The moderator band (MB) is an intracavitary structure of the right ventricle composed of muscular fibers encompassing specialized Purkinje fibers, separated each other by collagen and adipose tissue. In the last decades, premature ventricular complexes originating within the Purkinje network have been implicated in the genesis of life-threatening arrhythmias. However, right Purkinje network arrhythmias have been much less reported in the literature compared to the left counterpart. The MB has unique anatomical and electrophysiological properties, which may account for its arrhythmogenicity and may be responsible for a significant portion of idiopathic ventricular fibrillation. MB embodies autonomic nervous system cells, with important implications in arrhythmogenesis. Some idiopathic ventricular arrhythmias, defined as the absence of any identifiable structural heart disorder, can begin from this site. Due to these complex structural and functional peculiarities strictly interplayed each other, it is arduous to determine the precise mechanism underlying MB arrhythmias. MB-related arrhythmias should be differentiated from other right Purkinje fibers arrhythmias because of the opportunity for intervention and the unusual site for the ablation poorly described in the literature. In the current paper, we report the characteristics and electrical properties of the MB, their involvement in arrhythmogenesis, clinical and electrophysiological peculiarities of MB-related arrhythmias, and current treatment options. Moderator band (MB) related ventricular tachycardias (VTs) and premature ventricular contractions (PVC) are being increasingly recognized as a cause of idiopathic VTs. The MB is a muscular structure extending from the anterior septum to the anterior papillary muscle (APM) of the right ventricular (RV) free wall. This structure comprises a specialized Purkinje fibers network which allows for rapid activation of the RV-free wall . The MB The MB is an intracavitary structure of the RV which spans from the interventricular septum (IVS) to the RV-free wall at the base of the APM, and it is considered part of the septomarginal trabeculation. The MB has high interindividual variability in terms of origin and shape . It mighOriginally described by Leonardo Da Vinci, the MB takes its name from what it was thought to be its function, which is to prevent RV excessive distension thanks to the anatomic link of the IVS and RV free wall. Later, it was found that part of the right half of the Purkinje system is contained in the MB, allowing for synchronous activation of the RV-free wall during systole. The right Purkinje system is composed of the right bundle branch (RBB), the free-running Purkinje fibers (PF), which branch from the RBB along its length, and the terminal PF, which connects with the free-running PF in the parietal RV wall. The terminal PF account for the largest part of the right Purkinje network, forming a more complex network than that in the left ventricle that cover the majority of the RV free wall and extends toward the tricuspid valve . PF sprePF are a longitudinal assembly of Purkinje cells (PC) and are insulated from working myocytes by a connective tissue sheath that is lost before the PF form the terminal connections with the working myocytes through specialized junctions in the endocardium ,15. ReceThe MB vasculature is perfused by the anterior interventricular coronary artery and the right coronary artery from the base of the APM, forming an important collateral circulation between the left and right coronary artery systems .KACh current [Innervation of the MB is supplied by elements of the autonomic system, being the PF more sensible to the parasympathetic neurotransmitter acetylcholine (ACh) compared to ventricular muscle because of a higher expression of channels responsible for I current ,16.2+-handling proteins such as RYR2 (Ryanodine receptor 2), RYR3 (Ryanodine receptor 3), SERCA2a (sarcoplasmatic/endoplasmic reticulum Ca2 ATPase 2a), and NCX (Na+-Ca2+ exchangers). In contrast, they are fast conducting because of high upstroke velocity during phase 0 of action potential and high conduction velocity. These properties are explained by a higher expression of Na+ channels, particularly Na1.1, and of the fast-conducting connexin Cx40. Regarding the K+ channel profile, PC show a lower expression of Kv1.4 and a higher expression of Kv4.2, the first being a slow recovering isoform while the second being a fast one, both responsible for Ito (transient outward current). On the other hand, the K+ conductance involved in phase 2 and phase 3, namely IKs, IKr, and IKur , are predicted to be lower in PC as compared to working myocardium. In addition, the IK1 current generated by the Kir2 channels family (Kir2.1–2.4) responsible for the maintaining of resting potential is less represented in PC, and HCN 1 and HCN4, which underlie If current, are more expressed. All these differences account for the following differences in action potential: high upstroke velocity during phase 0, a prominent early rapid repolarization (phase 1), a negative potential plateau (phase 2), an increased APD, and a spontaneous diastolic depolarization (phase 4), which is normally inapparent because of overdrive suppression by the sinus node. Additionally, it has been shown that genetically determined upregulation of the DPP6 (dipeptidyl aminopeptidase-like protein 6) gene, which encodes for a beta subunit of Kv4 channels, enhances Ito in PF with consequent strong repolarization gradient between the PF and the adjacent ventricular myocardium, with possible phase 2 re-entry induced PVCs [PC are specialized myocardial cells that are responsible for the synchronous activation of the ventricles. Ion channel expression substantially differs from that of the working myocites and can explain the specialized electrical activity of the PC . Differeced PVCs .Moreover, the electrophysiological properties of MB may be influenced by its anatomic variability . Particu2+) but also to late Na+ currents during late phase 2/early phase 3 of the action potential. Moreover, PVCs may originate from a phase 2 re-entry because of the strong repolarization gradient between the two compartments of the MB [All arrhythmogenic mechanisms may be involved in the genesis of MB-related arrhythmias, particularly triggered activity and re-entry. PF are often involved in the genesis of ventricular arrhythmias due to their susceptibility to the development of early afterdepolarizations (EADs). EADs seem to be ascribable mainly to inward calcium currents  because multiple spiral waves break up with the consequent genesis of daughter spirals. MB-related VF still represents a rare but not neglectable percentage of IVF . Some caFurthermore, 3D-mapping and intracardiac echocardiography showed that sc-TdP predominantly originated from MB free wall and its PF network .As mentioned, the right Purkinje system is composed of the RBB, free-running PF, and terminal PF, which form a complex network at the RV free wall extending up to the tricuspid valve (TV); . The ele4), similar to those originating from APM [2 to V5) for those with a superior axis. On the contrary, left posterior fascicle arrhythmias usually mimic a typical RBB pattern with rsR’ and specifically have a QRS < 130 ms because of the rapid ventricular depolarization through the Purkinje system.The electrocardiographic (ECG) analysis may help clinicians in hypothesizing these specific arrhythmias. MB-related arrhythmias are typically classified among those with a superior axis configuration, such as those from inferior TV and left posterior fascicles ,27,28 F. Typicalfrom APM . SometimSometimes monomorphic VTs may sustain through a re-entry circuit involving both the right and left bundle branches , a single left fascicle (intrafascicular re-entry), or both left fascicles (interfascicular re-entry). However, the intrafascicular re-entry has not been demonstrated at the right Purkinje system level yet. Bundle branch re-entry VTs are often observed in patients with acquired heart disease, which might involve the His-Purkinje system, and, therefore, would lead to slow conduction within the Purkinje system necessary for the occurrence of re-entry. However, conduction disturbances in the His-Purkinje system of young patients with structurally normal hearts can also lead to susceptibility to bundle branch reentry VTs . FinallyPatients may have a high variability of clinical presentation, ranging from isolated PVCs, either symptomatic or asymptomatic, to electrical storm and cardiac arrest. Most of the cases of MB-related arrhythmias have been described in middle-aged males. The actual prevalence of these arrhythmias is unknown because of a lack of reports in the literature, and described cases are usually those who have experienced a major event such as cardiac arrest .4), but may also present with a DII/DIII discordance [The initial evaluation of patients presenting with an arrhythmic event does follow the generic algorithm proposed by the latest ESC guidelines on ventricular arrhythmias and sudden cardiac death until a specific diagnosis is reached . Patientcordance .On the contrary, in patients presenting with a cardiac arrest, usually, a complete ECG documentation of the arrhythmic event is unavailable; hence, it may initially remain unknown the involvement of the MB in the genesis of PVC triggers. Therefore, those patients who survive the event should be evaluated with the aim of excluding the ischemic etiology or other structural heart diseases, primary electrical diseases, metabolic or toxic causes, and extracardiac causes through brain and chest CT scan ,26.First-line testing for patients presenting with PVCs/NSVT/SVT includes a 12-lead ECG, a complete echocardiogram, and at least 24 h continuous ECG monitoring (Holter ECG in ambulatory setting). When there is suspicion of an underlying coronary artery disease or structural heart disease, coronary angiography and/or cardiac magnetic resonance should be performed. Otherwise, if a primary electrical disease is suspected, further evaluation should be considered, such as a genetic test, exercise test, and sodium channel blocker test. However, patients with moderator band-related arrhythmias usually show negative results of the abovementioned examinations; therefore, the arrhythmic events are to be labeled as idiopathic. Symptomatic patients with idiopathic PVCs/VTs could be subsequently referred for catheter ablation or treated with drug therapy, whereas asymptomatic patients with a high burden of PVCs (>10%) should undergo a regular follow-up and optionally be referred for catheter ablation ,26.Similarly, sudden cardiac arrest survivors in whom all diagnostic examinations have failed to provide a diagnosis should be labeled as IVF. In this case, it is important not to miss the opportunity to perform comprehensive clinical testing  of first-degree family members to prevent sudden cardiac death. In patients who have experienced IVF, an ICD implantation is mandatory, but the involvement of the MB in the genesis of PVCs that may trigger VF can remain ignored until further events occur or catheter ablation of PVC triggers is considered .Radiofrequency (RF) catheter ablation seems to be an effective approach in the treatment of MB-related arrhythmias. Several case reports have shown good results in suppressing PVCs-mediated VF and electrical storms ,9. An elThe anatomic variability of the MB could account for multiple PF-mediated PVCs morphology. Therefore, multiple sites of ablation, of which the whole MB, its insertion in the RV free wall and IVS and the APM, have to be considered in order to completely eliminate the PVCs source, even though it has been reported that ablation at the earliest PF potential recorded is generally effective in suppression of PVCs aside from their morphology ,33.Complete ablation of the MB and of its insertion points in the right ventricle is fundamental also to interrupt the macro re-entry circuit. Using contact force-sensing catheters with vector analysis in addition to ICE is fundamental to guarantee sufficient contact and stability of the catheter tip to the ablation site, as well as using higher RF energy. Cryoablation may configure a therapeutic option to achieve arrhythmic substrate disappearance and effective MB ablation ,31.to. Haissaguerre and colleagues demonstrated that repetitive activity from the distal PF network may cause VF even with minimal or no PVCs at baseline. Quinidine is a class Ia sodium channel blocker that also reduces the potassium currents IK1 and IKto. This combined effect may make quinidine uniquely effective in controlling arrhythmias associated with action potential duration dispersion and phase 2 reentry, postulated in IVF. Particularly, Ito is highly expressed in PF, possibly explaining the unique effect of quinidine. Several studies have demonstrated a reduced incidence of ventricular arrhythmias in patients with IVF treated with quinidine. The transient outward potassium current Ito is highly active in the Purkinje network of the MB, and its inhibition may be the mechanism by which quinidine has a therapeutic effect in these arrhythmias. It must be considered that the effective dose of quinidine may be poorly tolerated and should be cautiously tested in each patient [There is a lack of strong evidence concerning the pharmacological management of MB-related arrhythmias. Nonetheless, since PF are the most likely trigger for arrhythmias, it seems reasonable to manage them as usual for idiopathic VF. Quinidine has been reported to be effective in suppressing PVCs arising from the Purkinje network, considering its ability to suppress the I patient ,8. Moreo patient . Radiofr patient .Over the past 10 years, some reports have described insufficient pharmacological treatment due to the failure of amiodarone, b-blockers, Magnesium, lidocaine, quinidine, cilostazol, and verapamil . MedicalIn cases of sustained VTs/IVF causing cardiac arrest, ICD implantation in secondary prevention is mandatory . NeverthThere are no specific indications for patients presenting with MB-related arrhythmias regarding lifestyle modification and sport participation. Recommendations for these patients follow those of the latest guidelines on sports cardiology and exercise in patients with cardiovascular diseases . RecommePatients with asymptomatic PVC/NSVT who have not been referred for a specific treatment should be regularly followed-up, but no specific time lapse between visits has been suggested from recent guidelines. It is reasonable to perform a complete ambulatory visit comprehensive of echocardiogram and a Holter ECG each 6 to 12 months in order to monitor left ventricular ejection fraction for the exclusion of PVC-induced cardiomyopathy and evaluate arrhythmias’ burden. In case of the development of PVC-induced cardiomyopathy or an elevated burden of arrhythmias, specific treatment must be considered, and catheter ablation represents a valid therapeutic option.Patients who have undergone a specific drug treatment or catheter ablation should be equally followed-up in order to evaluate the efficacy of the chosen treatment, both in terms of symptoms and reduction/suppression of the arrhythmic burden and to exclude possible adverse events. For example, quinidine assumption may lead to overdose, which may present with symptoms linked to the involvement of the central nervous system  or cardiac side effects such as conduction disturbances and proarrhythmic effect. Of note, in case of quinidine overdose, it could be helpful to acidify the patient’s urine to favor excretion.Finally, patients who presented with a cardiac arrest due to IVF and who have undergone an ICD implantation should be regularly followed up to evaluate arrhythmic relapses and assess the delivery of ICD therapies such as ATP and shocks. For this purpose, it is of particular importance the implementation of a program of remote monitoring, which may promptly lead to an appropriate treatment. In case of recurrent ICD shocks, it is possible to implement a pharmacological therapy, if not present, and perform catheter ablation of the arrhythmic substrate. To conclude, survivors of a cardiac arrest due to IVF could also be referred for genetic counseling, which may identify a potential genetic predisposition to the development of arrhythmias, therefore, help in the prevention process of relatives of the proband.The moderator band is an intracavity structure of the right ventricle with unique anatomical and electrophysiological properties. In fact, the moderator band is composed of two distinct compartments of working myocytes and Purkinje fibers presenting a coaxial configuration, both excitable but electrically uncoupled, because of collagen and lipid droplet insulation. Moreover, they functionally distinguish each other by virtue of different ion channels expression, susceptibility to autonomic system modulation, and mechanical stretch influence, which finally translate into action potential duration gradients and repolarization dispersion. Hence, the conduction system compartment of the moderator band displays an intrinsic dynamic proarrhythmic behavior that needs the muscular compartment in order to initiate ventricular tachycardias. In the setting of the moderator band, structure and function are therefore difficultly discernible, and they ideally resemble two faces of the same coin.


Coronary microvascular dysfunction (CMD) is a pathophysiological mechanism underlying hypertrophic obstructive cardiomyopathy (HOCM). However, few studies have investigated the potential effect of transapical beating-heart septal myectomy (TA-BSM) on coronary microvascular function. This study aimed to evaluate coronary microvascular function in HOCM after TA-BSM using cardiac magnetic resonance (CMR) and to investigate the determinants of improvement in coronary microvascular dysfunction.max, Timemax, and Slmax). Univariate and multivariate linear regression identified variables associated with the rate of Slopemax change.28 patients with HOCM who underwent TA-BSM were prospectively enrolled in this study from March 2022 to April 2023. All patients received CMR before and after TA-BSM. CMR-derived parameters were compared, including the maximum wall thickness, native T1 value, T2 value, late gadolinium enhancement (LGE), and perfusion indexes (SlopeP < 0.05), although still lower than in healthy controls. In the analysis of the myocardial perfusion parameter rate of change, the rate of Slopemax change was the most significant (P = 0.002) in HOCM. In the multivariable regression analysis, age (adjusted β = 0.551), weight of the resected myocardium (adjusted β = 0.191), maximum wall thickness (adjusted β = −0.406), LGE (adjusted β = 0.260), and Δ left ventricular outflow tract (LVOT) pressure gradient (adjusted β = −0.123) were significantly associated with the rate of Slopemax change in HOCM .Compared with the preoperative parameters, left ventricular function and myocardial perfusion were significantly improved after TA-BSM (all Coronary microvascular dysfunction in both hypertrophic and non-hypertrophic myocardial segments was improved in patients after TA-BSM. Microcirculatory perfusion evaluated by CMR can be a potential tool to evaluate the improvement of CMD in HOCM. Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease presenting with segmental myocardial hypertrophy . ObstrucAccording to the latest guidelines , surgicaCardiac magnetic resonance (CMR), a unique tissue characterization technology, has become a powerful tool for evaluating HCM patients. CMR can accurately assess myocardial morphology and microvascular function due to its high temporal and spatial resolution . In addiTwenty-eight patients with HOCM who underwent TA-BSM at Tongji Hospital from March 2022 to April 2023 were prospectively enrolled in this study. All patients met the clinical diagnosis of HCM according to published guidelines : ventric2, matrix size = 189 × 154, and flip angle = 46°. T1 mapping images were acquired using the modified look-locker recovery sequence with 5b(3b)3b (b for heartbeat) scheme at the left ventricular basal, mid, and apical levels. The acquisition parameters were: echo time = 1.2 ms; repetition time = 2.8 ms, inversion time = 197 ms, increase step = 80 ms, flip angle = 35°, field of view = 360 × 324 mm2, matrix = 257 × 232, and slice thickness = 5 mm. The parameters for T2 mapping are as follows: echo time = 1.35 ms; flip angle = 12°, field of view = 360 × 323 mm2, matrix = 189 × 170 mm, and slice thickness = 5 mm, T2 preparation duration = 0, 30, 55 ms. The CMR perfusion image used a gradient echo sequence with 0.3 mmol/kg of gadolinium-based contrast agent . In addition, the scan parameters were: matrix size = 211 × 181, field of view = 380 × 326 mm2, slice thickness = 8 mm, repetition time = 2.0 ms, echo time = 0.97 ms, flip angle = 18°, and nominal inversion time = 130 ms. LGE used a phase-sensitive, inverse recovery sequence 10–15 min after contrast injection. The scan parameters were: matrix size = 192 × 173, field of view = 350 × 263 mm2, slice thickness = 6.0 mm, repetition time = 3.2 ms, echo time = 1.27 ms, flip angle = 10°, and nominal inversion time = 255 ms.All patients underwent a standard cardiac MRI on a 3 T MRI system . The CMR protocol included short-axis cine, native T1 mapping, T2 mapping, first-pass perfusion, and late gadolinium-enhanced (LGE) imaging. Cine images were acquired with ECG gating and breath-holding using a segmented, balanced, steady-state free-precession sequence. The typical parameters were: section thickness = 8 mm, section gap = 2 mm, echo time = 1.39 ms, repetition time = 3.2 ms, field of view = 360 × 360 mmmax) and minimum LA volume (LAVmin) were acquired with a combination of two- and four-chamber cine images at the end of ventricular systole and diastole. The LA ejection fraction (LAEF) was calculated as follows: LAEF = [(LAVmax−LAVmin) / LAVmax] × 100%. Left ventricular (LV) structure and functional parameters were measured on short-axis cines, including the maximum wall thickness, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), stroke volume (SV), cardiac output (CO) and LV mass (LVM). Some parameters were normalized to body surface area: LAVmax index, LAVmin index, LV end-diastolic volume index (LVEDVi), cardiac index (CI) and LV mass index (LVMi). In addition, the percent weight of the resected myocardium was calculated by dividing the surgically removed myocardial mass by the mass of the left ventricular myocardium at end-diastole.CMR analysis was performed using CVI 42 software . The left atrial (LA) anteroposterior and LA left–right diameters were obtained on three- and four- chamber cine images, respectively. The maximum LA volume (LAVmax), maximal upload of myocardial intensity enhancement (Slopemax), and maximal signal intensity (Slmax) were measured (The myocardium was divided into sixteen American Heart Association (AHA) segments for the perfusion assessment. Time-intensity curves were acquired for each segment through the entire perfusion process. The time-to-maximal signal intensity (timemeasured . Strengtx ± s). The data at baseline and follow-up were compared using the paired t-test. Data that did not conform to the normal distribution were indicated by medians and quartile M , and the data before and after surgery were compared using the paired Wilcoxon signed-rank test. The Pearson correlation coefficient or Spearman's rank correlation coefficient (r) was used to assess the association of continuous variables.Statistical data analysis was conducted using SPSS 25.0 software . The measurement data conforming to the normal distribution were expressed as means ± standard deviation  patients had asymmetric septal hypertrophy, and four (14.3%) had apical hypertrophy. The maximal LV wall thickness was 22.8 ± 1.1 mm. In total, 448 segments were analyzed. Perfusion, native T1 mapping and T2 mapping images were interpretable in all segments. Notably, the mean weight of the HOCM resected myocardium was 6.7 ± 0.6 g. Clinically, the primary symptom experienced by the patients was dyspnea (71.4%). The baseline characteristics of HOCM patients are shown in p < 0.001)  . At foll< 0.001) . Finally< 0.001) .max index, and LAVmin index were decreased, while LAEF was increased.Comparisons of the preoperative and postoperative LA parameters are shown in p < 0.001). In addition, LVEF, LVMi, SV, CI, native T1 value, T2 value and LGE volume were decreased , while LVMi, native T1 value, and T2 value were higher than the control group .The pre- and postoperative parameters of left ventricular function in the control and study groups are listed in max and Slmax were elevated, indicating that the blood filling rate and myocardial blood flow in the coronary microcirculation were significantly improved . However, there were no statistically significant differences in other perfusion parameters between the two subgroups .Patients were divided into two subgroups according to whether LGE was ≥15%. The rate of slopeubgroups . Given tr = 0.94 (0.89–0.97) and r = 0.95 (0.91–0.98), p < 0.05).Inter- and intra-observer agreement for the perfusion parameters was high  LVOT obstruction was relieved after the operation, and the overall myocardial microcirculation perfusion of the left ventricle, including hypertrophic and non-hypertrophic myocardial segments, was significantly improved; (2) patients with severe fibrosis (LGE ≥ 15%) had more pronounced improvement in microcirculation after TA-BSM; and (3) in addition to age, weight of the resected myocardium, maximum wall thickness, LGE, and Myocardial ischemia is a significant pathophysiological feature in HCM patients without combined epicardial coronary stenosis –12 and iMicro-arterial remodeling is one of the mechanisms of microcirculatory dysfunction and plays an important role in the regulation of microcirculatory blood flow , 18. Vasμm in diameter. In addition to intravascular resistance, extravascular compressive forces due to elevated left ventricular chamber pressure and wall stress caused by diastolic dysfunction and LVOT obstruction may also contribute to perfusion abnormalities (More than 90% of total resistance exists in vessels <300 malities , 23. Thimalities . This exmalities , 26. Commalities .Myocardial fibrosis and scar resulting in reduced myocardial blood flow and perfusion reserve and myocardial ischemia promotes fibrosis progression conversely. Dynamic coronary flow abnormalities of longer duration may exacerbate the progression of decompensation. According to a study of 35 HCM patients, perfusion reserve was reduced in proportion to the magnitude of hypertrophy, and the incidence of myocardial fibrosis decreased with increasing myocardial blood flow . A studymax change, suggesting that a myocardial structural abnormality, particularly myocardial fibrosis, could play a significant role in microvascular dysfunction in HCM. Distinct from progressive reactive interstitial fibrosis, chronic or recurrent ischemic injury may promote collagen deposition, leading to additional fibrosis (Similar to the findings of previous studies, we found that maximum wall thickness and degree of fibrosis correlated with the rate of slopefibrosis . This exfibrosis . Additiofibrosis , 32, as fibrosis , 34.The study also showed that myocardial mass removed in TA-BSM was a potential factor affecting the degree of improvement in myocardial perfusion. Therefore, the quality and extent of ventricular septal myocardial resection requires individualized treatment for different patients.The patient's LVEF decreased after TA-BSM, and the left ventricular hyperdynamic state was partially relieved. Our findings might provide new insights into the treatment of HCM. Currently, cardiovascular magnetic resonance research on myocardial perfusion in patients after surgery is limited, and the long-term effects of surgery on HCM patients require prolonged follow-up. Given the hemodynamic benefits, our study highlighted where and how much septal myocardium should be removed and will help improve the postoperative evaluation indicators.There were several limitations in our study. First, the sample was small due to this new form of myectomy, but it included HOCM patients of different ages. Second, this minimally invasive procedure has not been performed in other healthcare settings, so we could only conduct a single-center study. Third, there may have been a selection bias because we excluded patients who did not receive regular follow-up with CMR. Fourth, exploration of microvascular dysfunction in relation to diastolic function and LGE patterns was not included in this study. Fifth, CMR assessment of tissue features was not validated by histological samples. Last, prognosis, which requires longer follow-up of postoperative patients, was not included in this study.ΔLVOTG might be potential factors suggesting improvement in the coronary microcirculation. Further studies are needed to demonstrate the long-term effects of TA-BSM on myocardial perfusion in HOCM.Our study demonstrated improvement in coronary microcirculation in almost all myocardial segments in HOCM patients after TA-BSM, despite non-hypertrophic parts. After relieving the LVOT obstruction, the pressure load on the left ventricle decreased, and the blood perfusion rate and flow increased. Age, weight of the resected myocardium, maximum wall thickness, LGE, and


Right ventricular (RV) dysfunction and pulmonary hypertension (PH) have been previously associated with unfavorable outcomes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI), but little is known about the effect of right ventricle (RV) to pulmonary artery (PA) coupling. Our study aimed to evaluate the determinant factors and the prognostic value of RV-PA coupling in patients undergoing TAVI.n = 65) and impaired RV-PA coupling group .One hundred sixty consecutive patients with severe AS were prospectively enrolled, between September 2018 and May 2020. They underwent a comprehensive echocardiogram before and 30 days after TAVI, including speckle tracking echocardiography (STE) for myocardial deformation analysis of the left ventricle (LV), left atrium (LA), and RV function. Complete data on myocardial deformation was available in 132 patients  who formed the final study population. The ratio of RV free wall longitudinal strain (RV-FWLS) to PA systolic pressure (PASP) was used as an estimate of RV-PA coupling. Patients were analyzed according to baseline RV-FWLS/PASP cut-off point, determined through time-dependent ROC curve analysis, as follows: normal RV-PA coupling group , mainly due to PASP decrease (p < 0.001). LA global longitudinal strain (LA-GLS) is an independent predictor of RV-PA coupling impairment before and after TAVI , while RV diameter is an independent predictor of persistent RV-PA coupling impairment after TAVI . Impaired RV-PA coupling was associated with a worse survival rate  and emerged as an independent predictor of mortality  and of the composite endpoint of death and rehospitalization .A significant improvement of RV-PA coupling was observed early after TAVI (0.75 ± 0.3 vs. 0.64 ± 0.3 before TAVI, Our results confirm that relief of aortic valve obstruction has beneficial effects on the baseline RV-PA coupling, and they occur early after TAVI. Despite significant improvement in LV, LA, and RV function after TAVI, RV-PA coupling remains impaired in some patients, it is mainly related to persistent pulmonary hypertension and is associated with adverse outcomes. The treatment of severe aortic stenosis (AS) is guided by evidence-based recommendations –3. Trans2, indexed AVA < 0.6 cm2/m2, peak aortic jet velocity ≥4 m/s, or mean gradient ≥40 mmHg]. Exclusion criteria included: hypertrophic cardiomyopathy, prosthetic aortic valve, non-transfemoral TAVI, and poor acoustic window. All patients underwent Heart Team evaluation and were deemed eligible for TAVI based on current guideline recommendations. All procedures were performed in a hybrid operating room with participation of both interventional cardiologist and cardiovascular surgeon.Patients with severe symptomatic AS scheduled to undergo transfemoral TAVI in our center were prospectively enrolled between September 2018 and May 2020. Selection criteria included: age >40, severe AS [aortic valve area (AVA) < 1.0 cmAll patients underwent percutaneous transfemoral TAVI with balloon-expandable valve. The procedure was performed under general anesthesia and invasive hemodynamic monitoring. Transesophageal echocardiography was used during the procedure for additional guidance and assessment. Clinical, biological, and procedural data were collected. Coronary artery disease (CAD) was defined as the presence of coronary artery lesions, previously treated (PCI or CABG) or not requiring treatment at the time of procedure. The primary outcome was a composite endpoint of major adverse cardiac events (MACE) consisting of cardiac-related rehospitalization , and all-cause mortality , both performed 3 years after TAVI. No event was registered in the interval between intervention and follow-up echocardiography. The study was reviewed and approved by the institutional Ethics Committee.All patients underwent a comprehensive echocardiogram performed by experienced echocardiographers both before and 30 days after TAVI using a Vivid E95 ultrasound system . Data were digitally stored for offline analysis using commercially available software  and images were analyzed by a single trained cardiologist according to current guidelines . Evaluatε, reservoir function), LA systolic strain rate , LA early diastolic strain rate , late diastolic LA strain rate . Complete myocardial deformation analysis was possible in 132 out of 160 patients. Negative values of strain parameters are used as moduli (positive numbers) for ease of analysis. RV function was assessed by measuring TAPSE, the peak systolic myocardial velocity at the lateral site of the tricuspid annulus (S'RV), RV fractional area change (FAC) and RV longitudinal strain parameters by STE: peak values of global RV strain (RV-GLS), RV free wall longitudinal strain (RV-FWLS) and the interventricular septum longitudinal strain (RV-IVS). The right ventricular systolic pressure was calculated from the peak velocity of the tricuspid regurgitant jet using the Bernoulli equation and the right atrial pressure (determined by the diameter and inspiratory collapse of the inferior vena cava) was added (n = 65) and RV-FWLS/PASP < 0.63 as impaired RV-PA coupling group (n = 67) and were analyzed accordingly.Myocardial deformation analysis using speckle tracking echocardiography (STE) was performed to assess LV and LA function. Evaluation included STE analysis for LV function: LV global longitudinal strain (GLS); LA function: LA global longitudinal strain  between >2 groups have been used. Bonferroni method was used to adjust p-values for multiple comparisons.Continuous variables are given as mean ± standard deviation and compared using the Student Long-term clinical outcomes were estimated using the Kaplan-Meier method, with comparisons made using the log-rank test .p < 0.05), exclusion of variables showing collinearity (Pearson's coefficient >0.6), and multiple testing to ensure stability, a multivariable model has been fitted .Univariable analysis (linear and binary logistic) was used to identify potential predictors of RV-PA coupling from baseline characteristics. After careful selection of variables based on clinical judgment, univariable assessment  analysis was used to determine the associations between individual and combined surrogate parameters of RV-PA coupling and 3-year mortality  and is within the same range of previous studies associated with survival in AS or heart failure patients . Multivariable analysis was also performed in a similar fashion . A two-sided ortality . The baspatients , 16, 17.p = 0.031, and p = 0.008, respectively). Impaired LVEF was more frequent, and the impairment was more severe in patients with impaired RV-PA coupling (p < 0.001). Additionally, patients with impaired RV-PA coupling had more advanced cardiac damage as suggested by larger LA dimension and lower LA-GLS, larger RA and RV dimensions, and lower parameters of RV function compared to normal RV-PA coupling group (p < 0.001).Patients with impaired baseline RV-PA coupling were younger, had more often atrial fibrillation, prior myocardial infarction, angina, and higher NYHA functional class compared to patients with normal RV-PA coupling . There wp = 0.008) and decrease of LV mass index (p < 0.001). Additionally, mitral valve regurgitation decreased after TAVI (p = 0.003) and there was also a decrease of LA volume (p = 0.007), and an improvement of LA function (p < 0.001). We found a significant improvement in RV-PA coupling after TAVI (p = 0.007), mainly driven by a decrease in PASP (p < 0.001).All echocardiographic parameters describing AS severity improved significantly after the procedure . Comparep = 0.046). RV function improved after TAVI in the impaired RV-PA coupling group as measured by RV-GLS (p = 0.001), RV-FWLS (p = 0.003), RV-IVS (p = 0.003), S`RV (p = 0.026), but not by TAPSE (p = 0.187) and FAC (p = 0.060).Significant improvement of echocardiographic parameters describing AS severity after TAVI were further noted regardless of group . LV remoRV-PA coupling correlates at univariable and multivariable logistic regression analysis are presented in p-value = 0.001) and lower survival rate   and MACE  . During follow-up, MACE occurred in 38 patients (24.4%), of which rehospitalization in 19 patients (11.9%), and death in 25 patients (15.6%). At 3-year follow-up the survival rate was 82.1%. Kaplan Meier analysis revealed that impaired baseline RV-PA coupling was associated with worse outcomes: lower freedom from MACE  . Impaire= 0.012) .Our study provides evidence that baseline RV-FWLS/PASP ratio, as a non-invasive surrogate of RV-PA coupling in patients with severe AS undergoing TAVI, is a novel parameter that refines risk assessment and independently predicts outcomes. The main findings of our study are: 1. Baseline RV-PA coupling impairment is influenced by persistent pulmonary hypertension and is associated with a greater burden of cardiac damage; 2. cardiac damage is only partially reversible, despite significant improvement of LV, LA, and RV function after TAVI; 3. Baseline impaired RV-PA coupling improves early after the procedure but continues to present a higher mortality risk in the long term.Although some studies reported no correlation between AS severity and the presence of PH or RV dysfunction, we found that patients with impaired baseline RV-PA coupling had more severe AS with lower AVAi and had more often bicuspid valves , 18, 19.Even though the impact of impaired LVEF on RV-PA coupling has not been extensively studied, it has been previously reported that impaired LVEF is an independent predictor of PH . Due to Although LA function and dimensions have been previously shown to have an impact on morbidity and mortality in AS, little is known about the link between RV-PA coupling and LA function –28. In tIn our study impaired baseline RV-PA coupling was associated with larger LA dimensions and impaired LA function, especially the reservoir and booster-pump. Atrial fibrillation was also correlated with impaired baseline RV-PA coupling, indicating loss of LA booster-pump. LA-GLS was associated with impaired RV-PA coupling before and after TAVI, suggesting that persistently impaired RV-PA coupling may be linked to irreversibility of atrial dysfunction. From a clinical point of view, improvement of left atrial function in the context of impaired RV-PA coupling failed to offer a significant benefit in terms of morbidity and mortality. While both indexed LA area and volume decreased after the procedure, persistence of LA dilation predicts the persistence of RV-PA coupling impairment. This clinically translated into the fact that the degree of decrease in LA dimensions only marginally impacted outcomes. These data are consistent with previous studies which suggest that LA active emptying is impaired in the presence of severe LA dilation, and propose the exceeding of optimal Frank-Starling mechanism as the explanation .Baseline pulmonary hypertension (PH) is common in patients with AS undergoing TAVI and has been linked to increased morbidity and mortality –33. AlthThis is a prospective study conducted on consecutive AS patients meeting the eligibility criteria for TAVI, resulting in a heterogenous population in terms of associated comorbidities, but resembling the real-life clinical setting. More than half of the included patients had associated CAD , as CAD is the most common comorbidity in AS .One limitation of the study consisted in the short follow-up period as comprehensive echocardiographic evaluation was not routinely performed after the 1-month follow-up visit. Another limitation of the study is the lack of invasive measurements for comparison, but RV-FWLS/PASP has already been validated as a surrogate of RV-PA coupling as Ees/Ea in other populations , 41, 42 Our results confirm that relief of aortic valve obstruction by TAVI has beneficial effects on the RV-PA coupling, that occur early after the procedure. This is accompanied by a significant improvement in LV, LA, and RV function. The results show a significant correlation between LA function and RV-PA coupling before TAVI, suggesting the contribution of LA function in modulating right heart function in patients with AS. Persistence of impaired RV-PA coupling after TAVI is mainly influenced by persistent pulmonary hypertension and is associated with long-term adverse outcomes. The complex underlying mechanisms of RV-PA coupling impairment require further analysis of cardiac injury reversibility.


Diastolic dysfunction is increasingly identified as a key, early onset subclinical condition characterizing cardiopathologies of rising prevalence, including diabetic heart disease and heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction characterization has important prognostic value in management of disease outcomes. Validated tools for in vivo monitoring of diastolic function in rodent models of diabetes are required for progress in pre-clinical cardiology studies. 2D speckle tracking echocardiography has emerged as a powerful tool for evaluating cardiac wall deformation throughout the cardiac cycle. The aim of this study was to examine the applicability of 2D speckle tracking echocardiography for comprehensive global and regional assessment of diastolic function in a pre-clinical murine model of cardio-metabolic disease. Type 2 diabetes (T2D) was induced in C57Bl/6 male mice using a high fat high sugar dietary intervention for 20 weeks. Significant impairment in left ventricle peak diastolic strain rate was evident in longitudinal, radial and circumferential planes in T2D mice. Peak diastolic velocity was similarly impaired in the longitudinal and radial planes. Regional analysis of longitudinal peak diastolic strain rate revealed that the anterior free left ventricular wall is particularly susceptible to T2D-induced diastolic dysfunction. These findings provide a significant advance on characterization of diastolic dysfunction in a pre-clinical mouse model of cardiopathology and offer a comprehensive suite of benchmark values for future pre-clinical cardiology studies. Currently, while there are new advances in treatments for patients with HFpEF, the benefits are largely seen in those with advanced disease4, thus a substantial research effort is underway for drug-discovery in pre-clinical models. There is an urgent need for validated tools for systematic evaluation of diastolic function in small rodent models of disease. Clinically important conventional echocardiography approaches to assess diastolic function clinically  have been applied to tracking diastolic function in small rodents6, but high heart rates (> 400 bpm) and small cardiac anatomy present unique challenges7. A high level of training and expertise is required to generate reliable outcomes. Speckle tracking echocardiography is a post-processing tool to track deformation of the myocardial wall throughout the cardiac cycle, and is increasingly used in both clinical11 and pre-clinical studies15. Global cardiac strain is the most commonly reported variable from speckle tracking studies, which is typically associated with characteristics of systolic function. Notably, speckle tracking-derived strain rate can be determined over the full length of the cardiac cycle and peak strain rate during the diastolic period may provide a robust additional measure to support the evaluation of diastolic function in small rodent models for pre-clinical studies7.Diastolic dysfunction is characterized by impaired heart relaxation due to increased myocardial wall stiffness. Identification of early diastolic dysfunction has important prognostic value for progression to heart failure. Heart failure with preserved ejection fraction (HFpEF), a condition characterized by diastolic dysfunction, is highly prevalent in diabetic patients and has worse prognosis than in non-diabetic patients16. The extent and speed of deformation of a specific area of the myocardium is recorded, in relation to the initial dimensions. A significant advantage of speckle tracking echocardiography is that cardiac function can be assessed in long and short axis viewing planes to obtain information on longitudinal, radial and circumferential strain for any given area of interest. Tracking regional changes in myocardial wall deformation has proven to be useful particularly in identifying ischemic regions in studies of myocardial infarction15. This approach may also be applicable to generating a more advanced understanding of regional cardiac dysfunction in chronic disease states.Speckle tracking echocardiography is based on tracking the motion of speckle patterns created by interference of ultrasound beams in the myocardium over time19. Regional differences in diastolic function have not been examined. An evaluation of speckle tracking echocardiography to monitor diastolic function in more clinically relevant models of diabetes is lacking. Thus the goals of this study were to validate speckle tracking echocardiography as a tool to assess diastolic myocardial wall deformation and evaluate regional differences in diastolic dysfunction in a dietary (high fat high sugar) mouse model of obesity and type 2 diabetes (T2D).Whilst speckle tracking echocardiography is becoming more widely used, particularly for reporting global strain measures, its utility in expanding the available tools for assessment of diastolic function in small rodent models has not been fully realized. Given the escalating prevalence of diabetes, and the predisposition for diastolic dysfunction (and HFpEF) in diabetic patients, diastolic strain rate may be an important measure for pre-clinical studies investigating novel drug targets for treatment of diabetic heart disease. The few studies available reporting diastolic strain rate in diabetic rodent models have mostly used genetic models of advanced diabetesTo develop a mouse model of T2D, mice were fed a high fat high sugar diet for 20 weeks. T2D mice exhibited significantly increased bodyweight from 2 weeks of dietary intervention Fig. A, impairTo evaluate cardiac dimensions and systolic function, we performed M-mode echocardiography and B-mode 2D speckle tracking strain imaging in control and T2D mice. Exemplar M-mode and B-mode echocardiography images are shown in Fig. A key advantage of speckle tracking echocardiography is the ability to measure longitudinal, radial and circumferential myocardial deformation throughout the cardiac cycle, and therefore distinct measures of systolic and diastolic ventricular kinetics can be acquired  was larger than the extent of increase in E/e’ detected in diabetic mice (22% increase). The use of high frequency echocardiography for measurement of diastolic strain rate and velocity provides a less angle-dependent method of assessing diastolic dysfunction in settings of fast heart rates in mice (> 400 bpm). The pulse-wave Doppler signal is influenced by alignment of the ultrasound beam with the flow of blood and is heart rate dependent. Further, E/e’ is measured near the mitral annulus and consequently does not capture the global relaxation properties of the heart21. The acquisition of high quality B-mode images for strain analysis is largely dependent on the resolution and frame rates of the echocardiography platform, and is less dependent on the operator than Doppler methods. Post-processing of B-mode images does however incorporate some element of operator subjectivity, and development of artificial intelligence tools for strain analysis has emerged in the clinical literature to overcome this limitation23.Although speckle tracking echocardiography was first introduced as a tool for in vivo assessment of myocardial strain in mice over 15 years ago24 although clinical studies suggest that severe diastolic dysfunction (Grade III) is characterized by a shortening of isovolumetric relaxation time.25 Mitral valve E-wave deceleration time was significantly increased in T2D mice, consistent with previous studies5. However, the nature of changes in both parameters are of relatively small magnitude (1–2 ms), and the underlying biological significance is difficult to assess. Deceleration time in particular has been noted for limited significance in the rodent setting of high physiological heart rates7. Further work needs to be undertaken to achieve consistency of measurement of these indices in rodents and to enhance the interpretation of these very small data shifts.In the present study, T2D mice exhibited a small but statistically significant decrease in isovolumetric relaxation time. Typically prolonged (or unchanged) isovolumetric relaxation time has been reported in settings of diastolic dysfunction,Early diastolic strain rate has been proposed as a measure of left ventricular relaxation, capturing the rate of ventricular wall deformation during early diastole, similar to the Doppler measure of tissue movement at the mitral annulus during the early filling phase (e’ wave). Surprisingly, e’ was unchanged in T2D mice in the present study, despite differences in diastolic strain rate. Although inter-observer variability of Doppler analysis (E/e’) was lower than diastolic strain rate (evidenced by higher Pearson correlation coefficient), the technical difficulty of acquiring tissue Doppler images in mice with small anatomy and high heart rates could be considered to be more limiting relative to acquisition of b-mode images for strain analysis. These findings suggest that, at least in this setting, diastolic strain rate is more sensitive to detection of left ventricular relaxation impairment than e’ wave measured by tissue Doppler imaging.13. In the present study, regional analysis revealed that impairment in longitudinal diastolic strain rate in diabetic mice was most prominent in the anterior free wall. Impairment in circumferential diastolic strain rate was most prominent in the inferior free wall and anterior septum. The underlying mechanism of regional diastolic impairment is not clear, but may relate to focal areas of fibrosis and/or localized thickening of the ventricular wall, and further investigation is required. These findings are similar to regional changes in myocardial deformation reported in adolescents with type 1 diabetes using cardiac MRI26. Significant impairment in diastolic strain rate was observed in the inferior septal and free wall regions26. This previous study calculated the diastolic relaxation fraction  and reported that adolescent T1D patients exhibit early diastolic left ventricular discoordination, despite otherwise normal cardiac function and left ventricular size. Thus assessment of regional myocardial wall deformation may provide an early indicator of diastolic dysfunction by identifying disparate regions of impairment. In the present study, regional changes in diastolic strain rate were concordant with differences detected in the global values. In future studies of more mild diastolic dysfunction, regional analysis of diastolic strain rate may be valuable to provide evidence of localized dysfunction which may not be detectable in the global output.In the pre-clinical literature, regional analysis of myocardial wall deformation has primarily been used in studies of myocardial infarction for identifying areas of dyssynchrony in the ventricular wall29. Global longitudinal strain quantifies the maximum change in length of the left ventricle during contraction , and thus is a measure of systolic function. Interestingly, in heart failure patients where ejection fraction is preserved (HFpEF) and systolic function is generally considered to be normal, global longitudinal strain is frequently reported to be decreased30. In addition, there are differences in methods of measuring ejection fraction in clinical and preclinical studies. In rodents, ejection fraction is typically measured using M-mode analysis in a short-axis view, while in humans, guidelines recommend the use of biplane measurements in long-axis views31. In humans therefore, the longitudinal function of the ventricle will contribute substantially to the measurement of EF, while in rodents, the EF is primarily measuring short axis contraction. As long axis shortening contributes approximately 75% of stroke volume in humans, compared to a contribution of approximately 25% by short axis shortening32, this is likely to make EF measurements in rodents difficult to directly translate to human studies. However, in both rodents and humans, global longitudinal strain is measured in the long-axis view. In the present study, measures of systolic function acquired from the short-axis imaging plane  were unchanged in diabetic mice. In contrast, global longitudinal strain was reduced, suggesting that longitudinal systolic dysfunction is present. These findings are consistent with other pre-clinical literature reporting that diabetic mice with normal ejection fraction exhibit reduced global longitudinal strain and diastolic dysfunction34. Clinically, global longitudinal strain has been incorporated into recently updated European Society of Cardiology guidelines for diagnosis of HFpEF35. In chronic settings of progressive cardiac dysfunction, such as diabetes, global longitudinal strain may provide a robust measure of early subclinical systolic dysfunction, with high predictive value, and improved translatability to clinical studies.While left ventricular ejection fraction has been the most widely used clinical measure of cardiac function for decades, global longitudinal strain is increasingly recognized as an important clinical indicator, with prognostic value in predicting adverse outcomes in chronic systolic heart failure0). Given that velocity is the rate of change of wall motion, it is therefore not dependent on the initial size of the ventricular wall. Thus, in a setting of diabetes where changes in the ventricular wall dimensions would be expected (as is the case in the present study), subtle differences in strain rate and velocity may be detectable. Additionally, there is some evidence from the clinical literature that strain rate may be more independent of acute changes in loading conditions (preload & afterload) than tissue velocities36, but further work is required to validate these findings in chronic settings.In the present study, both peak diastolic strain rate and peak diastolic velocity have been incorporated into the assessment of diastolic dysfunction in diabetic mice. In most cases, these variables show the same impairment, with the exception of unchanged circumferential peak diastolic velocity. By definition, strain rate is the derivative of strain, and is therefore presented as relative to the initial dimension  is notoriously difficult in small rodents with high heart rates. In the present study the early peak in mitral valve blood flow (E wave), mitral annulus tissue movement (e’) and diastolic strain rate was distinct from the atrial contraction-related peak in most cases. Some traces displayed partially fused early and late peaks, and some displayed only 1 peak in the diastolic period. Although quality images with distinct early peaks were available for every animal, replicate images where the early peak was not discernable were excluded from analysis and may have introduced an unavoidable level of bias to the dataset.38.In this study echo measurements were obtained at the end of the treatment period only, and no intermediate time point data were collected. An investigation involving repeated echo measurements during the development and establishment of diabetic heart disease would certainly be informative, especially in relation to refining the mechanistic interpretation of the parameters E and e’. The potential importance of molecular studies in distinguishing the components of myocardial stiffness and impaired relaxation in driving diastolic dysfunction has been recently highlighted.In conclusion, here we provide evidence to support the utility of 2D speckle tracking echocardiography to document global and regional diastolic dysfunction in a pre-clinical setting of murine cardiopathology. Peak diastolic strain rate and peak diastolic velocity constitute reliable indicators of diastolic dysfunction in diabetic mice, significantly correlated with traditional Doppler measures of impaired ventricular relaxation. Some evidence of longitudinal systolic impairment was detected by global longitudinal strain, despite preserved ejection fraction. The anterior free left ventricular wall appeared to be most vulnerable to longitudinal diastolic impairment. These findings provide a significant advance on characterization of diastolic dysfunction in a pre-clinical mouse model of diabetes and offer a comprehensive suite of benchmark values for future pre-clinical cardiology studies. Given the unmet clinical need for effective treatment options for HFpEF patients, implementing diastolic strain rate analysis as a robust tool for evaluating diastolic function in mouse models will support the ongoing drug-discovery effort in this field.www.arriveguidelines.org). Animals were randomly assigned to experimental groups and were group housed (4 mice per cage) in a temperature-controlled environment with 12-h light/dark cycles. Food and water was provided ad libitum.All animal experiments were approved by the University of Auckland Animal Ethics Committee and complied with the guidelines and regulations of the Code of Practice for the Care and Use of Animals for Scientific Purposes. This study is reported in accordance with the ARRIVE guidelines . After an initial 1 week transitional feeding period, animals were fed a high fat high sugar diet  or control reference diet  for 20 weeks duration. Fresh diet was provided twice a week. This is an extensively used model of diet-induced type 2 diabetes that is characterized by obesity, glucose intolerance, mild hyperglycemia and cardiac dysfunction.Glucose tolerance testing was performed after 11 weeks of dietary intervention following 6 h fasting. Baseline blood glucose levels were measured using an Accu-Check glucometer with a small blood sample from a needle prick to the tail vein. Glucose (1.5 g/kg body weight) was injected i.p. and blood glucose was measured at 5, 10, 30, 60, 90 and 120 min after the glucose injection.40, thus the 20 week timepoint allowed for sufficient time for diastolic dysfunction and other features of diabetic heart pathology to be fully established. Animals were anaesthetized with 3% isoflurane (with 1L/min O2 gas) and transthoracic echocardiography was performed using the VEVO LAZR-X 3100 with a MX400 probe (20–46 MHz), linear array transducer coupled with digital ultrasound system . The mice were secured to a warm platform containing ECG lead pads, and anesthesia was maintained via a nose-cone at 1.5–2.5% isoflurane (with 1L/min O2) throughout the procedure. All analyses were performed by an investigator blinded to study group allocation.Cardiac function was assessed following 20 weeks of dietary intervention. Our previous studies have confirmed that diastolic dysfunction (increased E/e’) is evident after 14 weeks of high fat high sugar diet feeding3 − LVIDd3, with correction factor 0.8. At least 3 consecutive cardiac cycles were sampled per cineloop image and 3 images per animal were analyzed and averaged.Left ventricular (LV) M-mode two-dimensional echocardiography was performed in a parasternal short axis view at the mid papillary level to measure LV wall and chamber dimensions. LV volumes were derived from dimensions using the Teichholz equation (end diastolic volume (EDV) = )) × LVIDd; end systolic volume (ESV) = (7/(2.4 + LVID at end-systole (LVIDs))) × LVIDs). Systolic function parameters: % ejection fraction ((EDV − ESV)/EDV) × 100), and % fractional shortening ((LVIDd − LVIDs)/(LVIDd) × 100). LV mass was calculated: 1.053 × Pulse wave Doppler and tissue Doppler imaging were acquired from the apical 4 chamber view to assess LV diastolic function parameters: velocity of mitral inflow during early passive filling (E) and during atrial contraction (A), and velocity of mitral annulus during early passive filling (e’) and during atrial contraction (a’), isovolumetric relaxation time (IVRT) and E-wave deceleration time. At least 3 cardiac cycles were sampled per cineloop image and 2–4 images per animal were analyzed and averaged. Wave forms from trans-mitral and tissue records were evaluated with temporal registration to validate waveform identification.Two-dimensional echocardiography B-mode loops were acquired from the left ventricular long axis  and short axis  views with a frame rate of 215 fps, and analyzed using Vevo strain software . Endocardial and epicardial borders were traced and checked throughout three cardiac cycles to ensure optimal tracking. The time at maximum relaxation (end-diastole) was used to determine the starting phase of the strain trace. Endocardial strain and displacement analyses were performed providing global and segmental  values. Endocardial strain rate and velocity parameters were derived from the strain–time and displacement–time relations respectively. The strain rate and velocity profiles for each image were examined to confirm that the early (passive filling) peak was identified by the software. In some cases, manual identification of the early peak was required, and images where the early peak was not discernable were excluded from the analysis. Average values were calculated from 2–3 independent images per animal.Data are presented as mean ± SEM and statistical analysis was performed using Graphpad Prism v7.0. Statistical outliers (> 2 standard deviations from the mean) were excluded to avoid data selection bias due to stochastic measurement of sampling anomalies . All data sets were tested for normal distribution using Shapiro–Wilk test. Differences between two groups were analyzed by Students unpaired t-test. For analysis of body weight, glucose tolerance and regional strain parameters, a repeated measures ANOVA with LSD post hoc tests was used. For correlation analyses, Pearson’s correlation coefficient was used. A p-value of < 0.05 was considered statistically significant.Supplementary Information.


Mechanical insufflation‐exsufflation (MI‐E) is an effective airway clearance device for impaired cough associated with respiratory muscle weakness caused by neuromuscular disease. Its complications on the respiratory system, such as pneumothorax, are well‐recognized, but the association of the autonomic nervous system dysfunction with MI‐E has never been reported. We herein describe two cases of Guillain–Barré syndrome with cardiovascular autonomic dysfunction during MI‐E: a 22‐year‐old man who developed transient asystole and an 83‐year‐old man who presented with prominent fluctuation of blood pressure. These episodes occurred during the use of MI‐E with abnormal cardiac autonomic testing, such as heart rate variability in both patients. While Guillain–Barré syndrome itself may cause cardiac autonomic dysfunction, MI‐E possibly caused or enhanced the autonomic dysfunction by an alternation of thoracic cavity pressure. The possibility of MI‐E‐related cardiovascular complications should be recognized, and its appropriate monitoring and management are necessary, particularly when used for Guillain–Barré syndrome patients. We herein describe two cases of Guillain–Barré syndrome with cardiovascular autonomic dysfunction during MI‐E. While Guillain–Barré syndrome itself may cause cardiac autonomic dysfunction, MI‐E possibly caused or enhanced the autonomic dysfunction by an alternation of thoracic cavity pressure. The possibility of MI‐E‐related cardiovascular complications should be recognized, and its appropriate monitoring and management are necessary, particularly when used for Guillain–Barré syndrome patients. Guillain–Barré syndrome (GBS) is an immune‐mediated peripheral neuropathy and the most frequent cause of acute flaccid tetraplegia worldwide.MI‐E consists of insufflation of the lungs with positive pressure, followed by an active negative‐pressure exsufflation that creates a peak and sustained flow high enough to provide adequate shear and velocity to loosen and move secretions toward the mouth for suctioning or expectoration. MI‐E devices are useful for respiratory management in GBS. Risks of MI‐E include mechanical injury in the respiratory system, such as pneumothorax,2, and high‐frequency (HF) of 4.7 msec2, all of which were markedly low.A 22‐year‐old man was diagnosed with acute motor axonal neuropathy type GBS. He presented with acute motor paralysis of the four extremities and required ventilator support due to respiratory muscle paralysis. He had no history of cardiac or pulmonary disease. After transfer to our hospital, the systolic blood pressure was a maximum 212 mm Hg and minimum 42 mm Hg, with a daily variation of 160 mm Hg. He was admitted to the ICU for cardiovascular management. His heart rate showed sinus tachycardia of 100–120 bpm, but there was no apparent bradycardia. Heart rate variability (HRV) analysis, which evaluates autonomic nervous system function based on changes in electrocardiogram (ECG) R‐R intervals , showed a standard deviation of the normal‐to‐normal intervals (SDNN) of 5.49 msec, low‐frequency (LF) of 14.2 msec2O. The use of MI‐E was temporarily discontinued due to safety considerations after this episode. Such episodes occurred not only upon using MI‐E but also tracheobronchial suctioning. The longest observed pause was 6 seconds. A cardiac electrophysiology consultation was requested for multiple episodes of transient asystole, but the results at the time of the 12‐lead ECG did not show any arrhythmias. Transthoracic echocardiography revealed a left ventricular ejection fraction of 55% and a small amount of pericardial effusion, findings that were not suggestive of bradycardia or transient cardiac arrest. However, due to multiple episodes of bradycardia and transient asystole, the decision was made to insert a temporary pacemaker set to VVI mode at 60 beats per minute (bpm).In this case, MI‐E was used for airway clearance because of impaired cough and difficulty with expelling the airway using chest physiotherapy and tracheal suctioning. He experienced transient asystole upon the eighth use of the MI‐E device, but his heart rate immediately recovered without requiring any treatment and there was no hypotension. At the time of the episode's appearance, the insufflation/exsufflation pressure of the MI‐E was +30/−30 cm HAfter the insertion of a temporary pacemaker, MI‐E therapy was resumed. The heart rate decreased from 107 to 60 bpm and from 103 to 70 bpm on days 5 and 12, respectively, after the insertion of the temporary pacemaker. However, the pacemaker was not activated and the heart rate immediately recovered without any change in blood pressure in both episodes. After these episodes, he had no bradycardia or transient asystole, and the temporary pacemaker was removed 3 weeks after insertion. After the removal of the pacemaker, the patient was able to continue MI‐E without bradyarrhythmia, and airway clearance was maintained for 113 days without any respiratory complications such as marked atelectasis or ventilator‐associated pneumonia  and eventually allowed us to increase the MI‐E pressure setting to +30/−20 cm H2O. During and after the use of MI‐E, there was no ventilator‐associated pneumonia, atelectasis improved , bradycardia 13.54%), labile hypertension (12.5%), and fluctuating heart rate (11.46%) were common among a total of 96 patients.3.54%, laIn all cases, it is important to appropriately assess the risk and intervene at the right time. In Case 1, the patient had repeated bradycardia and sinus arrest not only during MI‐E but also during tracheal suctioning, and the insertion of a temporary pacemaker prevented the development of serious arrhythmias. In Case 2, we successfully minimized blood pressure fluctuations through a modified MI‐E approach . The use of MI‐E is not an absolute contraindication, even in severe cases of autonomic neuropathy such as bradyarrhythmia or the appearance of blood pressure fluctuations; with appropriate monitoring and management, it may be an effective strategy for maintaining airway clearance.All authors made substantial contributions to the conception, design, and critical revision of the work for important intellectual content, and gave final approval of the version to be published. In addition, Ryota Kuroiwa contributed to project administration and funding acquisition.This study was supported in parts by Japan Society for the Promotion of Science (JSPS) KAKENHI under Grant Number JP 20K19304. The role of the funding body: publication fee was supported by the funding. The funders had no role in study design, decision to publish, or preparation of the manuscript.None declared.The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.


Acromegaly is an uncommon systematic endocrine disease caused by the hypersecretion of human growth hormone and, consequently, of insulin-like growth factor-1 during adulthood. Acromegaly could cause a typical cardiomyopathy characterized by left ventricular hypertrophy associated with diastolic dysfunction, which later could progress to systolic dysfunction. Moreover, some valvular and vascular abnormalities are also associated with acromegaly. This present review aims to summarize available information regarding acromegaly-associated abnormalities in myocardial, valvular, and vascular structural and functional properties and their relationship to disease activity and treatment options. Acromegaly is an uncommon systematic endocrine disease caused by the hypersecretion of human growth hormone (hGH) and, consequently, of insulin-like growth factor-1 (IGF-1) during adulthood with physical changes occurring slowly over several years . UntreatIn the past decades, cardiovascular imaging has undergone significant development. Not only have new procedures such as computer tomography and magnetic resonance imaging spread in the routine practice, but echocardiography has developed significantly as well. Due to this development, more detailed volumetric and functional chamber quantifications and the assessment of valvular and vascular functions are available now. Moreover, a complete analysis of myocardial mechanics can now be performed. One of the latest developments is three-dimensional (3D) speckle-tracking echocardiography (STE), which is a relatively new non-invasive echocardiographic tool with the capability to see the chambers in 3D, allowing not only accurate volumetric measurements respecting the cardiac cycle but an assessment of the deformation (strain) and rotational features of cardiac chambers at the same time using the same acquired 3D echocardiographic datasets using virtual 3D models ,9,10,11.The aim of this publication was to review item by item the findings related to acromegaly in myocardial, valvular, and vascular structural and functional properties, including those first described in the MAGYAR-Path Study ,17,18,19In the bullet-shaped LV, subepicardial fibers run in a left-handed direction, fibers in the mid-layer run circumferentially, while subendocardial fibers run in a right-handed direction . In healIn a study assessing cats with acromegaly, 7 out of 11 subjects had LV concentric hypertrophy and showed signs of LV diastolic dysfunction . Early sPatients who develop hGH deficiency following the cure of acromegaly did not demonstrate elevated LV mass, in contrast to patients with a history of acromegaly but normal hGH levels or patients with active acromegaly . Using cDiastolic dysfunction is a frequent finding in acromegaly, which could be detected with different kinds of echocardiographic methods . LV diasSome of the cardiac involvements in acromegaly patients were reversible 12 months after transsphenoidal hypophysectomy with the consequent lowering of hormone levels, including reversed LV hypertrophy and recovered LV systolic dysfunction . In anotIn an earlier two-dimensional STE study, no impairment of LV strain could be demonstrated in acromegaly . In anotThe first findings, in which LV rotational mechanics were examined, impaired 3DSTE-derived LV apical rotation and twist could be demonstrated from the MAGYAR-Path Study. The near absence of LV twist, called LV “rigid body rotation” (LV-RBR), was found in 20% of acromegaly cases ,18. DiabLA is located on the left posterior side of the heart, and its walls consist of circumferential and longitudinal muscle bundles. The circumferential ones  are located at the base of the LA, while the longitudinal ones  predominate in the parietal walls ,54. The The number of studies in which LA was examined in acromegaly is limited. In an animal study, 6 out of 11 cats with acromegaly showed enlarged LA . Human sIn a recent detailed analysis from the MAGYAR-Path Study, LA volumes representing all phases of LA function were found to be increased in acromegaly. Moreover, these abnormalities were present regardless of the disease activity. From LA functional properties, systolic LA total atrial SV and late diastolic LA active atrial SV were increased without changes in early diastolic LA passive atrial SV and all LA-EmFs. Most LA volumes and volume-based functional properties were increased in inactive acromegaly patients, suggesting that preexisting LA volume changes do not resolve after proper treatment, and enhanced LA-SVs might suggest a compensatory mechanism. 3DSTE is not only suitable for measuring the volumetric and volume-based functional properties of LA at the same time. As with LV, LS, CS, and RS, as well as combined strains, can be measured, the clinical suitability of which requires further investigations. Strain analysis revealed decreased LA-CS and increased LA-RS and LA-3DS in acromegaly in the systolic reservoir phase. In contrast with volumetric data, in inactive acromegaly, decreased LA-CS receded . HoweverThe 3D saddle-shaped mitral valve (MV) has a dynamic motion during the cardiac cycle . MV invoMitral valve abnormalities ) were present in 64% and 55% of active and cured acromegaly patients . In anotThe semilunar aortic valve is located between the aorta and the outflow tract of the LV, having three thin leaflets ensuring one-way blood flow towards the systemic circulation .Aortic valve abnormalities  were present in 48% and 59% of active and cured acromegaly patients . In anotThe aorta is the largest artery, which significantly interacts with the LV and LA . The aorThere are confusing findings regarding aortic abnormalities in acromegaly. Dimensions of the aortic root and the ascending aorta (AA) were found to be larger in acromegaly patients than in healthy people ,68,69. MSeveral methods have been known for a long time that are available for the non-invasive determination of aortic stiffness . There iDespite successful surgery, acromegaly patients showed significantly decreased arterial distensibility . In patiIn addition to the altered function of the aorta, vascular endothelial function may also have abnormalities affecting both flow-mediated dilation and endothelial cell markers in acromegaly ,86. MoreThe right ventricle (RV) is a triangular-shaped heart cavity when viewed from the sides and crescent-shaped in cross-section, and its diameter is gradually increasing from the apex to the base. The RV curves over the LV on the right side. The RV fills from the RA during diastole via the tricuspid valve (TV) and empties to the pulmonary artery via the pulmonary valve (PV) during systole. The myocardium is more trabecularized and thinner in the RV compared to the LV, resulting in a lower muscle mass (RV muscle mass is only one-fifth to one-sixth of the LV). The normal sequence of right ventricular activation begins with the contraction of the inlet and ends with the contraction of the infundibulum. The RV is composed of muscle fibers located deep in the wall that are responsible for the longitudinal movement of the RV from base to apex, during which the RV axis is shortened, and the TV moves in the apical direction and superficially located circumferential muscle fibers that are parallel to the TV fibers and are responsible for movement towards the cavity of RV (“bellows” effect). The superficial muscle fibers of the RV are connected to those of the LV, connecting the two ventricles. Consequently, the RV contracts when the LV is contracting. It is important to emphasize that the rotation and twisting motions seen in the case of the LV do not play an essential role in the RV. Heart rate, the Frank–Starling mechanism, and the autonomic nervous system are the factors regulating the RV ,89,90.RV enlargement and systolic dysfunction could be detected in 4.3% and 2.2% of acromegaly patients, respectively . Early sThe walls of RA are partly similar in structure to LA, having circumferential and longitudinal muscular bundles, which are larger than those in the LA. The terminal crest and terminal pectinate muscles are the main muscles that make up the wall of RA. The terminal crest is arranged longitudinally, while pectinated muscles are connected to the muscles of the atrioventricular vestibule. The rim of the oval fossa plays an equally important role for both atria ,54. The Increased RA minor diameter could be detected in acromegaly, which correlated with hGH and IGF-1 levels . ProfounSimilar to the MV, the TV has a complex, saddle-shaped asymmetrical ellipsoid structure with a dynamic nature respecting the cardiac cycle. When the TV opens in diastole, blood flows from the RA to the RV in one direction, and the TV closes in systole without tricuspid regurgitation. The TV consists of the following components: fibrous tricuspid annulus, anterior, posterior, and septal leaflets, tendineal chords, and papillary muscles ,96 Figu.Tricuspid regurgitation is not a typical feature of acromegaly, and the ratio of different grades of TR is similar to that of controls .The semilunar pulmonary valve (PV) has a significant role in regulating one-way blood flow toward the pulmonary circulation. The PV opens in ventricular systole and closes in ventricular diastole ,97.No clinical study demonstrating detailed acromegaly-related special abnormalities of the pulmonary valve was found in the literature.The pulmonary artery is one of the large arteries that carries blood from the RV to the pulmonary circulation .The diameter of not only the aorta but that of the main pulmonary artery was increased in acromegaly, and these changes were related to disease duration instead of serum hGH and IGF-1 level .There are a wealth of knowledge about pathophysiological abnormalities associated with acromegaly. Shortly, both hGH and IGF-1 are vascular growth factors stimulating collagen deposition. Moreover, elevated hormone levels result in increased IGF-1 receptor activation in cardiac myocytes, leading to increased mRNA expression of sarcomeric proteins, including myosin light chain-2 and troponin, responsible for increased cardiac contractility, hypertrophy, and fibrosis . Direct Today, patients with acromegaly are discovered early to receive treatment that prevents late-stage acromegalic cardiomyopathy. These facts may explain why old studies have shown more severe results. Moreover, advanced cardiovascular imaging techniques can help to identify abnormalities early in treated patients with acromegaly. Findings from the literature detailed above can help to detect expected alterations.Acromegaly is associated with abnormalities in cardiac mechanics and vascular remodeling. Some of these alterations are related to the activity and/or the duration of the disease. Currently, due to modern treatment procedures, most acromegaly patients no longer show any signs of end-stage “classic” acromegalic cardiomyopathy, only slight cardiovascular abnormalities.


Current guidelines suggest that regular aerobic training might lower blood pressure in hypertensive individuals. However, evidence linking resistant hypertension (RH) with total daily physical activity (PA), including work-, transport-, and recreation-related PA, is limited. Therefore, this study assessed the association between daily PA and RH.A cross-sectional study was conducted using data acquired from a nationwide survey in the US . The weighted prevalence of RH was calculated, and moderate and vigorous daily PA was assessed using the Global Physical Activity Questionnaire (GPAQ). A multivariate logistic regression model determined the association between daily PA and RH.A total of 8,496 treated hypertension patients were identified, including 959 RH cases. The unweighted prevalence of RH among treated hypertension cases was 11.28%, while the weighted prevalence was 9.81%. Participants with RH had a low rate of recommended PA levels (39.83%), and daily PA and RH were significantly associated. PA exhibited significant dose-dependent trends with a low probability of RH (p-trends < 0.05). Additionally, participants with sufficient daily PA had a 14% lower probability of RH than those with insufficient PA [fully adjusted odds ratio (OR) = 0.86; 95% confidence interval (CI) = 0.74–0.99).The present study revealed that RH has an incidence of up to 9.81% in treated hypertension patients. Hypertensive patients tended to be physically inactive, and insufficient PA and RH were significantly associated. Sufficient daily PA should be recommended to reduce the RH probability among treated hypertension patients. Uncontrolled hypertension is a critical cardiovascular risk factor that increases the risk of coronary artery disease, heart failure, stroke, and chronic kidney disease progression . HoweverBesides medication, current guidelines recommend lifestyle modification for blood pressure control in RH patients, including weight reduction, consuming a diet rich in fruits and vegetables, low-fat dairy products, a low-salt diet, smoking cessation, and regular aerobic physical activity (PA) , 6, 8. RFirst, we retrieved data from the National Health and Nutrition Examination Survey (NHANES) conducted by the National Center for Health Statistics. The NHANES uses data collected from a cross-sectional sample of the noninstitutionalized US civilian population to evaluate its health and nutritional status . About 1We examined data from seven consecutive NHANES cycles 2005–2018). We included nonpregnant participants > 20 years old, comprising 45,000 participants. Then, we excluded those with missing blood pressure and PA questionnaire data. Next, we excluded participants under 20 years, pregnant, had no history of hypertension, had not used antihypertensive medication, and had not received adequate antihypertensive therapy   to assess PA , 16. TheThe WHO recommends that adults perform moderate-intensity PA for at least 150 min, vigorous-intensity PA for 75 min, or an equivalent combination of moderate- and vigorous-intensity PA achieving at least 600 metabolic equivalents (MET) minutes every week (Table 2), total cholesterol (mg/dL), aspartate aminotransferase , alanine aminotransferase , estimated glomerular filtration rate , body mass index , total t-test, whereas non-normally distributed data were analyzed using Wilcoxon signed-rank test. Categorical variables were analyzed using χ [p < 0.05 was considered statistically significant.Continuous variables are expressed as means ± standard deviations or medians , whereas categorical variables are presented as cases (n) and percentages (%). Non-normal distributions were transformed by conducting natural log or Box-Cox transformations. For comparisons between continuous variables, normally distributed data were analyzed using Student’s  using χ  tests. TFirst, we retrieved data on 59,843 participants from seven consecutive National Health and Nutrition Examination Survey (NHANES) cycles (2005–2018). Among them, 8,496 cases of treated hypertension were screened, including 959 cases of resistant hypertension (RH). The unweighted prevalence of RH among treated hypertension cases was 11.28%, and the weighted prevalence was 9.81%.After the screening, 6,049 participants were finally enrolled Fig. , includiThe results of the multivariate regression analyses are summarized in Table sufficient and PAinsufficient . After adjusting for demographic variables (model 2), PAsufficient was still significantly associated with RH . In model 3, participants with sufficient PA had a 14% lower probability of RH than those with insufficient PA after adjusting for confounding factors  .Moreover, PA2. This variation could be attributed to the relatively strict screening criteria, excluding treated hypertension patients who received inadequate treatment or had no recommended treatment strategy.In the current study, the prevalence of resistant hypertension (RH) was up to 9.81%, slightly lower than previous studies, ranging from 12 to 14% Patients with RH have poor cardiovascular outcomes. Therefore, it is necessary to use a comprehensive treatment strategy to enhance blood pressure control in these patients . PreviouGuidelines recommend lifestyle interventions for managing hypertension , 21. RanHypertensive patients tended to be physically inactive (46.6%). RH participants had lower rates of meeting the recommended PA levels than those without RH . Previous studies have found that physical inactivity might account for 5–13% of hypertension risk [Based on our results, the daily PA mentioned above can be recommended to reduce RH probability in treated hypertension patients. Daily PA is as effective as prescribed exercise to reduce RH probability. The present study defines daily PA in three settings: work, travel to and from places, and recreational activities. Specifically, the following moderate-intensity daily PA can be recommended to reduce RH risk : (1) daiTo determine whether there was an additional benefit from further increases in PA, we introduced another variable, the overfulfilled PA, defined as PA beyond 300 min of moderate-intensity PA. Overfulfilled PA could reduce the RH probability by 17% compared to insufficient PA. As mentioned above, moderate-intensity daily PA for at least 150 min or vigorous-intensity daily PA for at least 75 min comprises sufficient PA, reducing the RH probability by 14% compared to insufficient PA. Thus, the advantage of 300 min of moderate-intensity PA (overfulfilled PA) was less pronounced compared to sufficient PA. The effectiveness of the daily PA is probably dose-dependent and increases with increasing dosage. After fully adjusting for confounding factors, daily PA exhibited significant dose-dependent trends with a low RH probability when PA was the categorical variable (quartiles). Based on our results, adverse blood pressure response was not observed in overfulfilled exercising. Consequently, taking as much daily PA as possible could have further increased the reduction in RH probability. However, the additional benefit of overfulfilled PA compared to sufficient PA was small, and adherence to overfulfilled PA is a challenge to most patients. It is more reasonable to recommend basic sufficient PA for most hypertensive patients to reduce the RH probability .The major strengths of the present study included using a large sample size, which increased the power of our findings. The prevalence of RH among treated hypertension cases was reliable since a nationally representative sample of the US population was used. Additionally, the detailed information collected from the NHANES included a wide range of potential confounders, such as dietary intakes and laboratory results. Moreover, since 1999, the NHANES survey has become a continuous program focusing on various health and nutrition measurements. As a continuous program, it has a mature and reliable sampling process and methodological procedures across the surveys. To the best of our knowledge, the present study is the first to investigate the association between daily PA and RH probability based on a nationwide database. Second, The GPAQ is a valid and reliable tool for measuring PA. Although wearable devices improve the objectivity and accuracy of PA measurement, self-reported survey methods still confer the advantage of covering the general population due to their low cost . AssessmHowever, the present study also has some limitations. First, the cross-sectional design made causal inference problematic. Therefore, further studies involving high-quality prospective cohorts should be conducted to validate the present findings. Second, the blood pressure measurements included only office blood pressure but not ambulatory blood pressure measurements. Third, we did not consider the optimal dosage of each medication. However, medication use and dosage represented real-world management preferences, which effectively reflect PA effects in patients treated for hypertension.In summary, we showed that RH has an incidence of up to 9.81% in treated hypertension patients. Hypertensive patients tended to be physically inactive, and most of them, especially RH, did not perform sufficient PA. Furthermore, we found a significant association between insufficient daily PA and RH probability. Thus, sufficient PA should be recommended to reduce RH probability. Although this beneficial effect was dose-dependent and overfulfilled PA presented additional protection against RH, those who achieved sufficient PA (based on the PA guidelines) were also less prone to RH than those insufficiently active.


Aim. Pharmacologic reduction in heart rate with beta-blockers (BB) or ivabradine is associated with improved survival in heart failure (HF) with sinus rhythm. We analyzed the association of different heart rate-reducing drug treatments on outcomes in HF outpatients. Methods. Consecutive patients with HF in sinus rhythm referred to a specialized tertiary service were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting heart rate and different heart rate-reducing drug regimens on all-cause mortality and a composite endpoint of “all-cause mortality or heart transplantation” over a mean follow-up of 3.1 years. Results. Of the 278 patients included, 213 (76.6%) were male, the median age was 57.0 years (IQR 49.0–66.1), and 185 (73.7%) had an ejection fraction <40%. Most patients received BB in submaximal [n = 118] or maximum dose [n = 136]. Patients on BB in maximum dose plus ivabradine [n = 24] were younger (53.0 vs. 58.0 years) and had a lower EF (25 vs. 31%). Higher resting heart rate was associated with an increased risk of death or transplantation , even after adjusting for age and sex. There were no differences between the groups concerning all-cause mortality or the composite endpoint. Conclusion. Our prospective study confirms the association between low heart rate and survival in HF patients receiving various heart rate-reducing medications. We could not identify a specific effect of either regimen. Epidemiological studies demonstrate a correlation between resting heart rate (HR) and cardiovascular morbidity, and the beneficial effects of heart rate reduction in heart failure (HF) are well established ,2,3,4. IF) inhibitor ivabradine proved similarly beneficial in HF patients with an EF of 35% or lower and  underlined the important role of the HR in HF pathophysiology  or maximum dose  without ivabradine (group 3 or “ivabradine group”] were of younger age (53.0 vs. 58.0 years), had a lower LVEF (25 vs. 31%), and higher NT-proBNP levels  than those only on BB treatment. HF etiology and most of the cardiac and non-cardiac comorbidities were evenly distributed between the study groups . This effect persisted in a Cox regression model adjusting for age and sex , we were not able to demonstrate a significantly reduced risk of “death of any cause” or “death of any cause or heart transplantation” in the group of patients with BB in maximum dose  or ivabradine “on top”  years, 30 deaths occurred, and 11 patients underwent heart transplantation, adding up to 40 composite outcome events (avoiding double-counting), which corresponds to an event rate of 19.2% over the total follow-up. There were 12 deaths in the first year, 7 deaths in the second year, and 9 deaths in the third year. Upon regression analysis, resting HR at the screening was associated with an increased risk of death or heart transplantation  and the ivabradine dose  did not affect outcomes.Also, both the BB dose  than those on BB “monotherapy”, which not only confirms the guideline-coherent use of ivabradine in our study but could moreover be regarded as a hint at its beneficial effects in advanced HF. Despite “negatively” predisposing characteristics at baseline—both an elevated HR and a lower LVEF inversely affect prognosis in HF ,11,15,16Finally, there is, so far, conflicting evidence regarding the up-titration of BB but also RAS blockers and MRAs in HF. Biomarker-based up-titration schemes may have a superior effect on HF outcomes compared to up-titration to guideline-recommended doses, which are often not reached . BB up-tAs this analysis drew “real-world” data from a large tertiary heart failure center resulting in good and homogeneous therapy, treatment groups were not randomized. Also, the small sample size, which allowed for a detailed characterization of patients, is—along with the single-center nature of the study—a major limitation that reduces statistical power and limits generalizability. The small number of events, however, mirrors the extent of risk reduction achievable through the consequent use of guideline-recommended prognosis-modifying treatments, both pharmacologically and device-driven. These pharmacological prognosis-modifying treatments, however, included neither SGLT2 inhibitors  nor cardiac glycosides , both currently recommended in ESC HF guidelines  [In addition, there were no follow-up assessments of heart rate changes during the follow-up.Moreover, we saw a gender imbalance, with a predominance of male study participants (~77%), which has been observed in many recent HF trials and registries ,22 and mOur prospective study underlines the importance of heart rate reduction in HF with SR but failed to demonstrate a better risk reduction in the group of patients with up-titrated BB doses or on a combination of BB plus ivabradine. Despite unfavorable clinical characteristics at baseline, patients receiving a combination of ivabradine and BB, on the other hand, did not have a higher risk of adverse outcomes.