To evaluate whether CMR-derived RV assessment can facilitate risk stratification among patients undergoing transcatheter mitral valve repair (TMVR).In patients undergoing TMVR, only limited data exist regarding the role of RV function. Previous studies assessed the impact of pre-procedural RV dysfunction stating that RV failure may be associated with increased cardiovascular mortality after the procedure.Sixty-one patients underwent CMR, echocardiography and right heart catheterization prior TMVR. All-cause mortality and heart failure hospitalizations were assessed during 2-year follow-up.According to RV ejection fraction (RVEF) <46%, 23 patients (38%) had pre-existing RV dysfunction. By measures of RV end-diastolic volume index (RVEDVi), 16 patients (26%) revealed RV dilatation. Nine patients (15%) revealed both. RV dysfunction was associated with increased right and left ventricular volumes as well as reduced left ventricular (LV) ejection fraction . During follow-up, 15 patients (25%) died and additional 14 patients (23%) were admitted to hospital due to heart failure symptoms. RV dysfunction predicted all-cause mortality even after adjustment for LV function. Similarly, RVEDVi was a predictor of all-cause mortality even after adjustment for LVEDVi. Kaplan-Meier survival analysis unraveled that, among patients presenting with CMR indicative of both, RV dysfunction and dilatation, the majority (78%) experienced an adverse event during follow-up (p<0.001).In patients undergoing TMVR, pre-existing RV dysfunction and RV dilatation are associated with reduced survival, in progressive additive fashion. The assessment of RV volumes and function by CMR may aid in risk stratification prior TMVR in these high-risk patients. Transcatheter mitral valve repair (TMVR) with the MitraClip system has evolved into an established treatment for patients with mitral regurgitation (MR) who are at elevated surgical risk. While peri-interventional mortality is low and the majority of patients clinically benefits from MitraClip implantation, 1-year mortality is largely determined by prognosis of underlying heart failure (HF) and comorbidities. Right ventricular (RV) dysfunction is an established prognosticator in patients with HF and after cardiac surgery, respectively .In patients undergoing TMVR, only limited data exist regarding the role of RV function. Previous studies assessed the impact of pre-procedural RV dysfunction stating that RV failure may be associated with increased cardiovascular mortality after the procedure –5. In coThe aim of this study was to investigate the impact of pre-existing RV dysfunction assessed by CMR and right heart catheterization (RHC) on clinical outcomes after MitraClip procedure.Sixty-one patients undergoing MitraClip  implantation at the university hospital Duesseldorf, Germany were included between 2014–2019 and underwent CMR, echocardiography and RHC prior to TMVR. Patients enrolled had severe, degenerative or functional MR and were considered at elevated surgical risk by an interdisciplinary heart team. The study was approved by the ethics committee of the Heinrich-Heine University Duesseldorf (study number 6110R) and performed in accordance with the Declaration of Helsinki. All patients gave informed written consent.2, and in men ≥60 years RVEDVi >101 ml/m2 was defined as RV dilatation. In women <60 years, RVEDVi >96 ml/m2, and in women ≥60 years RVEDVi >84 ml/m2 was defined as RV dilatation .CMR was conducted with a 1.5 Tesla MRI scanner  using a 32-channel phased array coil. Functional and structural assessment was accomplished by cine steady state free precession images in standard long axis geometries  as well as in short axis orientation with full ventricle coverage from basis to apex  pressure, systolic and end-diastolic pressures of the RV and the pulmonary artery (PA), as well as mean PA pressure, PA wedge pressure (PAWP). Cardiac output was assessed by the Fick method and indexed with body surface area to calculate cardiac index. Pulmonary vascular resistance and systemic vascular resistance were calculated as previously described.All-cause mortality and heart failure (HF) hospitalizations were assessed during 2-year follow-up. The clinical course was monitored by follow-up examinations, phone calls to the referring cardiologists and the patients`primary physicians or the patients themselves.All analyses were performed using Graphpad Prism 8  and SigmaPlot . Data for continuous variables are presented as mean ± SD or median with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. Continuous variables were compared between two groups with independent-samples Student's t-test , Mann-Whitney U test , and chi-square test for categorical data. ROC analysis and Youden´s Index was used to calculate optimal cut-off values for RV systolic dysfunction (RVEF) and RV dilatation (RV dilatation). Correlations between continuous variables were assessed by Spearman’s rho. Unadjusted Cox proportional hazard model were performed to assess predictors of all-cause mortality and HF hospitalization. RV dysfunction was adjusted for LV ejection fraction, and RV dilatation was adjusted for LVEDVi. Multivariate analysis with more than two parameters was not performed due to the low number of events. The Kaplan-Meier method was used to determine the event-free rate. For all analyses, a p-value of <0.05 was considered to be statistically significant.2 (for RV dilatation) . According to RVEF <46%, 23 patients (38%) had RV systolic dysfunction prior MitraClip procedure. According to RVEDVi, 16 patients (26%) revealed RV dilatation. Nine patients (15%) had both, RV dysfunction and RV dilatation. The remaining patients  exhibited normal RV dimensions and systolic function. Patients with RV systolic dysfunction had higher logistic EuroSCORE (p<0.001) and lower estimated glomerular function (p = 0.007), while patients with RV dilatation more often presented with pre-existing atrial fibrillation (p = 0.004) (Baseline patient’s characteristics are shown in = 0.004) . In the CMR imaging showed increased right and left ventricular volumes as well as reduced LV ejection fraction in patients with RV dysfunction  . PatientRHC was performed in 56 patients (92%) prior MitraClip procedure and revealed a trend towards increased PA systolic pressure in patients with RV dysfunction (p = 0.058) , while p2) predicted all-cause mortality even after adjustment for LVEDVi (HR 1.023 (1.007–1.039); p = 0.004). Regarding the combined endpoint, mean RA pressure, LA area index, RA area index, RVEDVi, RVESVi and the combination of RV dysfunction and RV dilatation predicted the occurrence of an adverse event during follow-up  died, and additional 14 patients (23%) were admitted to hospital due to HF symptoms. Thus, 29 patients (48%) experienced an adverse event. In unadjusted Cox proportional hazard model, estimated glomerular filtration rate, diastolic RV pressure, mean RA pressure, LA area index, RA area index, RVEDVi, RVESVi, RV dysfunction and the combination of RV dilatation and RV dysfunction were predictors of all-cause mortality . Even afollow-up .Kaplan-Meier survival analysis for all-cause mortality illustrates that patients with RV systolic dysfunction had increased all-cause mortality compared to those with preserved RV function (log-rank test p = 0.006) . PatientRegarding the combined endpoint, patients with RV systolic dysfunction (log-rank test p = 0.088) and patients with RV dilatation (log-rank test p = 0.063) tended to have an unfavorable outcome compared to those without . Among pEighteen patients had pulmonary hypertension (defined by mean PA pressure ≥25 mmHg) and RV systolic dysfunction (RVEF <46%). These patients had an all-cause mortality of 47% compared to 14% in patients without (log-rank test p = 0.004) .In the current study, we evaluated the role of RV function and dimensions assessed by the current gold standard, CMR imaging, in patients undergoing TMVR with the MitraClip. Our study population represents a typical mixture of inoperable, high- and intermediate risk patients with symptomatic, severe MR that currently receive TMVR treatment in a real-world clinical setting. We demonstrate that pre-procedural RV systolic dysfunction and RV dilatation are associated with a poor prognosis, even following effective TMVR. The patient cohort presenting both, RV systolic dysfunction and RV dilatation, exhibit additive mortality. These findings suggest that the accurate assessment of RV function and dimensions may aid in risk stratification in patients undergoing MitraClip procedure.In our study, only 51% of patients had ordinary RV dimensions and function, while the majority of patients revealed RV systolic dysfunction (38%) or RV dilatation (26%). Nine patients (15%) presented with both. The presence of RV dysfunction was strongly associated with poor clinical outcome that fosters previous reports and underlines the importance of an accurate pre-procedural RV assessment. Overall, RV dysfunction is a known predictor of poor cardiovascular and overall outcome in different HF populations . In patitdi) <10 cm/s) was not associated with inferior outcome [tdi) had an increased risk for cardiovascular mortality despite MitraClip treatment [The role of pre-procedural RV dysfunction in patients undergoing MitraClip procedure has not yet been clearly defined. Several reports using an echocardiographic assessment of RV function in this context reported conflicting results: Godino et al. stated that RV dysfunction (defined by tricuspid annular systolic excursion (TAPSE) <16 mm; RV peak systolic velocity doppler imaging , thus, results cannot be directly transferred to patients with degenerative MR. Moreover, validation in larger cohort seems necessary. In this regard, multivariate analysis could not be performed due to the low number of events. Second, RVEF and RV dilatation are load-dependent and the presence of significant TR may influence both. Therefore, newer and more load independent measurements of RV function such as feature-tracking derived strain and strain-rate may provide a more precise measurement of RV function in future studies. Third, due to inclusion of patients with MRI-compatible pacemakers (only 5 out of 10), prevalence of patients with pacemakers represents 8% in our study cohort. Finally, we did not perform follow-up CMR imaging for assessment of RV function after MitraClip procedure, that might have yielded important information on the course of disease.An accurate assessment of RV function and RV dimensions is crucial in the screening process for TMVR as RV parameters provide important prognostic information that allow an estimation of HF severity and prognosis. In this regard, in our cohort with predominately functional MR patients, RV volumes and function were more sensitive variables than LV parameters for predicting adverse outcomes. Thus, a comprehensive RV assessment as can be performed by CMR in addition to echocardiography may aid in risk stratification prior TMVR.S1 Table(DOCX)Click here for additional data file.S1 Data(PDF)Click here for additional data file.


Heart failure (HF) is the fastest-growing cardiovascular disease globally. The autonomic nervous system plays an important role in the regulation and homeostasis of cardiac function but, once there is HF, it takes on a detrimental role in cardiac function that makes it a rational target. In this review, we cover the remodeling of the autonomic nervous system in HF and the latest treatments available targeting it. Despite the significant efforts and progress made in treating HF, the mortality rate remains high, with one in eight deaths linked to HF.2 Advanced therapies have been introduced to alleviate the broadening of HF such as left ventricular assist devices and cardiac transplantation but, given the limited available resources, more therapeutic targets need to be identified. The autonomic nervous system plays an important role in the regulation and homeostasis of cardiac function but, once there is HF, it takes on a detrimental role in cardiac function that makes it a rational target. In this review, we discuss the remodeling of the autonomic nervous system in HF and the latest treatments available that target it.Heart failure (HF) is the fastest growing cardiovascular disease globally, estimated to affect more than 37.7 million people.6 Excitation of the SNS promotes norepinephrine (NE) release from the nerve endings, while the adrenal glands and medulla release NE and epinephrine. These catecholamines act on the adrenergic receptors (ARs), which subdivide into further subtypes .7 In the human heart β-ARs constitute about 90% of ARs and α1-ARs constitute about 10%.8Cardiac function is determined by the complex interactions of the sympathetic (SNS) and parasympathetic (PNS) nervous systems together with regional responses and feedback from the central nervous system.9 NE and other neuromodulators support the maintenance of cardiac output by increasing the heart rate (HR) and contractility. In addition, NE also facilitates enhanced venous tone and systemic vasoconstriction to maintain blood pressure (BP). In contrast, chronic sympathetic stimulation in HF patients has detrimental effects. Persistently elevated NE levels increase cardiac stress via tachycardia, increased afterload, and high oxygen consumption, hastening the progression of ventricular remodeling. Simultaneously, elevated catecholamines bind with cardiac β-receptors and trigger G-protein-coupled receptor kinase upregulation inside cardiomyocytes, causing the downregulation and desensitization of β1 receptors at the plasma membrane.9 These reactions are considered to form a protective mechanism by which the heart is defended against excessive catecholaminergic toxicity, which has been found to cause cyclic adenosine monophosphate–mediated calcium overload, which can lead to cardiac cell death.9 Overexpression of β1 adrenergic receptors in mice resulted in early hypertrophy, interstitial fibrosis, and the upregulation of proapoptotic proteins, increasing the rate of apoptosis.10In acute HF, activation of the SNS is one of the first adaptations related to an increased release and decreased reuptake of NE induced by reduced stroke volume.11 Vagal efferent signaling originates from the caudal ventrolateral medulla and extends to the ganglionated plexi on the atria, activating cardiac nAChR on the postganglionic neuron.11 The postganglionic fibers then reach the mAChR located on the myocardium and the situation progresses to PNS activation; in particular, it decreases the HR with a less significant reduction in contractility.11 The muscarinic receptor family consists of five subtypes (M1–5) and M2 receptors in particular, located at cardiac nerve endings, are essential for the physiologic control of cardiac function.12PNS control of the heart is mediated by nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR) via neurotransmitter acetylcholine (ACh).14 Specifically, increased HR and decreased HR variability both correlate with increased mortality in HF.11 Regarding the mechanism at play, the stimulation of preganglionic vagal fibers was performed in HF dogs and controls and the HF group demonstrated a significantly lower response rate, confirming that functional abnormality was likely to be identifiable in the efferent limb.15 In addition, Vatner et al. demonstrated that, in a pacing-induced HF dog model, end-organ mAChR was upregulated, while downstream G-protein signaling was intact.16 Accordingly, dysfunction of nAChR is considered to be a strong candidate for abnormal vagal tone in HF. The abnormality of HR can be observed from early in the development of left ventricular (LV) dysfunction and how this process can be reversed is still unclear.The main physiological findings of PNS dysfunction in HF encompass the abnormal control of HR.Pharmacological medications of HF are fundamental for patient wellbeing and are well-established. In particular, the importance of neurohormonal modulation in HF is evident given that the guidelines-directed medications available for HF—which include β-blockers, angiotensin system blockers such as angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists—all mainly work via the nervous system.19 Interestingly, carvedilol (a mixed α1- and β-blocker) does not restore the number of β-ARs but does recouple the existing receptors and improves the signaling pathway efficiency.20 Long-term studies have shown β-blockers to reverse remodeling by decreasing LV mass and to revise ventricular shape to a more normal, elliptical appearance. β-blockers also inhibit pacemaker currents such as If to reduce the HR, which lessens the calcium entry into the failing myocytes to decrease cytosolic calcium overload.22 β-blockers also inhibit the phosphorylation of the cardiac ryanodine receptor at the sarcoplasmic reticulum that occurs in patients with HF. As a result, there is increased calcium recycling by the sarcoplasmic reticulum that promotes increased ejection fraction (EF).23β-blockers in HF inhibit the effects of long-lasting excessive NE levels on β-ARs due to the activated SNS. β-blockers contribute to the restoration of the downregulated β-ARs due to HF and, as a consequence, lead to an improvement in LV function.26 The major cardiovascular effects of angiotensin II are mediated by angiotensin II type 1 receptors (AT1 receptors), which can be found in the vascular, heart, kidney, adrenal glands, and central nervous systems.27 Considering the relationship with the autonomic nervous system, the activation of AT1 receptors in the paraventricular nucleus and rostral ventrolateral medulla is reported to increase the activity of the SNS.28 In addition, the sympatho-inhibitory effects of AT1 receptor blockade, an ACE inhibitor (lisinopril), and of an AT1 receptor antagonist  were examined in HF patients.29 Both lisinopril and valsartan significantly reduced plasma NE levels, although the reduction was significantly larger with valsartan than lisinopril . However, no significant differences were observed in the effects on LV function, arterial pressure, aldosterone plasma level, or autonomic control of HR. In general, no significant difference has been observed between ARBs and ACEIs in reducing total mortality or morbidity rates.25 The mechanisms of regulating RAAS activity in the central nervous system and their contribution to HF treatment remain unclear.In HF, the renin–angiotensin–aldosterone system (RAAS) is overactivated due to low renal perfusion and RAAS inhibitors such as ACEIs and ARBs play an important role in this pathological condition. As known from prior large-scale clinical trials, there is conclusive evidence that RASS inhibitors cause improvements in LV contraction, admission rates, death, and many other factors.31 However, in HF patients, 11β-HSC2 may be downregulated, causing cortisol to activate the MR. The activated MR is correlated with the generation of reactive oxygen species, increased renal mesangial fibrosis, endothelial dysfunction, myocardial fibrosis, and myocyte death.30 Spironolactone has also been found to decrease the release of cardiac NE32 and improve cardiac 123I-MIBG  scintigraphic findings.33Mineralocorticoid receptor (MR) blockers (MRBs) inhibit the effects of aldosterone and cortisol. In HF patients, MRBs help to alleviate sodium-mediated fluid retention and vasoconstriction. The speculated mechanism is that aldosterone is co-expressed with the enzyme 11β-hydroxysteroid dehydrogenase II (11β-HSC2) and cortisol is converted to cortisone, which cannot activate the MRs.35 Natriuretic peptides, degraded by neprilysin, have been found to increase renal perfusion, inhibit sodium reabsorption, and suppress RAAS and sympathetic activation. Neprilysin also increases the conversion of angiotensin I to angiotensin II, constituting the reason for why it is combined with the ARB valsartan. As HF progresses, the responsiveness to natriuretic peptides decreases, so the usage of ARNIs decreases RAAS activation and encourages diuresis. In the Angiotensin–Neprilysin Inhibition Versus Enalapril in HF (PARADIGM-HF) trial, ARNI therapy was compared with enalapril and found to achieve a 20% relative risk reduction in cardiovascular death and HF hospitalization.36Valsartan and sacubitril are part of a relatively new class of drugs referred to as angiotensin receptor–neprilysin inhibitors (ARNIs).Despite the remarkable progress made in pharmacological therapy for HF as shown by clinical trials, the morbidity and mortality rates of HF remain high. Recently, successful human studies of neuromodulation therapies that directly target the autonomic nervous system have been reported. We provide an overview of these studies in the following section of this review.38 and eliminates both afferent signaling and sympathetic postganglionic efferent to the heart. The beneficial effects of left-CSD (LCSD) have been well-investigated for the suppression of ventricular arrhythmias in long QT syndrome and catecholaminergic polymorphic ventricular tachycardia.43 Recently, the utility of CSD in refractory ventricular arrhythmia was shown in an international retrospective study assessing a total of 121 cases.40 CSD reduced 88% of the burden of ICD shocks (from 18 ± 30 to 2.0 ± 4.3 times per year) at a median follow-up of 1.1 years (p < 0.01).40In HF patients, excessive activation of the SNS plays an important role in cardiac remodeling and the occurrence of lethal arrhythmias. Cardiac sympathetic denervation (CSD) has primarily been adopted as an antiarrhythmic therapy for patients with severe ventricular arrhythmias. It is performed by surgically removing the lower half of the stellate ganglia through the T2–T4 thoracic ganglia44 All subjected patients were continued on optimal medical therapy during the study. Six months later, LCSD had suppressed the progression of HF and improvements were observed in LVEF  and six-minute walking test outcomes . Currently, a prospective randomized trial of LCSD is being performed.45The efficacy of LCSD in HF therapy has also been considered. Conceição-Souza et al. conducted a pilot study where 15 symptomatic HF patients (LVEF ≤ 40%) were randomized to an LCSD group (n = 10) or non-LCSD group (n = 5).46 This has been accomplished by surgically stripping the renal nerves or noninvasively treating by renal artery ablation. Elevated sympathetic nerve activity conducts through the renal efferent and causes NE spillover at the nerve endings. Consequently, α-AR activation leads to renal vasoconstriction.48 The NE level is reported to correlate with the development of HF. In addition, NE spillover in the heart is observed beginning in the early stage of HF, while its correlation in the kidney is more precise in severe HF.51 Simultaneously, vasoconstriction increases renal sodium retention and renin release, consequently raising the aldosterone level.51 High aldosterone levels provoke cardiac remodeling,52 influencing both morbidity and mortality. The afferent renal sympathetic nerves also contribute to the adjustment of BP largely through the actions of mechanoreceptors and chemoreceptors located in the kidney46 and, consequently, by modulating central SNS activity.Renal nerve denervation (RND) achieves an effect by eliminating the renal sensory afferent and sympathetic efferent nerve fibers.54 On the other hand, in recent studies, RND has been reported to reduce BP when targeting patients with moderate hypertension (systolic BP ≥ 140 mmHg or < 170 mmHg).55 In addition, the utility of RND in both atrial and ventricular arrhythmias.59The initial feasibility of RND was as a treatment for refractory hypertension. Several trials were completed but no significant effects were shown when targeting patients with severe hypertension.60 Patients with chronic symptomatic HF on optimal medical therapy underwent RDN. During six months of follow-up, RDN was associated with improvements in both symptoms and exercise capacity. No significant decrease in BP nor a worsening of renal function was observed and some patients were able to reduce their use of diuretic drugs. Consequently, more trials to prove the beneficial effects of RDN in HF patients were published. The Renal Denervation in Patients with Chronic HF and Renal Impairment Clinical Trial (SYMPLICITY-HF) was designed as a prospective randomized multicenter study including HF patients (n = 39) with LVEFs of less than 40%, New York Heart Association (NYHA) functional classes II to III, and receiving optimal medical therapy.61 Unfortunately, no significant improvement was shown in cardiac functions and symptomatic findings at 12 months after RDN. In this study, the ablated lesions were distributed only in the main renal artery from the ostium to the first major bifurcation and no treatments were applied distal to the main bifurcation of the renal artery, which may have been insufficient for RDN. Recent studies have found that targeting the renal artery branches or distal segment of the main renal artery resulted in markedly less variability of response than as seen with the conventional approach of only ablating the main renal artery.63 On the other hand, there was a 47% decrease in renal NE spillover and a 26% decrease in cardiac NE spillover at six months. Given the fact that renal spillover of NE is activated in HF patients and is predictive of mortality,49 it is still conceivable that RND might have a positive impact on HF symptoms and outcomes. In addition, more than 90% of patients were taking ACEIs/ARBs and β-blockers for optimal medical therapy; accordingly, the study may have not had an appropriate design or the numbers may not have been enough to accurately detect the effects of RDN.The utility of RDN in HF patients was first reported in the Rehabilitation Enhancing Aging Through Connected Health (REACH) Pilot study.64 A total of 60 symptomatic HF patients  were subjected and randomized to an RDN group and a medical therapy–only group. During six months of follow-up, the RDN group showed a salutary effect, with significant improvements observed in cardiac function, physical findings, and N-terminal (NT) prohormone B-type natriuretic peptide (pro-BNP) level. In this study, an irrigated catheter was used to obtain wide lesions and the physical conditions were also different. Further, the body mass index (BMI) of the patients included was 24.2 ± 2.8 kg/m2, while that for SYMPLICITY-HF patients was 31 ± 6 kg/m2, which may have influenced the distribution of the eliminated nerve fibers locating around renal artery.64 A reliable method to assess the completeness of RND still needs to be established to conclude the reactive nitrogen species effect in HF patients.Recently, a different pilot study investigating the effect of RDN in HF was reported.65 Meanwhile, when VNS was performed in a pacing-induced HF canine model, cardiac function was improved and levels of inflammatory markers and the neurohormone, which suggests excitation of the SNS, were decreased.66 To summarize, VNS suppressed ventricular arrhythmia, improved survival and cardiac function, and reduced inflammation in these HF models.The major goal of vagus nerve (VN) stimulation (VNS) in HF is to increase the parasympathetic tone. The beneficial effect of VNS in cardiac function has been reported in several animal studies. Vanoli et al. demonstrated that VNS prevents the occurrence of ventricular fibrillation during acute myocardial ischemia in dogs.67 With six months of treatment, VNS reduced the LV volume and was able to improve physical findings such as NYHA class and six-minute walking test outcomes. Recently, three randomized trials were performed to assess the utility of a VNS device in HF patients. The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in HF (ANTHEM-HF) trial was able to show a beneficial effect of VNS, while the Increase of Vagal Tone in Chronic HF (INOVATE-HF) and Neural Cardiac Therapy for HF (NECTAR-HF) trials revealed no significant improvement in HF.71 It is worth noting that each of these trials used a different stimulation protocol and titration of output. In the ANTHEM-HF trial, the titration of output was based upon the confirmation of autonomic engagement using changes in HR,68 while, in the other two studies, no significant reduction was observed in HR. Establishment of the optical pacing protocol for HF treatment, such as by the combination of pulse amplitude, pulse frequency, and pulse duration, is still needed. In addition, the VN is said to be composed of 20% efferent and 80% afferent fibers.73 The influence of afferent fibers in VNs also requires consideration to accomplish further development of VNS in HF.74VNS devices have initially been used for the treatment of epilepsy and refractory depression. Schwartz et al. reported the first pilot study to assess the feasibility and safety of vagal stimulation in patients with advanced HF.75 Stimulation of the tragus nerve preferably activates afferent rather than efferent vagal fibers, a phenomenon which appears to demonstrate a more significant inhibition of sympathetic activity.76 Also, this avoids additional stimulation of sympathetic fibers that may inadvertently be stimulated by the VNS.75 It was already shown that AF induced by rapid atrial pacing in canines and humans can be attenuated by tragus stimulation.78 In canines, this effect was observed to disappear following bilateral vagal transection.78 Another study found that patients receiving tragus stimulation for one hour daily for six months presented a 14-day continuous electrocardiogram atrial fibrillation burden that was 85% lower than in the sham earlobe stimulation group.79 Compliance with daily use was at a comparable rate to that in medication studies. In myocardial infarction–induced dogs, tragus stimulation after 90 days significantly reduced the infarct size by approximately 50%, together with reducing cardiac fibrosis and NE. The EF was significantly increased but the cardiac output was roughly unchanged.80 An ST-segment-elevation myocardial infarction study was conducted in which patients were randomly assigned to receive percutaneous coronary intervention and tragus stimulation or percutaneous coronary intervention and sham stimulation.81 The tragus and sham stimulations were initiated once the patient arrived in the catheterization room and lasted for two hours after balloon inflation. All patients were receiving guidelines-directed medical therapy and the results revealed markedly significant decreases in ventricular tachycardia, NT pro-BNP peptide level, and inflammatory markers in the tragus stimulation group. Also, the EF was significantly increased while the wall motion index was significantly decreased on echocardiography at just five to seven days after reperfusion, pointing to a possible application in HF.Given that the auricular branch of the VN is connected to the skin of the tragus, stimulation at this site was thought to be viable as a method to stimulate the VN noninvasively.75 The issue with tragus stimulation for the treatment of HF, however, is that optimal dosing and stimulation parameters have not been determined to date.75 This is more an issue due to the lack of studies performed on testing differences in stimulation then related to problems with the therapy itself. There have also been disappointing outcomes among related studies on VNS in HF as mentioned above. Overall, the heterogenicity of HF combined with different VNS stimulation parameters used in the available studies points to the lack of an optimal VNS stimulation protocol for HF. However, despite this, some secondary outcomes did show significant improvements.81These results are promising given that the therapy is self-administered, easily reversible, and contains essentially no significant risks. Tragus stimulation also possibly avoids the complications noted with cervical VNS such as dysphonia and coughing due to it being a noninvasive therapy.82 CCM is used in NYHA class II or III patients with an EF of less than 35% and normal or mildly prolonged QRS duration who do not meet the criteria for cardiac resynchronization therapy (CRT).82 CCM increases septal contractility, which has been shown in rats to cause a reflex activation of vagal afferent fibers.84 This causes a reduction in excess sympathetic activation similar to that in CRT. Muscle sympathetic nerve activity decreased after three months of CCM in a patient with HF with reduced EF (HFrEF).83 Other mechanisms of action include attenuating myocardial fibrosis, increasing contractility via the upregulation of L-type calcium channels causing calcium uptake into the sarcoplasmic reticulum, and gene-remodeling to cause the more juvenile cardiomyocyte phenotype of HF to revert back to the normal adult cardiomyocyte.84Cardiac contractility modulation (CCM) is accomplished by a biphasic impulse of 7.5 volts for 22 ms to the right ventricular septum during the absolute refractory period for five to 12 hours per day.85 The FIX-HF-5 study, a randomized longitudinal study of OMT versus OMT and CCM, found a safety analysis that was similar to CCM.86 Results for the primary endpoint, ventilatory anaerobic threshold, displayed no difference, while the secondary endpoints of NYHA class, normal mixed venous oxygen tension (pvO2), and Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score experienced significant improvement.86 Details on ventilatory anaerobic threshold were required by the United States Food and Drug Administration due to the study being unblinded despite it not commonly being of relevance in later stages of HF.82 A confirmatory study, FIX-HF-5c, also reported significant improvements in pvO2, MLWHFQ score, NYHA class, and six-minute walk test results together with a reduction in cardiovascular death and HF hospitalization rate from 10.8% to 2.9% (p = 0.048).87 A meta-analysis of CCM revealed significant improvements in pvO2, six-minute walk test results, and MLWHFQ score.88The Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects with Moderate-to-severe HF (FIX-HF-4) study was a double-blinded, prospective, crossover study where HFrEF patients on optimized medical treatment (OMT) received 12 weeks of CCM therapy and showed an improvement in both their exercise tolerance and quality of life.89 Stimulation of carotid sinus mechanoreceptors results in afferent signals to the dorsal medulla, causing SNS attenuation and increased vagal tone, which leads to decreases in BP and HR.90 In HF patients, there is reduced sensitivity of the normal inhibitory function of the baroreceptor due to carotid body alterations via angiotensin II–mediated augmentation of carotid chemoreceptor sensitivity and central nervous system dysfunction, which are two of the mechanisms available for excessive sympathetic tone.89 Impairments in baroreceptor sensitivity in HF are associated with increased mortality rates.91 In canine HF models, baroreceptor activation therapy (BAT) decreased NR and angiotensin II levels, reversed LV remodeling, and improved survival.93The carotid body and sinus are innervated by the PNS through vagus and glossopharyngeal fibers and the SNS via cervical sympathetic ganglia and contain a baroreceptor that encompasses both chemoreceptors and mechanoreceptors.® Hope for Heart Failure (HOPE4HF) phase II randomized controlled study noted improvements in six-minute walk test results, quality of life score, NYHA class, and NT pro-BNP level with no significant adverse events after six months.94 However, there was no significant difference in HF hospitalization or EF, possibly related to a placebo effect as the trials were not blinded.94 Recently, the Baroreflex Activation Therapy for HF (BeAT-HF) trial, a phase III multicenter randomized unblinded trial involving HF patients on OMT ineligible for CRT found that, after six months, BAT patients showed improved six-minute walk distances, MLWHFQ scores, and NT pro-BNP levels.95 This study lad to the provision of premarket approval by the Food and Drug Administration in 2019 for use of BAT therapy in HFrEF patients with NYHA classes II or III, an NT pro-BNP level of less than 1,600, or ineligibility for CRT. The postmarket phase will look at HF hospitalization and cardiovascular mortality rates.95 Nevertheless, the durability of treatment effects long-term and adverse effects years from implantation remain unknown.Efficacy and safety have already been shown for BAT therapy in hypertension. For HF, the BAROSTIM97 Stimulation will mitigate the signals that pass through the spinal cord—specifically, cardiac afferent through the dorsal root ganglia and preganglionic sympathetic efferent.98 The effects of SCS have been demonstrated by ischemic animal models, which suppressed ventricular arrhythmia and infarct sizes.97Spinal cord stimulation (SCS) is performed by placing electrodes into the epidural space at the thoracic level and stimulating at 50 Hz with a duration of 0.2 ms.100 Both studies were able to show safeness and feasibility; however, the SCS HEART study reported improvements in LV function and exercise tolerance, while the DEFEAT-HF trial did not. The main difference between the two studies was the stimulation areas and burden: the SCS HEART study stimulated at the T1-3 level continuously, while the DEFEAT-HF trial did so at the T2-4 level for 12 hours per day. The results indicate that the duty cycle, frequency, intensity of stimulation, and the area under stimulation can all affect the outcomes of SCS neuromodulation.Two clinical studies, the Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic HF (DEFEAT–HF) and the Spinal Cord Stimulation for HF (SCS HEART) trials, were performed to assess the utility of SCS in HF patients.Table 1, promising results from available studies suggest neuromodulation therapy is beneficial considering the potential side effects and complications. As a result, numerous trials are ongoing to assess the benefit of adding neuromodulation to HF management. The detection of pathological factors together with an optimal combination of pharmacological, device therapy, and invasive/noninvasive procedures can actively affect the progression of heart diseases from the early stages and may contribute to more significant improvements and better outcomes.Progression in the treatment of HF is ongoing and clinical data showing a significant improvement in treatment outcomes are constantly being published. Nevertheless, HF has remained a leading cause of death for decades. The cardiac autonomic nervous system and neurohormonal factors play important roles in cardiac function. Once an abnormality of the cardiovascular system occurs, an impact on disease development stemming from both the heart itself and the circumstances of the disease will occur. As summarized in


This study assessed ePLAR as an incremental echocardiographic assessment tool compared with traditional measures of right ventricular pressure and function. Methods: In total, 110 (57.4 ± 17.6 years) patients with confirmed sub-massive pulmonary emboli with contemporaneous echocardiograms (0.3 ± 0.9 days) were compared with 110 age-matched controls (AMC). Results: Tricuspid velocities were higher than AMC , although still consistent with “normal” right ventricular systolic pressures  with lower mitral E/e’ values . ePLAR values were higher than AMC  suggesting significantly elevated TPG. Detection of abnormal echocardiographic findings increased from 29% (TRVmax ≥ 2.9 m/s) and 32% (reduced tricuspid annular plane systolic excursion) to 70% with ePLAR ≥ 0.3 m/s. Conclusions: Raised ePLAR values in acute sub-massive pulmonary embolism suggest elevated trans-pulmonary gradients even in the absence of acutely increased pulmonary artery pressures. ePLAR dramatically increases the sensitivity of echocardiography for detection of hemodynamic perturbations in sub-massive pulmonary embolism patients, which may offer clinical utility in diagnosis and management.Background: Acute pulmonary embolism (PE) is characterized hemodynamically by abrupt obstruction in trans-pulmonary blood flow. The echocardiographic Pulmonary to Left Atrial ratio (ePLAR, tricuspid regurgitation V Clinically, presentations of acute pulmonary embolism typically include acute progressive shortness of breath with associated pleuritic chest pain, with or without cough/hemoptysis. Physiologic derangements manifest as tachycardia, syncope/presyncope, and in severe cases may result in systemic hypotension, hemodynamic instability, or shock. Physiologically, this phenomenon occurs due to a sudden impairment of blood flow from the right heart through the lungs to the left heart with a consequent reduction in systemic blood flow. Echocardiographically, the abrupt increase in trans-pulmonary gradient leads to acute right ventricular dysfunction (often with the classic distribution of McConnell’s sign), with or without increased right ventricular systolic pressure. Obstructed trans-pulmonary flow leads to a decrease in left atrial filling pressure, with consequently reduced left ventricular filling that may result systemic hypo-perfusion and/or cardiogenic shock.Acute pulmonary embolism (PE) presentations carry a mortality rate as a high as 25% in the first 30 days . As suchIn this setting, significant right ventricular dysfunction may be evidenced by reduced right ventricular function, e.g., McConnell’s sign  , reducedpre-capillary obstruction to trans-pulmonary flow. The novel parameter ePLAR  has been validated as a non-invasive surrogate to trans-pulmonary gradient [pre-capillary and post-capillary pulmonary hypertension in patients being investigated for consideration of specific pulmonary vasodilator therapies. Higher ePLAR values suggest higher trans-pulmonary gradients and pre-capillary pulmonary hypertension. Lower ePLAR values suggest higher left atrial pressures with minimal increase in trans-pulmonary gradient and post-capillary pulmonary hypertension  and RV dysfunction (reduced TAPSE or RV S’) in detecting hemodynamic perturbations in patients with acute sub-massive pulmonary embolism. Abnormally high ePLAR levels would likely be comprised of a small (if any) increase in TRVmax with significantly reduced mitral E/e’ . Increased ePLAR in these patients will suggest increased TPG even in the absence of actual elevated right heart pressures or right ventricular dysfunction. It is hypothesized that ePLAR (as a measure of trans-pulmonary gradient) may have a higher diagnostic yield than other previously utilized echocardiographic markers of elevated pulmonary pressures  or ventilation/perfusion (V/Q) scintigraphy were studied. Patients with massive embolic load associated with shock requiring resuscitation were not included in this study. All remaining patients were shown to have sub-massive embolic burden . All patients were studied at the time of diagnosis (< ±72 h) with comprehensive echocardiography. Human Research and Ethics Committee approval for review of data was obtained from each institution. A further cohort of age-matched, paired “normal subjects” was generated with permission from the echocardiography database of the referring institutions. These subjects were defined as normal via the criteria: normal left ventricular size and function (systolic and diastolic), normal right ventricular size and function, normal intracardiac valves, and no clinical history of pulmonary embolism, lung disease, or pulmonary arterial hypertension.All patients referred for transthoracic echocardiography with the diagnosis of suspected pulmonary embolism were studied with comprehensive 2D, Doppler and strain analysis (where available). Left heart function, size, and valvular function was assessed as per standard protocols. Left heart diastolic filling was assessed using pulsed wave Doppler at the mitral tips according to the ASE guidelines  Mitral ap < 0.05. Graphical patient data were compared with a previously generated “standardized population” of 1000 subjects as reference for ePLAR and TRVmax values, stratified by decade  or saddle emboli (n = 13) by CTPA/VQ scan. Echocardiography was performed at 0.3 ± 0.9 days from CTPA/VQ (range −3 to +3 days). Demographics of the patients are shown in There were 223 patients referred for acute echocardiography with the diagnosis of possible/probable/proven sub-massive pulmonary embolism. Of these, 88 patients were subsequently shown to either not have sub-massive pulmonary emboli  or had a delay of >72 h from CTPA/VQ to echocardiography. A further 25 patients were excluded with incomplete datasets. The remaining 110 patients  were shown to have bilateral pulmonary emboli , Group 2 , Group 3 , and Group 4 . Using these cut-off values, patients were separated analyzed in dichotomous assessments of ePLAR vs. TRVmax A, ePLAR max B, and ePmax C. For eamax demonstrated sensitivity 29% (CI 21–39%), specificity 98% (CI 94–100%), positive predictive value 94% (CI 80–98%), and negative predictive value 58% (CI 57–70%). Right ventricular function as assessed by TAPSE demonstrated sensitivity 22% (CI 14–33%), specificity 85% (CI 77–91%), positive predictive value 52% (CI 36–66%), and negative predictive value 61% (CI 58–65%). Right ventricular function as assessed by RV S’ demonstrated sensitivity 13% (CI 6–22%), specificity 85% (CI 76–91%), positive predictive value 37% (CI 22–55%), and negative predictive value 57% (CI 55–60%). Comparison of the predictive power of each parameter was assessed using ROC curves (see p < 0.05) compared with TRVmax , TAPSE , and RV S’ .Using the standardized cut–off values listed above, sensitivity and specificity data were calculated for the prediction of pulmonary embolism, in comparison to the age matched control cohort. As shown in rves see . ePLAR pSub-massive acute pulmonary embolism is associated with significant morbidity and mortality, in both the acute and chronic setting. It has been well documented that early treatment with anticoagulation, and in severe cases thrombolysis, is critical in the care of these patients . Anatomimax/RVSP values, and underfilled left-sided chambers. Quantitative measures of RV function help reinforce these subjective impressions of the constellation of findings of significant PE [However, echocardiography has two major roles in this disease spectrum . Firstlyicant PE . max performed poorly, with only 32 out of 110 patients having appropriately elevated TRVmax ≥ 2.9 m/s. Clinically, all three parameters had very low sensitivity for the detection of acute PE , though high specificity. ePLAR on the other hand was found to have much higher sensitivity (72%) with modest specificity (66%), 31/110 results being falsely normal. Although RV S’ was found to have a greater ROC AUC than ePLAR, ePLAR was found to have the highest negative predictive value of all parameters, and much higher positive predictive value than RV S’. Clinically, these data suggest that ePLAR, as a marker of impaired trans-pulmonary flow, is much more likely to register as abnormal than measures of right heart pressure (RVSP/TRVmax), or right heart function (TAPSE and RV S’), with a negative predictive value superior to these other parameters.In this study, patients with proven acute PE had mean TAPSE values of 21.1 mm and RV S’ of 13.5 cm/s, with 59/110 and 69/110 false negative results, respectively. As a binary diagnostic tool for RV dysfunction, TRVSecondly, and more logically, echocardiography in the setting of suspected or proven acute PE plays a major role in risk stratification and the assessment of hemodynamic distress of the right-sided circulation. Current Guidelines (both European and American) for thrombolysis or catheter-based intervention for PE recommend echocardiographic assessment of RV dysfunction ,19, and p = 0.013). Even though, as a group, these pulmonary embolism patients were not pulmonary hypertensive , ePLAR was markedly elevated, suggesting for the first time non-invasively, elevated TPG levels. Interestingly, for each of the three echocardiographic parameters assessed dichotomously with ePLAR  were significant younger than patients in Group 1 or 3 (TRVmax/TAPSE/RV S’ true positive). This may suggest an element of age related physiologic compensation or pulmonary vasculature reserve in the setting of an acute obstruction to trans-pulmonary flow [Finally, this study offers mechanistic insights into the hemodynamics of acute PE, and, specifically, the physiologic underpinning of systemic hypotension and shock . In thisth ePLAR , patientary flow . Consequary flow . Follow It should be noted that this a retrospective study, over several years, of a very large cohort of patients presenting with suspected or confirmed pulmonary embolus. Clinical practice varies from case to case, and across time and institutions. The subset of patients with complete datasets, adequate for calculation of all required parameters for this study, is reflected in the size of the final cohort. The age-matched control group was selected randomly from a very large database of normal individuals. The groups are reasonably well matched, but this is never a perfect process. The delay between echo and anatomic imaging study was set at a maximum of ±3 days. It could be well argued that an echocardiogram performed three days after diagnosis and onset of anticoagulation for PE may well have some dilution of the hemodynamic effects of the condition. pre-capillary obstruction to flow. This new parameter may well offer a more sensitive echocardiographic sign of abnormal hemodynamic disturbance in these patients. Future studies should focus on the value of ePLAR in acute patient triage, guidance of therapy, and prediction of prognosis in the setting of acute pulmonary embolism.The majority of patients with sub-massive pulmonary embolism, in the absence of shock, demonstrated normal estimated right ventricular systolic pressure and normal right ventricular function. Despite this, these patients exhibited a significant increase in the echocardiographic Pulmonary to Left Atrial Ratio (ePLAR), suggesting increased trans-pulmonary gradient with


Methods and Results. Haemodynamic status was evaluated in 97 patients with acute decompensated HF. Impedance cardiography, echocardiography, and N-terminal probrain natriuretic peptide (NT-proBNP) results were analysed. The study group was stratified into four subgroups according to LVEF (<40% vs ≥40%) and the presence of anaemia (haemoglobin <13.0 g/dL in men and <12.0 g/dL in women). Thoracic fluid content was higher (p=0.037) in anaemic subjects, while no significant relation between anaemia and NYHA was observed. Anaemic subjects with LVEF ≥ 40% were distinguished from those with LVEF < 40% by significantly higher stroke index (p=0.002), Heather index (p=0.014), and acceleration index (p=0.047). Patients with reduced LVEF and anaemia presented the highest NT-proBNP (p=0.003). Conclusions. In acute decompensated HF, anaemia is related with fluid overload, relatively higher cardiac systolic performance but no clinical benefit in patients with preserved/midrange LVEF, and increased left ventricular tension, fluid overload, and impaired cardiac systolic performance in patients with reduced LVEF.Anaemia is a common comorbidity in patients with heart failure (HF) and is associated with more severe symptoms and increased mortality. The aim of this study was to evaluate haemodynamic profiles of HF patients with respect to the presence of reduced left ventricular ejection fraction (LVEF) and anaemia.  Anaemia is a common comorbidity in patients with heart failure (HF) and is associated with increased symptom severity and higher mortality , 2. EvenThe haemodynamic response to tissue hypoxia induced by severe anaemia in patients without cardiac disease presents as tachycardia, high cardiac output induced by the activation of the sympathetic nervous system, low vascular resistance caused by generalised vasodilation, and fluid retention –5. In exThe unfavourable effects of anaemia in HF patients may overlap with pre-existing pathologies. A rise in sympathetic and renin-angiotensin-aldosterone system activity provokes vasoconstriction and reduces renal perfusion. The heart is burdened with an increased volume workload as a result of water and salt retention . Animal The reaction of the heart to anaemia may differ depending on HF aetiology. Tominaga et al.  revealedThe adverse haemodynamic effects of anaemia itself might be frequently missed or underestimated in clinical practice, mostly because of the lack of a simple bedside diagnostic tool. In order to enable timely patient-tailored treatment of acute decompensated HF (ADHF), the evaluation process of harmful haemodynamic effects of anaemia should be simple and fast. Our previous experience with impedance cardiography (ICG) , 9, a siTherefore, the aim of this study was to evaluate haemodynamic profiles of HF patients by means of ICG with respect to the presence of reduced left ventricular ejection fraction (LVEF < 40%) and anaemia.This retrospective secondary analysis included data of 97 patients who were enrolled to the prospective observational study. This study aimed to evaluate the complex pathophysiological background related to HF deterioration with respect to the in-hospital treatment received. The data on the usefulness of noninvasive haemodynamic assessment in admission diagnostics and monitoring of the effects of treatment in patients hospitalised due to ADHF have been previously published [NCT02355769) and was approved by the local Bioethics Committee .The participants were admitted to the hospital for ADHF (according to the definition of the European Society of Cardiology ). We recClinical examinations covered the history of symptoms, current medication and concomitant diseases by interviews, and review of available medical records. At the time of hospital admission, peripheral venous blood samples were collected for laboratory tests. The certified laboratory analysed the following parameters: creatinine, Hb, urea, haematocrit, high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP), serum iron, total iron-binding capacity, and transferrin saturation. Anaemia was defined as a Hb concentration of <13.0 g/dL in men and <12.0 g/dL in women .Echocardiographic examinations were conducted with the use of Vivid S6/Vivid 7  ultrasound devices by two experienced echocardiography specialists. We analysed the following parameters: right ventricular end-diastolic diameter ), left ventricular end-diastolic diameter ) and left atrial diameter ) measured in the parasternal long-axis view, and left ventricular ejection fraction ). The median time interval from admission to echocardiography was 3 days.2)) as stroke volume indexed to body surface area, and cardiac index (CI ((mL/min)/m2)) calculated as CI = SI × HR (heart rate), and the parameters of left ventricular-aortic outflow are as follows: acceleration index (ACI (1/100 ∗ Ohm/s2)), velocity index (VI (1/1000 ∗ Ohm/s)), Heather index (HI (Ohm ∗ s2), and systemic vascular resistance index (SVRI ((dyn × s)/cm5/m2)).Impedance cardiography (ICG) is an easy, noninvasive procedure which allows for the assessment of left ventricular (LV) output performance, vascular status, and chest congestion . The impp value of <0.05 was considered statistically significant.The statistical analysis was performed using Statistica 12.0 . The distribution and normality of the data were assessed using the Kolmogorov–Smirnov test. Categorical variables were presented as absolute and relative frequencies (percentages), and continuous variables were presented as mean ± standard deviation (SD). The study group was stratified by the presence of reduced LVEF (<40% vs ≥40%) and anaemia (anaemic vs nonanaemic). The subgroups were labelled as follows: subgroup A , subgroup B ), subgroup C , and subgroup D . They were compared in terms of clinical, echocardiographic, and haemodynamic parameters with the use of ANOVA/Kruskal–Wallis test for continuous variables and chi-squared or Fisher's exact test for categorical variables. A n = 77; 79.4%; n = 62/63.9%) reported symptoms of NYHA (New York Heart Association) class III and approximately one-third (n = 35/36.1%) had resting dyspnoea (NYHA class IV). The most common comorbidities were arterial hypertension, atrial fibrillation, and diabetes (The study group (mean age 71.5 ± 12.6 years) was predominantly male (diabetes . The meaAs compared with those with LVEF < 40% (subgroups A/B), subgroups with LVEF ≥ 40% (subgroups C/D) comprised older patients, with a relatively higher percentage of women who presented with arterial hypertension and lower NT-proBNP concentrations . At the Patients with significantly impaired systolic function (subgroups A/B) and those with anaemia and LVEF ≥ 40% (group C) were characterised by a more greatly extended left atrium in comparison with nonanaemics with LVEF ≥ 40% (subgroup D). Only the LVEF criterium was of significance with respect to the LV dimension  were distinguished by significantly higher markers of LV pumping performance  . In addiThe results of impedance cardiography suggest that the haemodynamic response to anaemia in HF patients is related to the severity of LV impairment. This simple and noninvasive diagnostic method complements traditional diagnostics. Impedance cardiography confirmed the presence of anaemia-related water retention despite LVEF, whereas increased LV performance  was observed only in subjects with LVEF ≥ 40%. However, the fact that NT-proBNP and NYHA class intersubgroup comparison did not reveal any clinical benefit of this phenomenon is of clinical importance. Moreover, hearts with significantly decreased LVEF seemed to be unable to respond effectively to anaemia-related compensatory mechanisms, consequently leading to an increased LV load and chest congestion.Anaemia is considered to be an independent risk factor for cardiovascular adverse outcomes, both in the general population and in cardiovascular patients –14. UndeThis effect can be observed even at the asymptomatic stage of cardiovascular dysfunction. Zhou et al.  observedAnaemia triggers several unfavourable effects. Vasodilation-related low blood pressure may stimulate neurohormonal activation. Increased sympathetic stimulation reduces renal blood flow and the glomerular filtration rate. Moreover, it contributes to the activation of the renin-angiotensin-aldosterone axis, nonosmotic release of vasopressin, as well as salt and water retention. Consequently, this leads to an increase in total body water, extracellular volume, and plasma volume , 16.In our cohort, the haemodynamic effect of anaemia was strongly demonstrated in subjects with mildly impaired LV systolic function (subgroup C). Relatively higher values of ICG-derived parameters characterising LV output performance  were accompanied by lower vascular tone (SVRI) and higher chest fluid accumulation (TFC). An increase in left atrium dimension appeared to complement the pattern of “high output, high volume, high left chamber pressure, and pulmonary congestion.” ICG proved to be useful in the haemodynamic profiling of HF patients. In our previous study conducted on this cohort, we proved its usefulness in identifying the differences between patients with significantly impaired LV systolic function versus those with mildly impaired and preserved LV systolic function .Natriuretic peptides are cardiac neurohormones released by the ventricles in response to ventricular wall tension and stretch . Therefon = 49,985), anaemia revealed to be related with increased risk of mortality or HF hospitalisations (composite endpoint), greater in patients with less impaired LVEF (HR for preserved ≥50% and midrange (40–49%) vs. reduced (<40%): 1.24 and 1.26 vs 1.14; pinteraction = 0.003) [p < 0.001) survived, representing a 10.4-fold increased risk of death. Listerman et al. [p=0.02) and the exercise peak VO2 was significantly lower  among the anaemic patients. No significant differences in parameters characterising cardiac output (stroke volume and cardiac index) at peak exercise were observed between anaemic and nonanaemic patients. This suggests that the desired compensatory haemodynamic response to anaemia may be limited in patients with significantly reduced LVEF.There are reports revealing the prognostic significance of anaemia in HF patients. In patients from the Swedish HF Registry (= 0.003) . Ralli e= 0.003)  conducten et al.  evaluate2, and reduced survival rate (an increase in relative risk of death of 1.13 per 1 g/dL decrease in Hb). Moreover, Wang et al. [2 and O2 uptake efficiency slope, as well as cerebral flow, during exercise. This may partly explain why subgroup C of our cohort failed to achieve better functional capacity (NYHA class) than the other subgroups, despite presenting with a resting high-output state.Anaemic patients are expected to have a more pronounced haemodynamic response to exercise with respect to increased cardiac output. However, exercise haemodynamic adaptation to anaemia in HF patients is insufficient and may partially explain poorer exercise tolerance. Horwich et al.  observedg et al.  reportedIt is also worth mentioning that our results confirmed the previously reported strong correlation between anaemia and comorbidities of negative prognostic value –3, 23. POur results show that the haemodynamic effects of anaemia may differ individually among HF patients. The results of ICG suggest that anaemia-related “high cardiac output” state is related to milder cardiac impairment. However, this is not tantamount to clinical benefit because this state is rather characterised as “high intravascular volume” than “high cardiac contractility” and should be targeted by individualised therapy. The harmful effect of anaemia in patients with low LVEF seems to be clearly depicted by high NT-proBNP and TFC. These results should be interpreted with consciousness that HF, as a complex syndrome, may involve other organs influencing haemoglobin level such as the lungs, kidney, liver, and haematopoietic system . The patOur results support recommendation to carefully investigate the causes of anaemia in HF patients, especially the potentially reversible ones  , 24. It The main limitation of our study was the small size of the evaluated subgroups, which undoubtedly affected the statistical power of the analysis. For this reason, the patients with non-reduced LVEF were combined into one subgroup. We also did not use cardiac magnetic resonance imaging that might provide additional data about heart morphology and function. Because of the small sample size, the analysis was underpowered for multivariate models, including potential confounders such as sex and age. We also did not differentiate in detail ADHF from end-stage HF patients that should be considered in future studies aimed to assess the prognosis. Another important limitation was the 24-hour window in which ICG assessment was performed because haemodynamic profiles can change less than an hour after initiating effective treatment. We would also like to emphasise the fact that only the fluid content within the thorax can be measured by ICG, and this significantly restricts any possible conclusions regarding the overall body fluid content. We also did not perform exercise evaluation, and this limits our ability to comment on the effect of anaemia on exercise capacity and haemodynamics. The effect of potential haemodilution should also be taken into consideration in patients with ADHF and low Hb .In ADHF, anaemia is related with fluid overload, relatively higher cardiac systolic performance but no clinical benefit in patients with preserved/midrange LVEF, and increased left ventricular tension, fluid overload, and impaired cardiac systolic performance in patients with reduced LVEF. Concomitant fluid overload and impaired renal function are suggestive of a poorer prognosis.


Reduced physical activity increases the risk of heart failure; however, non‐invasive methodologies detecting subclinical changes in myocardial function are not available. We hypothesized that myocardial, left ventricular, systolic strain measurements could capture subtle abnormalities in myocardial function secondary to physical inactivity.P < 0.0001), orthostatic heart rate responses , and diastolic blood pressure  increased, whereas cardiac output  decreased during bed rest. Left ventricular mass index obtained by MRI did not change. Echocardiographic left ventricular, systolic, global longitudinal strain  decreased, whereas left ventricular, systolic, global MRI circumferential strain increased not significantly . MRI values rapidly returned to baseline during recovery.In the AGBRESA study, which assessed artificial gravity through centrifugation as potential countermeasure for space travel, 24 healthy persons (eight women) were submitted to 60 day strict −6° head‐down‐tilt bed rest. Participants were assigned to three groups of eight subjects: a control group, continuous artificial gravity training on a short‐arm centrifuge (30 min/day), or intermittent centrifugation (6 × 5 min/day). We assessed cardiac morphology, function, strain, and haemodynamics by cardiac magnetic resonance imaging (MRI) and echocardiography. We observed no differences between groups and, therefore, conducted a pooled analysis. Consistent with deconditioning, resting heart rate (∆8.3 ± 6.3 b.p.m., Prolonged head‐down‐tilt bed rest provokes changes in cardiac function, particularly strain measurements, that appear functional rather than mediated through cardiac remodelling. Thus, strain measurements are of limited utility in assessing influences of physical deconditioning or exercise interventions on cardiac function. Reduced physical activity increases the risk of heart failure later in life.2, eight women). We obtained written informed consent prior to study entry. The study was approved by the North Rhine Medical Association Ethics Committee and prospectively registered (DRKS00015677).This study is part of the NASA/ESA/DLR 60 day −6° head‐down‐tilt bed rest study ‘Artificial Gravity Bed Rest with European Space Agency’ (AGBRESA) conducted at the DLR: envihab. The study enrolled 24 healthy persons  at baseline  and at the end of bed rest  to assess biplane end‐diastolic and end‐systolic volumes; mitral annulus plane systolic excursion; left ventricular, systolic, global longitudinal peak strain by speckle tracking; transmitral filling patterns ; and stroke volume index .Cardiac MRI  was performed at baseline (5 days before bed rest), on 56th day of bed rest, and on 4th day of recovery. We recorded two‐chamber, three‐chamber, and 4‐chamber cine loops  and a complete short‐axis stack  with retrospective electrocardiogram gating and analysed cardiac output; left ventricular mass index; ejection fraction; left ventricular, systolic, global circumferential strain and strain rate; and time to peak  , systolic blood pressure did not change, and diastolic blood pressure increased 8.8 ± 6.6 mmHg (P < 0.0001) at the end of bed rest. On Day 4 of recovery, blood pressure had returned to baseline, while resting heart rate remained elevated by 5.6 ± 8.4 b.p.m. (P < 0.001). With standing, heart rate increased 22.8 ± 10.5 b.p.m. at baseline and 45.6 ± 21.4 b.p.m. following bed rest  and 14.4% , respectively. Left ventricular end‐diastolic volume determined by echocardiography decreased 20.3 ± 15.4% (P = 0.0001) together with ejection fraction (6.4 ± 5.1%). Left ventricular mass index did not change , did not change in men  or in women . Mitral annulus plane systolic excursion and global longitudinal peak strain were reduced following bed rest , and programmatic funding of the German Aerospace Center (DLR). F.H. received funding from the German Aerospace Center (DLR) and the German Federal Ministry of Economy and Technology . J.R. was supported by the Fonds de la Recherche Scientifique (Mandat Aspirant F.R.S.–FNRS FC 29801).


Purpose: In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. On the other hand, oxidative stress is recognized as a player in the pathogenesis of HFpEF. Therefore, we performed a cohort study in HFpEF aimed to (1) define the multi-hormonal deficiency prevalence in HFpEF patients; (2) investigate the relationships between hormonal deficiencies and echocardiographic indexes; (3) explore the modulatory activity of anabolic hormones on antioxidant systems.Methods: 84 patients with diagnosis of HFpEF were enrolled in the study. Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, insulin, lipid pattern, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone  were evaluated. Hormonal deficiencies were defined according to T.O.S.C.A. multi-centric study, as previously published. An echocardiographic evaluation was performed. Plasma total antioxidant capacity (TAC) was measured using the system metmyoglobin –H2O2 and the chromogen ABTS, whose radical form is spectroscopically revealed; latency time (LAG) in the appearance of ABTS• is proportional to antioxidants in sample.Results: Multiple deficiencies were discovered. DHEA-S deficiency in 87% of patients, IGF-1 in 67% of patients, T in 42%. Patients with DHEA-S deficiency showed lower levels of TAC expressed by LAG . No differences between TAC in patients with or without IGF-1 deficiency were found. A trend toward high level of TAC in patients without hormonal deficiencies compared with patients with one or multiple deficiencies was found. Regarding echocardiographic parameters, Left Atrial and Left Atrial Volume Index were significantly higher in patients with low IGF-1 values .Conclusions: Our study showed high prevalence of anabolic deficiencies in HFpEF. DHEA-S seems to influence antioxidant levels; IGF-1 deficiency was associated with alteration in parameters of myocardial structure and dysfunction. These data suggest a role of anabolic hormones in the complex pathophysiological mechanisms of HFpEF and could represent the basis for longitudinal studies and investigations on possible benefits of replacement therapy. Heart Failure (HF) is a clinical syndrome characterized by typical signs and symptoms  associated with reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Classically, HF is classified according to left ventricle ejection fraction (LVEF) in two main variants: HF with reduced ejection fraction (HFrEF) characterized by LFEF <40%, and HF with preserved ejection fraction (HFpEF) when LVEF ≥ 50% .These two variants of HF, while sharing common clinical features, have been associated with different pathophysiological models  and therAbout HFpEF pathophysiology, diastolic dysfunction is the main mechanism involved, but several other alterations, such as left atrial dysfunction, right ventricular dysfunction, pulmonary hypertension, and increased vascular stiffness, have been identified, which contribute to HFpEF –7. Advanpost-hoc analyses of randomized trials suggest the need of accurate stratification of HFpEF patients, in order to implement “tailor-made” therapeutic strategies , dehydroepiandrosterone-sulfate (DHEA-S), testosterone (T), have an important role on cardiac morphology and function –21; AnabThe relationship between anabolic hormone deficiency and HFpEF has been poorly investigated. A study of Salzano et al.  showed aNo data were reported about the impact of hormonal deficiencies on oxidative stress parameters; therefore, we performed an observational cross-sectional study to quantify anabolic hormonal deficiency prevalence, and to investigate the relationships between anabolic alterations, echocardiographic parameters, and antioxidants levels, with the aim to gain insight into pathophysiology of HFpEF.2, left ventricular mass index left atrial volume index (LAVI) > 34 mL/m or a left ventricular mass index (LVMI) ≥ 115 g/m2 for males, and ≥95 g/m2 for females. Doppler parameters were a ratio of transmitral early filling velocity to tissue early diastolic mitral annular velocity (E/e′) ≥ 13 and a mean e′ septal and lateral wall <9 cm/s.Chronic HFpEF patients with NYHA functional class I–III, admitted to the Department of Internal Medicine of the “Fondazione Policlinico Universitario A. Gemelli IRCCS” between April 2016 and May 2019 were recruited. The HFpEF diagnosis was based on current European Society of Cardiology guidelines , angiotensin II receptor blockers (ARB), and beta-blockers (BBs) had to be stable for at least 2 months. We investigated the prevalence of the following comorbidities: arterial hypertension, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), renal failure, anemia, atrial fibrillation, peripheral artery disease, or coronary artery disease.2. All patients signed written informed consent, according to the declaration of Helsinki. The study was approved by the Local Ethics Committee.Body weight was measured in light clothes with an electronic scale  to the nearest 0.1 kg and height was measured with a stadiometer  to the nearest 0.1 cm. Body Mass Index (BMI) was calculated with the formula Body weight (kg)/[height (m)]In all patients, venous blood samples were collected in lithium-heparin tubes in the morning after an overnight fast and after a supine rest of at least 15 min, in order to evaluate plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), plasma fasting glucose, IGF-1, DHEA-S. In male subjects, total testosterone (T) was also assayed. All samples were centrifuged within 2 h after collection and separate plasma aliquots were stored at −80°C until assayed.A complete echocardiography evaluation was performed , calculating the following parameters: left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), septal thickness (IVS), posterior wall thickness (PW), peak E-wave velocity (E), peak A-wave velocity (A), E/A ratio, pulsed- wave TDI E′ velocity (E′), E/e′ ratio, deceleration time (DT), left atrial volume (LAV), indexed left atrial volume (LAVI), systolic pulmonary artery pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), right ventricular mid cavity diameter value (RVEDV), TAPSE/SPAP ratio, and tricuspidal peak velocity (TPV).NT-proBNP plasma concentrations, DHEA-S, T, and IGF-1 were measured using immunochemiluminometric assays on a Roche Modular E170 analyzer . The intra-assay and inter-assay CV for all hormones were, <5.0 and <7.0%, respectively. Echocardiographic and hormonal parameters were obtained in a stable clinical condition.Our laboratory considered the following ranges as normal: NT-proBNP (>126 pg/mL), DHEA-S , and T (2.5–8.4 ng/mL). Values equal or below the lower normal limit of normal were defined as deficiency. IGF-1 deficiency was defined according to T.O.S.C.A. registry criteria , referring to the 33th percentile of a male population with Chronic Heart Failure due to age-related variations .2O2 (75 μM). Aliquots of the frozen plasma were thawed at room temperature and 10 μL of the samples were tested immediately. The manual procedure was used with only minor modifications, as previously described  in the accumulation of ABTS•+ proportional to antioxidants concentration and expressed as length of such Lag phase (s). This assay mainly measures non-protein and non-enzymatic antioxidants that are primarily extra-cellular chain-breaking antioxidants, such as ascorbate, urate, and glutathione. Trolox, a water-soluble tocopherol analog, was used as a reference standard. Absorbance was measured with a Hewlett-Packard 8450A UV/Vis spectrophotometer  equipped with a cuvette stirring apparatus and a constant temperature cell holder. Measurements of pH were made with a PHM84 Research pH meter ; the electrode response was corrected for temperature. Intraassay CV was <8%.Plasma total antioxidant capacity (TAC) was evaluated using the method developed by Rice-Evans and Miller . The metescribed . The reaT-Test was used to evaluate the differences in echocardiographic parameters, NT-proBNP values, BMI, and age between patients divided in groups according to the presence or absence of hormone deficiency .Patients with normal values and hormonal deficiencies were identified for each single measured hormonal parameter. Mean and Standard Error of the Mean (SEM) were used to describe quantitative variables, absolute and relative frequencies for qualitative variables. Student U-Test was used to compare the same parameters between patients with or without DHEA-S deficiency. In order to investigate the associations between hormonal deficiency and comorbidities, Fisher's exact or Chi-squared test was used. A value of p < 0.05 was considered statistically significant and the analysis was performed using Prism 6.Mann-Whitney Our cohort of patients consisted of 84 patients, 36 men, and 48 women, aged between 59 and 98 years (mean ± SEM: 80.31 ± 0.94 years). No statistically significant differences in echocardiographic parameters and in prevalence of comorbidities were found in patients with or without T and DHEA-S deficiency.Our data showed high prevalence of anabolic hormones deficiencies in HFpEF. This confirms previous preliminary report of our group , underlyFurthermore, it is matter of discussion if alterations in anabolic drive observed in HF patients represent a cause or a consequence of the clinical syndrome. Our data, showing a reduced TAC in patients with DHEA-S deficiency, are in favor of a role of hormonal deficiency in influencing HFpEF pathogenesis and/or pathophysiology. In fact, over the past several decades, clinical and experimental studies –33 have Finally, a new important field is the differential response to medical therapy, suggested by recent studies about pharmacogenetics, in the view of personalized medicine; a great importance could be exerted by genetic variations of G-protein coupled receptors (GPCRs) which have been studied in some models of heart failure, in particular variants of the β adrenergic receptors have been linked to a worse clinical course of HF , 42. SomIn vivo and in vitro studies showed that DHEA-S counteracts lipid peroxidation (In this complex interplay between inflammation, oxidative stress and individual response to drugs, anabolic hormones impairment could be another mosaic tile. DHEA-S, in fact, is involved in the regulation of OS , and alsxidation , 57. Morxidation .GH/IGF-1 axis alteration is another factor with high prevalence in our cohort, with an impact on left atrium parameters, considered important indexes of myocardial dysfunction. Although GH is also a regulator of oxidative balance as previously showed, we did not find any influence on TAC in cohort object of our study. It is well-known that IGF-1 is a key factor in cardiomyocytes trophism and contractility. A higher IGFBP/IGF-1 ratio was associated with increased E/e′ ratio, NT-proBNP levels and left atrial enlargement . IGF-1 dAs antioxidants levels are concerned, we observed a trend toward higher levels of TAC in patients with normal hormonal milieu compared with patients with multiple hormonal deficiencies, although not significant. This pattern is not overlapping with one observed in HFrEF as previously described by our group ; this coNevertheless, some potential limitations of the present study can be identified. Firstly, the cohort of patients studied although greater than previous reports, needs to be further enlarged. Secondly, TAC as measure of OS should be coupled with other parameters of oxidative damage; finally, our study was focused on IGF-1 levels without evaluating GH secretion via dynamic tests. Therefore, further investigations should be performed to evaluate prevalence of GH deficiency in HFpEF.Our study, extending previous observation, confirmed a high prevalence of anabolic hormone deficiencies in patients with HFpEF, with particular relevance of DHEA-S. It seems to be related to antioxidants modulation, with higher levels of TAC in patients without DHEA-S deficiency; considering the role of OS in HFpEF pathogenesis, our data could suggest a pathogenetic involvement of this hormone.Another anabolic key factor could be IGF-1; patients with low IGF-1levels presented left atrial enlargement that is considered one of main diastolic dysfunction criteria.trait union between the three components of the systemic picture, typical of HFpEF.In conclusion, HFpEF seems to be a complex model with a reciprocal interaction between comorbidities, including anabolic deficiencies, and myocardial function. Oxidative stress could represent the Therapeutically consequences of these observations remain to be further investigated.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Ethics commitee of Fondazione Policlinico Universiario A Gemelli IRCSS, Largo A Gemelli 00168, Rome, Italy. The patients/participants provided their written informed consent to participate in this study.CB, AS, AF, and AMa were involved in conception and design of the study. CB, EV, and AS wrote the manuscript. EV, CB, RC, MN, and Cd'A were involved in acquisition and analysis of data. RL, EM, AMa, and AMo were involved in supervision. All authors were involved in critical discussion and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hepatitis C virus (HCV) infection has been noted with various cardiovascular (CV) diseases, and patients with detected HCV-RNA had higher CV mortality than uninfected individuals. The new direct-acting antiviral drugs (DAA) proved to be more effective with fewer side effects compared to interferon in eradicating HCV, but their effect on myocardium is still questionable. In order to get some answers for such question, two-dimensional speckle tracking echocardiography (2D-STE) was studied before and after treatment with different DAA regimens in HCV patients with either mildly impaired or normal basic left ventricular ejection fraction (LVEF).n = 100) and those with normal basic LVEF (n = 20) ; also, segmental strain showed significant worsening of many segments. Such worsening was significantly more in those with basic impairment of LVEF compared to those with normal basic LVEF (p = 0.036). No significant difference was observed in GLS and segmental strain when classifying and comparing patients according to gender, presence of diabetes mellitus, hypertension, ischemic heart disease and established cardiac medications, or according to DAA regimen received.Global longitudinal strain (GLS) significantly worsened after finishing antiviral treatment in patients with basic impairment of LVEF (DAA may have a cardiotoxic effect that could be early detected by 2D-STE, which was more significant in patients with pre-treatment impairment of LVEF. About 73% of the studied population were scheduled to receive dual DAA (SOF and DCV), while about 27% were scheduled to receive triple DAA .n = 100) and group II: those with basic LVEF ≥ 55% (n = 20). No significant difference was observed between both groups regarding age, gender, presence of DM, hypertension, and/or documented IHD, pre-medication with chronic cardiac treatments, and the DAA regimen used  and segmental strain  after receiving DAA regimens. Meanwhile, such difference was not observed regarding LVEF in the same group (p = 0.06) (Table p = 0.039) and segmental strain , while no significant difference was observed regarding LVEF in the same group (p = 0.089)  Table  and 3. Sp = 0.036), and similar pattern was observed in segmental strain of all analyzed segments, while change in LVEF did not follow the same pattern (p = 0.184) , hypertension (p = 0.957), IHD (p = 0.943), or cardiac pre-medication (p = 0.337). Also, the absolute changes that occurred in segmental strain of the 16-segments examined and LVEF did not show any significant differences.No significant difference was observed regarding the absolute changes that happened regarding GLS by receiving DAA regimens, when classifying and comparing the studied population according to the presence or absence of DM (p = 0.257) and LVEF (p = 0.176) .Moreover, when comparing the studied population according to the type DAA regimen received , no significant difference was observed in absolute changes that happened with treatment regarding segmental strain of all segments examined, GLS (6) Table . FurtherHCV infection is a persistent hepatic viral infection that constitutes a considerable health dilemma. It is estimated that more than 170 million individuals worldwide are infected, and 25% of them are suffering from its complications in form of liver cirrhosis, hepatocellular carcinoma, and/or hepatic cell failure . In EgypThe 2D-STE has recently emerged as a technique for evaluating LV systolic and diastolic functions. It measures the displacement of speckles on the 2D images, representing the myocardial deformation rather than volumetric change as seen by traditional LVEF estimation methods . The GLSn = 100) included patients with mildly impaired LV systolic function regardless of the cause . The 2D-STE was obtained for all studied patients before starting antiviral treatment and after finishing the 3-month treatment course.So, out of this importance of GLS in prediction and prognosis, the current study was performed using GLS in an attempt to predict the possible effect of DAA regimens on the myocardium. The study included 120 HCV patients, who were scheduled for receiving oral DAA regimens. The study cohort was divided into two groups according to their pre-treatment LVEF: group I  nor ECG changes were developed during the study  was stopped after a young male patient experienced rapidly progressive HF and passed away, and 41.2% of patients had some evidence of cardiac dysfunction, with a modest elevation of plasma levels of brain natriuretic peptide (BNP)—the sensitive marker of myocardial stress—in the majority of cases. The pathological myocardial analysis of that index case showed profound myocyte injury with very limited areas of necrosis and no appreciable infiltration of polymorph nuclear cells . This coAlthough the actual potential mechanisms of certain DAAs (as BMS-986094 and IDX-14184) related cardiotoxicity remains unclear, series of non-clinical in vitro and in vivo studies showed that it may be related to some potential changes in cardiac energy utilization rather than being a direct mitochondrial toxicant . FurtherTo the best of our knowledge, this was the first study to investigate the effect of different DAA regimens in patients with impaired LV systolic function, and significantly more worsening in the GLS and the segmental strain was observed in such patients compared to those with normal basic LVEF. This could be explained by the fact that patients with impaired LV systolic function had important modification in their contractile proteins, as proteolysis of the myofilaments (myocytolysis) and reduction in the volume of myofibrils per cell, also the alteration in the expression and/or activity of myofilament regulatory proteins, that is proposed to decrease the contractile function in HF . And basAnother important finding from the current study was that such effect of DAA regarding GLS, segmental strain and LVEF were not associated to a specific antiviral regimen, and no significant difference was observed when comparing the study population according to the type of received DAA regimens . This finding was in agreement with the recent results by Ibrahim et al., who studied 2D-echo and STE in 100 HCV patients before and after finishing DAA regimens, and classified them into two groups according to the presence of liver cirrhosis and the type of DAA regimen received . They found no significant difference regarding LV volumes, LVEF, and LV strain between both groups by receiving both regimens .The effect of different DAA regimens was also investigated by El-Adawy et al. using cardiac magnetic resonance (CMR), who studied 390 patients with chronic HCV infection and received different DAA regimens. The study cohort was divided into four groups according to the treatment regimen . CMR was done before, during and after 6 months of treatment. They reported that some patients who received regimens including SIM or DCV had expressed edema in CMR and different degrees of cardiomyopathy, with elevation of cardiac enzymes (CKmb), denoting their possible cytotoxic effect. Interestingly, those changes were fully reversible at the 6-month follow-up without leaving permanent cardiac damage .Furthermore, no significant difference was observed in the current study regarding the absolute changes that happened in GLS, segmental strain, and LVEF by receiving DAA regimens when classifying and comparing the studied population according to the presence or absence of DM, hypertension, IHD, or cardiac pre-medication.These findings regarding DM were concordant to those of Mazzitelli et al. who showed no significant difference regarding GLS and LVEF between diabetic and non-diabetic patients who received DAA therapy . InteresOur results regarding hypertension were also concordant to those of Mazzitelli et al., who showed no significant difference in GLS and LVEF regarding the presence of hypertension in their studied population . This coIn a recent study by Zuo et al. [who studied 84 patients with dilated LV with impaired LVEF (< 45%) and were classified according to their coronary angiography into 41 ischemic cardiomyopathy (ICM) and 43 non-ischemic cardiomyopathy (NICM) patients], no significant difference was present in GLS between those with ICM and NICM, although the lower LVEF and relative apical sparing with basal worsening of LV longitudinal strain observed in NICM patients. They owed such strain features to diffuse myocardial lesions throughout the entire LV in NICM, while ICM had homogeneously reduced longitudinal strains but greater reduction of radial strain along the obstructed coronary arteries territories .Oral DAAs may have a cardiotoxic effect that could be detected by 2D-STE rather than traditional LVEF estimation. This effect was more obvious in those with basic impairment in LV systolic function, irrespective of age, gender, presence of DM, hypertension, IHD or cardiac pre-medication, and regardless of the type of DAA regimen used.Lack of a longer-term follow-up of the LV function after finishing the DAA course, as the main target of the study was to assess the short-term effect of the drugs. No cardiac biomarkers were investigated, as our study focused mainly on assessing a possible affection of myocardial function by the commonly used DAA regimens. A larger scale of patients on different DAA regimens may be furtherly evaluated for confirming such possible cardiotoxic effect of those drugs.