The end-stage of the clinical combination of heart failure and kidney disease has become known as cardiorenal syndrome. Adverse consequences related to diabetes, hyperlipidemia, obesity, hypertension and renal impairment on cardiovascular function, morbidity and mortality are well known. Guidelines for the treatment of these risk factors have led to the improved prognosis of patients with coronary artery disease and reduced ejection fraction. Heart failure hospital admissions and readmission often occur, however, in the presence of metabolic, renal dysfunction and relatively preserved systolic function. In this domain, few advances have been described. Diabetes, kidney and cardiac dysfunction act synergistically to magnify healthcare costs. Current therapy relies on improving hemodynamic factors destructive to both the heart and kidney. We consider that additional hemodynamic solutions may be limited without the use of animal models focusing on the cardiomyocyte, nephron and extracellular matrices. We review herein potential common pathophysiologic targets for treatment to prevent and ameliorate this syndrome. In the latter stages of heart failure or kidney disease, the interdependence of these two organ systems has become known as cardiorenal syndrome. Although some mechanisms of the kidney  and heart muscle  dysfunction may be independent of each other, others are dependent. Understanding mechanisms common to injuries of both organ systems has led to critical advances. A review of commonalities, linking renal and myocardial cellular and organ dysfunction will be helpful. We examine mechanisms that contribute to the pathogenesis of myocardial dysfunction with pathophysiologic contributions of obesity, diabetes and kidney disease. Mechanisms of hemodynamic overload, ischemia-related dysfunction, ventricular remodeling, excessive neuro-humoral stimulation, abnormal myocyte calcium cycling, cytokine-induced proliferation of extracellular matrix and accelerated apoptosis are within the scope of this review.Heart failure in patients with diabetic kidney disease is associated with interstitial fibrosis and cross-linking of advanced glycated end products (AGE) between myocardial fibrils and within the glomerular filtration apparatus. There may be an intermediate stage of normal systolic function with abnormal diastolic function that may be associated with an increase in myocardial and renal interstitial matrix collagen as well as the binding of AGE to myofibrils and nephrons. Cardiomyopathy in diabetic patients with diminished kidney function may be present for years before the detection of fibrosis by noninvasive testing , such thVentricular diastole refers to the time between aortic valve closure and mitral valve closure, and in descriptive terms has previously been described as divided into four phases . AttemptCardiomyopathy has been described in type 1 diabetes (DM1) ,6,7,8, h2 of body surface area [Current 10-year risk calculators for cardiovascular disease may not provide measurements of renal function for risk estimation nor do they consider heart failure a defined clinical cardiovascular event . Among 1ace area .Both DM1 and DM2 may be complicated by capillary albumin leakage with sympathetic nervous system activation due to relative hypovolemia. Autonomic neuropathy with unopposed sympathetic nerve stimulation as part of the DM1 cardiorenal complex has been the focus of prior studies ,18,19,20A mouse model, genetically altered to reproduce disruption of the glomerular basement membrane, has been used to study left ventricular diastolic dysfunction . Two intEvidence for ventricular dysfunction increases as renal function decreases even with normal coronary anatomy. Increased pulse pressure associated with left ventricular dysfunction  results Uremic toxin removal by isovolemic hemodialysis improves ejection fraction and fiber shortening without blood pressure or diastolic volume change, demonstrating that these toxins impair myocardial function . Two ureAt each stage of renal dysfunction, the prevalence of cardiac arrhythmias and heart failure increases. In the pre-dialysis phase, fewer arrhythmias were noted among patients with advanced CKD on ambulatory EKG than among hemodialysis patients . Among dLong-term echocardiographic observations of dialysis populations have noted a survival advantage when ejection fractions were greater than 45%  with higPatients with heart failure due to myocardial infarction exhibit diminished utilization of fatty acids until ventricular dysfunction has stabilized. Both myocardium  and injuA previously under-appreciated dysfunction of cardiac muscle calcium signaling involving the tricarboxylic acid cycle is being studied in both humans  and the In kidney failure accumulating strands of collagen with or without cross-linking by AGE cause resistance to relaxation following contraction . Over exInhibition of the renin/angiotensin/aldosterone pathway by ACE inhibitors results in increased expression of bradykinin (BK), which promotes the degradation of collagen b. CollagAlthough the sodium glucose transporter-2 inhibitor (SGLT2i) empagliflozin may be beneficial in the reduction of HFrEF, it was not found to alter the accumulation of collagen in an experimental non-diabetic mouse model . Drugs tObesity and hypertension are closely linked through autonomic centers in the midbrain. The satiety hormone leptin controls appetite in the normal population; leptin resistance is present among obese adults. The center for autonomic nervous system activation, which is hyper-stimulated during cycles of weight gain and under-stimulated during weight loss , is locap = 0.028) [Even among normotensive populations, obesity is associated with excess aldosterone, which stimulates cardiomegaly . Outcome= 0.028) . ACE inh= 0.028) . The res= 0.028) .A high-sucrose or high-fat diet impairs systolic and diastolic function  by reducThe human heart normally generates up to 5 kg of ATP/day, amounting to an expenditure of its complete supply of ATP four times/minute. Fatty acid oxidation accounts for 70% of ATP production; glucose/lactate accounts for 30%. Since oxidation of glucose is more efficient than that of fatty acids, glucose oxidation may be recruited up to 40% of the total in times of cardiac stress. Among numerous steps in insulin post-receptor signaling, the Akt-1 position has a direct inhibitory effect on fatty acid oxidation. Down-regulation of fatty acid oxidation includes inhibition of the effect of carnitine palmitoyl transferase to convey palmitate into mitochondria and increased expression of uncoupling protein, both of which result in the diminution of ATP generation .The chemistry of adipose tissue includes systems for the synthesis of several active participants in hypertension. Excess mineralocorticoid synthesis and excretion appear to accompany obese hypertensive patients in chronic kidney disease stages 2–4 and aging ,95. InhiObesity is characterized by elevated levels of leptin and diminished adiponectin. Following weight loss after bariatric surgery ,104 leveRestriction of movement of misfolded proteins in association with ubiquitin from the cytosol into the endoplasmic reticulum of cardiomyocytes in the process of autophagy may lead to toxic accumulation of proteins in dilated cardiomyopathy with heart failure . Toxic aA recent review illustrates correlations between diabetes and HFpEF, describing a heterogeneous group of phenotypes driven in part by comorbidities . IrrespeWhile leakage of albumin into retinal macula has clinical significance, leakage through microvasculature in the heart and kidney may remain undetected until a more advanced state of disease  at whichAccumulation of advanced glycosylation end products (AGE) occurs with chronic insulin resistance and is associated with impaired ventricular relaxation (stiff ventricle). Simultaneously, renal glomerular filtration may be equally impaired through the same cross-linking of collagen molecules . AttemptHeart failure admissions have been associated with a marker for collagen cross-linking: a low ratio of carboxy-terminal telopeptide to matrix metalloproteinase indicates resistance to collagen degradation by matrix metalloproteinase, resulting in ventricular stiffness . Two AGEp < 0.001) and systole (p < 0.05), suggesting chamber stiffness. The higher A1c group demonstrated an increased incidence of LV hypertrophy, associated with higher blood pressure and increased carotid-femoral pulse wave velocity.Increases in tissue collagen or circulating procollagen result in resistance to cardiac chamber filling or “diastolic stiffness”. Production of AGE resulting from hyperglycemia leads to cross-binding from one collagen branch to another with resistance in diastolic filling and arterial distension. In addition to binding across branches of peptide chains, AGE also attaches to lipids, which can be deposited in the myocardium with toxic effects. Among 125 DM2 study subjects with normal ejection fraction and no cardiovascular disease, matched for age and gender, non-invasive measurements revealed significant differences in cardiac diastolic function and peripheral vascular stiffness . When suIn a nondiabetic left anterior descending artery occlusion porcine model, empagliflozin was compared to control over two months. Empagliflozin caused loss of glucose in the urine, forcing the failing heart to resume preferential oxidation of free fatty acids, ketone bodies, and branched-chain amino acids. Indices of heart failure included increased left ventricular mass, increased LV diastolic volume and increased LV end-systolic volume, decreased ejection volume and contractile reserve with dobutamine, as well as increased circulating levels of normetanephrine, B-natriuretic peptide, and troponin. Myocardial metabolism was monitored by cannulation of the coronary artery and coronary sinus. As glucose uptake decreased with empagliflozin, uptake of free fatty acids, ketone bodies (beta-hydroxy-butyrate), lactate, and branched-chain amino acids increased. Control animals demonstrated increased expression of lactate and pyruvate dehydrogenase, consistent with decreased glucose utilization. Empagliflozin treatment was associated with increased activity of succinyl CoA-oxoacid CoA transferase (key enzyme in ketone body oxidation); adenosine monophosphate kinase (regulator of cell metabolism), and carnitine palmitoyl transferase  .Myocardial energy depletion in diabetes is related to limited microvascular uptake of the substrate and to dysfunction in its utilization . MicrovaAnother area where mechanisms of heart muscle dysfunction may differ for persons with or without a diagnosis of insulin resistance looks at calcium flow following ventricular contraction. Passive ventricular filling requires a resetting of myocyte electrical potential through calcium flow out of the reservoir (sarcoplasmic reticulum). Cardiomyopathy in diabetes is associated with decreased movement of calcium in diastole as demonstrated by studies in the obese Zucker rat model of type 2 diabetes and heart tissue samples of type 2 diabetes patients with preserved ejection fraction congestive heart failure .Given the insidious development and progression of cardiomyopathy, indirect noninvasive quantitation of myocardial contraction and relaxation offers benefit, but requires a better understanding of cardiac physicochemical properties. Compliance measures how well tissue can conform to pressure and is measured as a change in volume/change in pressure. Elasticity, the reciprocal of compliance, describes how well tissue returns to its original shape when pressure is removed. Plasticity refers to the ability of living cardiac tissue to change its state in response to stimuli, depending upon the size, thickness, composition and perfusion of the heart muscle. Not all properties are measurable by available non-invasive testing. Early identification of pathologic changes in these physical properties may lead to early interventions to improve clinical outcomes. Ventricular compliance and elasticity indirectly can be measured noninvasively. Indirect measurement of plasticity, however, remains elusive as it depends upon constituents of wall composition . Attempts to define plasticity through deformation imaging radioisotope scan, magnetic resonance imaging, or positron emission tomography have been only partially successful.Elasticity and contractility were studied in juvenile rats after banding of the pulmonary artery. Female rats survived longer, demonstrating lower levels of right ventricular fibrosis, and lower degrees of expression of the calcium/calcineurin cascade .Diabetes-associated cardiomyopathy likely involves two large proteins, collagen and titin. Collagen, located within the interstitial matrix, can be cross-linked between chains of amino acids by AGE , resulting in resistance to both contractions in systole and relaxation in diastole. Titin, located in the cardiomyocyte sarcolemma, has an I region, capable of extension during ventricular diastolic filling, a property that limits resistance to the rhythm of relaxation/contraction. Energy for diastolic extension of the I band of titin derives from the insulin signaling pathway, involving phosphorylation via phosphatidyl-3-kinase. Decreased phosphorylation of titin through reduced activity of protein kinase G has been attributed to hyperglycemia . InsulinAn important study connects cardiac function in women to diabetic kidney disease . CardiacMineralocorticoid receptor antagonists may also improve cardiac contractility by ATP energy generation within muscle . Female An increase in matrix glycoprotein associated with collagen precedes interstitial fibrosis . During Allopurinol has been reported to improve arterial blood flow through a nitric oxide-dependent endothelial system activated by acetylcholine . This vaThe non-steroidal mineralocorticoid receptor agonist finerinone and SGLT2 inhibitors have shown positive effects on renal and cardiac outcomes in patients with DM2. Investigators now looking at the combination of the two drugs. Investigators studied the effects of a low dose combination of fenerinone and empagliflozin on cardiorenal outcomes in hypertensive and proteinuric transgenic rats (mRen)27Rats2. Endothelial dysfunction was induced by including nitrogen monoxide synthase inhibitor N (ω)-nitro-L-arginine methyl ester in drinking water . All ratA retrospective analysis of 232,656 patients (Get With the Guidelines-Heart Failure) demonstrated that persons with diabetes treated for heart failure remained in hospital longer, were directed to a rehabilitation center more often or were more likely to be readmitted for heart failure within 30 days ,180. A rStudies evaluating cardiovascular safety and efficacy of sodium-glucose transport inhibitors have revealed a lower incidence of cardiovascular events with empagliflozin (EMPA-REG)  and canaRenal proximal tubule losses of glucose, sodium, and fluid with empagliflozin  and dapaThe PARADIGM HF study of DM2 , using tResearchers have examined the effects on preservation of heart muscle anatomy and function by use of GLP-1 receptor agonists versus dpp4 inhibitors in a mouse model of cardiomyopathy in type 2 diabetes. Older mice fed a high-fat diet and subjected to constriction of the aorta develop an increase in ventricular mass/volume by echocardiography as well as increased end-diastolic pressure, eventually cardiac interstitial fibrosis. A very specific inhibitor of dipeptidyl peptidase was associated with all of these outcomes to a modest degree. By contrast, liraglutide produced no such changes . A prosp2 [Investigation into the relationships between left ventricular structure/function and hypertension with or without fluid overload is ongoing. For patients with both hypertension and kidney disease, increased ventricular mass due to obstructive arterial disease is associated with decreased survival . Reducti2 , that is2 ,205. The2  concentr2 . Inhibit2 ,28,29, c2 . A uniqu2 . This is2  with ass2 is associated with better outcomes than a BMI of 20 kg/m2 in the cohort [Diastolic dysfunction by clinical examination, chest x-ray, and transthoracic echocardiography was diagnosed in 11 of 190 (5.8%) candidates for live-donor kidney transplantation . Removale cohort .There is an interest in biomarkers for heart failure in the cardiomyopathy population which usually involved obesity, hypertension, and diabetes. Biomarkers for cell proliferation are associated with HFrEF fraction while biomarkers for HFpEF are associated with inflammation . Patient2, associated with diminished reflex constriction of the pulmonary artery [Cardiac autonomic dysfunction is associated with a more rapid progression of kidney dysfunction ,215. Obey artery .Attempts to reduce systolic blood pressure with interruption of sympathetic nerve signaling either above or below the diaphragm have been reported. Renal sympathetic denervation via renal artery catheter has at times been an effective treatment for selected individuals . CardiacCardiac autonomic function correlates with glomerular filtration rate. The normal balance of parasympathetic/sympathetic innervation accounts for increased heart rate  with increased intrathoracic pressure during inspiration versus decreased heart rate  with decreased intrathoracic pressure during expiration. Increased intrathoracic pressure is associated with decreased venous return to the right ventricle with a reflex increase in rate to sustain blood flow to the brain. Persons with diabetes mellitus (DM) may have loss of parasympathetic innervation resulting in a loss of variation in the length of the R-R interval during the respiratory cycle ,225. DurJust as kidney failure may affect cardiac hemodynamics, failure of the heart to provide adequate flow to the kidney will impair kidney function. Efforts have been made to develop a pathophysiologic taxonomy to classify various types of cardio-renal failure to provide a scaffolding for future research ,229. MetThe ongoing COVID pandemic is associated with a new form of cardiomyopathy not entirely reversible for individuals recovering from infection, usually demonstrating additional complications in the pulmonary or renal systems. Elevated troponin levels at the time of COVID infection may be associated with higher mortality . High ti2 or with acute kidney injury [More work needs to be done to understand this connection. The DARE-19 trial, an investigator-initiated trial, looked at whether dapagliflozin can reduce the incidence of cardiovascular, renal, respiratory complications, all-cause mortality, or improve recovery in 1250 patients hospitalized with COVID-19 but not critically ill on admission. Patients were included if they had one or more cardiometabolic risk factors for complications of COVID-19 and were randomized to dapagliflozin 10 mg or placebo . The risy injury .The pathologic interplay between heart and kidney dysfunction now classified as the cardio-renal syndrome demands a more nuanced understanding of the underlying disruption of common cellular pathways in the myocyte and the kidney . A bette


Background: Heart failure represents a life-threatening progressive condition. Early diagnosis and adherence to clinical guidelines are associated with improved outcomes for patients with heart failure. However, adherence to clinical guidelines remains limited in Kosovo. Objective: To assess the clinical decision-making related to heart failure diagnosis by evaluating clinicians’ preferences for clinical attributes. Method: Conjoint analysis with 33 clinical scenarios with physicians employed in public hospitals in Kosovo. Setting: Two public hospitals in Kosovo that benefited from quality improvement intervention. Participants: 14 physicians (internists and cardiologists) in two hospitals in Kosovo. Outcome measures: The primary outcome was the overall effect of clinical attributes on the decision for heart failure diagnosis. Results: When considering clinical signs, the likelihood of a heart failure diagnosis increased for ages between 60 to 69 years old  and a stable heart rate  and decreased for the presence of edema , orthopnea , and unusual fatigue . When considering clinical examination findings, the likelihood for heart failure diagnosis decreased for high jugular venous pressure , pleural effusion , hearing third heart sound, , heart murmur , troponin levels , and NTproBNP levels . Conclusions: We often found odd and wide variations of clinical signs and examination results influencing the decision to diagnose a person with heart failure. It will be important to explore and understand these results better. The study findings are important for existing quality improvement support efforts and contribute to the standardization of clinical decision-making in the public hospitals in the country. This experience and this study can provide valuable impetus for further examination of these efforts and informing policy and development efforts in the standardization of care in the country. Heart failure is a complex clinical condition caused by any functional or structural heart defect that impairs ventricular filling or blood ejection to the systemic circulation to meet systemic needs ,2. CurreHeart failure is the chronic stage of any disease that leads to cardiac functional dysfunction, making it difficult to pinpoint a particular cause . MultiplHeart failure remains a serious clinical and public health problem  and an eUsing clinical guidelines and protocols is not common in the Kosovo healthcare system. Treatment of cardiovascular conditions is not an exception. There is a limited state-of-the-art treatment ,11. ClinTo document practice variations and assess the early impact of the training (intervention), we have opted for conjoint analysis ,25. ConjThis study aims to understand the clinical decision-making related to heart failure diagnosis based on clinical signs or examinations by evaluating clinicians’ preferences through the discrete choice design of various hypothetical clinical scenarios. In addition, this study was interested in examining the quality measures’ early impact on reducing practice variations and improving service quality.We performed two conjoint experiments. The idea of using conjoint analysis stems from the need to evaluate how a physician makes clinical decisions for a specific condition, such as heart failure, and if they consider the combination of potential attributes during the decision-making process. The first experiment examines the role of clinical signs (mainly from examination of patient history) on the decision for heart failure diagnosis. The second experiment examines the effect of clinical examination findings on the decision for heart failure diagnosis. Standard conjoint analysis methodology was used to design and implement this study, including five steps: defining attributes, assigning attribute levels, creating scenarios, obtaining preference data, and estimating model parameters. The conjoint analysis design is consistent with previous studies ,25,27.A thorough literature review of textbooks and research papers through search databases such as Google Scholar, PubMed, and Scopus was performed to define each experiment’s attributes and attribute levels. This exercise was instrumental in identifying the most important and specific attributes related to heart failure. We chose attributes from symptoms, clinical signs, and biochemical markers of heart failure. The 2021 European Society of Cardiology (ESC) Guidelines for diagnosing and treating acute and chronic heart failure served as the main reference . InterviThe attributes were used to design the final scenarios, utilizing IBM SPSS Statistics V.22.0 software  orthogonal design facility. The orthogonal facility yielded a total of 32 scenarios for each experiment. An additional scenario (vignette) was added manually to each experiment for validation purposes, with features agreed upon in the literature as indications for heart failure.We used structured interviews to collect the data. The questionnaire had two main sections. The first part of the questionnaire collected information about the participants (physicians) of the study, including socio-demographics, education, experience, and exposure to scientific work. The second and main part of the questionnaire contained all 33 scenarios of each experiment that physicians had to read and make hypothetical clinical decisions. Examples of vignettes are provided in the The sample consisted of internal medicine or cardiology specialist physicians working in both intervention hospitals. To be considered for the study, each participant was required to treat heart failure daily. A small sample size was deemed appropriate as it contained most respondents out of the total population. The data collection for each experiment was performed by an experienced researcher (I.H.) using in-person interviews in most cases. Online interviews were conducted when in-person interviews were not possible due to COVID-19 restrictions. After explaining the process for both experiments, during the first part of the interview, we collected data on the participant characteristics  After that, in the central part of the interviews, the physicians were presented with a typical case history  and asked whether they would diagnose each scenario as heart failure. They had to examine and decide on each of the 33 scenarios of each experiment, in a total of 66 scenarios.We first performed a descriptive analysis of the key characteristics of respondents. For each experiment, the main analysis consisted of multinomial logistic regression models with robust variance estimates used to examine the effect of different clinical signs and attributes in the diagnosis of heart failure. Each clinical sign effect is represented by the Relative Risk Ratio (RRR). Statistical analyses were performed with STATA 17BE . The study protocol has been reviewed by the Ethical Review Committee at Heimerer College with protocol number 2045/21. Although initially planned, we were restrained from performing sub-group analysis due to the small sample size.The final sample comprised 14 respondents  out of 1Only one of the participants was female (7%), and the rest were male (93%). Internal medicine was the specialty of 12 participants, while ten participants reported having a sub-specialty. Eight participants reported the use of approved SOPs. None of the participants regularly attended continuous medical education (CME) activities. More than half of the participants reported they had benefited from the training, but a smaller percentage reported they had also benefited from study visits. Regarding the ward’s project benefits, five of them reported their ward had benefited (36%). In contrast, nine respondents reported no project benefits of the ward in the form of equipment or renovation of working space (64%).The attributes and levels (of attributes) used to generate case scenarios in both experiments are documented in For the first experiment, consisting of signs of heart failure, participants decided that a case was a heart failure for 257 (56.6%) out of 462 cases presented to them. The age of 60–69 increased the likelihood of the diagnosis of heart failure compared to <60 and >70 old patients . Furthermore, a stable heart rate also increased the chances of heart failure diagnosis compared to a decreased heart rate . On the other hand, the presence of edema decreases the likelihood of heart failure diagnosis compared to the non-presence of edema . Similarly, the presence of orthopnea and unusual fatigue decreases the chances of clinical diagnosis for heart failure compared to the lack of orthopnea  and unusual fatigue .In the conjoint experiment with attributes consisting of clinical examination parameters, participants decided that a case was a heart failure for 276 (59.7%) out of 462 cases presented to them. The presence of high jugular venous pressure decreased the chance of heart failure diagnosis compared to the non-presence of elevated jugular venous pressure . Similarly, the presence of pleural effusion , the third heart sound presence , heart murmur presence  decreased the likelihood of the diagnosis for heart failure. The troponin levels at >0.4 ng/mL decrease the chance of diagnosis of heart failure compared to the troponin levels at 0–0.4 ng/mL . In addition, NTproBNP levels at <400 pg/mL also decreased the chance of the diagnosis of heart failure compared to NTproBNP levels at >400 pg/mL .Using the multi-attribute compositional models , we explored various factors associated with the clinical decision for heart failure diagnosis in Kosovo. The likelihood of heart failure diagnosis is influenced by age, heart rate, orthopnea, edema, and unusual fatigue. In addition, the heart failure diagnosis was less likely to happen in the presence of high jugular venous pressure, pleural effusion, third heart sound presence and heart murmur, higher troponin levels, and lower NTproBNP levels.Few studies evaluated the symptoms, clinical signs, shared decision-making, ,31, and The strength of this study is a design informed by a literature review and testing performed to identify attributes used in the analysis of the stated preferences . By incorporating the conjoint methodology to design and implement this study, we could generate attribute combinations and further evaluate how a physician would decide the diagnosis of heart failure. However, the conjoint analysis also has its limitations, including the limited experience of the respondents in understanding the process . FurtherIt has been almost a quarter century since we entered the modern age of clinical guidelines to facilitate evidence-informed clinical decision-making, and several guidelines have been developed . The diaThe results of this study show a considerable variation in clinical decision-making regarding the diagnosis of heart failure, reflecting a somewhat limited use of the guidelines, protocols, and scientific evidence among staff in public hospitals in Kosovo. This fact does not come as a surprise, considering that it is common in low-income and low-middle-income countries , where oThe results also highlight the “skewness” of clinical decision-making for heart failure diagnosis toward factors, i.e., levels of attributes that are not correct or secondary for clinical diagnosis of heart failure . In most studies, an increased high heart rate is associated with heart failure ,39,40,41Shifting from a traditional to a more evidence-based approach in clinical decision-making in a country like Kosovo is challenging and needs time. The potential for improvements is high with different incentives and activities in place. The adoption of SOPs can be regarded as an important starting point. However, the guidelines used in highly developed countries are not always applicable to the circumstances and situations in low-income countries (LIC) and low and middle-income countries (LMIC). Therefore, adjustments should be made and the inclusion of local experts and stakeholders is highly important and recommended . ImproveThis study can be a useful introduction to the problems with standardization of care using advanced designs like the conjoint analysis. This initial work can help generate awareness based on facts and trigger discussions for moving forward. Replicating this design to a wider group of physicians in other public hospitals could provide more meaningful and robust results. Replication of similar study design and analysis for other procedures can extend the examination of standardization of care in a wider spectrum of clinical procedures and hence provide deeper insights into the issues with standardization in the country. This whole expertise can be useful for countries with similar problems. Our study attempted to evaluate the clinical decision-making and use of standard operating procedures for heart failure. We often found odd and wide variations of clinical signs and examination results influencing the decision for heart failure diagnosis. These findings should be further investigated and understood as quality improvement efforts move forward. The study findings are important for existing quality improvement support efforts and contribute to the standardization of clinical decision-making in the public hospitals in the country. This experience and this study can provide valuable impetus for further examination of these efforts and informing policy and development efforts in the standardization of care in the country.


Atrial septal aneurysm (ASA) is a rarely reported fetal finding. Its definition is variable, but the diagnosis is usually made when the foramen ovale flap extends at least halfway across the left atrium. It is considered a transient, self-limiting condition, but on occasion, it can be complicated by fetal arrhythmia or left ventricular (LV) inflow obstruction—if longstanding, this can lead to left heart hypoplasia. We present two cases of ASA diagnosed at the second trimester scan, one of which was subsequently complicated by LV inflow obstruction and prenatal suspicion of hypoplastic aortic arch. This report is a good illustration of how structure follows function: a small LV preload can lead to a decreased LV output, which in turn will end up in a hypoplastic LV and outflow tract—all this is reversible after birth, due to the physiological circulatory modifications that occur in the newborn.


Heart failure (HF) constitutes a significant clinical problem and is associated with a sizeable burden for the healthcare system. Numerous novel techniques, including device interventions, are investigated to improve clinical outcome. A review of the most notable currently studied devices targeting pathophysiological processes in HF was performed. Interventions regarding autonomic nervous system imbalance, i.e., baroreflex activation therapy; vagus, splanchnic and cardiopulmonary nerves modulation; respiratory disturbances, i.e., phrenic nerve stimulation and synchronized diaphragmatic therapy; decongestion management, i.e., the Reprieve system, transcatheter renal venous decongestion system, Doraya, preCardia, WhiteSwell and Aquapass, are presented. Each segment is divided into subsections: potential pathophysiological target, existing evidence and weaknesses or unexplained issues. Novel therapeutic devices represent great potential in HF therapy management; however, further evidence is necessary to fully evaluate their utility. Heart failure (HF) is a clinical syndrome resulting from structural and/or functional abnormality of the heart, leading to elevated intracardiac pressures and/or insufficient cardiac output. Increased cardiac filling pressures and neuro-hormonal disturbances resulting in fluid retention and redistribution are major factors responsible for congestion development and acute decompensation in heart failure .As the HF pathophysiology is multidimensional, device interventions allow direct or indirect targeting of biological HF pathways, e.g. methods to manipulate sympathetic nervous system (SNS) imbalance, respiratory dysregulation or volume overload have been developed . To presHF remains a major medical problem and is associated with a high occurrence of rehospitalization and deaths, which constitute a huge problem for patients as well as healthcare systems worldwide . Given tNovel devices are supported by a strong theoretical background and a number of positive early signs from several small studies. Nevertheless, all device therapies, especially those that are permanently implanted in the patient, should undergo thorough assessment in large-scale prospective studies before they can be used in clinical practice.Physiologically, the autonomic nervous system (ANS) may be described as a highly dynamic structure, driven by uncountable neurohormonal reactions to maintain homeostasis. The imbalance of the ANS plays a crucial role in the pathogenesis of HF as the SNS exceeds the buffer capabilities of the parasympathetic nervous system (PNS). The ANS is responsible for modulation of the heart rate, systemic vascular resistance, arterial blood pressure and cardiac afterload, whereby constant overactivity of SNS leads to undesired maladaptations and cardiovascular remodeling. This phenomenon is reflected in the treatment of HF. From the clinical point of view, there are several possible targets for ANS modulation. Modulation of selected subtypes of receptors  allows for interaction with specific ANS branches (sympathetic or parasympathetic). Via the afferent nerves, stimuli are transmitted from receptors to the central nervous system (CNS). On this level, impulses are analyzed and transferred to the effector pathways. The efferent nerves transmit impulses from the CNS to the neurochemical synapses. Modulation of this process directly influences PNS (Vagus nerve stimulation) or SNS (Splanchnic nerve modulation). In the end, impulses reach the presynaptic membrane resulting in the secretion of neurochemical transmitters , which react with receptors localized in the effector tissue. Crucial for HF is the overactivity of SNS mediated by adrenergic receptors . NumerouBaroreflex activation therapy (BAT) uses a physiological reflex pathway to rebalance the activity of the ANS. Electrical stimulation of the carotid bodies sends afferent nerve impulses to the CNS that reacts by increasing PNS firing and decreasing SNS outflow . The carp < 0.05) and reduced heart failure-related hospitalization rate. There were no side effects reported in this study [Several clinical studies have evaluated the effectiveness and safety of BAT. A multicenter, prospective, randomized, controlled trial–Baroreflex Activation Therapy for Heart Failure –showed that in the group of 264 patients with the FDA-approved enrolment criteria for BAT , BAT is a safe procedure that significantly improves quality of life, exercise capacity and functional status, while it decreases NT-proBNP and reduces the number of HF hospitalizations per year. The study reported that the overall major adverse neurological and cardiovascular event-free rate was 97.2%, while the system and procedure-related complication event-free rate was 85.9% [is study .Despite positive early results, there is a need for further, well-powered clinical trials before BAT can be incorporated into HF clinical practice. BAT needs at least larger-scale research that includes longer follow-up, a higher number of patients and clarified outcomes with mortality risks . The stuVagus nerve stimulation (VNS) is an autonomic system modulation that aims to level autonomic system imbalance by increasing PNS activity. Electrostimulation of the easily accessed right cervical vagus nerve induces neurohormonal reactions that buffer the overactivity of SNS .The Neural Cardiac Therapy for Heart Failure  trial was the first study that evaluated the usefulness of VNS in HFrEF. It showed improvements in quality of life, NYHA class and exercise capacity without changes in echocardiographic measures (primary endpoint defined as the change in left ventricle end-systolic diameter) in the VNS treated patients. There were no significant differences in the serious adverse event (SAE) rates between the control and therapy groups. The overall rate of implantation-related infections was 7.4% .Although VNS has a significant positive impact on a patient’s functional status, it does not impact the prognosis . The ANTThe splanchnic nerves are responsible for autonomic innervation of the upper abdominal viscera  and are highly connected with splanchnic vascular volume management, primarily caused by visceral vasoconstriction during exercise. The visceral vascular bed is a natural reservoir of blood volume that can be quickly relocated for an urgent need . Redistribution of blood volume from the extra-thoracic compartments into the central circulation is believed to be a significant contributor to elevated filling pressures in HF patients, including HF with preserved ejection fraction (HFpEF) . ModulatSNM may protect the central venous system from acute volume redistribution and subsequent cardiac filling pressure increase . SNM is p  <  0.001) and an increase in cardiac index (from 2.17 ± 0.74 L/min/m2 at baseline to 2.59 ± 0.65 L/min/m2 at 30 min p  =  0.007) were reported [The splanchnic-HF 1 NCT02669407) and 2 (NCT03453151) trials reported promising effects of SNM therapy in both acute decompensated (ADHF) and chronic heart failure (CHF). Eleven ADHF patients with advanced HFrEF underwent bilateral temporary percutaneous splanchnic nerve block with lidocaine. In this group, significant reduction in pulmonary capillary wedge pressure  and positive inotropic  effects without an influence on heart rate. Thus, this percutaneous device has at least theoretical potential to improve cardiac function and systemic perfusion and facilitate decongestion in ADHF .The first in-human, proof-of-concept, uncontrolled study (NCT04814134) revealed promising cardiac pulmonary nerve stimulation (CPNS) effects. CPNS in HF resulted in LV contractility improvement and an increase in mean arterial pressure without affecting the heart rate. Moreover, the CPNS 2 Feasibility Study demonstrated short-term safety (no SAE reported) and feasibility in chronic HF patients undergoing a catheterization procedure or implantable cardioverter-defibrillator/cardiac resynchronization therapy implantation .CPNS is a concept that needs further investigation. Well organized clinical trials are required to provide information about CPNS effectiveness, safety and impact on outcomes.The function of the respiratory system is essential not only in the context of the exchange of respiratory gases but also in generating resistance in the pulmonary circulation and pressure changes inside the chest. The constellation of these factors affects the function of the heart itself and the entire circulatory system.Sleep-disordered breathing is a common pathology, especially in patients with HF, affecting both cardiovascular and respiratory systems. There are two main types of sleep apnea syndromes: obstructive sleep apnea syndrome (OSA) and central sleep apnea syndrome (CSA) .OSA/CSA increases SNS, RAAS activation, oxidative stress, cell apoptosis, endothelial dysfunction and, as a result, remodeling and fibrosis of the heart ,32. ThesIn CSA, the lack of respiration is caused by pathological pauses in neurological impulses triggering breathing muscles contraction, which results in periods of apnea ,35. It wThe OSA is caused by excessive laxity and, as a result, the upper airways collapse during breathing. Several methods of treatment such as continuous positive airway pressure (CPAP), adaptive servo-ventilation, oral inserts, surgical treatment  was a multicenter, randomized study with 151 participants. It was meant to provide phrenic nerve stimulation and demonstrated a significant reduction in the apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation ≥4% index, percentage of sleep with rapid eye movement and sleepiness ) . Those fCostanzo et al. found that patients treated with phrenic nerve stimulation had an improvement in life quality and improvement in left ventricle ejection fraction (LVEF), with no significant difference in end-systolic and end-diastolic volumes .This method was relatively safe. In follow-ups, the AE were most common during the first year and predominantly included electrode dysfunction, electrode dislocation and infection of the implantation site. Cumulatively, in 5-year observations, the SAE occurred in 14% of patients. There was one episode of inadequate intervention by the high-energy implantable device related to hypersensitivity, which was resolved by changing the device settings ,41,42.The effect of phrenic nerve stimulation on mortality in HF patients with CSA syndrome is unknown and large scale clinical trials are required.Elevation of intrathoracic pressure causes chronic stress on the heart muscle and may worsen HF. The respiratory muscles can significantly influence intrathoracic pressure. Thus, a strategy for synchronic diaphragm stimulation was proposed. It involves implanting a device connected with an electrode that senses the heart rhythm and stimulates the diaphragm.This system aims to synchronize the cardiac work cycle to changes in diaphragm movement by stimulation of diaphragm’s muscle fibers , causing cyclical changes in their tension, which in turn reduces intra-thoracic pressure. It is imperceptible for the patient, as it does not cause contraction of the diaphragm leading to respiratory movement. Thus, it does not cause any discomfort to the patient. In the first study, entitled Epiphrenic II,  the elecIn Epiphrenic II (NCT00769678), a randomized study conducted on 33 participants, researchers found improvement in LVEF and HF symptoms on the NYHA scale. There was also an observed increase in maximal power and oxygen consumption during exercise testing. However, no significant improvement in the 6-min walking test (6 MWT) and BNP concentration was recorded in a group with optimized synchronized diaphragmatic stimulation. No SAE were observed .In the VisOne Heart Failure non-randomized study  improvement of LVEF and quality of life  and extended walking distance during the 6 MWT were observed at the 1-year follow-up. Best results were achieved in patients with over 80% diaphragm pacing synchronized to the heart cycle. No AE were observed at 12-month follow-up (primary and secondary endpoint) . The VisOne study was non-randomized, and both studies were conducted in a small group of patients. Due to the promising results of the trials, it would be worth performing further studies on an extensive study group with a control population.Loop diuretics remain the cornerstone of the decongestive therapy in HF; however, reduced responsiveness to them, especially in chronic use, constitutes a clinical challenge. Up to nearly 50% of the classically treated HF patients are discharged with residual congestion, which worsens prognosis ,44. ExtrReprieve therapy is a method which intends to provide a solution for the more accurately controlled decongestion for HF patients. The Reprieve System is designed to measure the urine output (via urinary catheter) and deliver (adjusted to urine output) a precise volume of replacement solution  to achieve the preset fluid balance . This tep < 0.05).TARGET-1 and TARGET-2 studies have assessed the safety and efficacy of controlled decongestion by the Reprieve System in AHF patients (NCT05015764). In both studies, patients in the study group achieved higher urine output, reduction in body weight and a decrease in central venous pressure (CVP), in comparison to the status before the initiation of the therapy. It is noteworthy that, while achieving greater fluid loss, the treatment was safe–systolic blood pressure remained stable. No renal injury makers or a decrease in renal function was observed. There were no SAE, and the most frequent AE was hypokalemia–mean serum potassium dropped from 4.1 to 3.6 mmol/L  . No deviCurrently, only pilot studies in a small population, regarding novel renal veins decongestion techniques, have been performed. Studies included a limited population and aimed to assess the feasibility of such strategies, rather than their clinical efficacy and impact on outcome. Further research (which is under way) is necessary to establish the clinical value of the methods mentioned above.The producers of the preCARDIA system proposed a distinct approach for congestion relief therapy. The device is inserted into the superior vena cava to cause intermittent occlusion, leading to a decrease in right ventricular preload.The VENUS-HF early feasibility study (NCT03836079) showed a decrease in right atrial pressure and PCWP compared to the pretreatment values. At 24 h of treatment, a 130 and 156% increase in the urine output and net fluid output, consequently, was observed. No device- or procedure-related SAE were observed . Prior sThe studies are the first in-human trials of the device. They had a non-randomized design and included a limited number of patients observed for a short period of time. Furthermore, larger studies with prolonged follow-up are warranted to evaluate the safety and precise clinical utility of the preCARDIA system and its impact on outcome.The role of the lymphatic system in HF pathophysiology has been underestimated, but it appears that it could play a role in decongestive therapy. Firstly, lymphatic drainage is essential for interstitial fluid removal. Furthermore, increased central venous pressure disturbs the lymph outflow through the thoracic duct and additionally stimulates lymph production, leading to oedema deterioration . These pThe WhiteSwell (NCT02863796) has been investigated in a sheep model and in one in-human case. In all studied sheep, WhiteSwell was successfully implanted and removed. The desired pressure gradient was achieved. As opposed to the controls with no implanted device, in studied sheep, WhiteSwell not only stopped the further fluid accumulation (understood as the extravascular lung water changes), but effectively initiated its removal . No evidBy now, one case of in-human implementation of the device was reported with positive early signals  of the intervention. After the procedure, the patient felt well and reported improvement in the orthopnea and oedema. No AE were reported.WhiteSwell, and the general perspective for incorporating the lymphatic system into the HF therapy, constitute a promising supplementation to the traditional, intravascular space-based approach.Except for all the limitations stemming from the animal model study, some issues need to be solved before wider clinical implementation. No reliable data about the impact of lymphatic system interventions and clinical outcome in HF patients is available. There were also some technical issues regarding the catheter implantation, and the second-generation catheter is now being constructed ,44.The AquaPass system has proposed another novel approach for direct interstitial fluid and sodium removal. The Aquapass system enhances sweat rate and thus fluid removal. It is a wearable machine constructed to increase the skin temperature of the lower parts of the body, with no effect on the core temperature .The AquaPass system was evaluated in a study (NCT04578353) including only 6 healthy subjects and 10 HF patients who underwent three treatment sessions for up to 4 h. The skin temperature increased, with no change in core temperature. The median weight loss was 219 ± 67 g/h, and heart rate, systolic and diastolic pressure remained stable. No AE occurred. Enhancing sweat rate in HF patients seems to be a safe possibility for decongestive therapy; however, further studies are warranted to evaluate the precise value of the method and its impact on outcome .Our study is not free from limitations. Importantly, this is a literature review and was not performed in accordance with systematic review guidelines. Furthermore, to preserve the article compactness, we decided not to include all the promising device-based techniques applied in HF, such as valvular interventions, atrial shunting or cardiac contractility modulation.The abovementioned techniques intend to leverage the pathophysiological aspects of heart failure, which have not been used in therapy by now. Notwithstanding the enormous potential of novel approaches, most are still distant from broad clinical appliance. Further, well-designed, randomized, controlled trials are warranted to evaluate their precise value in HF management.


Right heart remodeling occurs in a substantial proportion of patients with chronic thromboembolic pulmonary hypertension (CTEPH) and significantly affects their prognosis. Two-dimensional speckle-tracking echocardiography (2D-STE) can be used to evaluate myocardial deformation under physiological and pathological conditions. This study aimed to assess the feasibility of 2D-STE for evaluating right ventricular (RV) remodeling in CTEPH patients.This retrospective study included 21 CTEPH patients who underwent transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR). Data for the following parameters that can reflect RV function were collected: tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), right ventricular index of myocardial performance (RIMP), peak systolic velocity of the tricuspid annulus (S'), and CMR-right ventricular ejection fraction (CMR-RVEF). The following strain parameters were calculated using post-processing software: STE-RV global longitudinal strain (STE-RVGLS), STE-RV free wall longitudinal strain (STE-RVFWLS), and CMR-RVGLS.p < 0.05; CMR-RVGLS: mild vs. severe, p < 0.05; TAPSE: moderate vs. severe, p < 0.05). Moreover, the Pearson correlation coefficient for correlation with CMR-derived RVEF was stronger for RVFWLS than for CMR-GLS , and the strain values measured by 2D-STE showed a weak correlation with right heart catheterization data. Bland-Altman analysis showed good agreement between 2D-STE and CMR-feature tracking (FT) for RVGLS .As CMR-RVEF deteriorated, RV remodeling in CTEPH patients became more apparent and was mainly characterized by significant enlargement of the RV, weakening of myocardial deformation, and a decrease in RV contractility (RV area, STE-RVFWLS, STE-RVGLS: mild vs. severe and moderate vs. severe, For the measurement of RVGLS, 2D-STE is similarly feasible to CMR-FT and could sensitively identify right heart remodeling. Chronic thromboembolic pulmonary hypertension (CTEPH) is a common and significant type of PH characterized by increased pulmonary vascular resistance due to progressive pulmonary vascular remodeling . As the In view of the above-mentioned reasons, strain parameters that can quantify RV deformation were developed through the post-processing of images by the derivation technique. Strain refers to the degree of myocardial deformation in the specified direction from the original shape (end of diastole) to the minimal length (end of systole) and is expressed as a percentage, reflecting the contractile force of myocardial fibers in different directions. Previous research has confirmed that strain is also associated with clinical outcomes in patients with PH, suggesting that it could be used as a standard for quantifying RV function , 8. In rThe aims of the present study were twofold. First, we used two different algorithms to analyze RV strain parameters to evaluate the agreement and correlation between 2D-STE and CMR-FT. Second, we divided the research population into three groups according to the degree to which RVEF was reduced to verify the ability of 2D-STE to identify RV remodeling in CTEPH patients. Our research results provide insight into expanding the theoretical basis for the use of imaging techniques to guide treatment planning and prognosis prediction for CTEPH patients.This retrospective study included a total of 34 patients who had been diagnosed with CTEPH in Beijing Chaoyang Hospital from December 2016 to June 2021. All patients underwent transthoracic echocardiography (TTE) and CMR examination within a median interval of 5 days. The diagnosis of CTEPH was based on the patient's medical history, TTE, right heart catheterization (RHC), multidetector computed tomography (MDCT), and lung ventilation-perfusion scintigraphy according to established guidelines  and a Doppler ultrasound machine equipped with an X5-1 probe (1–5 MHz). After optimizing the sector size, gain, and depth, an RV-focused four-chamber(4Ch) view was acquired at a heart rate of 71 (±8) bpm. Data measurements were based on the guidelines of the American Society of Echocardiography . ConventBased on conventional apical four-chamber, two-chamber, and three-chamber views with a frame rate of 60–80 frames/s, images from five consecutive cardiac cycles were recorded in DICOM format, and offline analysis was performed using QLAB version 13.0 . The software then automatically tracked a region of interest, and if necessary, manual adjustment was performed to obtain the best image. Finally, the RV global longitudinal strain (RVGLS) and RV free wall longitudinal strain (RVFWLS) were obtained. All strain measurements were performed by an experienced physician (Wang) blinded to all clinical data.All patients underwent CMR scanning on a 3.0-T scanner  with a body-flex receiver coil following an ECG examination and breath-hold technique. After scout imaging, 8–12 continuous short-axis plane images were acquired to cover both ventricles from base to apex using Ture fast imaging with a steady-state precession sequence. The MR parameters used were: repetition time of 3.0–3.2 ms, echo time of 1.4 ms, flip angle 70°, the field of view 320 × 360 mm, matrix size 256 × 256 mm, slice thickness of 8 mm, and 25 phases per cardiac cycle and images along the long-axis plane were acquired in the four-, three- and two-chamber views as well.CMR image analysis was performed offline by two experienced observers (MX Liu and XJ Guo) using commercial software . The endocardial and epicardial traces were processed automatically in the serial short-axis plane images at the end-diastolic and end-systolic phases. The results were derived by excluding the papillary muscles and moderator bands. First, end-diastolic volume (EDV), end-systolic volume (ESV), and RVEF were calculated using a cardiac function analysis model; then, myocardial strain analysis was performed using a tissue tracking model importing long-axis slices . The glopost-hoc correction for multiple comparisons. Correlations between 2D-STE and CMR-FT findings were evaluated using Pearson correlation coefficients. Agreement between the two techniques was assessed by Bland-Altman analysis [bias and 95% limit of agreement (LOA)]. All statistical analyses were performed using Prism 8.0 software  and SPSS version 26.0 . Differences were considered significant if p < 0.05.Normal data distribution was tested using the one-sample Shapiro–Wilk test, and all the data are expressed as absolute values. Normally distributed data are expressed as mean ± standard deviation (SD), and non-normally distributed data are presented using median and interquartile range (IQR) values (expressed in percentage). According to established guidelines , 17, abnOf the 34 patients with CTEPH initially identified, we excluded eight patients due to poor image quality, three patients due to incomplete clinical information, one patient with WHO-FC IV PH, and one patient for whom more than 1 month passed between the two examinations. The baseline clinical characteristics and hemodynamic data of the 21 patients included in the final analysis are presented in n = 7), RVEF 24–36% showed a moderate decrease in RV function (n = 7), and RVEF < 24% showed a severe decrease in RV function (n = 7). The results of comparisons among these groups are presented in p < 0.05), which reflected structural RV remodeling with the progression of the disease. Additionally, TAPSE, a commonly used echocardiographic index reflecting RV systolic function, differed significantly between patients with moderate and severe RVEF reduction, while the other parameters showed no statistically significant difference between groups. Regarding strain values obtained from post-processing software, the RV strain measured by 2D-STE was higher than that measured by CMR-FT. Similarly, as the RVEF decreased, the strain values assessed by these two techniques decreased significantly. Significant differences were observed between cohorts . With regard to hemodynamic parameters, although no significant differences were detected between groups, a specific trend could still be seen.In this study, CMR-RVEF was used as the imaging gold standard to reflect patients' RV systolic function, and patients were divided into three groups according to the CMR-RVEF value. Among them, RVEF 36–45% represented a mild decrease in RV function . An example of RV strain measurement using post-processing of 2D-STE and CMR-FT images of a CTEPH patient is presented in r = 0.72, p < 0.001; r = 0.60, p < 0.05). Taking CMR-RVEF as the imaging gold standard to define RV systolic function, the results showed that STE-FWLS obtained from 2D-STE post-processing had the strongest correlation with CMR-RVEF , followed by CMR-GLS  and STE-GLS . Surprisingly, we also found weak correlations of STE-FWLS and STE-GLS with pulmonary vascular resistance (PVR) , while a similar result was not found for CMR-GLS .Bland-Altman plots showed that RVGLS values obtained from 2D-STE and CMR-FT were in good agreement (bias: −0.9648), and all points were within the 95% LOA  2D-STE can sensitively recognize right heart remodeling; (ii) compared with conventional parameters, the strain value can better reflect impaired RV function; and (iii) in patients with CTEPH, good agreement was observed between 2D-STE and CMR-FT for global LS quantification.CTEPH is caused by repeated pulmonary embolism due to incomplete dissolution of thrombus or repeated shedding of deep vein thrombus in the lower limbs and gradually develops into chronic pulmonary embolism . CTEPH gAccording to the 2022 ESC/ERC guidelines, echocardiography is still the most widely used non-invasive diagnostic tool to evaluate PH. It is clinically regarded as the primary choice for evaluating RV systolic function . TraditiRV remodeling is common in CTEPH. In this research cohort, the RV was enlarged with a decrease in RVEF, as reflected by the significant increases in RV EDA and RV ESA. Likewise, in the population with a severe reduction in CMR-RVEF, TAPSE also showed a statistically significant change. However, the same results were not found for other parameters, which may be related to the small size of the study population. Additionally, traditional echocardiographic parameters have not been sensitive enough to reflect local changes in the myocardium. Compared with conventional parameters, STE-FWLS and STE-GLS were decreased in the early stage of the disease. The strain values were significantly reduced with the reduction of RV systolic function, indicating that 2D-STE could sensitively detect the damage of myocardial deformation and be advantageous for identifying early RV remodeling. On the other hand, comparing the two imaging techniques showed good correlation and agreement between strain measurements derived from 2D-STE and CMR-FT. However, further research is still needed to determine whether the two techniques can replace or complement each other. Notably, the strain values determined by 2D-STE were statistically correlated with PVR. As an invasive examination method, the evaluation of PVR by RHC has been confirmed by several studies to be related to the long-term prognosis of patients with different types of PH , 25, whiTo our knowledge, previous studies have been conducted to validate STE compared to FT in patients with arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, and aortic valve stenosis , 26, 27,For clinicians, choosing a convenient and accurate method for evaluating RV function in CTEPH patients is of great significance, not only for diagnosing the disease but also for individualized treatment. The present study showed that 2D-STE could sensitively identify right heart remodeling and showed similar feasibility to CMR for assessing RV deformation. Considering that 2D-STE is easier and more economical in routine echocardiography and can be performed in most hospitals and that there are no guidelines providing normal reference ranges for the whole and segmental RV strain from CMR-FT, we propose that when CMR is not available, STE-RVFWLS can replace CMR-RVEF as an indicator of RV function.This study has several limitations. Firstly, this was a single-center, retrospective study with a small number of patients. Secondly, to our knowledge, the pathogenesis of CTEPH differs from other types of PH, and whether these results can be applied to other types of PH requires further study. Moreover, CMR and TTE were not carried out simultaneously. However, all patients maintained stable clinical conditions between the imaging examinations, and no significant volume changes were recorded between the two assessments. Future research with a larger study population must confirm our findings to address these limitations. As far as we know, the assessment of myocardial strain includes longitudinal and radial components and circumferential components. In the future, we will further evaluate myocardial motion in multiple directions to verify echocardiography's role in predicting the prognosis of PH. Although our results showed high reproducibility between the two post-processing methods, additional research is needed to confirm whether the measurement results can be used interchangeably.In conclusion, 2D-STE can sensitively identify the degree of RV remodeling in patients with CTEPH. Among the analyzed strain parameters, the present study demonstrated that RV strain values determined by 2D-STE showed a better non-geometric echocardiographic index and a strong correlation with CMR-RVEF. We also observed excellent reproducibility between 2D-STE and CMR-FT for determining RV strain values. Our results indicate that 2D-STE can offer a useful tool for the rapid and accurate evaluation of RV function in CTEPH.yeqingwang2021@163.com.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to YL and XG contributed to conception and design of the study. YY and XL organized the database. XZ and HH performed the statistical analysis. YW wrote the first draft of the manuscript. ML, HY, DG, and YW wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The study was funded by the National Natural Science Foundation of China (81871356) and the Beijing Municipal Administration of Hospitals Incubating Program (PX2019013).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Radionuclide ventriculography (RNVG) can be used to quantify mechanical dyssynchrony and may be a valuable adjunct in the assessment of heart failure with reduced ejection fraction (HFrEF). The study aims to investigate the effect of beta-blockers on mechanical dyssynchrony using novel RNVG phase parameters.A retrospective study was carried out in a group of 98 patients with HFrEF. LVEF and dyssynchrony were assessed pre and post beta-blockade. Dyssynchrony was assessed using synchrony, entropy, phase standard deviation, approximate entropy, and sample entropy from planar RNVG phase images. Subgroups split by ischemic etiology were also investigated.An improvement in dyssynchrony and LVEF was measured six months post beta-blockade for both ischemic and non-ischemic groups.A significant improvement in dyssynchrony and LVEF was measured post beta-blockade using novel measures of dyssynchrony. However, identifying the underlying cause is crucial to determine the most appropriate treatment. This research focuses on non-valvular heart failure with reduced ejection fraction (HFrEF). In HFrEF, LVEF is known to be a good predictor of outcome, and is included in the decision criteria for many HFrEF treatments.5Heart failure affects approximately 1%-2% of the adult population in developed countries, increasing to over 10% for those > 70 years.6 Despite promising results in single-center studies,8 the results have not been reproduced in larger multi-center trials,9 leaving many unanswered questions in this area.There is some interest in measures of left ventricular dyssynchrony for patients with HFrEF. For example, there have been many studies published investigating imaging parameters as predictors to cardiac resynchronization therapy response, with varying degrees of success as summarized in the review by Hawkins et al.5 Several large-scale clinical trials have demonstrated the benefits of beta-adrenoceptor blockers for heart failure patients, with a reduction in morbidity and mortality.11 It is known that post beta-blockade therapy, patients show significantly improved LVEF,12 but the effect of beta-blockade on cardiac dyssynchrony has not been widely investigated. There are several published studies that investigate the use of echo-derived dyssynchrony parameters, such as septal to lateral wall delay, for heart failure patients.15 However, the authors are not aware of any published studies investigating the effect of beta-blockade on dyssynchrony measured from radionuclide ventriculography (RNVG) imaging.Beta-blockade therapy is well established and currently recommended by the ESC guidelines as first-line treatment for patients in symptomatic HFrEF.ApEn), and standard deviation of the phase histogram (phase SD), can be used to provide additional information from planar RNVG images with high reproducibility.23 Sample entropy (SampEn)24 is novel for this application and has not been previously investigated.RNVG phase parameters offer an alternative index for the quantification of ventricular dyssynchrony and may be a valuable adjunct in the assessment of patients with heart failure. Various measures to quantify dyssynchrony, including synchrony, entropy, approximate entropy  scan pre titration of beta-blocker and a repeat RNVG six months post beta-blocker. Patients were initially given 1.25 mg of Bisoprolol, with the dose increasing stepwise to 2.5 mg, 5 mg, 7.5 mg, and 10 mg at intervals of two weeks. Before each step increase, patients underwent clinical review. Each patient continued on their maximum tolerated dose of Bisoprolol. Patients who did not tolerate the prescribed beta-blockers and those who did not attend the second RNVG scan were excluded from this study. Of the 12 patients who were excluded, 8 patients did not tolerate beta-blocker, 3 patients did not attend for the second RNVG for unknown reasons, and 1 patient died before the second RNVG. After the exclusion criteria were applied, there were 86 patients remaining.(i)A stenosis of more than 50% in at least one of the three major coronary arteries as assessed by coronary angiogram (where available)(ii)Previous MI or PCI(iii)Positive Thallium-201 MPI (defined by two experienced reporters).The patients were grouped depending on whether or not they had heart failure of ischemic etiology. Of this patient cohort, 54 were ischemic, and 32 were non-ischemic. A patient was categorized in the ischemic heart failure group if at least one of the following criteria was met: All patients underwent planar RNVG imaging before and six months after beta-blockade. In-vivo labeling was performed using intravenous administration of pyrophosphate 20 minutes prior to injection of technetium-99m pertechnetate. The administered dose for each scan was 600 MBq (16.2 mCi). The gamma camera was positioned to achieve the best septal separation between the left and right ventricles. Imaging was acquired on an Optima gamma camera  using list mode acquisition and processed using MAPS Link Medical 10000 software. The raw data were reconstructed into a 24 frame 64 × 64 matrix with the exclusion of heartbeats 10% greater than the mean inter-beat (R–R) interval. All data were reviewed to check heart rate, gating, image quality, and ensure adequate septal separation. The acquisition angle was recorded to ensure the same angle was used for the repeat scan.25The pre and post therapy images were anonymized and randomized before analysis. LVEF was calculated from the gated images by an experienced operator and reviewed by a second operator. To assess intra-operator variability each of the anonymized images were analyzed twice by the same operator, without reference to their first ROI. A manual single region of interest method was used following the standard clinical protocol at the time of the study. The single region of interest technique systematically underestimates the ejection fraction, but has good reproducibility. The locally established normal range for LVEF by this method is > 40% and the inter-observer variability is 3.1%.27 The phase angle defines the point in the time–activity curve where the Fourier function reaches its peak, representing the onset of contraction. An example of a phase and amplitude image with the associated time–activity curve and phase histogram for a patient with normal ventricular contraction is shown in Figure Phase images were created using a first-order harmonic fit of the time–activity curve for each pixel, representing the timing of ventricular contraction relative to the R wave of the ECG.ApEn, SampEn, and phase SD from the RNVG phase images both pre and post beta-blockade. To calculate synchrony, each pixel within the ROI was defined by a vector where the length was defined as the amplitude (maximum change in counts), and the direction was defined as the phase angle. Synchrony is then defined as the vector sum of the pixel values divided by the scalar sum. A ventricle with completely synchronous contraction would have a synchrony value of 1 and a completely asynchronous contraction would have a synchrony value of 0. Entropy, as derived from Shannon information theory,28 was used as a measure of randomness in the phase histogram.16 A higher value of entropy indicates a more random contraction.In-house software was used to calculate synchrony, entropy, ApEn and SampEn were calculated using Eqs. ApEn and SampEn calculate the probability that a series of pixels of length m from the phase image remains similar within a tolerance r at the next sequence in the data series. SampEn is a modification of ApEn described by Richman and Moorman,24 but unlike ApEn, SampEn displays relative consistency regardless of sequence length and tolerance values used, and it is independent of data length. ApEn is defined asN is the length of data, m is the sequence length, and r is the tolerance. SampEn is defined asm that are within tolerance r, excluding self matches, and m are similar.m and r significantly affect the results so they must be optimized for the application. Based on the previous optimization work, ApEn was calculated using sequence length m = 2 and tolerance r = 7 and SampEn was calculated using sequence length m = 2 and tolerance r = 423. To calculate ApEn and SampEn, each group of m = 2 pixels within the region of interest in the phase image was compared to every other group of m = 2 pixels within the region of interest. If they were similar within the defined tolerance r, it was counted as a match. This was carried out for every group of ‘m’ pixels then repeated with groups of ‘ApEn and SampEn take into account the similarity of adjacent pixel values. A higher value of ApEn and SampEn would indicate a more dyssynchronous contraction. Correlation with LVEF and intra-operator variability was assessed for these novel dyssynchrony parameters.The values of input parameters 30 Shapiro–Wilk’s test was used to check the normality for each parameter, and significance testing was performed, using the t-test or Wilcoxon rank-sum test, depending on the outcome of the univariate test of normality. For paired data, a paired two-sample t test or Wilcoxon signed-rank test was used. The chi-squared test was used to test the significance of categorical parameters. The correlation between the parameters was tested using Pearson’s correlation. A P value of < .05 was considered significant for all tests.All data analysis and statistics were performed in R 3.6.3.P < .001) and baseline heart rate (P = .02) when comparing the ischemic  and non-ischemic  patients. The correlation coefficients between LVEF and each dyssynchrony parameter were calculated to be .538 (P < .001) for synchrony, − .780 (P < .001) for entropy, − .338 (P = .001) for ApEn and − .675 for SampEn (P < .001) and − .602 (P < .001) for phase SD.At baseline, there was no significant difference in sex, NYHA class, presence of hypertension, diabetes or ICD between the ischemic and non-ischemic groups. However, there was a significant difference in age (Intra-operator variability results are shown in Table ApEn for the non-ischemic group. There was no significant difference in dyssynchrony between the ischemic and non-ischemic groups at baseline (P > .05). There was a weak relationship  between change in heart rate and change in LVEF post beta-blockade.Comparison was made pre and post beta-blockade as summarized in Table 31 Both studies used septal to lateral delay as measured by echo to assess dyssynchrony and did not include any patients with ischemic heart failure. Kaya et al. found that beta-blockade improved LV synchrony and LVEF for heart failure patients with idiopathic dilated cardiomyopathy and LV dyssynchrony. Taketmoto et al. also found that patients with a QRS <120ms and sinus rhythm experienced an improvement in both LVEF and dyssynchrony after beta-blocker therapy. The mechanism for this improvement is not fully understood. Improved dyssynchrony has been linked with improved survival, as shown in CRT studies. For example, a sub-study of the EchoCRT trial found that persistent or worsening dyssynchrony six months post CRT was associated with worse clinical outcomes, in particular, heart failure hospitalizations.32The results suggest that beta-blockers improve dyssynchrony for HFrEF of both ischemic and non-ischemic etiology. As expected LVEF also improves post beta-blockade. The results are consistent with the studies by Kaya et al and Takemoto et al.34While the effect of dyssynchrony and beta-blockers on survival would be of clinical interest, this cohort is too small to provide any meaningful results. Treatment for these patients would have varied, and some went on to have PCI, CABG, or heart transplant after the study. Previous attempts to create models to predict mortality for heart failure patients have had only moderate accuracy, and those trying to predict a combined endpoint of hospitalization or death had even poorer results.35 Heart failure treatment may benefit from further investigation of mechanical dyssynchrony in larger trials.There are currently no studies using newer echo dyssynchrony parameters, such as global longitudinal strain, to investigate the effect of beta-blockers on cardiac dyssynchrony. This study is the only work to date assessing dyssynchrony for heart failure patients using RNVG phase parameters. Further work to investigate the inter-operator variability should also be carried out, but good intra and inter-operator variabilities have been previously demonstrated for synchrony, entropy, and phase standard deviation.The results are from a single-center study, limited by a small patient sample with no control group. This study also assumes patient compliance with taking prescribed drugs. The authors also acknowledge the complexity in defining heart failure etiology. Some of the patients in the non-ischemic group may have mild ischemia.An improvement in dyssynchrony and LVEF was measured six months post beta-blockade for both ischemic and non-ischemic heart failure patients using novel phase parameters. A larger study with data from multiple centers would be desirable to confirm the results of this study.A significant improvement in dyssynchrony after beta-blockade therapy has been demonstrated for heart failure patients using novel measures of dyssynchrony from RNVG phase images.


This study is to assess the application of combined detection of echocardiography and serum N-terminal pro B-type natriuretic peptide (NT-ProBNP) in the diagnosis of diastolic heart failure (DHF) and its effect on left ventricular morphology and diastolic function.  Thirty patients with DHF with enrolled in our hospital between January 2019 and January 2021 were included in the experimental group, and thirty healthy individuals during the same period were included in the control group. The blood pressure, heart rate (HR), left ventricular morphology, diastolic function, and serum NT-ProBNP levels were compared between the two groups. P < 0.05).  DHF was associated with higher levels of diastolic blood pressure (DBP), systolic blood pressure (SBP), HR, left ventricular diameter (LVD), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), left atrial volume index (LAVI), left ventricular end-diastolic volume (LVEDV), serum NT-ProBNP, maximum early ventricular filling velocity/early diastolic velocity of the mitral annulus (E/Ea) ratio, and aortic regurgitation (AR) and lower levels of left ventricular ejection fraction (LVEF), flow propagation velocity (VP), and systolic/diastolic (S/D) ratio versus healthy subjects (all at  The combined detection of echocardiography and serum NT-ProBNP yields a high clinical value in the diagnosis of DHF deficiency, as it can accurately evaluate the patient's left heart morphology and diastolic function, so it is worthy of clinical promotion and application. Diastolic heart failure (DHF) is a heart failure that occurs due to impaired filling of the left ventricle during diastole, reduced stroke volume, and increased left ventricular end-diastolic pressure, as a result of impaired active relaxation of the left ventricle in diastole, reduced myocardial compliance, and cardiomyocyte hypertrophy with interstitial fibrosis. DHF usually precedes systolic heart failure and is closely related to cardiomyopathy, pulmonary hypertension, and atrial fibrillation –5. DHF iEchocardiography is a key method to evaluate the structure and function of the heart. It is noninvasive and can accurately evaluate the heart function and structural information, which is of great significance in the diagnosis of heart failure , 7. HumaP > 0.05). This study was approved by the Xianghe County People's Hospital, No. 90717s/19.Thirty patients with DHF admitted to our hospital from January 2019 to January 2021 were included in the experimental group, and 30 healthy patients during the same period after physical examination were included in the control group. In the experimental group, there were 18 males and 12 females, ranging from 52 to 70 years, with an average age of (64.5 ± 4.7) years; among them, there were 13 cases of ischemic heart disease, 8 cases of hypertensive heart disease, and 9 cases of dilated cardiomyopathy. According to the New York Heart Academy (NYHA) cardiac function classification, there were 14 cases in class II, 10 cases in class III, and 6 cases in class IV. In the control group, there were 14 males and 16 females, ranging from 50 to 73 years, with an average age of (65.1 ± 4.9) years. The two groups presented no significant difference regarding the general information  > 50%; ④ those with evidence of left ventricular diastolic dysfunction confirmed by echocardiography; ⑤ those without heart valve disease confirmed by echocardiography.β-blockers (metoprolol succinate tablets 23.75–47.5 mg 1 time/day), and sodium and water restriction and oxygenation. The efficacy was evaluated after two weeks of continuous treatment.The patients received baseline treatment with diuretics (furosemide tablets 20 mg 1–2 times/day), ACEI (perindopril tablets 2–4 mg 1 time/day), Before the examination, the diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) of the two groups were measured. PHLIPS IU elite Color Doppler ultrasound system was used, with a sector probe frequency of 1–5 MHz. The long-axis view of the left ventricle next to the sternum was used to detect the left ventricular diameter (LVD), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), and left ventricular end-diastolic volume (LVEDV). The dynamic images of the apical four-chambered heart and two-chambered heart were used to measure the left atrial volume index (LAVI) and LVEF. The apical four-chambered section was used to determine the flow propagation velocity (VP), maximum early ventricular filling velocity/early diastolic velocity of the mitral annulus (E/Ea) ratio, systolic/diastolic (S/D) ratio, and aortic regurgitation (AR).Serum NT-ProBNP level determination: 4 ml of morning peripheral venous blood was collected after the patients fasted for 12 hours, placed in a heparin anticoagulation tube, and centrifuged at 4000 r/min for 5 minutes to separate the serum. Fluorescence immunoassay  was used to determine the serum NT-ProBNP levels. The operation was carried out in strict accordance with the instructions of the kit.(1) The DBP, SBP, and HR were compared between the two groups. (2) The LVD, IVST, LVPWT, LVEDV, LAVI, LVEF, VP, E/Ea ratio, S/D ratio, and AR were compared between the two groups. (3) The serum NT-ProBNP levels were compared between the two groups.x ± s), using a t-test. The count data were represented by (n(%)), using the X2 test. P < 0.05 indicated that the difference was statistically significant.In this research, the data were processed by SPSS20.0 and GraphPad Prism 7  was used to plot the graphics. The research included count data and measurement data. The measurement data were represented by (‾P < 0.05)  .P < 0.05)  .P < 0.05)  .P < 0.05)  .P < 0.05).As shown in Clinically, heart failure can be divided into systolic heart failure and DHF according to different pathologies, with growing morbidity in recent years . The patP < 0.05, suggesting that echocardiography can accurately reflect the left heart morphology of patients with heart failure). The study by Deanacristian et al. [P < 0.05), and the NT-ProBNP levels were positively correlated with the LVEDV levels. It demonstrates that the heart function of patients with DHF is correlated with the level of serum NT-ProBNP and the combination of echocardiography and serum NT-ProBNP is more accurate in the detection of DHF. The experimental group had higher E/Ea ratio and Ar levels but lower VP and S/D ratio levels than the control group (P < 0.05), which was consistent with the results of a prior study [Heart failure is a progressive disease that can be monitored by conventional echocardiography, but patients with an atrial cavity, ventricular wall thickening, valve damage, or systolic-diastolic function during disease progression show normal echocardiographic performance. In the presence of risk factors, the septum thickens and the left atrium enlarges , and in n et al.  has confor study , indicatOphiopogonis Radix exhibits stabilizing and positive inotropic effects on cardiac myocyte membranes , and FruThe combined detection of echocardiography and serum NT-ProBNP yields a high clinical value in the diagnosis of DHF, as it can accurately evaluate the patient's left heart morphology and diastolic function, so it is worthy of clinical promotion and application. The innovation of this study lies in the use of combined echocardiography combined with the serum NT-ProBNP test in the diagnosis of diastolic heart failure, which provides promising medical guidance. The limitation lies in the absence of diagnostic efficacy and the lack of evaluation of the specificity and sensitivity of the combined detection of the two methods in the present study, which will be further investigated in the future to obtain more reliable clinical data.