 4133 patients) assessing its role in the treatment of HF. Lixivaptan and satavaptan (SR-121463) are other selective V2-receptor antagonists being assessed for the management of hyponatremia.Tolvaptan, conivaptan, lixivaptan and satavaptan are some of the vasopressin antagonists that have been tried in HF patients. The outcomes were initially promising with the relief of symptoms and adequate aquaresis without aggravating hyponatremia or kidney function; however, they did not succeed to demonstrate any influence on the death rate in HF . With thA hemodynamic study with the pure V2 antagonist tolvaptan indicated minimal hemodynamic influences . In anotSeveral clinical studies with tolvaptan as add-on treatment in acute HF have demonstrated advantageous effects on fluid balance and shortness of breath, with no deterioration in renal function or neurohormonal activation . SimilarImportantly, vaptans, which promote aquapheresis, appear useful in treating chronic nonhypovolemic hypotonic hyponatremia, as all four available vaptans  have been demonstrated to improve serum sodium concentration without altering renal hemodynamics ,40.With regard to the impact of vaptans on the death rate in HF patients, some studies were not powered to assess mortality, but a post hoc analysis of a study with tolvaptan (ACTIV in CHF) indicated a decrease in a short-term death rate . In keepp < 0.001) among all subgroups. Serum sodium was significantly increased by tolvaptan at day 1  and at day 7 or discharge . Dyspnea  and edema  improved significantly, whereas there was no difference in rales and pulmonary congestion. There were no important adverse events.Finally, a meta-analysis of eight RCTs examined the efficacy and safety of tolvaptan in treating HF in 13,453 hospitalized patients . There wRenin catalyzes the conversion of a plasma protein, angiotensinogen, which is produced in the liver, to create angiotensin I, a peptide with only mild vasoconstrictor effects . The angDuring its persistence in the tissues, angiotensin II raises blood pressure by two mechanisms that include vasoconstriction with an attendant rise in peripheral resistance and venous return and a concomitant diminution in the renal excretion of sodium and water, raising extracellular fluid volume, either directly and/or via the stimulation of aldosterone secretion from the adrenal glands . In HF, natriuretic peptides (NPs)   releasedCardiac remodeling is defined as a cluster of genetic, molecular, cellular and interstitial alterations that are set in place after cardiac load or injury, which results in increased heart volume and changes from elliptical to a spherical shape, leading to LV systolic and diastolic dysfunction . In patiCurrent guidelines recommend agents targeting this system, specifically in patients with HF with reduced ejection fraction (HFrEF), to extend survival and stabilize or reverse cardiac remodeling ,61. ThesACE Inhibitors vs. Angiotensin Receptor Blockers. Some investigators have suggested an advantage of ACEi vs. ARBs in treating HF, as in their meta-analysis, the data indicated that ACEi, but not ARBs, lowered the all-cause death rate and CV deaths [p = 0.001) and the respective value for the CV death rate was 14% . Interestingly, ARBs had no advantage in decreasing all-cause and CV death rate. However, in a head-to-head analysis, treatment with ACEIs was not superior to ARBs for all-cause and CV deaths.V deaths . Thus, tV deaths . Of all While the adverse effects of angiotensin II (Ang II) in HF are well established, the biological actions of angiotensin 1–7 (Ang 1–7) are less clear. Chronic administration of Ang 1–7 or its agonist AVE 0991 exerted important diuretic, natriuretic and kaliuretic effects in HF rats, but not in sham controls . Serum cAldosterone receptor blockade. In patients with mild–moderate HF, spironolactone decreased neurohumoral activation (as reflected by BNP levels) and an indicator of collagen turnover (PIIINP) but worsened renal function and quality of life [ of life . The ben of life . As ment of life . Importa of life . The cav of life . Neverth of life . Finally of life .Angiotensin Receptor–Neprilysin Inhibitor (ARNI). In recent years, the RAAS blockade has been refined by the introduction of the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides [peptides . The PARpeptides . Furtherpeptides .The introduction of ARNi has ushered in a new therapeutic era in managing HF patients with the intent to raise vasodilatory natriuretic peptides and avert counterregulatory activation of the RAAS. Indeed, ARNi treatment is very efficacious in lowering the risks of death and hospitalization for HF in patients with HF and New York Heart Association (NYHA) functional class II to III symptoms, but trials have failed to demonstrate any advantages with ARNi versus ACE inhibitors or ARBs in patients with advanced HFrEF or in patients after myocardial infarction with attendant LV dysfunction but without HF . These sAlthough HF with preserved ejection fraction (HFpEF) is a heterogeneous syndrome involving the interaction between heart diseases, comorbidities and ageing, the activation of neurohormonal axes is also implicated in its pathophysiology, particularly the activation of the RAAS and the sympathetic nervous system, albeit to a lesser degree compared with HF with reduced ejection fraction (HFrEF) . Thus, nNevertheless, as detailed below, recent data support the use of these agents in a wide range of HF, regardless of LVEF. Among 12,251 patients with HF with mildly reduced or preserved LVEF in the DELIVER and EMPEROR-Preserved trials, SGLT2 inhibitors lowered the composite endpoint of CV or first hospitalization for HF (HR 0.80) with consistent decreases in both components of CV death (HR 0.88) and first hospitalization for HF (HR 0.74) .Biomarkers, such as markers of the activation of neurohormonal pathways, that include the natriuretic system and the sympathetic nervous system, may all be used to better understand the mechanisms of HF drugs and also aid in the definition of subgroups of patients who might take advantage from specific therapies, irrespective of LVEF . ClassicCertain neurohormonal biomarkers  and cytokines  could predict survival in patients hospitalized for acute HF. It has been shown that measuring ET-1 levels provides significant predictive information on the risk of death after hospital discharge ,84. FurtNatriuretic Peptides. Among the various pathophysiological mechanisms that influence the secretion of the brain natriuretic peptide (BNP) in patients with HF, which include neurohormonal activation, cardiac dysfunction, myocardial stretch and elevated filling pressure, neurohormonal activation remains cardinal [cardinal ,86. Thiscardinal . The biocardinal .Natriuretic peptides (NP), the brain natriuretic peptide (BNP) and N-Terminal-pro-BNP  represent the most extensively employed biomarkers in HF patients; their role has been stablished in diagnosis and risk stratification in these patients ,89. TheyEndothelin. Among several biomarkers, endothelin-1 (ET-1) seems to be involved in many facets of the pathogenesis of acute HF including neurohormonal activation, endothelial dysfunction, cardiac remodeling, inflammation, atherosclerosis and altered renal function [function . Since ifunction ,84.Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2). GRK2 levels mirror myocardial β-adrenergic receptor function in HF and have been demonstrated to have additional independent prognostic information regarding ANS activation [tivation .Neprilysin. Neprilysin is a transmembrane endopeptidase implicated in the breakdown of various vasoactive peptides and may serve as a therapeutic goal in HFrEF. According to a study investigating the relation of circulating neprilysin with neurohumoral activation and the influence of plasma neprilysin activity on prognosis in HFrEF in 369 chronic HFrEF patients, no correlation was found between plasma neprilysin levels and neurohumoral activity  [p = 0.003) and the tertiles of the N-terminal pro-B-type natriuretic peptide levels (p < 0.001), whereas neprilysin levels did not . There was no link between plasma neprilysin levels and neurohumoral activity, as determined by absolute renin level  or norepinephrine concentrations . Neither circulating neprilysin levels nor activity were linked with the outcome. p = NS) . Plasma Plasma Renin Activity (PRA). The prognostic role of PRA as a specific neurohumoral biomarker of the RAAS and sympathetic activation pathways in HF was assessed in a population of 996 patients with HFrEF on optimal therapy treatment , who were followed up for a median 36 months (range 0 to 72) for CV death and appropriate implantable cardioverter device (ICD) shock [D) shock . A totalCatestatin. Catestatin is a multifunctional 21-aminoacid peptide involved in metabolic homeosta-sis and in the regulation of the CV and immune systems; it inhibits catecholamine se-cretion and thus mitigates the deleterious activity of the SNS [ the SNS . Catesta the SNS ,98. High the SNS .++ concentrations by direct inhibition of Ca++/calmodulin-dependent protein kinase IIδ activity and a consequent decrease in the phosphorylation of phospholamban and ryanodine receptor 2 actions which provide evidence for a direct functional role of catestatin in the failing heart [In the peripheral system, catestatin has a hypotensive effect by stimulating histamine secretion from mast cells, blocking catecholamine release from the sympathoadrenal system and producing vasodilation . Centralng heart .Heart failure is linked with enhanced sodium avidity and overload of extracellular volume, with its dire consequences of lung congestion and peripheral edema that may culminate into pulmonary edema or ascites and anasarca, respectively ; in such+ and water by the kidneys by blocking their reabsorption from the proximal and distal tubules and from the loop of Henle; however, these agents lead to substantial neurohormonal activation, resulting in the limited improvement in intravascular volume often observed with these agents. On the other hand, the proximal tubular site of action of the SGLT2 inhibitors might bypass these limitations. Empagliflozin produces significant natriuresis, particularly when combined with loop diuretics, causing an improvement in blood volume. However, renal dysfunction, off-target electrolyte wasting and neurohormonal activation have not been encountered [Sodium glucose cotransporter-2 (SGLT2) inhibitors or gliflozins improve HF-related outcomes and this beneficial influence occurs irrespective of the presence or absence of type 2 diabetes ,106,107.ountered . This adThus, SGLT2 inhibitors could be viewed as neurohormonal antagonists when prescribed for the management of HFrEF . Their bAs already mentioned, recent data support the use of these agents in a wide range of HF, independent of LVEF. Among 12,251 persons participating in the DELIVER and EMPEROR-Preserved trials, SGLT2 inhibitors lowered the composite endpoint of CV or first hospitalization for HF (HR 0.80) with consistent decreases in both the components of CV mortality (HR 0.88) and the first hospitalization for HF (HR 0.74) . In the Importantly, antiarrhythmic actions have been ascribed to SGLT2 inhibitors via various mechanisms including reverse atrial and ventricular remodeling, improved mitochondrial function, fewer hypoglycemic events with a consequent reduction in their proarrhythmic effects, curtailed SNS activity, better control of sodium and calcium homeostasis and shortening of lengthened ventricular repolarization .Neurohormonal Blockade in Older Patients with HF. As detailed above, due to the sustained neurohumoral activation that occurs in HF patients in response to compromised (systolic) pumping and/or (diastolic) filling properties of the heart, the clinical utility of neurohormonal blockers has revolutionized the management of these patients over the past 30 years. This neurohormonal blockade has led to reduced morbidity and mortality in this population, particularly in those with HFrEF and sinus rhythm [p = 0.033), but those having ≥50% of target dose had similar benefit with those who achieved target dose. The clinical outcome of beta blocker treatment was not dependent on the drug dose when the target heart rate could be attained.s rhythm . The surs rhythm . A potens rhythm . Half toRegistry data from 48,711 patients (aged ≥65 years) hospitalized with HFrEF have been recently analyzed showing important links between beta blocker and/or RAS inhibitor usage at hospital discharge and decreased 30-day and 1-year death rates, including in those over the age of 85  . FurtherWorsening Renal Function. Renal failure presents an obstacle and is a major challenge in managing HF patients. On the one hand, HF can compromise renal function due to decreased cardiac output and kidney perfusion, while HF medications may worsen renal function. The impact of HF medications on worsening renal function (WRF) and the link to outcome was examined in a post hoc analysis of TIME-CHF (NT-proBNP-guided vs. symptom-guided treatment in chronic HF) trial which comprised patients with LVEF ≤45% and ≥1 follow-up visits (n = 462) [p = 0.0002) and higher spironolactone dose (p = 0.02), while the doses of beta blockers (p = 0.69) were similar and the doses of RAS blockers were lower (p = 0.09). There were important interactions between WRF III, medication and clinical outcome. Therefore, WRF III conferred poor prognosis if increased loop diuretic doses were administered (p = 0.001), but not with low doses (p = 0.29). The opposite was true for spironolactone . A protective action of beta blockers was confirmed in all patients (p < 0.001), but mostly in patients with WRF III (p < 0.05 for interaction). RAS blockers led to better outcome (p = 0.006), regardless of WRF III. The authors concluded that increased doses of loop diuretics might have deleterious effects, particularly when combined with significant WRF, whereas spironolactone and beta blockers might protect these patients.n = 462) . WRF IIIWith regard to diuretics having an adverse effect on kidney function, one needs to consider this in light of evidence indicating that when a diuretic is used as part of combined HF management, the prognosis is improved . Indeed,interaction = 0.32) and PARAGON-HF . The influence of sacubitril/valsartan therapy was still consistent across a range of eGFR decreases. The authors concluded that the long-term benefits in HF remain even after a moderate eGFR decrease is observed when transitioning from RASi to sacubitril/valsartan therapy and early eGFR fluctuations should not influence treatment with sacubitril/valsartan or avert up-titration.A recent investigation where data from two RCTs (PARADIGM-HF and PARAGON-HF) were reanalyzed dealt with the caveat of worsening renal function when transitioning from the RAAS inhibitor therapy to ARNi therapy . Among pNeurohormonal Modulation in Heart Failure with Preserved Ejection Fraction. Although HF with preserved ejection fraction (HFpEF) is a heterogeneous syndrome resulting from the interaction between various CVDs, comorbidities and ageing, this type of HF is also characterized by the activation of neurohormonal axes, particularly of the RAAS and the SNS, albeit to a lesser degree compared with HF with reduced ejection fraction (HFrEF) [ (HFrEF) . Importa (HFrEF) .Neurohormonal Blockade in End-Stage HF. Finally, beta blocker and ACEi/ARB therapies have been applied and even conferred a reduction in HF recurrence and survival rate during the late period in patients with LV assist devices (LVAD) [p = 0.013) principally due to a 12.1% absolute decrease in HF-related hospitalizations (p = 0.046) attributed to a significant reversal in adverse myocardial remodeling and a decrease in morbidity and mortality versus LVAD support alone [p = 0.02) and a 6 min walk test (p < 0.001).s (LVAD) ,121,122.rt alone . Also, aNeurohumoral Blockade in Cardiac Resynchronization Therapy. Cardiac resynchronization therapy (CRT) has been shown to improve morbidity and mortality in patients with chronic HF on top of optimized medical treatment [p = 0.001) and beta blockers (p < 0.001) as well as therapy with lower doses of loop diuretics (p < 0.001) reduced the risk for the primary combined endpoint and for the all-cause death rate. Echocardiographic super-responders to CRT were able to receive higher mean dosages of ACEI/ARBs  and beta blockers . In the follow-up, the mean dose of loop diuretics was reduced by 20% in super-responders but raised by 30% in non-super-responders (p < 0.03). The authors concluded that, whenever possible, increasing neurohormonal blockade with the usage of higher dosages of neurohormonal blockers and lower dosages of diuretics had a beneficial effect with decreased morbidity and mortality after CRT implantation.reatment . A studyreatment . Over a As mentioned, CRT has been shown to improve cardiac sympathetic nerve activity in responders and thus lead to reverse remodeling . SimilarDietary salt consumption in patients with HF has been a controversial issue. Increased salt intake may cause arterial stiffness in susceptible individuals as it lowers nitric oxide (NO) release and increases endothelin-1 expression, overactivity of the renal SNS and also through aldosterone-independent activation of the mineralocorticoid receptor . Salt reNot only the high BP values are related to an elevated sodium consumption, but also arterial stiffness, oxidative stress and systemic inflammation seem to occur ,131. EleCombined anticongestive therapies in patients with HF is common clinical practice. A systematic network meta-analysis of 75 clinical trials encompassing 95,444 individuals indicated that combined treatment with an ARNi, beta blocker, MRA and SGLT2i was most efficacious in lowering all-cause mortality (HR: 0.39); followed by an ARNi, beta blocker, MRA and vericiguat (HR: 0.41); and an ARNi, BB and MRA (HR: 0.44) . The outnatriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), are useful as biomarkers to confirm the presence and severity of HF [As detailed above, ty of HF ,137. Howty of HF . Howeverty of HF ,139. Alsty of HF . This trty of HF ,141. Othty of HF . Geograpty of HF . Thus, ity of HF , such thty of HF ,145. In ty of HF . Howeverty of HF . In contty of HF . The finty of HF . In ordeSeveral relevant issues need to be addressed when attempting to use NPs for HF treatment . UnfortuCardiac arrhythmias in HF patients may relate to the imbalance of the autonomic nervous system (ANS) in these patients where there is preponderance of the SNS activity accounting for both atrial and ventricular arrhythmias ,153,154.There are more data available for the arrhythmogenic effects of the SNS, which, when overactive, can trigger atrial and/or ventricular “adrenergic” arrhythmias in susceptible individuals , while it can also reverse or negate the protective effects of the antiarrhythmic drugs ,155. HowSudden cardiac death (SCD) accounts for up to 50% of deaths in patients with HF  , dependiKs [Ks with its attendant clinical implications on electrical instability and arrhythmogenesis [As detailed herein, HF is associated with neurohormonal activation that includes sustained elevations in SNS and RAAS signaling, which lengthen the action potential duration (APD) and predispose to arrhythmogenic SCD via pathologic control of ion channels, including IKs ,164. In ogenesis . Importaogenesis . ImportaNa), calcium  and potassium currents  along with calcium-handling proteins, such as the ryanodine receptor, the sodium–calcium exchanger and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, in HF [Kr and the inward rectifier potassium current, the arrhythmogenic potential of reductions in IKs is amplified in HF [Ks contribute to the proarrhythmic effects of other calcium-related ion carriers that are activated in response to β-AR stimulation  [Furthermore, HF is also known to pathologically regulate a broad spectrum of ion channels and calcium-handling proteins, which contribute to HF-linked ventricular arrhythmogenesis. Prior evidence has pointed to pathological regulation of ventricular sodium  ,173.+-Ca2+ exchanger in end-stage HF; current data lend support to the hypothesis that enhanced Na+-Ca2+-exchange could promote malignant ventricular arrhythmias [Sympathetic overactivity may amplify the expression of Nahythmias . Thus, tAlthough the prediction of SCD in HF remains an unmet need, recent prospective cohort data indicate that the proportion of SCD in outpatients with HF seems to be lower than expected; whether this is the result of the implementation of guideline-directed therapies in HF remains to be shown .p = 0.01; I2 = 17%) [With regard to the impact of countering the RAAS on arrhythmias in HF, a recent meta-analysis of ten trials, including six RCTs and four observational studies /ARB group) indicated that over a median of 15 months, a considerable decrease was noted in the composite outcomes of SCD and ventricular arrhythmias in patients receiving ARNIs vs. those on ACEIs/ARBs  . ARNI th+/H+ exchanger (NHE) activity but also via the suppression of aberrantly enhanced late Na+ current and thus may participate in the prevention of SCD and/or VAs via the restoration of the lengthened repolarization phase in the failing myocardium. In keeping with their promising and favorable hemodynamic effects, a recent meta-analysis of 11 trials reporting on SCD in patients receiving SGLT2 inhibitors, indicated that these agents seem to have a favorable effect on SCD [p = 0.003; I2 = 0%). Nevertheless, further data will be needed from prospective trials in order to establish the long-term influence of SGLT2i agents on ventricular arrhythmias.With regard to the effect of SGLT2 inhibitors on SCD, the data are promising. The primary pharmacological action of SGLT2 inhibitors is to block the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to facilitate urinary glucose excretion . Many clt on SCD . SCD wasKs remodeling. Nevertheless, more research is required to examine the therapeutic potential of these new targets with regard to arrhythmogenic SCD, besides offering other avenues in HF therapies. The next therapeutic paradigm may comprise an integration of current and newer hemodynamic modulators with more patient-specific targeting of maladaptive molecular pathways.While aiming at the SNS and RAAS signaling in HF has beneficial effects ,179, novPatients with HFpEF. In patients with HF with preserved ejection fraction (HFpEF), SCD is responsible for about 25–30% of the all-cause death rate and 40% of the CV death rate [ath rate . The mecDevice Therapy. Although several editorials allege that guideline-directed therapy, of which the major part involves agents that counteract neurohumoral activation in HF patients, the risk of SCD remains crucial and despite a relative SCD risk reduction noted in HF trials, the residual risk is still substantial , which justifies the need for device therapy, either as an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) defibrillator (CRT-D) [ (CRT-D) ,183. Ind (CRT-D) .According to the latest (2021) European guidelines , ACEi orPer the latest (2022) American guidelines, guideline-directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF) should now comprise four medication categories including sodium-glucose cotransporter-2 inhibitors (SGLT2i) . These fThe neurohormonal activation is now recognized as one of the most important mechanisms underlying the progression of HF, and the therapeutic antagonism of the involved neurohormonal systems has become the cornerstone of contemporary pharmacotherapy for HF. In this regard, all three neurohumoral systems  seem to have a significant, albeit variable, role and impact in HF progression, prognosis and outcome , Table 1Although the activation of these neurohormonal systems preserves CV homeostasis in the beginning of HF and for the short-term, a plethora of studies, both pre-clinical and clinical trials, have demonstrated that the bioactive molecules generated by the activation of these three systems  are becoming toxic to the heart at higher levels. Thus, counteracting and blocking these molecules by respective agents such as the β-blockers, ACE inhibitors, ARBs, aldosterone antagonists and vaptans, and more recently with the use of ARNIs, can negate the deleterious consequences of such neurohormonal activation. The recent use of the novel ARNI drug class has led to superior efficacy of multiple-acting neurohormonal blockade in chronic HF. Some of these agents also restore the imbalance between endogenous vasoconstrictors (such as angiotensin II) and vasodilators (such as the natriuretic peptides) that emanate from sustained neurohormonal activation. However, although neurohormonal antagonists aid in the stabilization of the symptomatology of HF and enhance reverse LV remodeling, the “remission” from HF is self-limiting and symptoms eventually recur. Thus, although the hypothesis of the neurohormonal activation has greatly expanded our understanding of the HF syndrome, this model does not fully explain and justify the disease progression. Further studies focusing directly on individual biological mechanisms and components of the neurohormonal axes participating in LV remodeling might furnish new insights into the pathophysiology of HF progression and usher in and guide the development of newer remedies. Finally, patients with HFpEF and HF with concomitant AF represent major remaining clinical challenges that seem to be less responsive to current pharmacotherapy. Novel neurohormonal blocking agents and the refined use of current drugs, as well as up-titration to recommended target doses, are direly needed to curtail the adverse clinical events and to ameliorate the outcomes in HF.


Oxygen consumption is an important index to evaluate in cardiac patients, particularly those with heart failure, and is measured in the setting of advanced cardiopulmonary exercise testing. However, technological advances now allow for the estimation of this parameter in many consumer and medical-grade wearable devices, making it available for the medical provider at the initial evaluation of patients. We report a case of an apparently healthy male aged 40 years who presented for evaluation due to an Apple Watch (Apple Inc) notification of low cardiac fitness. This alert triggered a thorough workup, revealing a diagnosis of familial nonischemic cardiomyopathy with severely reduced left ventricular systolic function. While the use of wearable devices for the measurement of oxygen consumption and related parameters is promising, further studies are needed for validation.2). We discuss the possible advantages of measuring oxygen consumption using wearables and propose its integration into routine patient evaluation and follow-up processes. With the current evidence and limitations, we encourage researchers and clinicians to explore bringing wearable devices into clinical practice.The aim of this report is to investigate the potential utility of wearable devices as a screening and risk stratification tool for cardiac fitness for the general population and those with increased cardiovascular risk, particularly through the measurement of peak oxygen consumption  are still necessary.The Apple Watch data provided by the patient demonstrated reduced peak VO2 measurements by wearable devices for early identification and screening of cardiac fitness for the general population and those at increased risk of cardiovascular disease. The integration of wearable devices into routine patient evaluation may allow for earlier presentation in the diagnostic workflow. Cardiac fitness can be serially measured using the wearable device, allowing for close monitoring of functional capacity parameters. Devices need to be used with caution, and further studies are warranted.This case report highlights the potential utility of peak VO The Apple Watch estimates peak VO2 with an average error of less than 1 metabolic equivalent (MET) compared to CPETs. Apple Watch peak VO2 measurements were found to be more reliable than submaximal treadmill tests (ICC of 0.87 vs 0.75), which are performed if a patient cannot complete a full CPET. Limitations to algorithm performance include pacemakers, medical conditions causing chronotropic incompetence, exercise intolerance, and arrhythmias. Apple supports the development of measuring cardiac fitness and addresses limitations such as rate-limiting medications through algorithm adjustment [Wearable devices have gained tremendous popularity in recent years and were traditionally divided into consumer products and medical-grade devices. However, these distinctions are rapidly fading as top-selling consumer devices now provide validated and regulatory-approved medical-grade measurements of physiologic parameters, including heart rate and oxygen saturation, using a 1-lead electrocardiogram and photoplethysmography. Companies such as Apple, Garmin, Fitbit, and Samsung distribute wearable devices that allow for validated peak VOillation ,16. In 2justment . Ongoingjustment  includesThe technological advancement of wearable devices, combined with their fast distribution and adoption by many, sets the stage for using this data in the preemptive screening of wide populations, including apparently healthy individuals. To demonstrate this concept .Initial workup included a stress echocardiography exam demonstrating reduced global LV systolic function and an LV EF of 20%  without valvular malformations or regional wall abnormalities. Following these results, the patient was hospitalized and underwent a comprehensive workup, including repeated echocardiography, a 24-holter exam, and cardiac magnetic resonance imaging (MRI). Repeat echocardiography demonstrated a mildly dilated LV, severe diffuse global LV dysfunction with an EF of 23%, grade I diastolic dysfunction, a right ventricle with normal size and function, a normal left atrium, an aortic valve with minimal regurgitation, mild mitral regurgitation, and minimal tricuspid regurgitation with normal systolic pulmonary pressure. The rest of the exam was within normal limits. Cardiac MRI demonstrated a dilated LV with an LV end-diastolic diameter of 63 mm. There were no signs of late gadolinium enhancement. Normal T1 mapping was up to 1150 milliseconds and T2 mapping was up to 52 milliseconds ; the measured LV EF was 47%. The next step in the cardiomyopathy workup was genetic testing, which revealed a titin mutation  is associated with a decreased risk of developing HF and subsequent hospitalization later in life, independent of other cardiac or noncardiac risk factors (1 MET increase was associated with a 17% risk reduction) [2 was monitored before the procedure and 1 month after. Peak VO2 max after the procedure significantly increased, suggesting that low peak VO2 accompanies AF, perhaps related to tachycardia-induced cardiomyopathy [2 max group were almost 2 times more at risk of developing hypertension and that striving for a higher VO2 max may be protective against hypertension [Oxygen consumption has been shown to be decreased in various cardiac conditions, including heart failure (HF), ischemic heart disease (IHD), atrial fibrillation (AF), valvular disease, cardiomyopathy, hypertension, and other pathologies -23. HF pizations . Additiomodeling . From a modeling , making duction) . Interesmyopathy . Hypertertension .2 measurement is also relevant in noncardiac diseases. Studies have shown that increased oxygen consumption is associated with a lower risk of developing metabolic syndromes such as diabetes through several mechanisms. First, exercise, as reflected by improved VO2, builds muscle that uses and removes glucose from the blood, while other reports discuss the potential role of oxidative pathway regulation in mitochondria as a potential linker between oxygen consumption and metabolic risk [2 can also be seen among patients with chronic obstructive pulmonary disease (COPD) and is associated with reduced all-cause mortality [2 and other chronic medical conditions is warranted, as low peak VO2 is associated with ongoing disease progression in patients with rheumatoid arthritis, as estimated by inflammatory markers and subjective assessment. Cardiovascular risk factors linked to rheumatoid arthritis, such as atherosclerosis and changes in fat and muscle distribution, were decreased among patients with improved aerobic capacity [2 is protective against brain pathologies such as stroke, depression, and dementia [2 was associated with a 68% lower risk of stroke death when compared to those with a low VO2, and a moderate VO2 was associated with a 63% decrease [Peak VOlic risk ,31. CRF lic risk . Additiolic risk . The bencapacity . Moreovedementia -37. To idecrease . As disc2 to reduce all-cause mortality and hospital admissions. For patients with acute coronary syndrome (ACS) or surgical interventions, cardiac rehabilitation is imperative for secondary prevention. Future directions for rehabilitation intend to maximize the incorporation of exercise to achieve greater aerobic capacity, which can be monitored through changes in peak VO2 [2 also allows for assessing patients’ readiness for cardiovascular and noncardiovascular surgery, with studies demonstrating its association with postoperative complications and mortality in procedures such as gastrointestinal and vascular surgeries, hepatic transplantation, lung tumor resection, and coronary artery bypass grafting [2 measurement is evaluating a patient’s need or readiness for heart transplantation. A study with 181 HF patients reported that the actuarial 1- and 2-year survival of the 89 patients who achieved a VO2 equal to or <50% of predicted peak VO2 was 74% and 43%, respectively, compared with 98% and 90% in the 92 patients who achieved >50% predicted peak VO2 [2’s role in triaging for cardiac transplantation and proposed a peak VO2 greater than 14 ml/min/kg as an appropriate cutoff value [Cardiac rehabilitation is perhaps the best proof of practice for following peak VOpeak VO2 . Additiopeak VO2 . Peak VOgrafting . Thus, tpeak VO2 . Other sff value . Further2 is preliminary and the true scope of the asymptomatic cardiac patients’ burden is uncertain. However, serial peak VO2 measurements have been shown to be advantageous in certain populations, such as those with congenital heart diseases. In a study with 1375 adult cyanotic and noncyanotic heart disease patients followed for 10 years while undergoing serial CPETs, the combination of peak VO2 and heart rate reserve provided strong prognostic insight for mortality [2 is a predictor of death or transplant, regardless of initial peak VO2 [2 measurements may be a useful prognostic marker for heart disease burden due to congenital heart defects, and perhaps in individuals similar to our patient after further studies are performed. We suggest there may be a place for using peak VO2 data among both apparently healthy adults and those in high-risk populations as a first warning sign, triggering further workup. With most screening tools, there is a concern that false-positive data will cause unnecessary, costly, and, at times, hazardous workups. We believe that a more precise role for this tool will be only determined after a careful assessment is performed with robust scientific methodology and sufficient statistical power.As with this patient’s case, most individuals with cardiomyopathy accompanied by decreased left ventricular systolic dysfunction are asymptomatic until the development of advanced disease . It is dortality . Anotherpeak VO2 . These s2 into various clinical scenarios. The option to access data routinely and continuously using a wearable device necessitates reconsidering peak VO2’s ideal place in clinical settings. Wearable devices can at least partially replace a patient’s need to seek a CPET, which remains a logistically complex exam mostly limited to medical institutions, resulting in inconvenience for patients and poor accessibility. Reports recognize the potential of wearables for primary and secondary prevention but also identify barriers and limitations such as cost, data security, and false-positive results leading to unnecessary intervention and subsequent burden on the health care system [2) and anaerobic threshold values, which serve as additional prognostic factors measured during CPETs. Peak VCO2 is the amount of carbon dioxide exhaled from the body over time and reflects exercise capacity, whereas the anaerobic threshold is the point of substantially increased minute ventilation relative to VO2 and represents a rise in lactic acid production. The anaerobic threshold suggests the functional capacity of HF patients, with a lower measurement indicating decreased capacity. It can also distinguish between cardiac and noncardiac conditions, with fatigue before the threshold point being less indicative of a cardiac condition [As reviewed here, a large body of evidence suggests the potential role of integrating peak VOe system . The hete system . Other re system . Furtherondition .2 or parallel indices by the patient through wearables at an early phase or as the trigger for a diagnostic workflow before other modalities, especially among HF patients. Moreover, routine peak VO2 measurement in HF patients allows for another objective variable to assess, in addition to standard parameters such as weight, blood pressure, and heart rate, which addresses the issue of sparse, unbiased indices by broadening the opportunity for concrete data collection. Measuring this index continuously and remotely, which is not relevant for CPETs and other conventional methods that calculate peak VO2, allows patients to present earlier in the usual diagnostic workflow. After diagnosis and treatment initiation, peak VO2 can be monitored using the wearable device, as demonstrated in this patient’s case. Health care providers and patients can be more informed about cardiac fitness during a treatment or rehabilitation regimen and accordingly adjust interventions while preventing clinical exacerbations. There is potential to improve clinical outcomes through enhanced monitoring of functional capacity parameters and cardiac fitness; however, devices should be used cautiously and only for adult populations in the appropriate clinical setting to prevent adverse use. Additional prospective studies are needed to enable this change while being supported with scientific evidence and an official classification as a medical-grade device. With the exponentially growing distribution of wearable devices, it may be less of a challenge to conduct these studies and obtain policy-changing evidence in a short period of time.We demonstrated that wearable devices could streamline the process from the onset of disease manifestation to therapeutic intervention. Indeed, a potential new trend that medical providers will need to address is the presentation of peak VO2 measurement for screening cardiac and noncardiac diseases to elucidate therapeutic options for patients in an accelerated timeframe and leverage widespread technology to initiate early interventions. Peak VO2 provides a glimpse into risk stratification, rehabilitation, and perioperative care. Greater awareness of cardiorespiratory fitness among apparently healthy adults and those with high cardiovascular risk is needed and may result in impactful interventions.This report demonstrates the potential utility of routine peak VO


Dilated cardiomyopathy (DCM) is a common cause of non-ischaemic heart failure, conferring high morbidity and mortality, including sudden cardiac death due to systolic dysfunction or arrhythmic sudden death. Within the DCM cohort exists a group of patients with familial disease. In this article we review the pathophysiology and cardiac imaging findings of familial DCM, with specific attention to known disease subtypes. The role of advanced cardiac imaging cardiovascular magnetic resonance is still accumulating, and there remains much to be elucidated. We discuss its potential clinical roles as currently known, with respect to diagnostic utility and risk stratification. Advances in such risk stratification may help target pharmacological and device therapies to those at highest risk. Cardiomyopathies are myocardial disorders in which the heart is structurally and functionally abnormal. They are currently sub-classified on the basis of cardiac morphology as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM), and left ventricular noncompaction cardiomyopathy (LVNC). The European Society of Cardiology (ESC) divides dilated cardiomyopathy into two groups, familial and nonfamilial . ConventDilated cardiomyopathy accounts for up to one-third of heart failure cases and is one of the leading causes for cardiac transplantation. The reported prevalence of DCM from epidemiological data is 36.5/100,000 individuals in Western populations .familial DCM range widely, between 2% to 65%, averaging 23% in a meta-analysis of 23 studies [Estimations of the prevalence of  studies . The pen studies .TTN) mutations are the most common aetiology of familial DCM, occurring in ~25% of familial cases of DCM and in 18% of sporadic cases [Amongst familial DCM, monogenic causes account only for approximately 30–40% of cases ,9. The iRare variants in more than 30 genes can produce a DCM phenotype, some of which also underlie other cardiomyopathies, inherited muscle diseases, or myopathic syndromes. These genes encode both contractile and non-contractile proteins, such as cytoskeletal proteins, abnormalities of which result in the DCM phenotype. This results in reduced resistance to mechanical stress as well as abnormalities of intracellular calcium handling, myocellular energetics, and sarcolemmal ion channel function . De novoLamin A/C (LMNA) mutations [SCN5A and desmin gene (DES) mutations present with conduction disease or ventricular arrhythmias as the dominant features [Specific genetic mutations predict the unique course of DCM. Presentations with arrhythmias and premature conduction disease preceding DCM are often associated with utations . DCM assfeatures .The diagnostic process consists of a detailed clinical history alongside at least a three-generation family pedigree, comprehensive cardiac imaging, biochemical profile, and genetic testing, where clinically indicated. Systematic screening with electrocardiography (ECG) and echocardiography of first-degree relatives of patients with idiopathic DCM has been proposed to identify subclinical forms. European Society of Cardiology Guidelines recommend screening with an ECG and echocardiogram in all first-degree relatives of an index patient with DCM, irrespective of family history .familial DCM by either the presence of two or more affected relatives within a single family or in the presence of a first-degree relatives of a DCM patient with SCD below age 35 years [Mestroni et al.  define f35 years . Criteri35 years .Studying the genetic basis of DCM requires either multigeneration DCM pedigrees or genome-wide sequencing. Most studies use the latter approach, and once DCM-associated variants are identified, the numbers of DCM patients with these variants are compared with the number of individuals in the reference datasets carrying the same variants. A probability of 90% or more is required to be labelled pathogenetic, although this does not necessarily reflect causation . SequencSeveral genome-wide sequencing association studies (GWAS) have identified genetic variants associated with DCM. However, the yield has been limited by modest sample sizes (< 5000 cases). The prevalence of these pathogenic genetic variants is greater than the estimated disease prevalence. Hershberger suggested this mismatch is due either to lower penetrance of the mutations, non-pathogenicity of some, or that the actual DCM prevalence is higher than estimated . VillardDCM has been defined by echocardiography by the degree of systolic impairment, that is, fractional shortening (FS) less than 25% (> 2SD) and/or ejection fraction less than 45% (> 2SD) and the degree of LV enlargement; or LV end diastolic diameter (LVEDD) greater than 117% (2SD (112%) plus 5%) or end diastolic volume (LVEDV) greater than 2SD of the predicted value, as corrected for age and body surface area, excluding any known cause resulting in the myocardial abnormality observed .Echocardiography is often the first imaging test for assessing LV remodelling and also provides associated data, such as the presence and severity of functional mitral regurgitation. Speckle-tracking echocardiography uses the distinct speckle pattern in the myocardium to assess myocardial deformation. Abnormalities of strain and strain rate can be detected by echocardiography in first-degree relatives of patients with DCM, indicating a subclinical phenotype .Cardiovascular magnetic resonance imaging (CMR) is the reference standard for measurement of ventricular volume, ejection fraction, and myocardial mass. In addition, CMR detects myocardial oedema, which, when present, may suggest an inflammatory basis for the observed phenotype. Long native myocardial T1 time and high extracellular volume (ECV) fraction may be helpful in differentiating DCM from athletic heart adaptation or iron overload cardiomyopathy. The presence, pattern, and burden of late gadolinium enhancement (LGE) may be helpful in determining the risk of malignant ventricular arrhythmias. Echocardiography may be suboptimal in certain individuals when CMR is recommended as an alternative. Progressive increases in chamber dimensions, strain abnormalities, and LGE are features of early DCM . LongituAmin et al.  demonstrImaging traits of DCM have been used to investigate genetic variants involved in a DCM phenotype ,20. valuThe cardiac MRI protocol for DCM involves cine imaging and tissue characterisation, including mapping and gadolinium-enhanced images; flow mapping, oedema, and stress perfusion imaging may be considered. Cine images use a balanced steady-state free processing (SSFP) sequence, which provides high signal-to-noise ratio and myocardial blood pool contrast or flash (spoiled gradient echo) sequence in case of cardiac device or at 3T. These are usually retrospectively ECG gated along with breath-held-in expiration, with a minimum of 25 reconstructed phases, with a slice thickness and gap of 8 mm and 2 mm to give temporal resolution less than or equal to 45 ms and spatial resolution 2 mm.Gadolinium-enhanced late images are inversion recovery or phase-sensitive inversion recovery gradient echo sequences, segmented as a routine, while single shot for patients with difficulty holding their breath or irregular rhythm. In plane resolution, it should be ~1.4–1.8 mm. These are generally acquired 10 min after the contrast injection; however, the delay should be tailored to the dose and protocol; images are acquired every other beat but can vary according to heart rate. A TI scout can be used as a guide for choosing inversion time to null myocardium; however, inversion time can be different due to different readout parameters. The late gadolinium-enhanced images are acquired in the same planes and slices as cine images.T1 mapping sequences most frequently involves shortened MOLLI (ShMOLLI) during breath-holding, with the trigger delay set to end-diastole, slice thickness 6–8 mm, with in-plane resolution 1.6–2 mm. The native and 15 min post contrast maps are acquired as short axis slice, but number and plane of slices can be modified. Other sequences, such as SASHA, which involve saturation instead of inversion, are also available.T2 mapping uses either a T2-prepared SSFP sequence or fast spin echo sequences, usually with motion correction.Black blood T2-weighted short tau inversion recovery (STIR) sequence is used for oedema imaging. Images are usually acquired in three short axis slices as well as long axis views.Septal linear mid-wall fibrosis is characteristic of, although not specific to, familial DCM. Furthermore, its presence carries adverse prognosis . In a meLMNA mutations can manifest as isolated LV dilatation, isolated LV dysfunction, or a typical DCM phenotype, but marked dilatation and wall thinning is not characteristic and does not recur post-transplantation [antation .LMNA mutation carriers, male patients appear to have a higher prevalence of ventricular arrhythmias and progression to end-stage heart failure [A meta-analysis of 299 lamin A/C mutation carriers showed a high risk of ventricular arrhythmias, heart failure, and a SCD rate of up to 46% . In a mu failure . There i failure . The dis failure . Biventr failure . Mid-wal failure . Moreove failure .LMNA mutations, regional wall motion abnormalities are typical in the basal segments and correlate with the presence and degree of LGE [Extracellular volume is increased early, while extensive fibrosis is not found until late in the disease course ,29. Withe of LGE . ECG feaDuchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked disorders affecting the synthesis of dystrophin. Dystrophin has an important role in stabilizing the cell membrane and transmits forces generated by sarcomere contraction to the extracellular matrix. Dystrophin-associated cardiomyopathy features a mild reduction in left ventricular systolic function, without morphologic abnormalities in early childhood. Disease progression leads to the typical phenotype of a dilated LV with global hypokinesia. Regional wall motion abnormality and thinning of the basal to mid lateral segments, less often the inferior wall or septum, are also seen. There may be mid-wall or subepicardial fibrosis in the same segments, with transmural fibrosis in advanced disease . The subThe pattern of LGE in BMD is similar to DMD, with initial involvement of the subepicardial inferolateral wall, followed by age-dependent progression of both fibrosis and systolic dysfunction. Thus, transmural late enhancement of the lateral wall and mid-myocardial septal fibrosis are consistent with advanced disease . LV remoDisease-specific studies in patients with muscular dystrophy also highlight the prognostic power of LGE. In 88 male patients with BMD and DMD, transmural LGE combined with an LVEF ≤ 45% independently predicted hospitalization for heart failure and/or occurrence of non or sustained ventricular tachycardia after a mean follow-up time of 47 ± 18 months . In a smSince myocardial fibrosis detected by LGE imaging  may be oOther Dystrophin mutation diseases include Emery–Dreifuss muscular dystrophy (EDMD), caused by mutations in the nuclear membrane proteins. The myocytes are replaced by fibrosis and fat starting in the atria , then eventually affects the ventricles (progressive dilatation and systolic failure) and atrioventricular node  . CardiacFLNC) are responsible for both arrhythmogenic cardiomyopathy (ACM) and DCM, and they are characterized by non-ischaemic fibrosis, ventricular arrhythmias, and risk of sudden death [Mutations in filamin-C  mutation is an uncommon cause of DCM, with a frequency of DES gene mutation of < 1% reported in FDCM [DES p.Q113_L115del has been associated with DCM, with markedly increased left ventricular trabeculation [Desmin  compared with DCM patients without TTN [Tayal and colleagues showed that CMR-derived LVEF, presence of mid-wall LGE, and indexed left atrial volume determines prognosis in s of DCM ,53. Mutapositive . Moreove of LVEF . A similmutation . The aut5 months . Despitehout TTN .Most mitochondrial diseases are caused by mutations in the nuclear DNA (nDNA), with only 15% caused by mutations in the mitochondrial DNA (mtDNA), which are transmitted through the maternal line ,56. WherDanon disease may be associated with DCM less commonly than HCM phenotype. Late gadolinium enhancement has been reported in the LV, sometimes extensive, with sparing of mid-septum, but with involvement of right ventricular insertion points . Increasp = 0.007) [Traditionally, stratifying patients with a LVEF ≤ 35% as having an increased risk of morbidity and mortality have not translated to benefits in non-ischaemic DCM patients receiving implantable cardiac defibrillators . Myocard= 0.007) .The absence of LGE in patients with DCM increases the likelihood of left ventricular recovery (LV reverse remodelling). In a meta-analysis of 4554 patients, the absence of LGE was a strong independent predictor of LV reverse remodelling  at 2 years . The extp < 0.001) [p < 0.001) [Diffuse fibrosis by native T1 mapping may hold prognostic value. In a prospective longitudinal study of 131 cardiomyopathy patients (59 non-ischaemic), native T1 mapping was an independent predictor of ventricular arrhythmia . Later, < 0.001) . Moreove< 0.001)  followed< 0.001) . Further< 0.001) .p < 0.01) and in those with LGE (p < 0.001) [Longitudinal strain assessed by feature-tracking CMR analysis may also have utility in predicting risk in DCM patients. In a study of 210 patients with DCM followed up for a median of 5.3 years, GLS as measured by CMR had independent and incremental prognostic value, surpassing traditional biomarkers, such as NT-proBNP, LVEF, and LGE. GLS of > −12.5% predicted outcome, even in patients with LVEF < 35% (< 0.001) .p < 0.001) [Right ventricular structure and function is complex and difficult to accurately assess. CMR is currently the imaging modality of choice to assess RV function with high reproducibility. Adverse RV remodelling is common in HF and DCM, and studies are continuing to unravel the clinical relevance of such changes ,70. In 2< 0.001) p for interaction = 0.79) [In patients with DCM, the presence of LGE in CMR coupled with an LVEF ≤ 50% suggests consideration of an implantable cardiac defibrillator (ICD) for primary prevention . In a st = 0.79) .p < 0.0001) or HF hospitalizations  [CMR can also be used to predict and guide response to device therapy. Chalil et al.  derived  0.0001) .Diffusion tensor imaging by CMR assesses the motility of the sheetlets that form the microarchitecture of the LV. In a small study of 19 DCM patients, compared with 13 healthy controls, sheetlet function was abnormally characterised by altered systolic conformation and reduced mobility . KhaliquFlow assessed by 4D-CMR to ascertain the forces on the myocardium through LV filling were investigated in a small study of 10 stable DCM patients versus 10 healthy controls . The autMore than half of familial DCM cases have an undefined genotype, even though rapid advances in genetic analysis have improved the diagnostic yield. Genotype determines the unique course and features of DCM, and, thus, genetic diagnosis may significantly influence management. Identifying the genetic basis of DCM may differentiate phenocopies of DCM, improve family screening pathways, provide insight into disease pathogenesis, and trigger investment into novel treatment strategies directed at molecular targets. CMR accurately identifies the DCM phenotype, reliably detects the early subtle changes in cardiac structure and function in the silent stage, and provides characteristic pointers towards an underlying genotype. CMR has a fundamental position in the diagnosis and management of familial DCM along with genetic testing. CMR provides disease-specific imaging biomarkers for risk stratification, including strain, ECV scarring detected by LGE. This may reflect a tendency for reverse remodelling as well as adverse events in DCM, such as arrhythmias, SCD, and hospitalisation due to heart failure. Novel CMR techniques continue to provide insight into the underlying pathophysiology of cardiomyopathy and perhaps detect subsets of patients with a tendency to recurrent drop in systolic function after recovery. Finally, CMR may identify patients to be prioritised for genetic analysis and help target specific DCM cohorts that might benefit most from a defibrillator or resynchronisation device, creating a more individualised DCM management approach.


P < 0.001). Binary logistic regression analysis revealed that elevated serum AP , presence of the left anterior descending (LAD) artery as the infarct-related artery (IRA) , and triglyceride (TG) levels  were protective risk factor for an admission LVEF < 40% following AMI. The serum alkaline phosphatase and LAD as IRA are independent risk factors for severe reduction in LVEF during hospitalization for AMI. Conversely, triglyceride are independent protective factor for severe reduction in LVEF during AMI hospitalization.The occurrence of heart failure following acute myocardial infarction (AMI) significantly increases the risk of post-infarction mortality. Alkaline phosphatase (AP) is considered to be an independent predictor of cardiovascular disease (CVD) and adverse outcomes. Furthermore, in recent years, alkaline phosphatase has been associated with insulin resistance (IR). Our aim was to investigate the correlation between IR substitutes (triglyceride-glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio), AP, and LV dysfunction in patients admitted after AMI. The retrospective study included 810 patients who underwent coronary angiography for myocardial infarction at the First Hospital of Hebei Medical University from August 2018 to December 2021. Patients were categorized into three groups based on their serum AP levels. Clinical characteristics at admission, cardiac echocardiography findings, coronary angiography results, and biochemical markers such as serum AP levels and triglycerides (TG) were recorded during hospitalization. Left ventricular ejection fraction (LVEF) was assessed using cardiac echocardiography conducted from the time of admission until the coronary angiography procedure. A total of 774 patients with AMI were included in this study. The TyG index is significantly correlated with the TG/HDL-C ratio. (R = 0.739,  In search of prognostic biomarkers, IR surrogate markers and serum AP levels have garnered considerable interest among researchers.The incidence of myocardial infarction (MI) has been increasing over the years, attracting significant attention. Although the mortality rate from AMI has decreased with the advent of percutaneous coronary intervention (PCI), myocardial cell loss resulting from heart attacks remains a major cause of heart failure. Heart failure significantly increases the risk of mortality after a myocardial infarction. Patients with LVEF < 40% are defined as having severely reduced LVEF, and compared to patients with LVEF ≥ 40%, those with LVEF < 40% exhibit a significantly lower one-year survival rate4. However, direct measurements of IR (such as hyperinsulinemic-euglycemic clamp and insulin suppression test) are invasive, costly, and complex procedures5. Epidemiological studies require simple and easily obtainable markers of IR. In this context, the TyG index and TG/HDL-C ratio have been confirmed by studies as surrogate markers of IR7. The TyG index, composed of TG and FBG (fasting blood glucose), is calculated using the formula: TyG = ln[fasting triglycerides (mg/dl) × fasting blood glucose (mg/dl)/2]8.Insulin resistance is a hallmark of metabolic syndrome (MetS), and high IR levels not only increase the risk of CAD but also significantly correlate with adverse cardiovascular outcomes10. In recent years, Professor Da-Hye Son discovered Serum AP levels are independently and positively associated with surrogate markers of insulin resistance in Korean adults11. Elevated serum AP levels not only contribute to vascular calcification12 but are also associated with adverse prognosis in CAD13. Therefore, our aim was to investigate the relationship between IR surrogate markers (TyG index and TG/HDL-C ratio) and serum AP with severe reduction in LVEF at admission in a population of first-time AMI patients, providing insights for predicting adverse cardiovascular events.Furthermore, alternative markers of IR are associated with poor prognosis in patients with acute ST-segment elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS) after percutaneous coronary intervention (PCI) treatmentThe study is a retrospective study that selected a total of 810 patients who underwent coronary angiography due to AMI at the First Hospital of Hebei Medical University from August 2018 to December 2021 as the study subjects. The inclusion criteria were as follows: (1) AMI (2) undergoing coronary angiography. The exclusion criteria were as follows: (1) previous coronary intervention, thrombolytic therapy, or coronary artery bypass grafting; (2) history of heart failure, cardiomyopathy, congenital heart disease, or valvular heart disease; (3) chronic dialysis; (4) chronic liver disease, active hepatitis, or severe liver dysfunction; (5) severe acute infection; (6) acute or chronic hepatobiliary diseases, including chronic inflammatory diseases involving the skeletal system; (7) malignancy; (8) suspected familial hypertriglyceridemia [plasma triglycerides (TG) ≥ 500 mg/dL (5.65 mmol/L) or having a first-degree relative with TG ≥ 500 mg/dL]; (9) incomplete clinical data. The study was performed according to the guidelines of the Helsinki Declaration and was approved by the Ethics Committee of The First Hospital of Hebei Medical University .8. The triglyceride to high-density lipoprotein cholesterol ratio was calculated as TG (mg/dL) divided by HDL-C (mg/dL). Diabetes mellitus was defined as fasting blood glucose (FBG) ≥ 7.0 mmol/L, 2-h postprandial blood glucose (PBG) ≥ 11.1 mmol/L, glycated hemoglobin (HbA1c) ≥ 6.5%, or use of any hypoglycemic medications or self-reported history of diabetes. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, use of any antihypertensive medications, or self-reported history of hypertension. Dyslipidemia was defined as any self-reported history or use of lipid-lowering medications or total cholesterol (TC) ≥ 5.17 mmol/L. Left ventricular systolic dysfunction was defined as LVEF < 40%. Atrial fibrillation (AF) was defined as AF on admission electrocardiogram or a history of AF. Ischemic time was defined as the time from the onset of typical AMI symptoms to admission. The time for revascularization is defined as the duration from hospital admission to the performance of PCI or CABG. In this study, acute myocardial infarction included STEMI and non-ST-elevation myocardial infarction (NSTEMI), and was in accordance with the guidelines of the European Society of Cardiology15.Clinical data were collected by trained clinical doctors from medical records, including medical history, baseline clinical and demographic characteristics. The records indicated that all patients had blood biochemical parameters, complete blood count, and cardiac echocardiography collected upon admission. All blood samples were collected from the antecubital vein after a 12-h overnight fasting following admission. Left ventricular ejection fraction was obtained through cardiac echocardiography at admission and before coronary angiography. Systolic and diastolic blood pressures were measured in the right arm of the patients using a standard mercury sphygmomanometer after the patients had been seated and rested for 10 min. The triglyceride-glucose index was defined as TyG = Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]16.The angiographic data were retrieved from the records of the cardiac catheterization laboratory. Coronary angiography procedures were conducted by three specialized interventionists, either through the radial or femoral route, based on the operator's discretion. To ensure consistency and minimize inter-observer variability, the assessment of coronary arteries was performed by three senior cardiologists. If the degree of coronary artery stenosis is equal to or greater than 50%, we consider the presence of significant CAD. The complexity of coronary atherosclerosis was quantified using the Gensini score, which takes into account both angiographically significant and nonsignificant stenosis. The Gensini score for each patient was determined by summing up the scores of individual coronary arteries. To facilitate the calculation of the Gensini score, a minimum of five different views were obtained for each patient. The degree of stenosis and the coronary artery lesion site were scored as follows: 1 point for ≤ 25% narrowing, 2 points for 26–50% narrowing, 4 points for 51–75% narrowing, 8 points for 76–90% narrowing, 16 points for 91–99% narrowing, and 32 points for total occlusion. Thereafter, multiply the score assigned to each lesion by the relevant coefficient based on the location and significance of the lesion within the coronary artery . Finally, add up the obtained scores to calculate the Gensini score2 test or Fisher exact test was used for categorical variables, as appropriate. Univariate regression analysis was performed to evaluate the association between clinical variables and severe reduction in LVEF. Variables with P < 0.05 on univariate analysis were considered as confounding factors and entered the multivariate regression analysis. The calibration was assessed using the Hosmer–Lemeshow goodness-of-fit test. A two-sided analysis with a P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 26.0.Serum AP tertile were categorized as follows: Low: < 66 U/L, Middle: 67–85 U/L, High: > 85U/L. Continuous variables were presented as mean ± standard deviation for normally distributed variables and as median (interquartile range) for non-normally distributed variables. Student's t-test was employed to compare the normally distributed values between different serum AP levels groups. Mann–Whitney U test was used to assess differences in non-normally distributed values among different serum AP levels groups. The correlation between the TyG index and other parameters was assessed using the Spearman rank correlation test.The χThe study was performed according to the guidelines of the Helsinki Declaration and has been approved by the ethics committees at the First Hospital of Hebei Medical University, China. Since data were evaluated retrospectively, pseudonymously and were solely obtained for treatment purposes, a requirement of informed consent was waived by the Ethics Committee of the First Hospital of Hebei Medical University.P < 0.05). No statistically significant differences were found for other variables (Table P = 0.022). No significant differences in the TG/HDL-C ratio were observed among the various groups categorized by serum AP   Table .Table 2CP = 0.005), LAD as IRA . Conversely, triglyceride  are independent protective factors for severe reduction in LVEF during AMI hospitalization  examinations on patients with acute coronary syndrome (ACS) to indicate AP as a potential predictive biomarker for calcification and plaque vulnerability23. Professor Wannamethee et al. not only found a strong correlation between AP and various cardiovascular risk factors but also conducted an 11-year follow-up study on a baseline population without CVD, revealing a significant association between elevated serum AP levels and increased risk of CAD events24. Another study investigating 470 stable angina patients found that higher serum AP levels were associated with higher Gensini scores and more severe forms of CAD25. In a study establishing a link between liver parameters and narrow diameters of coronary vessels in AMI patients, AP was identified as the most important variable for predicting coronary vessel diameter narrowing ≥ 50% or coronary vessel diameter < 50%26. Elevated serum AP during AMI, although below the upper limit of normal, still independently correlate with a higher risk of adverse cardiovascular and cerebrovascular events requiring primary percutaneous coronary intervention27. Moreover, research has found an independent relationship between AP and adverse outcomes in myocardial infarction survivors28. Research has also indicated that AP is a predictive factor for mortality, MI, or stent thrombosis after coronary artery drug-eluting stent implantation13. In recent years, studies have discovered that excessive tissue nonspecific alkaline phosphatase (TNAP) exacerbates myocardial fibrosis induced by MI29.Serum alkaline phosphatase is a hydrolytic enzyme responsible for dephosphorylation processes in various types of molecules. It is expressed in multiple tissues, with the highest concentration found in bone, liver, and kidneys, and lower levels in the intestine, placenta, kidneys, and white blood cells30. In recent years, some new and simple indicators have been considered reliable surrogate markers for IR, such as the TyG index and TG/HDL ratio31. Numerous studies have found these surrogate markers to be independent risk factors for CVD and prognosis34. Recent research has also shown a positive and independent correlation between serum AP and surrogate markers of IR in the general population11. However, in our study population, we did not find a significant correlation between the two, but we did observe a significant correlation between the previously established surrogate markers of IR, TyG index, and TG/HDL-C ratio, which is consistent with previous research4.Insulin resistance is typically defined as a reduced sensitivity or responsiveness to the metabolic actions of insulin. Currently, the hyperinsulinemic-euglycemic clamp technique is considered the "gold standard" for assessing IR. However, the technique is time-consuming, labor-intensive, expensive, and requires experienced operators, making it impractical for epidemiological studies and large-scale clinical investigations35. Impaired LV function indicates a higher risk of cardiac arrest and death38. Some studies have indicated that higher TyG index is an independent and causal risk factor for heart failure in the general population39. However, we did not find a significant association between TyG index and severe LV dysfunction in patients hospitalized after AMI. Another study analyzed factors contributing to the decline in LVEF after PCI in patients with STEMI and found that infarction involving the LAD was a significant determinant of LVEF decline in young STEMI patients40, which is consistent with our results. It may be due to the LAD supplying 40% to 50% of the LV myocardium, and patients with LAD as IRA tend to experience more pronounced LV remodeling and dysfunction compared to those without LAD as IRA41. Elevated TG are often associated with CVD and adverse prognosis42.Left ventricular function after AMI is the most important predictor of long-term prognosis45. Furthermore, a meta-analysis found that an increase in TG levels is associated with a dose-dependent elevation in the risk of cardiovascular disease and all-cause mortality46. In our study, triglycerides appear to act as a protective factor against heart failure following MI, although the specific mechanism remains unclear. We consider that this may be due to a decrease in triglyceride levels following myocardial infarction-induced heart failure. Several factors could contribute to this phenomenon: Firstly, evidence suggests a significant enhancement of non-cardiac lipolysis processes in heart failure patients47. Secondly, post-myocardial infarction, sympathetic nervous system activation stimulates the adrenergic system, which not only increases heart rate but also promotes the breakdown of non-cardiac fat tissues48. Thirdly, severe left ventricular dysfunction often accompanies insulin resistance, and damage to insulin signaling during heart failure can lead to non-cardiac fat breakdown49. Lastly, severe inadequacy in left ventricular contraction, leading to elevated B-type natriuretic peptide (BNP) levels, can further stimulate fat tissue lipolysis processes50.Our study found that elevated TG were a protective factor for LVEF < 40% in patients hospitalized after AMI, but the specific mechanisms are unclear. The epidemiological studies from multiple previous cohorts consistently indicate a direct relationship between serum triglyceride levels and the risk of coronary heart disease27. However, the specific mechanism underlying the AMI remains unclear. We speculate that the elevation of serum AP levels may lead to: first, aggravated myocardial fibrosis, promoting ventricular remodeling51; second, endothelial dysfunction leading to poor microcirculation 18; third, inadequate collateral circulation of coronary arteries52; fourth, slow coronary blood flow53, ultimately resulting in severe impairment of LV function after AMI. Based on the first-time confirmation from our study, we have discovered an association between alkaline phosphatase and heart failure following myocardial infarction, prior to the administration of relevant treatments. Our research finding provides crucial evidence for the early prevention of left ventricular dysfunction after myocardial infarction. Furthermore, our research has concluded that alkaline phosphatase cannot serve as a substitute marker for insulin resistance in patients with myocardial infarction, as there is no significant correlation between the two.Hypoxic liver injury caused by AMI may result in a slight elevation of serum AP, but studies suggest that it does not cause significant confounding of resultsOur study had several limitations. Firstly, our study is retrospective in nature and cannot establish causal relationships between certain outcomes. Secondly, The sample size is relatively small, which may affect the reliability of the results. Thirdly, due to the lack of recorded insulin concentration data, we were unable to compare serum AP levels with HOMA-IR and the clamp test for hyperinsulinemia. Finally, our study population consisted exclusively of the Han Chinese ethnicity, thus making it difficult to generalize the current research findings to all countries and ethnic groups. Although adjustments were made for other potential risk factors, we cannot completely rule out the possibility of residual or unassessed confounding factors.Serum alkaline phosphatase and left anterior descending artery as infarct related artery are independent risk factors for severe reduction in LVEF during hospitalization for AMI. Conversely, triglyceride are independent protective factors for severe reduction in LVEF during AMI hospitalization. We also found a significant association between previous IR surrogate marker TyG index and TG/HDL-C ratio in AMI patients, but no significant correlation was observed between serum AP and IR surrogate markers.


A small percentage of paediatric patients supported with a ventricular assist device (VAD) can have their device explanted following myocardial recovery. The goal of this systematic review is to summarize the current literature on the clinical course in these children after weaning.A systematic literature search was performed on 27 May 2022 using Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar to include all literature on paediatric patients supported by a durable VAD during the last decade. Overlapping study cohorts and registry-based studies were filtered out.Thirty-seven articles were included. Eighteen of them reported on the incidence of recovery in cohort studies, with an overall incidence rate of 8.7% (81/928). Twenty-two of the included articles reported on clinical outcomes after VAD explantation (83 patients). The aetiologies varied widely and were not limited to diseases with a natural transient course like myocarditis. Most of the patients in the included studies  were supported by a Berlin Heart EXCOR, and in 66.3% (55/83), only the left ventricle had to be supported. The longest follow-up period was 19.1 years, and multiple studies reported on long-term myocardial recovery. Fewer than half of the reported deaths had a cardiac cause.Myocardial recovery during VAD support is dependent on various contributing components. The interactions among patient-, device-, time- and hospital-related factors are complex and not yet fully understood. Long-term recovery after VAD support is achievable, even after a long duration of VAD support, and even in patients with aetiologies different from myocarditis or post-cardiotomy heart failure. More research is needed on this favourable outcome after VAD support. Every year the number of paediatric patients receiving a ventricular assist device (VAD) for end-stage heart failure is increasing, with currently over one-third of the patients receiving transplants being bridged with one . Every year the number of paediatric patients receiving a ventricular assist device (VAD) for end-stage heart failure is increasing, with currently over one-third of the patients receiving transplants being bridged with one , 2. AccoAlthough explantation of durable VADs has been reported, less is known about post-explantation outcomes. It is uncertain whether this gain in myocardial function is sustainable or if these hearts cannot last without mechanical support and deterioration at a certain point is inevitable. In adults, survival without recurrence of heart failure of 88% after 2 years has been reported . In chilThe goal of this systematic review was to search the recent literature on the explantation rate of durable VADs due to myocardial recovery in children and investigate the clinical course after explantation.A systematic literature search using Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar was performed by staff of the medical library of the Erasmus Medical center on 27 May 2022. Google Scholar was added only to assure that no articles were missed. The complete list of search terms can be found in the In this systematic review, we answered 2 questions: In the first section, we investigated the incidence of recovery in paediatric patients supported by durable VADs. To this end, all cohort studies with at least 20 children supported by a durable VAD were included and tabulated.In the second section of this paper, the follow-up after explantation of a durable VAD due to myocardial recovery was examined. To do so, all papers reporting a clinical course after weaning were included and tabulated.Further inclusion and exclusion criteria are depicted in Table Patients supported by a right ventricular assist device (RVAD) only were excluded from this review because the aetiology of right ventricle failure and recovery is essentially different from the aetiology and possible recovery of the left ventricle . HoweverTwo researchers (SR and MS) reviewed the papers independently and created a list of papers that met the inclusion criteria. Any discrepancies between the 2 lists were resolved through discussion until a consensus was reached.Multiple studies were found to have overlapping cohorts. In case of overlapping study cohorts, only the most recent cohort study was included.From the included studies, the following data—if available in the full text—were extracted:Information on baseline characteristics: age, sex, aetiology, prior extracorporeal membrane oxygenation (ECMO) and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) classification;Type and duration of support;Outcome: (cause of) death, transplant, myocardial recovery, need for mechanical circulatory support and VAD reimplant and heart function.For the outcomes after VAD support, percentages were calculated and presented.Due the scarcity of VAD explants after myocardial recovery and the therefore often small studies, all data, including outlier data, are presented and summarized in the tables. No statistical analysis other than calculation of percentages was performed due to the heterogeneity and the small size of the patient population.After the search, 4185 articles were identified. A total of 1581 articles were excluded because they were published before 2012. Another 2372 articles were excluded based on title or abstract. Of the remaining 232 articles, the full text was screened and an additional 195 manuscripts were excluded. Finally, 37 articles were included in this systematic review  or case series (6/22). Table In the 22 identified articles, a total of 83 patients with durable devices were identified. Aetiology varied widely and was not limited to diseases with a natural transient course like myocarditis  died during the follow-up period. Causes of death varied and were not all related to heart failure. Cardiac causes of death included cardiogenic shock in 1 patient, cardiac failure in 1, ventricular arrhythmias in 1 and persistent cardiopulmonary failure (hypoxia and hypercarbia) with concomitant multiple organ failure in 1. Other causes of death included a massive haemorrhagic cerebrovascular accident in 1, septic shock in 1 and redirection of care due to mitochondrial disease plus failure to wean from ventilator support and poor long-term prognosis in 1. In 5 cases the cause of death was not reported Tables .During the follow-up period, at least 3 patients needed VAD reimplants and 2 needed cardiac transplants. Caution should be taken since the different studies reported outcomes in various ways. For example, some studies only reported a survival rate, without describing cardiac function.This systematic review summarizes the recent literature on the incidence of myocardial recovery in children supported with a durable VAD. Most studies reported an incidence between 0 and 15% with an overall incidence of 8.7%. This finding is in accordance with the reported incidence of recovery in large registries .P = 0.771) [The researchers reported a wide range of recovery rates up to 38.1% . Inciden= 0.771) . This reSecond, the type of device seems to matter. It is thought that the key mechanism to myocardial recovery is left ventricular unloading, which pulsatile devices seem to achieve better than continuous devices . In a stThird, the duration of VAD support is likely to affect recovery. A diseased heart needs sufficient time to recover but, on the other hand, it is plausible that in children in whom recovery does not occur in the first months, myocardial recovery is unlikely to happen suddenly thereafter. This observation is supported by the results of a molecular study by Madigan et al.  that shoAnother factor that is sometimes suggested to influence recovery rates is the general condition of the patient. One could argue that sicker children (reflected for example in their INTERMACS classification or the need for ECMO prior to VAD support) have less favourable outcomes and therefore a lower chance of myocardial recovery. On the other hand, in the included study with the highest recovery rate (38.1%), 60% of the children were classified as INTERMACS I and one-third were supported by ECMO prior to VAD support . INTERMA2 compared to children with a higher body surface area  [Furthermore, age and body surface area are associated with myocardial recovery. A previous report from our group showed significantly higher recovery rates in BHE-supported children with a body surface area < 0.53 m0.00534) . Similar0.00534) , 21, 25,0.00534) , 35.Lastly, the lack of universally accepted, evidence-based protocols for both implanting and possible weaning of VAD support are likely to shape outcome as well as recovery rates . In the One important question after durable VAD explantation remains long-term follow-up. As seen in this review, many studies do not report long-term data, but some papers show that long-term myocardial recovery after a VAD is explanted is achievable. Twelve of the 83 (14.5%) patients previously supported by a durable VAD died during follow-up. The actual proportion might be higher due to limited follow-up time in some papers and due to publication bias. Post-explantation causes of death were not always cardiac, although most of them probably are related to the hospitalization and a certain general weakness or vulnerability of the body linked to the underlying original cardiac diagnosis. Furthermore, at least 5 children had to undergo ECMO support, a VAD reimplant or a heart transplant (HTx). Besides the aforementioned reasons for possibly underestimated mortality rates, which also apply to the rates of ECMO/VAD and/or HTx, the latter might also be higher due to the various ways of reporting on outcomes in the different case reports. For example, sometimes only a survival percentage is mentioned, without further specifying any possible recurrent heart failure.In adults, explantation due to myocardial recovery only occurs in a small percentage of the patients , 40. IndThis systematic review summarizes the available literature on the incidence and follow-up after weaning from a durable VAD due to myocardial recovery. Conclusions from this study have to be interpreted cautiously because of the high heterogeneity of this population. Children of all ages, with various aetiologies and INTERMACS classifications, supported for different durations by different types of VADs, were included. A meta-analysis was not possible due to the heterogeneity of the population; thus this paper merely serves as an overview of what is known. No analyses to determine risk factors for recovery could be done.Another important limitation of this study is publication bias. It is possible that, especially for case reports on follow-up after recovery, successful clinical courses were more likely to be reported and published. Furthermore, this review depended on what was reported. Therefore, we were limited to providing a homogeneous and extensively detailed overview. For example, it cannot be ruled out that some of the devices registered as LVAD or RVAD were actually single ventricular assist devices.Furthermore, although pharmacological therapy is of paramount importance in this specific population, drug therapy was rarely reported in the included studies. Therefore, it was not mentioned further in this manuscript.Lastly, one must consider that the VAD experience summarized here is an experience from the last few decades. In these years, many potentially contributing factors have changed: Experience has increased, devices have evolved and protocols have been developed and altered. This situation hampers the interpretation of the results.Myocardial recovery during VAD support is a scarce but the most favourable outcome, especially in light of high waiting list mortality, scarcity of donor hearts and the higher morbidity and mortality after a cardiac transplant. This outcome is, however, dependent on various contributing components. The interactions among patient- , device- , time-  and hospital-  related factors are complex and not yet fully understood. However, long-term survival after explanting a VAD seems achievable, even after long-term VAD support and even in patients with aetiologies different from myocarditis or post-cardiotomy heart failure. This valuable outcome should be better investigated in order to optimize this therapeutic strategy. To do so, joint efforts are needed, and we encourage large registries to include follow-up data after explantation.ezad263_Supplementary_DataClick here for additional data file.