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While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused on catecholamines and the sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including β-adrenergic receptor signalling, G-protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Severe aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries. Heart failure (HF) is a frequent comorbidity of this condition and represents a diagnostic and therapeutic challenge. The spectrum of both conditions has become progressively wider in the last decade; HF has been divided in three groups according to left ventricular ejection fraction (LVEF) and severe AS has been reclassified into four groups according to aortic valve (AV) gradient, AV flow measured by LV stroke index, and LVEF. Although all four AS types may be found in patients with signs and symptoms of HF, low-flow AS with low or normal gradient is the most common type in these patients. Several studies have documented that patients with low-flow severe AS have a higher mortality risk than patients with normal-flow and high-gradient AS not only during the natural progression of the disease, but also after either interventional or surgical AV replacement. Existing data support transcatheter AV replacement (TAVR) in patients with severe AS, irrespective of AV gradient, AV flow, and LVEF. Controversial issues, however, are still present on this topic, which has not been adequately addressed by large studies and trials. This clinical review summarizes the epidemiology of the different HF types in patients with severe AS, as well as the impact of HF and LVEF on clinical outcomes of AS patients either untreated or after AV replacement. In particular, we addressed the influence of AV gradient and AV flow on all-cause and cardiovascular mortality in AS patients after TAVR., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was previously considered a benign self‐limiting condition, but it is now known to be associated with substantial short‐ and long‐term morbidity and mortality. Because of the poor understanding of its underlying pathophysiology, there are few evidence‐based interventions to treat TTS. The hypotheses formulated so far can be grouped into endogenous adrenergic surge, psychological stress or preexisting psychiatric illness, coronary vasospasm with microvascular dysfunction, metabolic and energetic alterations, and inflammatory mechanisms. Current evidence demonstrates that the infiltration of immune cells such as macrophages and neutrophils play a pivotal role in TTS. At baseline, resident macrophages were the dominant subset in cardiac macrophages, however, it underwent a shift from resident macrophages to monocyte‐derived infiltrating macrophages in TTS. Depletion of macrophages and monocytes in mice strongly protected them from isoprenaline‐induced cardiac dysfunction. It is probable that immune cells, especially macrophages, may be new targets for the treatment of TTS. [ABSTRACT FROM AUTHOR]

Systemic iron deficiency (SID), even in the absence of anaemia, worsens the prognosis and increases mortality in heart failure (HF). Recent clinical–epidemiological studies, however, have shown that a myocardial iron deficiency (MID) is frequently present in cases of severe HF, even in the absence of SID and without anaemia. In addition, experimental studies have shown a poor correlation between the state of systemic and myocardial iron. MID in animal models leads to severe mitochondrial dysfunction, alterations of mitophagy, and mitochondrial biogenesis, with profound alterations in cardiac mechanics and the occurrence of a fatal cardiomyopathy, all effects prevented by intravenous administration of iron. This shifts the focus to the myocardial state of iron, in the absence of anaemia, as an important factor in prognostic worsening and mortality in HF. There is now epidemiological evidence that SID worsens prognosis and mortality also in patients with acute and chronic coronary heart disease and experimental evidence that MID aggravates acute myocardial ischaemia as well as post-ischaemic remodelling. Intravenous administration of ferric carboxymaltose (FCM) or ferric dextrane improves post-ischaemic adverse remodelling. We here review such evidence, propose that MID worsens ischaemia/reperfusion injury, and discuss possible molecular mechanisms, such as chronic hyperactivation of HIF1-α, exacerbation of cytosolic and mitochondrial calcium overload, amplified increase of mitochondrial [NADH]/[NAD+] ratio, and depletion of energy status and NAD+ content with inhibition of sirtuin 1–3 activity. Such evidence now portrays iron metabolism as a core factor not only in HF but also in myocardial ischaemia. [ABSTRACT FROM AUTHOR]

While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF. [ABSTRACT FROM AUTHOR]

Background: H2FPEF is a recently introduced score for the diagnosis of heart failure with preserved ejection fraction (HFpEF). Many patients with severe aortic stenosis have clinical/subclinical HFpEF and have worsening heart failure even after trans-catheter aortic valve replacement (TAVR). We investigated the prognostic impact of the H2FPEF score in TAVR candidates. Methods: Patients undergoing TAVR procedures at a single academic center between 2015 and 2022 were included. The H2FPEF score was calculated using baseline characteristics before TAVR. The prognostic impact of the score on the post-TAVR composite endpoint, consisting of all-cause death and heart failure readmissions during the 2-year observation period, was evaluated. Results: A total of 244 patients (median age 86 years, 70 males) were included. The median value of H2FPEF score was 3 (2, 4). The score was significantly associated with the primary outcome with a hazard ratio of 1.33 (95% confidence interval 1.02–1.74, p = 0.036). We constructed a modified H2FPEF score by adjusting cutoffs of several items for better prognostic stratification (i.e., age and body mass index). A modified score had a higher area under the curve than the original one (0.65 vs. 0.59, p = 0.028) and was independently associated with the primary outcome with an adjusted hazard ratio of 1.22 (95% confidence interval 1.01–1.49, p = 0.047). Conclusions: A modified H2FPEF score, which was originally developed to diagnose the presence of HFpEF, could be used to risk-stratify elderly patients receiving TAVR. The clinical utility of this score should be validated in future studies. [ABSTRACT FROM AUTHOR]

Objectives: This study examined the prognostic value of the get-with-the-guidelines heart-failure risk score (GWTG-HF) on mortality in patients with low-flow–low-gradient aortic valve stenosis (LFLG-AS) after transcatheter aortic valve implantation (TAVI). Background: Data on feasibility of TAVI and mortality prediction in the LFLG-AS population are scarce. Clinical risk assessment in this particular population is difficult, and a score has not yet been established for this purpose. Methods: A total of 212 heart failure (HF) patients with real LFLG-AS were enrolled. Patients were classified into low-risk (n = 108), intermediate-risk (n = 90) and high-risk (n = 14) groups calculated by the GWTG-HF score. Clinical outcomes of cardiovascular events according to Valve Academic Research Consortium (VARC-2) recommendations and composite endpoint of death and hospitalization for heart failure (HHF) were assessed at discharge and 1 year of follow-up. Results: Baseline parameters of the groups showed a median age of 81.0 years [77.0; 84.0] (79.0 vs. 82.0 vs. 86.0, respectively p < 0.001), median EuroSCORE II of 6.6 [4.3; 10.7] (5.5 vs. 7.2 vs. 9.1, p = 0.004) and median indexed stroke volume of 26.7 mL/m2 [22.0; 31.0] (28.2 vs. 25.8 vs. 25.0, p = 0.004). The groups significantly differed at follow-up in terms of all-cause mortality (10.2 vs. 21.1 vs. 28.6%; p < 0.035). There was no difference in intrahospital event rate (VARC). Postprocedural mean gradients were lower in high-risk group (7.0 vs. 7.0 vs. 5.0 mmHg, p = 0.011). No differences in postprocedural aortic valve area (1.9 vs. 1.7 vs. 1.9 cm2, p = 0.518) or rate of device failure (5.6 vs. 6.8 vs. 7.7%, p = 0.731) could be observed. After adjustment for known predictors, the GWTG score (HR 1.07 [1.01–1.14], p = 0.030) as well as pacemaker implantation (HR 3.97 [1.34–11.75], p = 0.013) turned out to be possible predictors for mortality. An increase in stroke volume index (SVI) was, in contrast, protective (HR 0.90 [0.83–0.97]; p = 0.006). Conclusions: The GWTG score may predict mortality after TAVI in LFLG-AS HF patients. Interestingly, all groups showed similar intrahospital event and mortality rates, independent of calculated mortality risk. Low SVI and new conduction disturbances associated with PPI after THV implantation had negative impact on mid-term outcome in post-TAVI HF-patients. [ABSTRACT FROM AUTHOR]

Background: CD34+ cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34+ cell differentiation in vivo during heart failure and explore its intervention strategy. Methods: We performed single-cell RNA sequencing (scRNA-seq) of the total non-cardiomyocytes and enriched Cd34-tdTomato+ lineage cells in the murine (male Cd34-CreERT2; Rosa26-tdTomato mice) pressure overload model (transverse aortic constriction, TAC), and total non-cardiomyocytes from human adult hearts. Then, in order to determine the origin of CD34+ cell that plays a role in myocardial fibrosis, bone marrow transplantation model was performed. Furthermore, to further clarify the role of CD34 + cells in myocardial remodeling in response to TAC injury, we generated Cd34-CreERT2; Rosa26-eGFP-DTA (Cre/DTA) mice. Results: By analyzing the transcriptomes of 59,505 single cells from the mouse heart and 22,537 single cells from the human heart, we illustrated the dynamics of cell landscape during the progression of heart hypertrophy, including CD34+ cells, fibroblasts, endothelial and immune cells. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone-marrow-derived CD34+ cells give rise to fibroblasts and endothelial cells, while bone-marrow-derived CD34+ cell turned into immune cells only in response to pressure overload. Interestingly, partial depletion of CD34+ cells alleviated the severity of myocardial fibrosis with a significant improvement of cardiac function in Cd34-CreERT2; Rosa26-eGFP-DTA model. Similar changes of non-cardiomyocyte composition and cellular heterogeneity of heart failure were also observed in human patient with heart failure. Furthermore, immunostaining showed a double labeling of CD34 and fibroblast markers in human heart tissue. Mechanistically, our single-cell pseudotime analysis of scRNA-seq data and in vitro cell culture study revealed that Wnt-β-catenin and TGFβ1/Smad pathways are critical in regulating CD34+ cell differentiation toward fibroblasts. Conclusions: Our study provides a cellular landscape of CD34+ cell-derived cells in the hypertrophy heart of human and animal models, indicating that non-bone-marrow-derived CD34+ cells differentiating into fibroblasts largely account for cardiac fibrosis. These findings may provide novel insights for the pathogenesis of cardiac fibrosis and have further potential therapeutic implications for the heart failure. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS) is a severe but reversible acute heart failure syndrome that occurs following high catecholaminergic stress. TTS patients are similar to those with acute coronary syndrome, with chest pain, dyspnoea and ST segment changes on electrocardiogram, but are characterised by apical akinesia of the left ventricle, with basal hyperkinesia in the absence of culprit coronary artery stenosis. The pathophysiology of TTS is not completely understood and there is a paucity of evidence to guide treatment. The mechanisms of TTS are thought to involve catecholaminergic myocardial stunning, microvascular dysfunction, increased inflammation and changes in cardiomyocyte metabolism. Here, we summarise the available literature to focus on the molecular basis for the pathophysiology of TTS to advance the understanding of the condition. [ABSTRACT FROM AUTHOR]

Aims Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. Methods and results An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P  = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P  < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P  > 0.0001). Both lactate and pyruvate were lower (P  < 0.05) despite increases in LDH-RNA and PDH (P  < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P  < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P  = 0.01) with decreased fatty acids and acyl-carnitines levels (P  = 0.0001–0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P  < 0.05) as was cellular ATP reporter dihydroorotate (P  = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P  < 0.0001), inducing the oxidation of NAD(P)H and FAD (P  = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated—increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P  < 0.05). Conclusion Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity. [ABSTRACT FROM AUTHOR]

Aims  Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. Methods and results  miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects. Conclusion miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy (TTC) is a clinical condition of transient acute heart failure correlated to regional wall motion abnormalities extending beyond the distribution of a single epicardial coronary artery. It is classified into four major types: apical, basal, mid-ventricular and focal. Sympathetic nerve stimulation and catecholamine storm are the main players in the pathogenesis of TTC. The clinical course of disease is generally benign but it may end with life-threatening complications. Coronary angiography, left ventriculogram, transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) are the main tools for making diagnosis. Except for critical cases with hemodynamic instability and/or complications, the overall management is limited to conventional heart failure therapy. [ABSTRACT FROM AUTHOR]

Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind β-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases. [ABSTRACT FROM AUTHOR]

Aims Worldwide applications of extracorporeal circulation for mechanical support in cardiac and circulatory failure, which are referred to as extracorporeal life support (ECLS) or veno‐arterial extracorporeal membrane oxygenation (va‐ECMO), have dramatically increased over the past decade. In spite of the expanding use and the immense medical as well as socio‐economic impact of this therapeutic approach, there has been a lack of interdisciplinary recommendations considering the best available evidence for ECLS treatment. Methods and Results In a multiprofessional, interdisciplinary scientific effort of all scientific societies involved in the treatment of patients with acute cardiac and circulatory failure, the first evidence‐ and expert consensus‐based guideline (level S3) on ECLS/ECMO therapy was developed in a structured approach under regulations of the AWMF (Association of the Scientific Medical Societies in Germany) and under use of GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. This article presents all recommendations created by the expert panel, addressing a multitude of aspects for ECLS initiation, continuation, weaning and aftercare as well as structural and personnel requirements. Conclusions This first evidence‐ and expert consensus‐based guideline (level S3) on ECLS/ECMO therapy should be used to apply the best available care nationwide. Beyond clinical practice advice, remaining important research aspects for future scientific efforts are formulated. [ABSTRACT FROM AUTHOR]