This study aimed to profile the changes in non‐invasive clinical, biochemical, and imaging markers during withdrawal of therapy in patients with recovered dilated cardiomyopathy, providing insights into the pathophysiology of relapse.2 ] and LV end‐diastolic volume [3.9 mL/m2 ] and a reduction in mean LV ejection fraction [−4.2 ] were seen by 16 weeks, the earliest imaging follow‐up. Plasma N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) fell immediately after withdrawing beta‐blockers and only tended to increase 6 months after beginning therapy withdrawal [mean change in log NT‐proBNP at 6 months: 0.2 ].Clinical, biochemical, and imaging data from patients during phased withdrawal of therapy in the randomized or single‐arm cross‐over phases of TRED‐HF were profiled. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks, and 6 months. Amongst the 49 patients  who withdrew therapy, 20 relapsed. Increases in mean heart rate [7.6 beats per minute ], systolic blood pressure [6.6 mmHg ], and diastolic blood pressure [5.8 mmHg ] were observed within 4–8 weeks of starting to withdraw therapy. A rise in mean left ventricular (LV) mass [5.1 g/mChanges in plasma NT‐proBNP are a late feature of relapse, often months after a reduction in LV function. A rise in heart rate and blood pressure is observed soon after withdrawing therapy in recovered dilated cardiomyopathy, typically accompanied or closely followed by early changes in LV structure and function. Left ventricular (LV) reverse remodelling frequently occurs amongst patients with dilated cardiomyopathy (DCM).A previous report from the TRED‐HF trial suggested that a greater rise in heart rate during therapy withdrawal was associated with a higher risk of relapse.In this study, we profiled the serial changes in non‐invasive clinical, biochemical, and imaging markers during withdrawal of therapy in patients with recovered DCM to provide insights into the sequence of changes that occur during adverse remodelling and relapse.The TRED‐HF was an open‐label, randomized trial examining the safety and feasibility of phased withdrawal of pharmacological therapy for heart failure in asymptomatic patients with DCM and improved LVEF and low plasma concentrations of natriuretic peptides (NCT02859311).Overall, 51 patients with a previous diagnosis of DCM, whose LVEF had improved from <40% to ≥50% and who now had normal left ventricular end‐diastolic volume (LVEDV) and plasma N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) < 250 ng/L and who were still taking at least one heart failure therapy  were included. Patients were randomized 1:1 to phased withdrawal or continuation of heart failure therapy for 6 months. After 6 months, patients assigned to the control arm subsequently entered a single‐arm cross‐over phase. Between Months 6 and 12, they had therapy withdrawn in the same fashion as the randomized phase of the study.Therapy withdrawal was done in a step‐wise fashion over a maximum of 16 weeks. Changes were made every 2 weeks following review by the study team. Heart rate, blood pressure, and plasma concentration of NT‐proBNP were measured every 4 weeks with interim reviews taking place via telephone, if feasible and safe. All patients had cardiovascular magnetic resonance (CMR) at baseline, 16 weeks, and 6 months with gold‐standard volumetric assessment of cardiac chambers by two EACVI Level 3 accredited operators.Loop diuretics were withdrawn first, followed by MRAs, beta‐blockers, and finally ACE inhibitors or ARBs at separate visits. The medication was stopped if the participant was taking 40 mg or less of furosemide , 50 mg or less of spironolactone, or 25% or less of the recommended dose of beta‐blocker or ACE inhibitor or ARB. If participants were prescribed larger doses of any of the above, these were reduced by 50%, rather than stopped, every 2 weeks.The primary relapse endpoint was defined by any one of the following: (i) a reduction in LVEF by >10% and to <50%, or (ii) an increase in LVEDV by >10% and to above the normal range, or (iii) a two‐fold rise in NT‐proBNP from baseline and to >400 ng/L, or (iv) clinical evidence of heart failure. Treatment was restarted if any of the primary endpoint criteria were met. The management of patients who suffered adverse events but did not meet the primary endpoint was determined by the research team and the patient's physicians.t‐tests. Percentage change in variables from baseline along with 95% CIs are presented at different time points. The same data are presented stratified by the occurrence of relapse in the supplementary data for those variables not included in the primary endpoint composite. Serial changes in clinical variables collected at each study visit were modelled using fractional polynomial models with four knots. We also examined changes in NT‐proBNP before, during, and after the withdrawal of beta‐blockers and ACE inhibitors/ARBs, individually.The mean and mean change from baseline are presented at the different time points for each variable with 95% confidence intervals (CIs). Patient data were included until the end of the study, which was defined as the final follow‐up visit or the time at which the primary endpoint was first met. Change from baseline was analysed using paired Statistical analyses were performed using Stata Version 16.0 . The investigators had complete access to all raw and derived datasets.TableOf the 51 patients enrolled and randomized, 49 attempted withdrawal of therapy during the study; 25 patients were randomized to have therapy withdrawn between 0 and 6 months, whilst 24 of 26 patients initially randomized to continue therapy, attempted to withdraw therapy in the single‐arm cross‐over phase between 6 and 12 months. Of the 49 patients who withdrew therapy, 20 (41%) met the primary endpoint for relapse. Of the 20 patients who relapsed, 10 fulfilled more than one element of the primary composite relapse endpoint; 12 (60%) met the LVEF criterion, 11 (55%) the LVEDVi criterion, 9 (45%) the NT‐proBNP criterion, and 1 (5%) developed peripheral oedema. Four participants restarted therapy without meeting the primary endpoint, two for hypertension, one following an episode of atrial fibrillation, and one following an episode of non‐sustained ventricular tachycardia. Baseline characteristics are presented in P < 0.0001], which was followed by a rise in systolic and diastolic blood pressure between baseline and 8 weeks  (SupportTableThere was a rise in mean heart rate between baseline and 4 weeks   to 4.2 ], with a non‐significant trend to increase from baseline seen at 6 months  Figure1. As eP < 0.001], which was accompanied by an increase in LVEDVi  and left ventricular mass indexed to body surface area (LVMi)  , P = 0.009]  to 55.2% ; change from baseline −4.2% , 1] FigureTable2FigureTableP = 0.01].There was a reduction in mean log NT‐proBNP during withdrawal of beta‐blocker therapy [change in log NT‐proBNP during withdrawal of beta‐blocker: −0.25 ] FigureTable3P = 0.82].There were trends towards increases in mean log NT‐proBNP during and after withdrawal of ACE inhibitors or ARBs, although this did not reach statistical significance . The change in log NT‐proBNP following withdrawal of ACE inhibitor/ARB was not different between those who relapsed and those who did not [0.21  vs. 0.15 ; The TRED‐HF trial provides a unique opportunity to evaluate patients with DCM remission undergoing therapy withdrawal, prospectively and serially, using a standardized protocol with gold‐standard imaging investigations including CMR.TTN.A rise in heart rate and blood pressure within 4–8 weeks after the start of therapy withdrawal reflects withdrawal of neurohormonal blockade and increasing sympathetic stimulation. The resulting increase in heart rate and afterload places greater workload on a vulnerable myocardium and appears likely to be the initial driver for relapse. Deterioration in LV systolic dysfunction and LV hypertrophy closely follow. It is possible that systolic dysfunction is caused by impaired energetic function, with insufficient adenosine triphosphate delivery caused by mitochondrial dysfunction and driven by increasing sympathetic stimulation.The demonstration that NT‐proBNP typically rises months after the development of LV systolic dysfunction and hypertrophy is important for clinical practice. Increases in NT‐proBNP were seldom observed until a drop in LVEF of >10%. This suggests that the left ventricle can compensate for changes in systolic function for a prolonged period before ventricular and atrial stretch occurs and intracardiac pressures begin to rise. The late increase in LAVi, which was only found in patients who had met criteria for relapse, is in‐keeping with this concept.The fall in NT‐proBNP after withdrawal of beta‐blockers is interesting. This supports the concept that beta‐blockers chronically increase plasma concentrations of NT‐proBNP, due to delayed myocardial relaxation, negative inotropic effects, or slower heart rate with consequent increase in left atrial volume and wall stress. We stress, however, that this does not support the withdrawal of beta‐blockers in such patients. These medications are likely to play an important role in the maintenance of heart failure remission. It is possible that increased secretion of natriuretic peptides might even contribute to the therapeutic action of beta‐blockers. Moreover, following the withdrawal of beta‐blockers, we observed a secondary increase in NT‐proBNP that was greatest amongst patients who relapsed. A similar observation was not seen following the withdrawal of ACE inhibitor/ARB. As heart failure therapy was not standardized at baseline and withdrawal of agents followed in quick succession, it is difficult to reliably determine the effects of withdrawing individual agents on different variables. We also recognize the limitations of these analyses with small numbers of patients and stress the exploratory nature of them.The absence of clear changes in RVEF is in‐keeping with primary LV pathology. However, we have previously reported reduction in right ventricular (RV) global longitudinal strain amongst patients who had therapy withdrawal compared with those who continued therapy.The use of CMR to detect imaging changes provides gold‐standard reproducibility that affords the ability to detect subtle structural and functional changes in both the LV and RV within small numbers of patients. It is possible that more subtle changes in some measures, such as RVEF, may have been missed due to the relatively small sample size. Whilst it was not feasible to perform imaging at the same frequency as clinical examination and blood sampling, our protocol enabled us to demonstrate changes in mean LVMi and LVEF that clearly preceded change in NT‐proBNP. We have reported randomized comparisons of ventricular strain and tissue characterization markers; however, the current report is the first to demonstrate the time course of serial changes in LV and RV structure and function and how these relate to other clinical and biochemical variables.We report for the first time that withdrawing therapy from asymptomatic patients with DCM and improved cardiac function leads to rapid increases in heart rate and blood pressure, which are accompanied or closely followed by changes in LV structure and function. Increases in NT‐proBNP typically occur later in the remodelling cascade, with increases in LAVi only seen amongst those with the most marked changes in ventricular structure or function. This confirms that tracking of simple clinical variables, such as heart rate, accompanied by regular imaging may be more effective than serial measurement of natriuretic peptides in detecting relapse.Prof. Pennell has received research support from Siemens and speaker's fees from Chiesi and Bayer and is a Director and owns stocks in Cardiovascular Imaging Solutions. Prof. Cowie reports consultancy work for AstraZeneca, Servier, Roche Diagnostics, and Amgen. Prof. Cleland reports personal fees from Abbott, grants and personal fees from Amgen, grants and personal fees from Bayer, personal fees and non‐financial support from Medtronic, grants and personal fees from Novartis, grants and personal fees from Pharmacosmos, grants and personal fees from Vifor, grants and personal fees from BMS, and grants and personal fees from Servier, outside the submitted work. All other authors have nothing to declare.) and a Clinical Lecturer Starter Grant from the Academy of Medical Sciences (SGL021\1025). J.G.F.C. received support from a Centre of Research Excellence award from the British Heart Foundation (RE/18/6/34217).The TRED‐HF was an investigator‐led trial sponsored by Royal Brompton and Harefield NHS Trust. The study was funded by a Clinical Research Training Fellowship from the British Heart Foundation (FS/15/29/31492) awarded to B.P.H. and S.K.P. and received additional support from the Alexander Jansons Foundation, the Cardiovascular Research Centre and NIHR Biomedical Research Unit at Royal Brompton Hospital, and the NIHR Imperial College Biomedical Research Centre and grants from Rosetrees Trust awarded to S.K.P. B.P.H. is also supported by a BHF Intermediate Fellowship (FS/ICRF/21/26019Figure S1. Mean change from baseline in variables stratified by the occurrence of relapseTable S1. Summaries of variables over follow‐up stratified by relapseClick here for additional data file.


Prolonged population aging and unhealthy lifestyles contribute to the progressive prevalence of arterial hypertension. This is accompanied by low-grade inflammation and over time results in heart dysfunction and failure. Hypertension-induced myocardial structural and ion channel remodeling facilitates the development of both atrial and ventricular fibrillation, and these increase the risk of stroke and sudden death. Herein, we elucidate hypertension-induced impairment of “connexome” cardiomyocyte junctions. This complex ensures cell-to-cell adhesion and coupling for electrical and molecular signal propagation. Connexome dysfunction can be a key factor in promoting the occurrence of both cardiac arrhythmias and heart failure. However, the available literature indicates that arterial hypertension treatment can hamper myocardial structural remodeling, hypertrophy and/or fibrosis, and preserve connexome function. This suggests the pleiotropic effects of antihypertensive agents, including anti-inflammatory. Therefore, further research is required to identify specific molecular targets and pathways that will protect connexomes, and it is also necessary to develop new approaches to maintain heart function in patients suffering from primary or pulmonary arterial hypertension. Herein, we focus on pro-arrhythmic disorders elicited by primary hypertension (HTN). This is a prevalent risk factor for cardiovascular disease in the general population that includes younger people. HTN is defined as systolic blood pressure above 140 mmHg or diastolic blood pressure above 80 mmHg. These can result in hypertensive heart disease from pressure overload. HTN-induced compensated myocardial hypertrophy can aggravate left heart dysfunction over an extended period. This is mainly due to fibrosis, and it results in heart failure (HF). HTN also promotes the occurrence of cardiac arrhythmias, including ventricular fibrillation (VF) and atrial fibrillation (AF). In addition to HTN, there is also an increased incidence of pulmonary arterial hypertension (PAH) which affects right heart function. PAH is caused by pulmonary vasculopathy, and it results in elevated pulmonary arterial pressure above 25 mmHg at rest. This is a most serious clinical problem and has adverse prognosis due to heart disease progression and the accompanying myocardial fibrosis contributing to HF. There is also a further risk of VF and AF. Further research is also essential to differentiate gender differences in both primary HTN and PAH for efficient treatment.It has been established that myocardial connexin-43 (Cx43) channels ensure electrical coupling between cardiomyocytes and are crucial in the development of malignant cardiac arrhythmias . The avaResearch suggests that it is important to consider connexomes and “area composite”, complex proteins which underly the interaction of Cx43-formed GJs, D, and AJs at the intercalated discs. This is highlighted in conditio sine qua non for synchronized myocardial contraction, and this is impaired in heart disease [It is most important that the connexomes affect both cardiomyocyte electrical coupling through Cx43 channels and mechanical force transduction by adhesive junctions. It is  disease ,9,20. In disease . Therefo disease . These wThe heart can “die” due to the following three major events: electromechanical dissociation, asystole, and VF, which is the most frequent case. In addition, AF is the most frequent arrhythmia in the population. AF deteriorates heart function and can cause stroke. The basic electrophysiological mechanisms of cardiac arrhythmias include the following: (1) abnormal electrical impulse generation through ectopic pacemaker-like activity or triggered activity and (2) abnormal electrical impulse propagation, due to blocks of conduction and re-entrant excitation. Simultaneous operation of abnormalities 1 and 2 may occur ,23,24,252+ handling, Ca2+-overload, and ischemia-related acidosis induce Cx43-GJ uncoupling. When this is combined with ion current abnormalities, it can trigger the electrical disorders that initiate AF or VF occurrence [Research indicates that abnormal Cacurrence ,24,29,30Modulating factors, such as humoral and autonomic tone misbalance ,32, inflAlthough the basic mechanisms that can cause cardiac arrhythmias are known, there is little understanding of the changes in cardiac electrical properties in heart disease, and this includes those in HTN and PAH. These properties appear to be the immediate cause of the operation of the arrhythmogenic mechanisms which occur in cardiac conditions and disease. Both AF and VF are assumed to occur due to ectopic impulse initiation, blocking conduction, and circuit re-entry. Although, AF can self-terminate and VF can be transient in the heart, avoiding arrhythmogenic substrates under the control of modulating factors. However, sustained AF or VF can aggravate the myocardial injury and connexome function . TherefoPrimary or essential HTN is a prevalent risk factor jeopardizing cardiovascular health, and its increase in younger people is very alarming ,38. HTN 2+ handling, and Cx43 disorders of the left ventricle. These are crucial in impaired conduction, electrical instability, heart mechanical dysfunction, and cardiac arrhythmias [Numerous animal and human heart studies indicate that HTN-induced structural remodeling involves hypertrophy, a shift in myosin heavy chains, cytoskeletal proteins, fibrosis, channelopathy, altered Cahythmias ,68,69,70In addition, the progression of left ventricular alterations to HF is associated with right ventricular dysfunction and electrical instability . This coAvailable literature indicates that HTN results in altered connexomes on the cardiomyocyte lateral sides, in addition to its multiple locations in ID. The subcellular alterations indicate connexome abnormalities. These include the AJ dehiscence, internalization, and GJ degradation, as demonstrated in HTN-induced structural remodeling causes Cx43 redistribution from GJs to the cardiomyocyte lateral sides ,62,67,74It is important that Cx43 cardiomyocyte lateralization is accompanied by the remodeling of D and microtubule-associated proteins . This reLVH is associated with increased intracellular resistivity which can be solely attributed to increased junctional resistance between adjacent cells . CardiacGJ remodeling in human decompensated cardiac hypertrophy is associated with increased interaction of Cx43 with zonula occludens-1 (ZO-1) ,92. ThisData in the literature indicate proposed factors and mechanisms that may be involved in pro-arrhythmic “connexome” dysfunction in chronic arterial hypertension, as outlined in The spontaneously hypertensive rat (SHR) is the most frequent experimental model used to imitate human primary HTN. The SHR treatment with the phenylbutyrate short-chain fatty acid derivative and captopril both improved myocardial function, regressed cardiac hypertrophy, and enhanced recovery from HF . It is iThe literature cites the following treatment influences on cellular communication, impulse conduction, and adhesive junctions:(1) The distribution of Cx43 GJs became more regular and confined to the ID and attenuation of LVH in SHR after treatment with the atorvastatin 3-hydroxy-3-methylglutaryl coenzyme A inhibitor . It is a(2) The activation of Ang II and AT1 receptors decreases GJ conductance in the failing heart, with consequent impairment of impulse propagation . In addi(3) The arrhythmias was attributed to inflammation, interstitial fibrosis, reduced transcripts of potassium channel subunit Kv4.3, and gap-junction Cx43 that was partly abolished by losartan. However, a chronic losartan blockade of the Ang II AT1 receptors increased intercellular communication, reduced fibrosis, and improved impulse propagation in the failing heart . Ventric(4) Candesartan is a further receptor blocker, but its action did not cause fibrosis regression in the SHR’s left atrium at a dose sufficient to reduce blood pressure and left ventricular hypertrophy . In cont(5) Gap junction A1-20k is required for Cx43 passage to the intercalated disc. This attenuates LVH by regulating GJ formation and mitochondrial function .(6) Resolvin D2 protected cardiovascular function and structure when administered before and after the development of Ang II-induced HTN by attenuating inflammation and fibrosis . It is a(7) This concept is supported by recent reviews which stressed the pleiotropic antiarrhythmic properties of cardioprotective agents affecting inflammation and oxidative stress ,106. The(8) However, defective fatty acid uptake is involved in myocardial remodeling in the SHR . In cont(9) Omega-3 fatty acids decreased the protein kinase PKCδ involved in SHR extracellular matrix remodeling . These a(10) Dietary omega-3 fatty acids and renin inhibition with aliskiren improved both electrical remodeling and the antiarrhythmic effects attributed to improved Cx43 expression. This also prevented Cx43 redistribution in the model of high human renin primary hypertension . In addi(11) Finally, early primary HTN therapy can attenuate myocardial structural remodeling and suppress myocardial LVH and fibrosis in the SHR . For exaThere is an increasing incidence of pulmonary arterial hypertension (PAH) in the general population. This is in addition to problems caused by primary HTN. The elevated pressure in PAH affects the pulmonary circulation and right heart function, and the attendant proliferative vasculopathy results in ongoing increased right ventricular afterload, structural remodeling, and mechanical HF. PAH is multi-factorial, and its etiopathogenesis is not completely understood because of its relationship with underlying somatic disease .PAH is similar to primary HTN, as it is influenced by genetic, epigenetic, and environmental factors. However, hypertension is the most common causative factor of cardiac remodeling ,114. PAHVarious authors consider that Cx43 downregulation, its dephosphorylation and internalization, and the dysregulated Cx43-mediated signaling in the right ventricle offer crucial intervention targets. ,118,119.Disorganized GJ distribution and altered anisotropic conduction predispose re-entrant arrhythmias . There iFinally, right heart disease maintains AF due to re-entrant activity, and its underlying substrate involves fibrosis and consequent conduction abnormalities .PAH is characterized by reduced angiotensin-converting enzyme-2 activity (ACE2). In contrast, ACE2 augmentation improves pulmonary hemodynamics and reduces oxidant and inflammatory mediator markers . TargetiThere were also the following therapeutic interventions:The benefit of combined nicorandil and colchicine therapy and associated Cx43 preservation in the PAH rat model  and atteThe bosentan dual endothelin receptor antagonist partly reversed Cx43 remodeling in the PAH hypertrophied right ventricle , and comFinally, sildenafil confers protection in the PAH rat model by suppressing pro-fibrotic signaling and enhancing Cx43 in the right ventricle , and carIn the context of the topic of this article it should be emphasized that arterial hypertension and high blood pressure-related cardiovascular disease remain global health hazards posing a major socio-economic and healthcare challenge. The global prevalence of hypertension is estimated to be in the range of 30–45% . In EuroLifestyle interventions are an essential and established part of hypertension management and, in combination with anti-hypertensive drug treatment, provide a most effective strategy to achieve recommended blood pressure targets and reduce cardiovascular mortality. Indeed, guidelines for the management of arterial hypertension strongly recommend lifestyle advice. Mediterranean diet, salt, sugar, and alcohol reduction, smoking cessation, elimination or overcome of stressful events and regular physical activity as well as prevention obesity are essential components not only for the management of hypertension but also for prevention of development of hypertension. As suggested by most actual systematic reviews ,134 non-Research confirms that oxidative stress, a low-grade inflammatory state, and ischemia are involved in hypertension-induced cardiomyocyte junction impairment. Herein we introduce the “connexome” term which combines desmosomes, gap junctions, adherens junctions, and ion channels; and the term is thus defined. The connexome is most important in cardiomyocyte adhesion and the propagation of contractile force, and it is essential for cardiomyocyte coupling which enables electrical and molecular signal transmission. The connexome, therefore, ensures appropriate synchronized heart function; and its impairment is a major component in life-threatening cardiac arrhythmias and heart failure in primary hypertension and pulmonary hypertension. However, there has also been the expressed opinion that preserving the connexome in arterial hypertension treatment can hinder myocardial structural remodeling, hypertrophy, and fibrosis, as well as the occurrence of cardiac arrhythmias.In conclusion, while major research confirms the beneficial pleiotropic effects of anti-hypertensive and anti-inflammatory agents, further research is essential to identify specific molecular targets and pathways that protect the connexome. This combination will help formulate new clinical approaches to maintain heart function in patients with arterial hypertension. Moreover, lifestyle advice remains one of the crucial pillars of both anti-hypertensive treatment and hypertension prevention.


Sepsis‐induced cardiomyopathy represents a challenging disorder for critical care practitioners in terms of diagnosis, monitoring and treatment. Strain echocardiography may help to identify ventricular dysfunction at precocious stage in critically ill patients. In this manuscript, we describe early impairment in left ventricular systolic function using speckle‐tracking echocardiography. Management of septic cardiomyopathy remains challenging in terms of diagnosis, monitoring, and treatment. This report reminds us that the conventional measurement of LVEF is not a sensitive indicator to investigate cardiac function in septic shock. Strain echocardiography enables identification of septic cardiomyopathy by detecting subtle myocardial dysfunction at precocious stage.  Physical examination revealed purpura and ecchymoses Figures . Blood a2Profound but reversible myocardial depression in septic shock patients has been described in the literature. Transthoracic echocardiography is the first‐line tool to assess patients in shock. Conventional echocardiographic variables may be affected by loading conditions. STE is a novel technological modality allowing early detection of LV dysfunction, prior to decrease in LVEF. Normal value of GLS is reported in the range of −20% in healthy subjects.3Identifying cardiac failure in sepsis remains challenging. GLS represents a more sensitive indicator of septic LV dysfunction compared to conventional measurement of LVEF. This clinical picture illustrates that strain echocardiography may help to identify cardiac dysfunction at precocious stage in critically ill patients at risk of myocardial depression during a fulminant sepsis. However, the clinical impact of GLS measurement in septic patients remains unclear.All authors have made substantial contribution to the preparation of this manuscript. JH acquired the images, interpreted the data, and drafted the manuscript. YB performed literature research. PB made critical revision and approved the final manuscript.The authors have no conflicts of interest to declare.Written informed consent was obtained from the patient to publish this report for educational/research purposes in accordance with the journal's patient consent policy.Video S1Click here for additional data file.Video S2Click here for additional data file.Appendix S1Click here for additional data file.


Cardiac damage is the leading cause of death in uremic patients. This study aimed to evaluate the application of non-invasive myocardial work index (NIMWI) by echocardiography in assessing the left ventricular (LV) systolic function in uremic patients.t-test. Receiver operating characteristic (ROC) curves were constructed for MW parameters to detect abnormal LV systolic function in uremic patients.Twenty-six uremic patients and 27 age- and sex-matched healthy volunteers were enrolled in the study. Except for the conventional echocardiographic parameters, the LV myocardial work (MW) parameters including GWI , GCW , GWW , and GWE  were calculated in study participants. Differences in MW parameters between the uremic and normal groups were compared by independent-sample P < 0.05). Area under the curve (AUC) for GWE by the ROC analysis was 0.966. The best threshold, sensitivity and specificity values of GWE to detect abnormality of LV systolic function in uremic patients were 92.5%, 0.89 and 0.96, respectively.Compared with the normal group, GWW was significantly increased and GWE decreased in the uremic group (NIMWI may be applied to assess the global MW of uremic patients. The presence of reduced GWE can help identify impaired left ventricular myocardial function in uremic patients with preserved LV ejection fraction with a high sensitivity and specificity. Chronic kidney disease (CKD) is a common disease which seriously threatens patients’ health and life. The disease causes damage to multiple systems and organs, especially in its end-stage (i.e. uremia). Indeed, cardiac damage is the leading cause of death in uremic patients . EarlierThe pressure–volume loop method measured by cardiac catheterization can assess the LV systolic function and myocardial oxygen consumption accurately . HoweverPrevious studies have indicated that the NIMWI can evaluate the LV MW in patients with CKD without dialysis , but theP < 0.05). There were no differences in gender, age, heart rate (HR) and body surface area (BSA) between the two groups (P > 0.05)  and diastolic blood pressures (DBP). The differences between groups were statistically significant (both 5) Table .Table 1CP < 0.05). There were no significant differences in LVEF between the two groups (P > 0.05) , LV posterior wall end-diastolic thickness (LVPWTd), LV end-diastolic diameter (LVEDd), LV mass index (LVMI) and decreased GLS. The differences between groups were statistically significant (5) Table .Table 2CP < 0.05). However, differences in global work index (GWI) and global constructive work (GCW) between the two groups were not statistically significant (P > 0.05)  and decreased global work efficiency (GWE). The differences observed between groups were statistically significant (5) Table , Fig. 1.r = − 0.83, P < 0.001 and r = 0.72, P < 0.001, respectively).GWE and GWW showed a good correlation with SBP  of GWE and GWW were 0.966 and 0.925, respectively. GWE was the best diagnostic index for identifying impaired LV myocardial function in uremic patients with preserved LV ejection fraction. The sensitivity and specificity were 89% and 96%, respectively. The best threshold of GWE was 92.5% , but the uremic group showed increased GWW and decreased GWE (P < 0.05), indicating that the NIMWI can identify LV systolic dysfunction in uremic patients with preserved ejection fraction. GWE was the best diagnostic index for identifying impaired LV myocardial function in uremic patients with preserved LV ejection fraction, and its sensitivity, specificity and optimal threshold were 89%, 96% and 92.5%, respectively.Uremia is the final stage of CKD progression. Serious damage to the kidney functions promotes the production and accumulation of toxins in the body, resulting in multi-organ dysfunction and poor health. Cardiovascular complications are the main cause of death in patients with uremia . TherefoTraditional evaluations of MW mainly rely on invasive pressure measurement, the feasibility of which is limited in conventional clinical practice , 11. TheCompared with the normal group, there were no difference in GWI and GCW, but GWW increased and GWE decreased in the uremic group, indicating that a decreased GWE of the left ventricle in uremic patients. GWE is the ratio of GCW to the sum of GCW and GWW, and there is no obvious change in the GCW. Thus, it can be seen that the decrease of GWE is mainly related to the increase of LV GWW. GWW refers to the work done by the left ventricle that is not conducive to ejection, including the total work done by cardinal elongation at systole and cardinal shortening at isovolumic diastole. Any factor affecting myocardial elongation at systole and myocardial shortening at isovolumic diastole may increase GWW. An earlier study  demonstrIn this study, GWE and GWW showed a good correlation with SBP, which is consistent with the rationale that the NIMWI technique evaluates myocardial work based on stress and strain. AUC for GWE by the ROC analysis was 0.966, which indicates that the GWE accurately evaluated LV systolic function in uremic patients. The best threshold, sensitivity and specificity values of GWE to detect abnormality of LV systolic function in uremic patients were 92.5%, 0.89 and 0.96, respectively. It can provide some reference values for the early detection of the LV systolic dysfunction in uremic patients with preserved left ventricular ejection fraction..However, this study had some limitations that should be noted. It was a single-centre study with a relatively small sample size and no long-term follow-up of uremic patients, which will be encompassed in the next phase of the study.NIMWI may be applied to assess the global MW of uremic patients. AUC, sensitivity, and specificity for GWE parameter by ROC analysis were high, revealing the accuracy of GWE for the detection of the LV systolic dysfunction in the uremic patients. The reproducibility of MW parameters can help to improve its application in clinical practice.A total of 26 uremic patients who were treated in the nephrology department of our hospital from November 2020 to June 2021 were consecutively identified. All uremic patients were treated with regular haemodialysis three times a week and with LVEF ≥ 50% according to the 2016 European Society of Cardiology Guidelines [Twenty-seven healthy volunteers matched for sex, age and body surface area (BSA) were selected as the normal group. All volunteers had no history of heart disease, hypertension, diabetes or medication. Their physical examination, electrocardiogram, chest radiograph, renal function and echocardiography results were normal.All subjects provided informed consent prior to participating in this study, and the study protocols were approved by the Hospital Ethics Committee. The participant selection process is illustrated in the flowchart in Fig. GE Vivid E95  colour Doppler ultrasound system equipped with M5Sc-D 1.4–4.6 MHz probe was used for echocardiographic image acquisition.The subjects were instructed to assume the left-lateral position and an electrocardiogram was attached. Transthoracic echocardiography was used to measure the LVEDd, LVPWTd and IVSTd of the participants. The modified biplane Simpson method was used to calculate LVEF from the apical four- and two-chamber views. The LVMI was calculated as LV mass divided by BSA. We obtained the dynamic two-dimensional images from the LV apical four-, two- and three-chamber views at frame rate of 58—69 frames/s (average of 67.4 ± 6 frames/sec) for at least three cardiac cycles in the resting state. The images were copied, saved and exported to the workstation in Digital Imaging and Communication in Medicine (DICOM) format on a mobile hard disk for offline analysis.All two-dimensional images and measurements were performed according to American Society of Echocardiography guideline , and allThe stored images were analysed offline by an Echo PAC BT203  workstation. The durations of the LV isovolumic systole and ejection period were first determined according to the opening and closing of the aortic and mitral valves, and then the automatic functional imaging mode was selected. The endocardium of the LV long axis, four-chamber and two-chamber view were depicted from the level of the mitral valve annulus to the LV apex in sequence. The software automatically tracked the endocardium and epicardium of the left ventricle. The intracardiac and epicardial wrap were manually adjusted to ensure satisfactory tracking. Finally, Approve was clicked, and the blood pressure measured by the bronchial artery cuff was entered into the MW menu to obtain the LV pressure–strain loops (PSL), GLS and NIMWI. The NIMWI parameters included GWI, GCW, GWW and GWE, as shown in Fig. t-test was used to compare continuous variables between the uremic group and normal group. The Chi-squared test was used to compare count data. Correlation between continuous variables was carried out using Pearson’s or Spearman’s correlation coefficient as appropriate.All statistical analyses were performed using SPSS version 25.0 . Continuous variables were expressed as mean ± standard deviation if normally distributed. Independent-sample P-value < 0.05 was considered statistically significant.ROC curves were performed to determine the optimal sensitivity and specificity of MW parameter. The AUC was calculated to assess the performance of MW parameter for the detection impaired myocardium in uremic patients. According to the Youden index, the best threshold of each tested MW parameter was estimated. Ten subjects were randomly selected, and two observers used infra-class correlation coefficients to carry out repeatability tests for the myocardial work parameters GWI, GCW, GWW and GWE. A


Modern cardiac pacemakers are equipped with a function that allows the heart rate to adapt to the current needs of the patient in situations of increased demand related to exercise and stress ("rate-response" function). This function may be based on a variety of mechanisms, such as a built-in accelerometer responding to increased chest movement or algorithms sensing metabolic demand for oxygen, analysis of intrathoracic impedance, and analysis of the heart rhythm . The latest technologies in the field of rate-response functionality relate to the use of an accelerometer in leadless endocavitary pacemakers; in these devices, the accelerometer enables mapping of the mechanical wave of the heart’s work cycle, enabling the pacemaker to correctly sense native impulses and stimulate the ventricles in synchrony with the cycles of atria and heart valves. Another modern system for synchronizing pacing rate with the patient’s real-time needs requires a closed-loop system that continuously monitors changes in the dynamics of heart contractions. This article discusses the technical details of various solutions for detecting and responding to situations related to increased oxygen demand  in implantable pacemakers, and reviews the results of clinical trials regarding the use of these algorithms. Chronotropic incompetence (CI) refers to a heart’s inability to adapt (increase to reach 85% of the maximum age-predicted heart rate) its rate to improve cardiac output to meet metabolic demands during exercise and stress. In this disorder, an inadequate heart rate is generated relative to the needs of the organism, resulting in an insufficient blood supply, fatigue, shortness of breath, limited ability to exercise, and a reduced quality of life . CI is aThe sympathetic branch of the autonomic nervous system is responsible for accelerating the heart rate according to the current body state, among other functions. The primary neurotransmitter released by the sympathetic nervous system is norepinephrine. The autonomic system innervates the heart through the jugular ganglia and the cardiac plexus—the body’s natural pacemakers. The heart rate reflects the balance between the sympathetic and parasympathetic parts of the autonomic nervous system . The sinThe most commonly used definition of chronotropic failure is an inability to reach 85% of the maximum heart rate limit for one’s age during maximal exertion; however, it also encompasses delayed achievement of heart rate appropriate to the exercise intensity, inadequate variation in heart rate during exercise, or inadequate dynamics in returning to resting heart rate after exercise . DisordeCI is a common problem in the heart failure patient population. According to the literature, it affects 25–70% of patients with heart failure; the wide range observed for this measure may result from the lack of a unified definition of CI and the use of different methods of assessment . It is nA typical implantable cardiac pacemaker consists of a pulse generator and one, two, or three leads that are implanted, depending on the patient’s needs, endocavitary, into the muscularis of the right atrium, into the right ventricle, epicardially to the left ventricular wall, or directly or indirectly to the fibers of the conduction pathways or in their vicinity  ,31,32. BThese pacemakers use built-in sensors to detect a signal that indicates the need for a faster heart rate and, in accordance with the programmed settings for the dynamics of the response and the permitted limit of the change in the pacing rate, calculates the number of sensor stimulations proportionally to the effort intensity; it increases the atrial  or dual-chamber sequential-responsive pacing (DDDR mode)) or ventricular (in single-chamber ventricular-responsive pacing (VVIR mode)) pacing rate to match the performed effort, up to the maximum pacing frequency limit defined by the parameter value (most often referred to as the "upper sensor rate") or until the effort ceases. In the parameters of the rate-response function, there is also a mechanism for setting the dynamics of a gradual return to the basic rate of pacing after the end of the exercise. This prevents sudden, significant drops in the stimulation frequency in situations where the effort is stopped abruptly. The parameters for the dynamics of increase and the dynamics of decrease, and for the limitation of the pacing rate, are programmable in order to individually adapt to the patient’s age, condition, needs, and lifestyle, taking into account their health history  ,37.Each type of sensor (categorized by the factor to which it responds) has its own specific capabilities, advantages, and limitations. A common solution involves two different sensors combined in one system in order to increase the sensitivity and specificity of stimulus perception by the system, optimizing the stimulation frequency change under the influence of the received factor and reducing the susceptibility to disturbances caused by interference from other stimuli acting on the sensed parameters . According to the order in which they sense and react to the body’s increased demand for oxygen and the consequent need to increase the pacing frequency, the rate-response sensors can be divided into primary, secondary, and tertiary categories. The least physiological are the tertiary sensors, which detect parameters resulting from exercise, e.g., accelerometers. Secondary rate-response sensors detect parameters resulting from metabolic demand, e.g., minute ventilation. The most physiological sensors, termed primary sensors, detect parameters influencing cardiac function during exercise, e.g., closed-loop stimulation . In termThe simplest, most commonly used system for sensing a patient’s activity and the related need to adjust the pacing rate to their effort is an accelerometer that is built into the pacemaker’s pulse generator. In this type of sensor, the device detects the patient’s movement on the basis of the change in the position of the pulse generator, i.e., the deflection that naturally accompanies the movement of the chest while walking or running. The device continuously counts the number and frequency of recorded movements. It then converts this information into a proportional change in the pacing frequency in accordance with the dynamics programmed for a given patient, as well as the difference between the baseline pacing rate and the maximum limit to which stimulation may be increased during exercise. This sensor, however, has several significant disadvantages: it responds to increased effort with a delay and it is susceptible to disturbances in the form of external vibrations unrelated to, or disproportionately related to, the patient’s activity  ,41.The operation of an activity sensor based on the incorporation of a circuit with a piezoelectric crystal works similarly. In pacemakers with a rate-response function based on a built-in piezoelectric crystal, the sensed mechanical energy related to vibration, muscle tension, and body movement is converted into electrical signals, triggering an algorithm responsible for adjusting the pacing rate. Research studies have shown that sensors based on accelerometers more quickly and precisely select the frequency of stimulation appropriate to the effort than pacemakers with sensors based on the piezoelectric effect ,42. DespAdjustment of the stimulation frequency can also be based on a minute-ventilation sensor, which acts as a physiological sensor of increased metabolic demand associated with stress or exercise. Minute ventilation, which is calculated on the basis of respiratory rate and tidal volume, correlates well with heart rate in patients without sinus node dysfunction; it may, therefore, serve as an ideal pattern to utilize for adjusting the pacing frequency to exercise in patients receiving cardiac pacing ,48. ThisUnfortunately, this parameter has its limitations. It is susceptible to disturbances and changes in intrathoracic impedance that are not related to effort. Previously conducted measurements showed that the accuracy of this sensor may be impaired in situations of different body position (sitting vs. lying) and depending on the required effort (running vs. cycling) . This seStudy results have shown that the use of this combination produces a greater improvement in heart rate scores compared to the use of an accelerometer alone; this is a measure that determines the risk of death in patients with an implanted cardioverter-defibrillator and allows for the identification of patients that may benefit more from rate-responsive stimulation . The resElectrocardiographic QT-interval-based sensors provide a completely different solution for analyzing physiological increases in the body’s metabolic demand. These pacemakers continuously record the heart rhythm by calculating the potential difference between the poles of the pacing leads (bipolar pacing) or between the pole of the lead and the can of the pulse generator (unipolar pacing). This registration is called an intracardiac electrogram (EGM). An example of an intracardiac EGM obtained from the recording leads of a dual-chamber pacemaker in bipolar mode is shown in Correct registration of intracardiac EGM signals forms the basis for the proper functioning of these pacemakers. Based on the EGM recording, the pacemaker calculates the time from the occurrence and sensing of a native or paced impulse. This allows it to send stimulation impulses at the appropriate time and control the heart rhythm according to programmed settings. The pacemaker also makes changes to basic pacing and sensing parameters using EGM. By automatically adjusting the sensitivity of the electrodes by adjusting the low- and high-pass filters, the pacemaker reduces the risk of incorrect pacing that could be caused by following incorrect signals registered by the lead .Based on the EGM recording, the pacemaker can also automatically assess the effectiveness of stimulation during periodic tests of the pacing threshold. In the absence of a deflection corresponding to the excitation of the atrium or ventricle after sending the test pacing impulses, the pacemaker can register ineffective stimulation. It can then change the amplitude of the stimulation output, reducing the risk of asystole. Additionally, the accurate recording of beats by the EGM allows for the use of algorithms that can change the atrioventricular interval to limit the pacing of the right ventricle. Excessive stimulation of the right ventricle  increases the risk of developing poststimulating cardiomyopathy . In the majority of currently used cardiac implantable electronic devices, it is possible to automatically manage the pacing of the right ventricle. This is achieved by gradually extending the atrioventricular (A-V) interval in order to evaluate whether a native ventricular beat can be detected after a sensed or paced atrial beat .QT interval analysis is a tool for the management of pacing rate during exercise (rate response) based on electrographic recordings (EGM) ,68. ThisUnfortunately, pacing rate control based on the analysis of changes in the QT interval has been associated with a susceptibility to malfunction and inadequate acceleration or deceleration of pacing under nonexercise conditions affecting QT interval duration. Additionally, inappropriate control of rate modulation pacing has been reported in association with drugs that affect the duration of myocardial repolarization . In patiIn patients with an implanted pacemaker that modulates the pacing rate based on QT interval analysis, changes in the pacing rate have been observed both during and after fever . Due to An innovative type of rate-response sensor is based on the closed-loop stimulation (CLS) algorithm. The principle behind this method is the continuous observation (in a closed loop) of changes in unipolar intracardiac impedance related to the filling of the ventricles with blood in the diastolic phase and the change in the ratio of the volume of fluid (blood) to tissue  in the contraction phase, under the direct influence of stimuli from the autonomic nervous system . Figure In CLS systems, a series of subthreshold electrical pulses are sent to enable impedance measurements in the tissue immediately surrounding the tip of the pacing lead placed in the chamber. A pacemaker with a CLS system adjusts the pacing rate by continuously analyzing the rate of change in impedance associated with changes in myocardial contractility during increased metabolic demand caused by emotions, exercise, or other conditions. It then calculates the difference between gradient sums of actual and reference impedance measurements . CLS senCLS  works based on the measurement of intracardiac impedance of the area of about 0.5–1 cm diameter around the ventricular electrode , on the basis of which it builds a model of the instantaneous work of the heart  is used to prevent vasovagal syncope. This function is based on the short period of overstimulation after an episode of sudden decrease in heart rate is detected .The main disadvantage of this function is the late reaction. The rate-drop response is activated after the beginning of the vasovagal mechanism, which often starts with a hypotensive reaction. The pacemaker detects a decrease in heart rate, which can precede syncope as a result of hypotension. Consequently, patients with vasovagal syncope achieve only partial improvement in the form of reducing the number of syncopes and prolonging the prodromal period, allowing them to adopt a safer body position before the syncope.Furthermore, the rate-drop response function is based on a nonphysiological, sudden increase in the pacing rate, which is sometimes not well tolerated by patients, interpreted as long-lasting (even up a minute) attacks of palpitations which accompany the feeling of upcoming syncope . Closed-In clinical trials comparing the effectiveness of CLS and RDR in preventing vasovagal syncope, superior efficacy of CLS devices has been evidenced . This efMoreover, this sensor is capable of detecting and responding to fluctuating demands of cardiac output due to blood flow and electrolyte changes associated with hemodialysis renal replacement therapy . In a reThe limitation of this method is the need to implant a right ventricular lead . Furthermore, some patients experience accelerated pacing that is unsuitable for their needs and individual tolerance range. Additionally, the use of negative inotropic drugs and the presence of postinfarction scars in the area of the implanted right ventricular lead may reduce the effectiveness of the algorithm . CurrentAnother solution for using an accelerometer as the basis for a rate-response function is to optimize the pacing rate in response to isovolumic contraction (and the first cardiac tone) and isovolumic relaxation (and the second cardiac tone) intervals. Technically, this is performed by analyzing endocardial vibration sensed using an accelerometer built into the tip of the ventricular lead . This solution allows for the assessment of systolic isovolumic peak acceleration—mechanical activity of the heart which increases during adrenergic stimulation, a parameter of heart contractility. It can also be used to follow the changes in heart rate and demand during exercise. The disadvantage of this solution is the need to use a dedicated electrode compatible with the pulse generator . This prevents this solution from being used in patients in whom there are no indications for replacement or additional implantation of the leads from previously used systems, even when replacing the pulse generator itself due to battery depletion ,114,115.An example of pacing rate modulation based on hemodynamic parameter analysis is the rate-response function based on measurements of and changes in transvalvular impedance (TVI). TVI is measured via electrical impulses in a circuit created between the ends of the atrial and right ventricular leads. This method is based on the fact that changes in the impedance of this area are associated with changes in the filling of the heart chambers with blood during the heart cycle. The TVI reaches a minimum value during atrial systole (which corresponds to the end-diastolic phase of the cycle) and a maximum at the end of the QT period (which corresponds to the end-systolic phase) ,117. TheChanges in the TVI waveform correspond to echocardiographic recordings of filling parameters used in the evaluation of myocardial contractility under the influence of right ventricular stimulation. This allows for an indirect assessment of changes in ventricular contractility with stimulation from the septal region compared to the apical region of the right ventricle . DiagnosEach manufacturer uses different technological solutions in the process of translating information about registered movement into an adjustment in pacing rate. The possible setups of pacemakers produced by different manufacturers are presented below. The information is the individual opinions of the authors, based on commonly available materials, mainly product manuals, and our own interpretations supported by clinical experience. The statements are not authorized by medical equipment manufacturers and may only be used by medical personnel under their own responsibility ,124,125.In the most commonly used devices, the rate-response sensor setup can be programmed as on, off, or passive. In passive mode, rate-response sensors do not adjust pacing parameters to patient movement, but only register the activities (in range of time spent on activity and exertion intensity expressed as percent of heart rate maximum) for diagnostic purposes  or set the parameter fixed on one constant value. Setting a threshold value over the automatic assessment makes the pacemaker less sensitive to movement . Proper setup of threshold parameters prevents unnecessary overreaction of the pacemaker during slight movements of the body caused by factors other than physical activity .The slope (or response factor) is responsible for determining the change in pacing rate when the threshold recognizes activity. Slope defines the proportion of pacing rate change, taking into account the intensity of effort and the difference between the lower rate and max sensor rate, linearly dividing this difference for 16 degrees of intensity . Similar to the threshold parameter, the slope can be programmed in automatic mode, which can be adjusted  or set as a fixed value in range of 1–16. Reaction time is responsible for mitigation of the change from a lower pacing rate to a rate assessed by the pacemaker as adequate to ongoing activity. The purpose of this function is to prevent abrupt changes in the pacing rate. The reaction time parameter can be set in different modes, e.g., slow/medium/fast/very fast. Recovery time is responsible for mitigation of the change of pacing rate from the highest stage of activity to a lower rate after the effort has ended. Recovery time can be set in modes, e.g., very slow/slow/medium/fast.Apart from the lower rate/base rate and max sensor rate/upper sensor rate, in Medtronic/Vitatron devices, another parameter is applied to define rate-response pacing: the ADL rate (activities of daily living rate). This parameter defines the target desired pacing rate during light/moderate activities of daily living . In devices manufactured by Medtronic/Vitatron, the function of Rate Profile Optimization is available. This algorithm, based on registered physical activities, adjusts the increase of pacing rate in the first stages of physical effort as well as during training with volatile intensity in the ADL rate range and exertion rate range. In devices commonly used in Europe, blended rate-response sensors are available, for example accelerometer and minute-ventilation (MV) sensors. This kind of pacemaker is described below, based on devices manufactured by Boston Scientific. In these devices, both sensors (or one of them) can be programmed to be active or inactive simultaneously.During mechanical ventilation of a patient, deactivation of the MV sensor is indicated. In patients with respiratory disorders or other states in which risk of incorrect functioning of MV sensors is higher, individual assessment of deactivation or modification parameters should be considered  and the patient’s lifestyle, determined by the fitness level parameter in terms of sedentary/active/athletic/endurance sports  is helpful in optimizing the device for the activity of the rate-response function parameters.For patients with both sensors active, the pacemaker averages calculations of the rate estimated as appropriate by each of these sensors separately. In a situation where the rate indicated by the accelerometer is lower than that indicated by the minute-ventilation sensor, then the pacemaker will pace 100% according to the indications from the minute-ventilation sensor.If the accelerometer indications are higher than those calculated from minute ventilation, the pacemaker will take into account both sensors, changing the dominance of these sensors depending on the heart rate indicated by the accelerometer (from lower rate to max sensor rate), starting at approximately 80% for the accelerometer decision, 20% for MV sensor decision if accelerometer rate is at the lower rate limit, reaching 40% for accelerometer and 60% for minute ventilation if the rate estimated by the accelerometer is at the max sensor rate.Leadless pacemakers are an alternative to classic pacemakers, with leads placed intravenously in the heart cavities. This solution is especially recommended for patients in whom implantation of a classic pacemaker is impossible or difficult for various reasons  and in patients at a particularly increased risk of infectious complications (including infective endocarditis) related to the presence of a foreign body in the cardiovascular system ,127.®, Medtronic, MN, USA) consists of a small, capsule-shaped generator with hooks at the end that allow fixation of the pacemaker in the wall of the right ventricle. Inside the pulse generator, in addition to the battery and the computer system that controls the pacemaker’s algorithms, there is an accelerometer that allows the pacemaker to properly control the rate of stimulated impulses [This risk is increased in patients with a prior history of infections related to cardiac implantable electronic devices  and in patients with systemic diseases, diabetes mellitus, or kidney failure . The leaimpulses .In the single-chamber leadless system, working in the VVIR mode, the accelerometer provides the signals for the rate-response algorithm. The system reacts by accelerating the stimulation rate when it detects an increased frequency and intensity of vibration related to the patient’s physical effort and adjusting the pacing within the set parameters, i.e., according to the dynamics of the increase and decrease of the stimulation frequency and according to the set maximum frequency . This sy®, Medtronic, MN, USA), the accelerometer, in addition to the typical function of sensing increased metabolic demand in situations of physical exertion, senses the mechanical wave associated with blood flow through the valves after atrial contraction. The registration of the mechanical wave accompanying the outflow of blood after atrial systole, during the opening of the mitral and tricuspid valves, allows for the appropriate timing of ventricular pacing in a patient with impaired atrioventricular conduction. This solution allows ventricular pacing to be controlled by the intrinsic function of the atria without physically inserting the lead into the right atrial cavity. The highly advanced version of the leadless pacemaker is a device adapted to sense and control pacing under the influence of sensed atrial activity (VDD mode pacing). In leadless VDD pacemakers (Micra AV The main role of an implanted pacemaker is to support the work of the heart in disorders such as sinus node insufficiency or conduction blocks. Proper pacemaker programming—in accordance with the individual needs resulting from the type of arrhythmia, the indications for pacemaker implantation, and the patient’s lifestyle and preferences—has a crucial impact on improving heart function. It is also important to avoid replacing the intrinsic rhythm with pacing unnecessarily, due to the risk of pacing-induced cardiomyopathy .Modern implantable cardiac electronic devices are equipped with numerous algorithms, the task of which is to optimize the pacing settings to match the physiological function of the heart as closely as possible. It is difficult to imagine the heart functioning without being able to adapt the heart rate to situations related to physical effort of various intensities or stress levels. The technological solutions used for recording and processing information based on the real-time demand and volatility of minute capacity differ. This creates the opportunity to select an appropriate device, equipped with the functionalities that offer the greatest potential benefit to the patient. The daily experience of working with patients with cardiac implantable electronic devices, combined with many years of case observation, has revealed no shortage of evidence or examples of diametrical changes in well-being following pacing parameter adjustments in terms of rate-response settings. This is especially true in patients with a high percentage of atrial pacing. However, with regard to the impact of the rate-response function on the change in patients’ physical capacity, the data are not clear; there are only a few results from contemporary studies available, though further studies exploring this issue are in progress .There is evidence to support the use of rate-responsive pacing in patients with permanent atrial fibrillation and VVIR pacing systems . HoweverThe lack of unequivocal results from clinical trials on this subject may be due to differences in the effectiveness of the adaptation of the stimulation frequency resulting from technological differences in the types of sensors described in this article, as well as differences in the way they are used. This includes the parameters that are programmed related to the function, such as maximum pacing values during exercise and the settings for the dynamics of the increase and decrease of the pacing rate. The method used to calculate the maximum pacing frequency limit appropriate for a given patient may also be important. A study conducted from 2017 to 2019 showed that programming the rate-response function in patients with heart failure with reduced left ventricular ejection fraction under the control of echocardiography improved the duration of physical effort; this was in contrast to the most commonly used programming of this function depending on the patient’s age, which, in the study’s opinion and based on their results, may cause deterioration of cardiac systolic function and the worsening of heart failure in patients with CI and heart failure ,139,140.Currently, the most commonly used method for evaluating the distribution of heart rate in a patient with a cardiac-implanted device, when assessing the applied pacing parameters, is the analysis of the heart rate histograms stored in the memory of the pacemaker. These are based on the recorded intervals of successive heartbeats on the intracardiac EGM . Based oIn summary, the use of the pacemaker rate-response function is a promising tool that can potentially improve the quality of life and physical capacity of patients, but this tool requires additional research efforts and further clinical trials; this will allow for a better understanding of the mechanisms responsible for the effect of this therapy. Additional data are needed to broaden and popularize knowledge relating to the complexities of the technical aspects underlying the process of optimizing the stimulation parameters, giving medical personnel the opportunity to take full advantage of the option to program this function.


Introduction: Myriad disorders cause right ventricular (RV) dilation and lead to tricuspid regurgitation (TR). Because the thin-walled, flexible RV is mechanically coupled to the pulmonary circulation and the left ventricular septum, it distorts with any disturbance in the cardiopulmonary system. TR, therefore, can result from pulmonary hypertension, left heart failure, or intrinsic RV dysfunction; but once it occurs, TR initiates a cycle of worsening RV volume overload, potentially progressing to right heart failure. Characteristic three-dimensional RV shape-changes from this process, and changes particular to individual TR causes, have not been defined in detail.Methods: Cardiac MRI was obtained in 6 healthy volunteers, 41 patients with ≥ moderate TR, and 31 control patients with cardiac disease without TR. The mean shape of each group was constructed using a three-dimensional statistical shape model via the particle-based shape modeling approach. Changes in shape were examined across pulmonary hypertension and congestive heart failure subgroups using principal component analysis (PCA). A logistic regression approach based on these PCA modes identified patients with TR using RV shape alone.Results: Mean RV shape in patients with TR exhibited free wall bulging, narrowing of the base, and blunting of the RV apex compared to controls (pConclusion: The multiple causes of TR examined in this study changed RV shape in similar ways. Logistic regression classification based on these shape changes reliably identified patients with TR regardless of etiology. Furthermore, pulmonary hypertension without TR had unique shape features, described here as the “well compensated” RV. These results suggest shape modeling as a promising tool for defining severity of RV disease and risk of decompensation, particularly in patients with pulmonary hypertension. The tricuspid valve sits between the right atrium and the right ventricle, anchored to the walls of the right heart. In the healthy heart, the tricuspid valve preserves one-way blood flow, preventing blood from returning to the right atrium during RV contraction. Many diseases disturb tricuspid valve function, including direct valve injury during pacemaker implantation, dilation of the RV as it faces high resistance to flow in pulmonary hypertension or left ventricular failure, and dilation of the right atrium in atrial fibrillation . Any disAn estimated 1.6 million Americans currently live with moderate or greater TR . The dia1) Develop a population-level anatomical description of RV shape, directly from detailed three-dimensional (3D) models of RVs generated from cardiac MRI.2) Discover statistically significant group differences.3) Classify the RV shape changes characteristic of TR.4) Examine whether those changes are similar in various TR etiologies.In this study, we sought to:To accomplish these aims we obtained cardiac MRI in three groups: healthy volunteers; patients with diverse cardiac diseases resulting in moderate or greater TR; and a matched cohort of patients with cardiac disease without TR. We then employed a particle-based shape modeling tool, the open-source software package, ShapeWorks, which provides a computational approach to automatically parse shape into population-level numerical representations . Using t1) Here we included a matched cohort of patients with cardiac disease without TR, allowing analysis of progression of RV shape along a spectrum from complete health to significant impairment.2) Beyond identifying changes in TR compared to healthy patients, here we also highlighted unique changes occurring in the specific disease states of pulmonary hypertension and congestive heart failure (CHF).3) We increased the number of cases and improved the statistical power of our study. To mitigate the bias of the classification model due to the imbalanced dataset, we performed minority upsampling and increased the predictive performance of the model.4) To gain insight into the geometric differences that are most statistically significant between subgroups, we performed linear discrimination of variation using the mean shape of the groups and mapping the high dimensional differences to a single scalar value.In our recent publication, we used this technique to compare the RV shape of patients with TR to those of healthy volunteers . The curWe propose that these techniques will form the foundation of future predictive tools, with the potential to identify patients at risk for RV dysfunction in TR before their disease progresses.1) Patients with moderate or greater TR2) Comorbidity-matched controls with cardiac disease but without TR3) Healthy volunteers without cardiac disease or risk factorsThis study included three groups of patients:Groups 1 & 2 were identified retrospectively using the University of Utah medical data warehouse and a combination of procedure (cardiac MRI) and diagnosis (TR) codes. Each patient chart was manually reviewed to verify TR and sort patients by TR grade. This study was declared to be of minimal risk and granted exemption by the University of Utah IRB. Healthy volunteer images were obtained during a previous study at Weill-Cornell Medical College, after IRB approval .All MRI images were reviewed for quality, as well as for grade of TR and to classify ventricular volumes, by a board-certified cardiologist with additional certification in cardiac MRI (M Ibrahim). Images without clearly defined RV endocardial borders, or which did not include the entirety of the RV from tricuspid valve to apex, were excluded from analysis. TR grade was classified based on MRI regurgitant volume, or echocardiographic criteria if an echo had been obtained within 30 days of the MRI .The overall method of image processing is depicted in MRI was performed on a 3T Prisma scanner  using body and spine array coils. Cine MRI images were acquired as a stack of 12–16 short axis slices covering the RV from above the tricuspid valve to beyond the cardiac apex. Typical scan parameters for Cine MRI were true-FISP pulse sequence with TE/TR = 1.5/3.3 ms, flip angle (FA) = 50°, 6 mm slice thickness, spatial resolution of 1.25 × 1.56 mm, and temporal resolution of 23.4 ms.https://github.com/borkild/CINEtoVolume/releases/tag/1.0.To create three-dimensional models of the RV at end-diastole, a volume stack was created from a series of CINE MRI scans. CINE MRI time stacks capture one short axis slice of the heart through time (multiple heart beats). From each CINE short axis time stack, an image of the heart at end diastole was extracted to create a volume image stack. End-diastole was manually identified as the time point immediately after tricuspid valve closure. Image extraction was performed using a custom-built MATLAB image processing tool, available at z-direction using a box interpolation. This upsampled segmentation was then manually edited to remove artifacts or errors. The final segmentation was exported as a binary mask volume for further analysis.From the volume stacks, RV segmentations were created using the open-source Seg3D software . RV endocardial segmentations were semi-automatically created using the “implicit model” tool. Implicit model seed points were placed along the endocardial border at each slice of the volume stack. Prior to running the implicit model tool, the image was upsampled in the Prior to shape analysis, segmentations were pre-processed using ShapeWorks tools, wherein the segmentations were isotropically resampled and rigidly aligned to have identical dimensions and centroids. Segmentations were then converted to distance transforms for shape analysis.1) Statistical shape-model construction with ShapeWorks2) Modeling shape variation with the method of Principal Component Analysis (PCA)Statistical shape modeling (SSM) is a valuable and powerful tool to generate a detailed representation of complex anatomy that enables quantitative analysis and the comparison of shapes and their variations. The steps involved in shape modeling were:1) Train-test split and upsampling of training data2) Feature selection using lasso regression and classificationTo study the differences between controls and pathology subjects, we have designed downstream classification tasks that help us verify if the shape model obtained contains clinically relevant morphological features that capture the population level variability. Workflows for downstream classification tasks included:1) Linear discriminant analysis2) Determining statistical significance of shape differencesAnalyzing specific pathology characteristics involved:Each of the workflow steps is explained in detail in the following section.http://sciinstitute.github.io/ShapeWorks/) software. The methodology of ShapeWorks has been described previously  was used to reduce the correspondence data to a smaller set of linearly uncorrelated components, determining the number of modes explaining significant shape variation. We mapped each RV shape to its respective PCA loading vector.scikit-learn.org)  . The traarn.org) . This tesi is the PCA loading vector for shape i and yi is its corresponding label. We set yi equal to 1 for patients and 0 for control subjects. Our objective was to identify the principal components  that were most predictive of the patient group. In this regard, we solved the lasso regression for 1000 random subsets of data, and accordingly found a weight vector, w, such that:λ is the regularization parameter. A non-zero entry in w shows the relevance of its respective PCA component to predicting patients. Then, we found the dominance probability of each PCA component, defined as the number of times it appeared as a non-zero entry in w divided by the 1000 times the regression was run. We used sklearn.linear_model.LassoCV  of the group of patients with CHF but without TR, was compared to the mean shape of the group with CHF and TR. The linear discrimination between the two groups was defined as the difference vector between the two mean shape vectors. The shape of each subject was then mapped/projected onto this vector by taking the dot product between the subject-specific shape representation (the particle correspondences) and this difference vector. This mapping results in a single scalar value (or a “shape-based score”) that places a subject-specific anatomy on a group-based shape difference that is statistically derived from the shape population. For the purpose of interpretability, the mappings of the group mean shapes were normalized to −1 (patients with CHF and TR) and 1 (CHF without TR). The mappings of all the other subjects were then similarly normalized relative to these values, giving a shape distribution of individual members of the population relative to the mean shapes of their respective groups. A univariate Gaussian distribution was then fit to the normalized mapping of each group, to define the probability density function of the shape scores for each group. The same process was repeated for the group of patients with pulmonary hypertension.To analyze shape variation between the subgroups of patients with CHF and with pulmonary hypertension, and the distribution of individual shapes among these groups, a linear discrimination of variation was created, as follows: In the group of patients with CHF, the mean shape , 24 were excluded due to inadequate image quality. The remaining 54 MRIs comprised: 21 patients with TR; 27 comorbidity-matched controls; and 6 healthy volunteers. In the patient group, TR was secondary to pulmonary hypertension in three patients ; congestive heart failure (CHF) in 9 patients; and other causes  in 9 patients. In the control group, four patients had a diagnosis of pulmonary hypertension, 12 had CHF, and 11 had other cardiac diagnoses . The healthy volunteers had no diagnosis of cardiac disease and no cardiovascular risk factors.p values approaching zero for the protrusion of the RV free wall, and <0.05 for large regions of the RV , as shown in The technique of particle-based shape modeling was then applied to identify differences in group-level RV shape. To identify granular features of RV shape specific to patients with TR, we divided the overall group of controls  and patients with TR into training and testing sets and performed a principal component analysis (PCA). Thirty-one distinct modes of shape variation accounted for 99% of the shape variability between the group with TR and the control group. We identified the four most dominant modes shown in Applying this analysis to the testing set, these four modes of variation correctly distinguished between RV shapes with TR compared to matched controls with 82% recall, 87% precision, and 82% accuracy. The F1 score for this model was 82%.We used sklearn.metric  to calcuvia hypertrophy of muscle fibers and increased expression of cytoskeletal contractile proteins, allowing for increased force generation . While many of the diseases leading to CHF may affect primarily or initially the left ventricle, there is a more global distribution of disease than in pulmonary hypertension. RV dysfunction can occur due to direct involvement in the underlying disease process, such as ischemia or genetic cardiomyopathy, or as a secondary response to volume overload as the left ventricle fails. As the RV becomes affected by volume overload, it may initially compensate in a way similar to that seen in pulmonary hypertension (if the RV itself is uninjured by the pathologic process causing the CHF) . HoweverWhile common modes of shape variation characterized the RV changes seen in TR regardless of etiology, the model had different abilities to discriminate between patient and control RVs due to the distinct changes seen in pulmonary hypertension compared to CHF. 1) Develop a population-level anatomical description of RV shape, directly from detailed 3D models of RVs generated from cardiac MRI2) Discover statistically significant group differences3) Classify the RV shape changes characteristic of TR4) Examine whether those changes are similar in various TR etiologiesIn this study, we aimed to:Constructing 3-dimensional models of 54 RVs, we quantified mean RV shape in healthy controls, patients with cardiac disease, and patients with TR. Highlighting the complexity of RV shape in general, our principal component analysis identified 31 individual modes of shape variation required to explain 99% of the variation between the mean RV shape of patients with TR compared to controls.p < 0.05 for large regions of the RV, p approaching 0 for the protruding RV free wall, see We demonstrated that the fine details of RV shape in patients with TR are significantly different over large regions (250 out of 512 correspondence points) of the RV when compared to comorbidity-matched controls. This heterogeneity was particularly noted with bulging of the free wall, blunting of the apex, and widening of the RV base (Patients with TR showed a consistent bulging along the free wall of the RV regardless of etiology , 6, 7, ci.e., with outward bulging of the RV free wall. This shape change is characteristic and was detectable in a computational algorithm; for example, analyzing each 3D RV shape individually using a linear discrimination of variation, the majority of RV shapes in our pulmonary hypertension groups clustered into regions marked by either the TR or control shapes, (While our overall subgroup analysis of mean RV shape in patients with CHF and pulmonary hypertension did not reach statistical significance, likely due to the small number of patients in each group, there were striking qualitative differences which correlate well to the known pathophysiologies of each condition, and with distinct relevance to our understanding of RV/pulmonary arterial coupling. First, as seen in  shapes, . Compara shapes, . As suchTo date, cardiac shape analysis has focused primarily on the left heart. It has, for example, been used to predict stroke risk based on the shape of the left atrial appendage . When apIn our study, across all groups, we observed a progression of RV shape from healthy, to compensating for pulmonary hypertension and CHF, to poorly compensated with TR. The fact that this progression occurs on a spectrum, both in the overall cohort and in the subgroups of patients with the particularly vexing problems of pulmonary hypertension and CHF, favors the idea that the RV shape for a particular patient can be scored along this spectrum, from health to decompensated disease. As such, we posit that this shape analysis pipeline will become the backbone of future diagnostic and prognostic tools. Such a toolkit will aid in identifying those at highest risk of RV dysfunction, guiding therapy and prompting intervention before time is up.This study was obtained using retrospective data. The size of our dataset was limited due to the historically small numbers of patients undergoing cardiac MRI for TR—although this number will continue to increase in the future, as MRI is now part of the standard armamentarium for TR evaluation . Consequ