Sacubitril/valsartan (S/V) is a pharmaceutical strategy that increases natriuretic peptide levels by inhibiting neprilysin and regulating the renin-angiotensin-aldosterone pathway, blocking AT1 receptors. The data for this innovative medication are mainly based on the PARADIGM-HF study, which included heart failure with reduced ejection fraction (HFrEF)-diagnosed patients and indicated a major improvement in morbidity and mortality when S/V is administrated compared to enalapril. A large part of the observed favorable results is related to significant reverse cardiac remodeling confirmed in two prospective trials, PROVE-HF and EVALUATE-HF. Furthermore, according to a subgroup analysis from the PARAGON-HF research, S/V shows benefits in HFrEF and in many subjects having preserved ejection fraction (HFpEF), which indicated a decrease in HF hospitalizations among those with a left ventricular ejection fraction (LVEF) < 57%. This review examines the proven benefits of S/V and highlights continuing research in treating individuals with varied HF characteristics. The article analyses published data regarding both the safeness and efficacy of S/V in patients with HF, including decreases in mortality and hospitalization, increased quality of life, and reversible heart remodeling. These benefits led to the HF guidelines recommendations updating and inclusion of S/V combinations a key component of HFrEF treatment. Heart failure (HF) is a prevalent disease these days, having a variety of etiologies. This syndrome involves the ventricle’s structure and function and affects patients’ quality of life, which means that work capacity, effort tolerance, sleep and psychosocial profile are altered. Even though HF is debilitating, and deadly, continuous research has developed more effective therapies. HF is the final stage of most types of heart disease. As a result, established risk factors play a crucial role in developing HF. High blood pressure, metabolic syndrome, low physical activity, dyslipidemia, and smoking ,2 have aDecompensated heart failure (DHF) can be defined as an exacerbation of a chronic HF or an acute condition . DHF usuThe persistent burden of HF has lately been highlighted by data on cardiovascular mortality in the United States ,13. HF iThe New York Heart Association categorizes the relationship between dyspnea symptoms and physical activity: class I: no symptoms; class II: minor symptoms when engaged in regular physical activity; class III: patients still have no symptoms at rest but occur at a lower-than-normal activity; and class IV: extreme breathlessness even when patients are resting.Drug therapy is gradually introduced according to the symptoms and stages of HF. Stage A  focuses on treating risk factors and comorbidities. Stages B  and C  require drug therapy. If bundle branch block is present, it should be considered cardiac resynchronization; if acute myocardial infarction is a problem, revascularization (PCI and CABG) must be performed. Finally, refractory symptoms require intervention in stage D: VAD (ventricular assisted device) and transplantation. Since neurohormonal involvement in HF has been recognized, there has been increased attention to the renin-angiotensin-aldosterone pathway (RAAS) and sympathetic activation. Thus, by suppressing the two, a decrease in mortality and rehospitalizations was demonstrated; moreover, some beta-blockers (BB)  have also been shown to improve left ventricular function. Drug classes such as mineralocorticoid receptor antagonists (MRAs), angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARBs) showed improved prognosis when combined ,16,17,18Since the 2000s, a new range of drugs has been introduced in HF therapy ,20,21,22Neprilysin is an endopeptidase that degrades natriuretic peptides (NPs) and other endogenous vasoactive peptides. Sacubitril inhibits neprilysin, which raises the quantities of these peptides, and counteracts the opposite effect of neurohormonal overactivation [Sacubitril and valsartan (S/V) formed this new drug class—ARNI, because ACEI and sacubitril combined produced significant angioedema. tivation . The clitivation . Experimtivation . ACEI altivation .MiRNAs are small molecules that can be identified at the blood level and are potential biomarkers to monitor in cardiovascular pathology, more precisely in heart failure . These mIn patients who have a poor therapeutic effect of cardiac resynchronization therapy with defibrillator (CRTd) and a worse prognosis, ARNI leads to significant improvement in clinical symptoms, cardiac pump, and reduction in NYHA class . These eThis study would like to present the modern therapeutic options, adapted according to the pathophysiological mechanism of the diseases, in HFrEF and HFpEF, and to emphasize the role of sacubitril/valsartan in heart failure therapy based on the data provided by the large trials. The review also aims to raise awareness to the medical public, starting from the general practitioner to the cardiologist, about the benefits of inclusion of S/V in the complex management of HF that led to its inclusion in the cardiology guidelines for heart failure.Cardiac dysfunction, both structural and functional, causes decreased cardiac output and increased intracardiac pressures, which dictate the signs and symptoms of HF . CardiacConsidering only the ejection fraction, HF was divided into two major categories: HFpEF and HFrEF, which helped to make the diagnosis more accessible to establish the therapeutic course as quickly as possible, having an essential predictive value. Besides the two categories which consider EF < 40% and > 50%, a third category should be mentioned (that covers the gray area of 40–50%), namely HFmrEF. When more than one variable is considered, research has shown that myocardial dysfunction can be global, both systolic and diastolic, and that fibrosis, cardiomyocyte cell loss, oxidative stress, and coronary heart disease contribute at the onset of HF too. Moreover, the negative involvement of the RAAS in varying degrees in both types of HF has been shown, but the NPs counteracts the effects of RAAS by vasodilation, decreased wall thickness and inflammation of the heart, but also by its action on the nervous system . Figure Evidence-based therapy improves symptoms and prognosis in HFrEF, and less in HFpEF. These variations underscore the importance of understanding the pathophysiological differences between HFrEF and HFpEF, which may influence therapeutic targets. The rising incidence and high mortality rates are standard features of both. It has been noticed that differences in giant spring titin, fibrosis, endothelial malfunction, and inflammation, as well as cardiomyocyte hypertrophy and apoptosis, vary in HF pathology. Cardiomyocyte hypertrophy, intercellular fibrosis, abnormal cardiomyocyte relaxation, and inflammation are all characteristics of HFpEF, resulting in the LV’s inability to relax adequately. Most of the time, HFpEF is associated with other chronic diseases, which can lead to its aggravation, and implicitly to an increase in the hospitalization rate. Non-cardiomyocytes are made up of about 60% endothelial cells, and endothelial dysfunction, which can be recognized early in cardiovascular disease, being less common in HFrEF vs. HFpEF. Several adaptive mechanisms can cause endothelial dysfunction in response to low cardiac output, such as vasoconstriction, nitric oxide imbalance, enhanced oxidative stress, neurohormonal activation and energy bioavailability . Figure The HF presence is suggested by various signs and symptoms such as shortness of breath, cough, disrupted sleep, exercise intolerance, edema, and fatigue; in addition, displacement apex shock and increased jugular venous pressure may also be present. However, these variables are not always sufficient for the definite diagnosis of HF, because they can appear in other disorders as well , and obesity) .Thus, in addition to clinical evaluation and routine laboratory tests, specific laboratory tests are sometimes required—brain natriuretic peptides (BNP) and N-terminal proBNP  . The twoComorbidities, numerous risk factors, and pre-existing illnesses contribute to HF, harming heart’s function and structure. The first choice of HF medications aimed to improve quality of life by reducing morbidity and death in HFrEF while reducing symptoms and slowing disease progression. However, to date, no HF therapy has been reported to reverse (constantly and permanently) the evolution of structural and functional degeneration of the heart ,44. DespThe decrease in cardiac output causes an inadequate circulating volume that will be ameliorated, at the onset of HF, by the compensatory mechanisms through neurohormonal involvement: sympathetic activation, RAAS, and release of antidiuretic (ADH). Chronic activation of these mechanisms will cause vasoconstriction and fluid retention, depletion of catecholamines, and a weak response to the action of circulating catecholamines, contributing to myocardial hypertrophy and cardiac remodeling, which are present in HF ,49,50. ALow levels of ATII promote the elimination of Na from the body, decreased vasoconstriction and blood pressure (BP). These effects are due to decreased sympathetic activity, ADH production and aldosterone. Low preload and afterload results from low venous and arterial pressure lead to improved ventricular filling and better blood ejection. ACEI can help prevent ventricular remodeling by limiting cardiac hypertrophy and myocardial fibrosis and reducing cardiomyocyte death by acting at the cellular level. ACEI have been demonstrated to have positive benefits in chronic HF ,56,57,58In patients with HFrEF, ACEI enhance symptoms, life quality, and physical function. When compared to placebo, ACEI reduced death by 23% and HFrEF-related mortality or hospitalization by 35%, according to an analysis of 32 randomized clinical studies in people with HFrEF. ACEI improve survival and lower the risk of HF and coronary events in patients with a reduced LVEF, but no HF ,60,61.Angiotensin receptor blockers (ARBs) suppress the RAAS by blocking angiotensin II from binding to its receptor, preventing constriction of the blood vessels and aldosterone release; ARBs do not inhibit kininase, which lowers cough compared to ACE inhibitors. Therefore, ARBs should be used to minimize morbidity and fatality in those patients which cannot be administered ACEI (considering their side effects) , or in pAccording to the guidelines, in patients having HFrEF NYHA class II/III, ARB medication should be replaced with an ARNI . The CanRAAS inhibitors have been shown to have cardioprotective effects. In the study published by Marfella et al. in 2022, the effect of RAAS blockers was analyzed in heart transplant patients with/without T2DM. When the research started, no significant differences were observed in terms of myocardial fibrosis, but at one year of follow-up, there were differences between patients who did not have T2DM and those who were diagnosed with T2DM, and more than that, differences were observed in patients who had a more rigorous glycemic control. It should be clarified that all patients followed a similar therapy with ACEI or ARB. The study evaluated the involvement of Ang 1–7 and Ang 1–9 molecules responsible for the antifibrotic effects at the cardiac myocyte level and observed that their levels are higher in patients without T2DM and in patients with better glycemic control .Beta-blockers bind to beta-adrenoceptors and prevent adrenaline and noradrenaline from binding to these receptors, reducing the SNS’s functions. Fundamental studies have shown that giving a BB to symptomatic patients with decreased LVEF reduces mortality and morbidity. In the SENIORS, MERIT-HF, COPERNICUS, and Cardiac Insufficiency Bisoprolol Study (CIBIS)-II trials, this was proved with nebivolol, carvedilol, bisoprolol, and controlled-release metoprolol ,69,70,71Because of detrimental inotropic effects, it is not indicated that BB be started during an HF exacerbation; instead, this class is recommended when the patient is volume-stable ,72. OnlyMineralocorticoid receptor antagonists work by inhibiting the mineralocorticoid receptor, which counteracts the effects of aldosterone since MRAs provide diuretic properties and can contribute to a fluid balance. The main beneficial effects are observed in decreasing mortality, respectively, the number and duration of hospitalizations due to HF  ,75,76. SSodium-glucose cotransporter-2 inhibitors (SGLT2i) consider a newer class of drugs, with antidiabetic effect, that improve natriuresis and osmotic diuresis, while increasing the excretion of glucose in the urine to reduce blood glucose levels.The Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure Trial (DAPA-HF) randomized trial with dapagliflozin was designed in the HFrEF group, even if patients did not have DM .When compared to placebo, the study main purpose was to see how adding 10 mg of dapagliflozin to the optimal treatment for HFrEF affects the primary endpoint’s occurrence, aggravation of HF (decompensated HF) and cardiovascular mortality. The dapagliflozin-treated group exceeded the placebo-treated group in every parameter tested throughout the course of an average 18-month follow-up. In addition, concerning the first exacerbating HF event and death from cardiac or other causes, the group using dapagliflozin (as treatment) had a reduced risk. Empagliflozin improves physical performance and life quality, while lowering the risk of HF hospitalization in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced study) .In HFrEF patients, the two approaches joined (inhibition of NP breakdown and blockage of the RAA) proving to be the most effective together . In realNew information concerning the mechanisms of this drug class in HFrEF was revealed after researchers analyzed the effect on inflammation, functional ability, and peripheral vascular activity. A group of patients with HFrEF (LVEF~28%) were administered S/V and investigated prospectively. Patients were evaluated at the beginning of treatment, then monthly for up to three months, and a decrease in pro-inflammatory markers, improvement in functional capacity and peripheral vascular activity were observed .The development and progression of HFpEF are linked to abnormal activation of the RAAS. In addition, the RAAS reduced LV diastolic performance  and caused LV hypertrophy ,87. As aAldosterone has implications for the development of myocardial fibrosis that will cause adverse effects on the heart muscle. MRAs act on aldosterone receptors and are useful in treating HF regardless of the left ventricular ejection fraction. The ALDO-HF study proved the usefulness of this class in HFpEF from a cardiac point of view but not showing improvements in symptoms or in the life’s quality . The TOPARNI combines RAAS blockade and endogenous natriuretic peptide pathway upregulation. In HFrEF, S/V is an emerging and game-changing disease-modifying drug. Inhibition of neprilysin increases endogenous natriuretic/vasoactive peptides, such as cGMP, which are reduced in HFpEF and linked to myocardial stiffness. In a phase II study of patients with HFpEF, S/V was linked to LA reverse remodeling, a more considerable reduction in NP levels, and symptoms improvement ,97. PatiIn the last three decades, HF treatment has experienced an unparalleled evolution, based on evidence, with an increase in the quality of living and the survival of patients suffering from HF. International guidelines support this progress, especially the ESC Guide. Compared to the guide published in 2016, the 2021 guide focuses on patient involvement in managing the treatment of their disease, of course with a multidisciplinary team. Along with conventional therapy , ARNI and SGLT2i are added to the therapeutic regimen of subjects with HFrEF. These medication classes have both independent and additive therapeutic effects ,101.In the PARADIGM-HF, patients with HFrEF and NYHA class II, III, or IV HF have been randomly selected to be administered either S/V or enalapril, in addition to standard therapy. The study aimed to identify the variations in mortality rates from CV causes. The study ended earlier in agreement with predetermined rules because the threshold for an overwhelming advantage with S/V had been crossed. A total of 17% of patients treated with S/V and 19.8% with enalapril died, but S/V reduced the rehospitalization rate due to HF by 21% and improved symptoms. Hypotension and angioedema were more pronounced in the ARNI group, but fewer patients developed coughs, electrolyte imbalances, and kidney damage . A blindIn the PIONEER-HF trial, subjects suffering from HFrEF hospitalized due to IC decompensation were randomized into two groups: one was treated with ARNI and another with enalapril. Shortly afterward, a more considerable reduction in NT-proBNP levels was observed in the group treated with ARNI. The decrease in NT proBNP, which indicates neurohormonal activation and hemodynamic stress, was linked to a decrease in high-sensitivity cardiac troponin, indicating myocardial damage. Compared to enalapril, S/V subjects were unlikely to be re-hospitalized for HF at eight weeks. This trial was the first to show that starting S/V in the hospital was tolerable and safe .The goal of the TITRATION trial was to offer information on how to start and up titrate S/V in people with chronic HFrEF. TITRATION included patients who had never been treated before or had varying levels of ACEI/ARB pre-treatment ,42. PatiPRIME study aimed to show that S/V has a favorable effect on remodeling in HFrEF patients. In the PRIME study patients suffer from chronic functional mitral regurgitation due to left ventricular malfunction and reduced EF. These subjects received guideline-directed medical therapy in a double-blind experiment. Valsartan or S/V were given to the patients. The S/V group developed a decrease in EROA, thus proving that the drug has a better effect on heart remodeling than the valsartan group; additionally, an improvement in the regurgitant volume was noticed. Some other noticeable results show that the S/V group had a higher decrease in LV end-diastolic volume index, but on partial mitral leaflet closure area, other measures of the LV, or changes in blood pressure, it was not a remarkable difference. PRIME is considered a modest trial being the first to demonstrate the reverse remodeling impact of S/V in people with HFrEF, associated with suffering from FMR .In the PARADIGM-HF study, a lower NT-proBNP level was linked to a better result in patients using S/V. The PROVE-HF wanted to investigate this further because NT-proBNP lowering during guideline-directed healing therapy has already been associated with cardiac remodeling reversal. PROVE-HF was open-label research in which 794 individuals suffering from chronic HFrEF were distributed to S/V and had their echocardiogram carried out before starting treatment, six months later, and 1 year later. At each study visit, the concentration of NT-proBNP was assessed. Following the completion of all research procedures, at a core laboratory, echocardiograms were blindly analyzed temporally and clinically. After starting S/V, the researchers found a significant 37 percent reduction in NT-proBNP and reverse cardiac remodeling intimately tied to it. At the starting point, the LVEF was ~28%, but after 12 months of treatment, it increased by 9.4%, with a significant improvement in other patients. Additionally, more variables were modified: diastolic function, measured by E/e′ proportion, improved, and the mass index of LV and volumes of LV and LA reduced. These results are maintained in patients who were newly diagnosed with HF or those who had not previously been treated with ACE inhibitors or ARBs or patients who did not achieve the target dose of S/V. The PROVE-HF research adds to the growing body of evidence supporting reversible cardiac remodeling and the drop of NT-proBNP levels when ARNI is administered .Whether aortic impedance can contribute (from the pathophysiologic point of view) in patients diagnosed with HFrEF and treated with ARNI was one of the questions answered in the EVALUATE-HF trial. Patients were divided into two groups: one that received S/V and the other one, enalapril. It resulted that the S/V group showed a decreased aortic impedance, while the valsartan’s group was increased; still, the dissimilarity was not eloquent. Compared to the enalapril group, the S/V group exhibited considerably lessened NT-proBNP levels and a significant reduction in numerous echocardiographic parameters . An exploratory secondary goal was to show a substantial increase in the general summary score for the 12-module Kansas City Cardiomyopathy Questionnaire (KCCQ). Despite three months of S/V medication, these findings demonstrate a clear remodeling benefit compared to usual care. The EVALUATE-HF research found that, while no considerable improvement was observed when administering S/V in aortic impedance, in contrast with enalapril, it did show more substantial cardiac reverse remodeling and improved quality of life .A summary of the results obtained from the above presented clinical trials is presented in the Associations between S/V post-discharge adherence (PDC) and clinical outcomes after readmissions for HFrEF revealed that 32.9% patients who received ARNI therapy were compliant when discharged (PDC ≥ 80%), but 67.1% were not compliant to the treatment (PDC < 80%). Between groups, baseline attributes were evenly distributed. Subjects with PDC ≥ 80% presented considerably decreased adjusted risk of all-cause readmission to hospital and mortality after 90 days and one year compared to patients with PDC < 80%. At one year, patients saw a significant reduction in rehospitalization for every five-percentage point rise in PDC. Finally, the trial proved that compliance to the therapy with S/V, 90 days after discharge was related to diminished rehospitalization rates and death in patients hospitalized for HFrEF and discharged on S/V. In HFrEF, more work is needed to increase adherence to S/V and other guideline-directed medical therapy .The researchers assigned HF patients with LVEF > 45%, NYHA II-IV, high NP values, and structural heart disease to receive target doses of S/V and valsartan . Renal function, safety, functional class, KCCQ score, CV death, and HF hospitalizations were monitored. The results favor S/V except for hospitalizations and CV deaths, where there was no statistically significant difference .A randomized, parallel-group, double-blind clinical experiment included subjects with HF, LVEF > 40%, high NT-proBNP concentrations, structural heart disease, and bad quality of life registered from 396 facilities in 32 countries. The aim of the research was to compare the results of S/V on NT-proBNP levels, 6-min walk test (6MWT) and life quality in subjects suffering from chronic HF and LVEF greater than 40% to background medication-based individualized comparators. The trial was completed by 87.1% of patients. At the baseline, the levels of NT-proBNP were comparative in both groups . After 12 weeks, the group that received S/V had a considerable reduction in NT-proBNP levels compared to the other group. A big difference was not noticed regarding the 6MWT after 24 weeks (at the baseline 9.7 m and at the end 12.2 m) nor in NYHA class and KCCQ score . S/V treatment determined a more notable decrease in plasma NT-proBNP peptide concentrations compared to standard RAAS inhibitor treatment or placebo. However, it did not significantly enhance the 6MWT in subjects suffering from HF and a LVEF > 40% .A systematic review on four randomized controlled studies of S/V for HFpEF patients showed a reduced rate of HF hospitalization in HFpEF patients when compared to the control group. S/V did not exhibit any clear benefits in cardiovascular mortality, mortality of all causes, or improvement in the NYHA class. Even though S/V was connected to an increased risk of symptomatic hypotension, there were no signs of deteriorating renal function or hyperkalemia. Except for the hospitalization rate, in which the S/V treatment group favored HFpEF patients, the study found no differences between the two groups compared to valsartan or personalized medical therapy .Previous research has validated S/V’s efficacy in treating HFrEF. However, the role of S/V in HFpEF is still an area of research. S/V is a combination therapy that includes sacubitril and valsartan and functions as neprilysin inhibitor (ARNI) and a first-generation angiotensin receptor blocker. Using animal models, the effect of S/V was evaluated in a high sodium diet that causes HFpEF and vascular damage, in addition to the primary mechanism. Thus, a considerable amount of salt (68 mg/kg) was administered intragastrically before S/V treatment. According to the findings of functional tests, it has been observed that a high sodium diet leads to lesions in the heart and vascular system. These effects were reversed by S/V administration; in addition, S/V had an antifibrotic impact by decreasing the amount of type 1 and type 3 collagen and decreasing the MMP3/SMAD3 ratio. The most plausible explanation for the favorable effects on HFpEF is the action of S/V on the TGF1/SMAD3 signaling pathway. Following this experiment, S/V proved its therapeutic potential in HFpEF, reversing the effects of HFpEF induced by a high sodium diet. However, this study had some drawbacks: to corroborate the findings, the study did not identify the agonists or antagonists of the TGF-/Smad signaling pathway; instead, it merely examined the biochemical effects of a high-salt diet and S/V. HFpEF is still controversial in high salt-induced rat models even after thorough reports by the team of Y Sakata/M Hori. For the thorough verification of these data, in vitro experiments are also necessary . S/V hasAccording to estimates, 1% to 10% of people with heart failure have advanced heart failure . HoweverThe first study (PARAGLIDE-HF) is a multicenter, randomized, and double-blinded clinical trial that is expected to enroll 450 participants. Following hospitalization for acute decompensated HF, this study will assess the effects of S/V compared to valsartan monotherapy on clinical outcomes, safety, tolerability and NT-proBNP levels in decompensated HFpEF patients that were stabilized, and the treatment with S/V will be instituted at the time or in 30 days after patient stabilization . A total of 50 people will be enrolled in the second study. It will look at the effects of S/V on the autonomic cardiac nerve system in HF patients by measuring HR variability .The third study will assess the effects of S/V vs. valsartan on cardiac oxygen demand and cardiac work efficiency in 60 participants with NYHA II-III HFrEF after six weeks of therapy .The fourth trial will enroll 48 patients and will examine S/V vs. placebo in terms of neurohormonal activation and physical function in people presenting right ventricular dysfunction (moderate/severe) and those that have present NYHA II-III symptoms The researchers will enroll 100 patients in the fifth study, which will be a phase 3 randomized controlled trial to see if S/V can reverse heart hypertrophy and fibrosis .The SHORT trial, the sixth study, is a randomized experiment on HF patients with LVEF < 35%. Its goal is to see if a quicker protocol translates to faster optimization and a higher degree of optimization than the current standard protocol .A multicenter prospective randomized study will assess the effect of in-hospital initiation of S/V on the NT-proBNP concentrations in patients admitted due to AHF (PREMIER) and is estimated to include 400 participants .Recent ACC AHA 2022 HF recommendations indicate the use of ARNI as first line therapy to lessen morbidity and fatality in subjects suffering from HFrEF and those that present NYHA class II/III symptoms. Subjects with HFrEF, NYHA II-III that are under treatment with ACEI/ARBs should be switched to ARNI due to favorable morbidity and mortality results. ARNI is indicated as a de novo medication in subjects suffering from AHF and chronic symptomatic HFrEF, given the improved prognosis, decreased NTproBNP value, and cardiac remodeling .From the perspective of mortality and morbidity, none of therapies described in this review have been shown efficient in HFpEF; it is crucial to understand the mechanisms underlying this condition. However, the PARAGON-HF study revealed a lower readmissions rate in those patients with HF and LVEF < 57%, and a systematic review that included PARADIGM-HF and PARAGON-HF trials showed a decrease in CV mortality and HF hospitalization in patients that had an LVEF lower than the normal interval . FDA graS/V is a breakthrough drug in HF therapy. Compelling benefits of ARNI therapy in HFrEF were demonstrated in PARADIGM HF with a reduction in CV mortality and hospital admission for HF, and a decrease in all-cause mortality. Sudden cardiac death was reduced by 22%, as were all-cause and HF readmissions and AHF. S/V reduced symptoms and physical constraints linked to HF, as assessed by the KCCQ, and this advantage expanded to almost all areas of the score when examined individually. There is an expanding body of evidence supporting S/V’s role in cardiac reverse remodeling process correlated with a significant reduction of NT-proBNP level in EVALUATE HF and PROVE HF. The PRIME study demonstrates for the first time the result of S/V treatment on reverse remodeling in HFrEF subjects with functional mitral regurgitation. S/V decreased the rate of cardiovascular mortality and readmissions in subjects suffering from HFpEF in PARAGON-HF, though the results are not statistically significant. In addition, advantages for life quality and renal function have been reported, but also from a clinical perspective. S/V treatment reduced the symptoms of HFpEF produced by a high-salt diet, most likely by decreasing fibrosis, highlighting S/V’s therapeutic promise for HFpEF. For patients admitted to hospital for HFrEF and discharged on S/V, increased adherence to therapy was connected to considerably lower readmission rates and death.


Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance—IR or diabetes mellitus—T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF.Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D.2) in TD2 vs EU and IR patients was recorded . Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group .Compared with EU and IR, T2D was associated with increased filling pressures  and worse right ventricular(RV)-arterial uncoupling (RVAUC) . Likewise, impairment in peak oxygen consumption (peak VOThe higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis.Trial registration ClinicalTrials.gov identifier: NCT023358017 There is an intimate link between heart failure (HF) and type 2 diabetes (T2D) –6. Both However, little information is available on the relative impact of IR and T2D on LV architecture and function as well as on cardiopulmonary performance, in HF cohorts. More importantly, no study dwelled upon the independent effect of IR or T2D on longitudinal changes of left and right chamber architecture and function, their coupling with the pulmonary circulation as well as cardiopulmonary. Therefore, the aims of the present investigation were to explore the separate impact of T2D and IR on left and right chambers morphology and function and cardiopulmonary performance and their longitudinal changes in relation to the cardiovascular outcomes.The study design has been previously described –12. In bFor cross-sectional data, we considered as primary endpoints differences in echocardiographic and cardiopulmonary exercise test parameters comparing 3 groups: patients without IR impairment (EU), IR patients, and T2D patients.2) from baseline to the 36-months visit (or the last available before the outcome) in the 3 groups.With regard to longitudinal data, we compared the delta change  in left ventricular dimension and function , RV dimension, function, and RV to pulmonary arterial uncoupling (RVPUC)  and peak oxygen consumption  and apical views. Echocardiographic exams were performed by expert trained physicians in each center, and data were revised in blind by two independent expert physicians of the core center according to previously published methods , 11.2 was recorded as the mean value of VO2 during the last 20 s of the test. The ventilatory anaerobic.All patients underwent an incremental symptom-limited cardiopulmonary exercise test (CPET) on a bicycle ergometer. After a 1-min warmup period at 0-W workload, a ramp protocol of 10 W/min was started and continued until limiting symptoms or other indications for exercise termination appeared , 8. Respthreshold was detected using the V-slope method. The ventilation per min (VE) versus carbon dioxide production (VCO2) relationship was measured by plotting ventilation against VCO2 obtained every 10 s of exercise (VE/VCO2 slope). The VE/VCO2 slope was calculated as a linear regression function, excluding the nonlinear part of the relationship after the onset of acidotic drive to ventilation.Normally distributed continuous variables were expressed as mean ± standard deviation (SD), whereas continuous data with skewed distributions were expressed as median [interquartile range (IQR)]. Categorical variables were expressed as counts and percentages. The distribution of the variables was tested with the Kolmogorov–Smirnov test.2max levels were assessed through the ANCOVA model, considering all the baseline variables resulting statistically different between groups . Age sex, NYHA class, BMI, electrolytes, and clinical or biological plausible variables were tested in a univariate analysis and used as a covariate in the ANCOVA model or used to calculate a propensity score if more than 5. Moreover, the relationship between VO2max and HOMA-IR (including the presence and absence of diabetes) was explored through Pearson or Spearman coefficient. A linear regression model was also provided, together with the related fitting curve. In order to test if there’s a relationship between HOMA-IR classes  and VO2 max, a logistic regression model was fitted providing the odds ratios and 95% confidence interval, considering as reference class both the absence and the presence of diabetes. P-values < 0.05 were considered statistically significant. All data were analysed using R version 3.0 (http://www.r-project.org).Normally distributed variables were compared between groups using the two-sided, unpaired Student’s t-test, assuming unequal variance. Non-normally distributed variables were compared between groups using the nonparametric Mann–Whitney U-test or the Kruskal- Wallis test. Rates and proportions were compared between groups of interest using the chi-square test or correction for continuity test. For continuous variables normally distributed, statistical comparisons between groups were established by carrying out the one-way ANOVA test. P-values from the analysis of variance were adjusted using the Holm approach. When the ANOVA test revealed a statistical difference, pairwise comparisons were made by Tukey’s HSD (Honestly Significant Difference) test. Difference between groups and continuous VOFrom the original cohort of 525 patients, complete data about insulin impairment were available for 480 patients; as a result, these patients represent the baseline population of the present analysis.Baseline demographic characteristics of the final cohort are depicted in Table No differences were found regarding sex, duration of disease, NYHA classes, current smoke habitus, NT-proBNP, and HF treatment except diuretics, which were employed less frequently in euglycemic patients (p < 0.05).2 vs 43 ± 19 ml/m2 and 38 ± 17 ml/m2, p < 0.01), and particularly by a higher E/e′ ratio  when compared with both IR and EU patients, respectively. Indexes of systolic RV function (TAPSE and RFAC) are not different between the three groups  as well as higher percentage of moderate/severe TR were recorded in T2D patients compared with both IR and EU patients. In addition, when T2D patients were compared with regard to glycosylated-hemoglobin levels , despite displaying similar values with regard to indexes of systolic RV function, patients with higher HbA1C displayed a more frequent RV-AP impairment, as testified by an impaired TAPSE/PASP ratio .Baseline echocardiographic findings are depicted in Table as a whole, more than the progressive impairment of a single factor.Particularly intriguing were the longitudinal data Fig. . The med2 slope. A logistic regression model was performed to test the relationship between IR class and peak VO2 considering as reference class both the absence (euglycemic) and the presence of diabetes   and  respectively. Our results showed a relationship between HOMA-IR classes  and peak VO2. Finally, an ANCOVA model was performed, considering all the baseline variables resulting statistically different between groups , showing peak VO2 as an independent variable even after the adjustment for the covariates between the three groups .Baseline exercise capacity was more compromised in T2D patients when compared with both euglycemic and IR patients, as shown by a significant lower distance on the 6-min walking test , (Table 2 slope between groups (data not shown).Longitudinal changes in cardiopulmonary performance were also intriguing Fig. B, pointi2) and right ventricular pulmonary arterial coupling  were burdened by a worse prognosis. Indeed, overall, patients with delta changes > 10% in CPET, and TAPSE/PAPS also displayed a worse prognosis  p < 0.01). Notably, patients with a greater impairment of RV dynamics were significantly more common in the T2D group than in the IR and EU group. For example, with regard to peak oxygen consumption, respectively, 80%, 39%, and 30% of patients displayed delta change > 10% in T2D, IR and EU, respectively .As elsewhere described , T2D andThe present report sheds new light on the differential role of insulin resistance and hyperglycaemia in the natural history of heart failure, as well as on the pivotal role of right ventricular architecture and dynamics. Several are the principal findings herein described: (a) T2D rather than IR further impairs left and right chambers morphology and function in HF, as well as cardiopulmonary performance, as shown by a broad variety of echocardiographic and CPET indexes; (b) T2D equally heavily impacts on longitudinal changes in cardiac morphology and function, and exercise capacity suggesting the concept that hyperglycaemia rather than IR induces further pathologic remodeling and exercise impairment; and (c) the rate of deterioration of RV architecture and function over time is associated with a worse prognosis, underlying the pivotal role of RV dynamics in HF progression.To the best of our knowledge, the present study represents the most comprehensive investigation dwelling upon longitudinal changes of right and left cardiac morphology and function combined with cardiopulmonary performance comparing HF patients with regard to T2D, IR and EU status. Further, these data enhance the understanding of how T2D acts as an accelerator of disease progression in patients with HF.Longitudinal population-based data have demonstrated that IR predicts worsening of LV function and remodeling when compared to euglycemic patients . FurtherAlthough neglected in the past, mounting evidence is congruent on the pivotal role of right heart in driving prognosis in HF, especially when the backward transmission of LV filling pressures rises up to generating an increased RV afterload . A critiCongruent with our results, serum insulin was inversely associated with right ventricle function and lung volumes in the general population suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment  in HF pa2 in the general population  have recently proved to be effective in reducing mortality and hospitalization in patients with HF , 46. IndOn the other hand, our data showed a pivotal role of the right ventricle in determining the poor prognosis of T2D patients in HF, with RV-PA uncoupling as key-player of the more impaired cardiovascular performance and of the poorest outcome displayed by these patients in the T.O.S.CA. registry . This isIn conclusion, compared to patients without diabetes, heart failure patients with type 2 diabetes display a higher degree of progressive right ventricular dysfunction and exercise impairment, associated with a poorer outcome. Findings from the T.O.S.CA. Registry shed light upon the key role of the right ventricle in HF, which appears a pivotal player in underlying the poor outcome faced by T2D HF patients.The observational nature of the current study precludes the elucidation of the putative biological mechanism(s) underlying the progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus . Despite


The impact of postero-anterior and medio-lateral mitral valve (MV) tethering patterns on outcomes in patients undergoing transcatheter edge-to-edge repair (M-TEER) for secondary mitral regurgitation (SMR) is unknown.The ratio of the posterior to anterior MV leaflet angle (PLA/ALA) in MV segment 2 was defined as postero-anterior tethering asymmetry. Medio-lateral tethering asymmetry was assessed as the ratio of the medial (segment 3) to lateral (segment 1) MV tenting area. We used receiver-operating characteristics and a Cox regression model to identify cut-off values of asymmetric anteroposterior and medio-lateral tethering for prediction of 2 year all-cause mortality after TMVR.p = 0.02). A multivariable Cox regression model identified both types of asymmetric MV tethering to be associated with increased all-cause 2-year mortality .Among 178 SMR patients, postero-anterior tethering was asymmetric in 67 patients . Asymmetric medio-lateral tethering (tenting area ratio > 1.49) was observed in 49 patients (27.5%). M-TEER reduced MR to ≤ 2 + in 92.1% of patients; MR reduction was less effective in the presence of asymmetric postero-anterior tethering (Asymmetric postero-anterior and medio-lateral MV tethering patterns are associated with increased 2-year mortality in patients undergoing M-TEER for SMR. A detailed echocardiographic analysis of MV anatomy may help to identify patients who profit most from M-TEER.The online version contains supplementary material available at 10.1007/s00392-021-01961-5. Severe secondary mitral regurgitation (SMR) has a poor prognosis and causes substantial morbidity in patients with heart failure and reduced ejection fraction (HFrEF) . TherefoIn HFrEF patients, left-ventricular ejection fraction (LV-EF) progressively deteriorates and left heart geometry alters due to ventricular, atrial, and annular dilation , 8. VentIn patients undergoing MV surgery for SMR, asymmetric leaflet tethering patterns have been shown to be associated with increased rates of residual MR and worse long-term outcome , 20. SinWe included consecutive patients with moderate-to-severe (3+) or severe (4+) SMR undergoing M-TEER between July 2013 and March 2019 using MitraClip NT, NTR or XTR  at our center. Due to significant changes of MV leaflet anatomy, patients with prior surgical or transcatheter mitral valve repair have been excluded from the analysis, as well as interventions being performed as bridge to heart transplantation or interventions with concomitant tricuspid transcatheter valve repair. Furthermore, patients without a detailed preprocedural echocardiographic assessment of the MV pathology were excluded from this study. After transthoracic (TTE) and transoesophageal echocardiographic (TEE) assessment, all patients were discussed by an interdisciplinary heart team and deemed at high or prohibitive surgical risk. Follow-up included survival status and New York Heart Association (NYHA) function class. Patients unable to attend follow-up examinations at our center were interviewed per telephone or seen by their local practitioners.Echocardiographic evaluation of the cardiac chambers and MV was performed according to the recommendations of the European Association of Cardiovascular Imaging (EACVI) . DetaileEffective regurgitant orifice area (EROA) and regurgitant volume (RegVol) were measured by the proximal isovelocity surface area method. The LV sphericity index was defined as ratio of LV length and width in an end-diastolic apical four-chamber view. LV width was measured as the broadest diameter of the LV in an apical four-chamber view. End-diastolic (LV-EDV) and end-systolic left-ventricular volume (LV-ESV) were measured using apical two- and four-chamber view according to Simpson’s biplane summation of disc method. Left-ventricular end-diastolic and systolic diameters, as well as MR vena contracta (MRVC) were obtained in a parasternal long-axis view. Systolic pulmonary artery pressure was estimated by addition of maximum systolic tricuspid valve pressure gradient with estimated right atrial pressure derived from inferior vena cava width. Grading of SMR severity was performed using a comprehensive approach integrating EROA, RegVol, MRVC, and jet morphology based on current guidelines , 23. IntTwo-year all-cause mortality was defined as primary endpoint. Postprocedural MR severity was assessed at the end of M-TEER procedure. Symptomatic improvement was evaluated using NYHA functional class.Postero-anterior MV leaflet tethering asymmetry was defined as the PLA/ALA ratio in MV segment 2 Fig. A. Medio-U or Pearson’s Chi-square test were used for inter-group comparison, as appropriate. The development of NYHA functional class and MR severity after M-TEER for each patient was analysed using the Wilcoxon test. We used receiver-operating characteristics (ROC) analysis and Youden’s J to identify the best discriminatory cut-off values for postero-anterior and medio-lateral asymmetric leaflet tethering in terms of 2-year all-cause mortality and residual postprocedural MR. Multivariable cox analysis and logistic regression included all parameters presenting with p < 0.05 in univariable statistics. The relationship of tethering symmetry and logarithmic hazard ratio was visualized using spline curves. Kaplan–Meier curves were used for showing survival after M-TEER. The difference of impact of tethering asymmetry on survival was calculated using the log-rank test. Results are displayed as hazard ratio (HR) with 95% confidence interval (CI) and p value. A p value of < 0.05 was defined as statistically significant. Statistical analyses were performed with SPSS  and R (R version 4.0.4).Normality of data was assessed using Kolmogorov–Smirnov and Shapiro–Wilk test. Mann–Whitney n = 148, 83.1%), NTR , or XTR . One patient (0.6%) received both, MitraClip NTR and XTR.Overall, 178 patients undergoing M-TEER for moderate-to-severe or severe SMR and sufficient echocardiographic MV assessment  before the procedure were included. Patients mean age was 72 ± 11 years. The etiology of SMR was ischemic in 106 patients (59.2%). Mean LV-EF was impaired with 35.3 ± 11.2%. All patients had MR grade 3 + (59.6%) or 4 + (40.4%). LV-EDV and LV-ESV were 178.9 ± 69.9 ml and 117.0 ± 57.8 ml, respectively. Most patients presented highly symptomatic in NYHA functional class III (74.2%) or IV (25.7%). Average renal function was impaired in the majority of patients (estimated glomerular filtration rate [eGFR] 53.6 ± 22.8 ml/min). Clinical and echocardiographic baseline characteristics are shown in Table M-TEER led to a procedural decrease of MR severity to grade ≤ 1 + in 117 (65.7%) patients, and ≤ 2 + in 164 (92.1%) patients. Postprocedural MR was 3+ and 4+ in 12 patients (6.7%) and 2 patients (1.1%), respectively. Clinical follow-up rates in eligible patients were 88.8% at 1 year and 82.1% at 2 years. Overall survival rates were 80.4% and 70.6% at 1- and 2-year follow-up, respectively. NYHA class follow-up was available in 121 patients (70.0%).p = 0.03} provides discriminatory power regarding prediction of 2-year all-cause mortality. Subsequent calculation of Youden’s J identified a PLA/ALA ratio > 1.54 as best discriminatory value for asymmetric postero-anterior tethering regarding 2-year survival prognosis . Figure Table p = 0.042, Supplementary Table 1) in patients with asymmetric postero-anterior tethering. MR severity expressed by MR EROA, RegVol, and VC was comparable in both groups. A logistic regression model identified CAD {Odds ratio [OR] = 2.19, CI 1.13–4.23, p = 0.02} and MV mean PG  to be associated with asymmetric postero-anterior tethering (Supplementary Table 2). Implantation of at least one clip was successfully performed in 167 patients (93.8%) in the total cohort. Postprocedural MR remained higher in patients with asymmetric postero-anterior tethering (p < 0.01), while there was no difference at baseline .Clinical baseline characteristics did not differ between patients with symmetric and asymmetric postero-anterior tethering, except for a higher prevalence of previous coronary artery bypass graft (CABG) surgery and coronary artery disease . Figure Medio-lateral MV leaflet tethering asymmetry was defined as the ratio of the MV tenting area in MV segment 3 compared to segment 1. ROC analysis and subsequent calculation of Youden’s J revealed an S3/S1 ratio > 1.49 as being associated with survival; thus, we termed this pattern asymmetric medio-lateral tethering . Furthermore, logistic regression did not identify parameters being independently associated with asymmetric medio-lateral tethering (Supplementary Table 4).Of note, there were no between-group differences in clinical or echocardiographic parameters at baseline , except for a higher degree of TR severity in patients with asymmetric medio-lateral tethering (Supplementary Tables 1 and 3). Correspondingly, sensitivity analysis did not identify a significant cut-off for the association of medio-lateral tethering symmetry and residual MR , eGFR , prior CABG , extracardiac arteriopathy , asymmetric postero-anterior leaflet tethering , and asymmetric medio-lateral tethering  to be associated with increased all-cause 2-year mortality  are needed to clarify the exact pathophysiologic mechanism.The current study outlines the importance of asymmetric MV leaflet tethering on both procedural MR reduction and mortality following a transcatheter treatment approach for severe SMR. In MV surgery, both asymmetric postero-anterior and medio-lateral tethering have been identified as conditions associated with higher rates of residual MR, and mortality , 20, 28.This is a retrospective, single-center analysis of M-TEER treated patients without core-lab supervision whose follow-up data were acquired prospectively. Three-dimensional and multiple high-quality biplane two-dimensional imaging in various planes are state-of-the-art echocardiography in evaluating MV anatomy and function, which was necessary to perform the current analyses. Accordingly, a few patients, in whom such detailed imaging was not available, had to be excluded from this analysis. Even after application of a multivariable Cox model, we cannot rule out that further parameters not included into the manuscript may have an impact on the predictive value of asymmetric tethering patterns. Due to the retrospective character of this study, no information on the exact localization of previous MI was available. Since patients with asymmetric tethering had worse survival after M-TEER, there could be bias for NYHA follow-up examination. We further acknowledge that the newly defined cut-offs for the definition of postero-anterior and medio-lateral tethering need further prospective validation in larger M-TEER patient cohorts, especially in the light of possible differences in baseline characteristics between patients.Asymmetric tethering of the mitral valve leaflets—either in the postero-anterior or medio-lateral direction—is identified as strong independent predictors for all-cause 2-year mortality in patients with severe SMR undergoing M-TEER. Accordingly, we recommend including the precise evaluation of asymmetric tethering patterns into the routine pre-interventional assessment of SMR to account for potential challenges in MR reduction as well as considering alternative devices including transcatheter mitral valve implantation which may be associated with improved outcomes in such patients. Further randomized-controlled trials are needed to compare different interventional MV repair devices and techniques.Supplementary file1 (DOCX 298 KB)Supplementary file2 (DOCX 59 KB)Below is the link to the electronic supplementary material.


Level of Difficulty: Advanced.)Restrictive cardiomyopathy (RCM) has a poor prognosis and limited treatment options apart from heart transplantation (HTx). We report on the first-in-human interventional atrial flow regulator (AFR) implantations in 3 children with RCM, leading to marked clinical and hemodynamic improvement. We propose the AFR as bridge to HTx or destination therapy in RCM. (  The consequent left atrial (LA) hypertension causes pulmonary congestion and postcapillary pulmonary hypertension (PH), which is associated with high mortality and morbidity.Device-based solutions to improve cardiac physiology in HFpEF and to prevent the aforementioned isolated postcapillary PH and its progression combined pre- and postcapillary PH have been proposed:,Although the AFR device has been implanted in older adults (>60 years of age) with HFpEF/HFrEF and LA hypertension,A 12-year-old girl first noticed dyspnea on exertion and general weakness, followed by progressive fatigue and fading exercise tolerance, to the extent that she could barely walk . Echocardiography enabled the diagnosis of LV-predominant cardiomyopathy with LA enlargement.2) and a nondilated, nonhypertrophied LV (LVEDV 77 mL/m2) with preserved systolic function (LVEF 58%). There was no late gadolinium enhancement, no clear evidence of myocardial edema, and no signs of noncompaction of the LV. Subsequent cardiac catheterization, 1 year after the first symptoms revealed low right-sided and very high left-sided filling pressures, mildly elevated mean pulmonary artery pressure  and diastolic pulmonary artery pressure (dPAP 16 mm Hg), a pulmonary vascular resistance (PVR) index <3 WU/m2, and normal cardiac index, qualifying her as having HFpEF with mild PH (Cardiac magnetic resonance (MR) on admission showed a severely enlarged LA  (2 to 37 mL/m2 (−52%) and pulmonary blood flow index/systemic blood flow index had increased from 0.94 to 1.52 after the AFR implantation (2), and improved left-sided filling pressures   . Subsequ2) . The sizantation , Table 1antation . AlreadyA 9-year-old girl with a diagnosis of RCM in severe heart failure  required frequent hospitalizations to intensify pharmacotherapy . At the TNNI3 gene, encoding for troponin I3. She had gradual deterioration in hemodynamics and experienced a few incidents of deterioration/decompensation despite pharmacotherapy , so that she was listed for heart transplantation (HTx) at the age of 4 years. Cardiac catheterization with AFR implantation (6-mm fenestration) was performed: Subsequently, her clinical condition, NTproBNP, and LA size  improved within 1 month of follow-up care , and endomyocardial processes . The prognosis of familial and nonfamilial RCM is poor and is even worse in children than in adults: According to the Pediatric Cardiomyopathy Registry, the 1-year and 5-year transplantation-free survival rates for pure RCM in children are only 48% and 22%, respectively.A meta-analysis of 6 studies on a total of 226 patients explored the feasibility and efficacy of transcatheter interatrial shunt devices for chronic heart failure (3 different devices).The prospective, nonrandomized, multicenter phase 2 PRELIEVE study  reported the first-in-human use of the AFR for older patients with HFpEF  or HFrEF . The resting PAWP decreased by 5 mm Hg (median) at 3 months after the AFR implantation.Here, we report the first-in-human transcatheter AFR device implantations in RCM. The transcatheter procedure was feasible and safe in 3 children, 6 to 13 years old, and it improved LA dilation, postcapillary pulmonary hypertension, and HF symptoms. The AFR creates permanent interatrial communication, improves quality of life, and likely extends survival in HFpEF/HfrEF; however, these findings should be confirmed in future prospective studies in patients with cardiomyopathy and LA hypertension.Creating an interatrial communication is a therapeutic option for patients with HFpEF and HFrEF, including RCM. Early AFR device implantation can be considered a bridge to HTx in young patients with RCM and a destination therapy in those who are not HTx candidates.www.pvdnetwork.org). Dr. Sabiniewicz is a consultant for Occlutech, the producer of the atrial flow regulator device. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.This report was funded by a grant from the German Research Foundation . Dr. Hansmann has received funding from the Federal Ministry of Education and Research  and the European Pediatric Pulmonary Vascular Disease Network (


Mean pulmonary artery wedge pressure (PAWP) represents a right heart catheter (RHC) surrogate measure for mean left atrial (LA) pressure and is crucial for the clinical classification of pulmonary hypertension (PH). Hypothesizing that PAWP is related to acceleration of blood throughout the LA, we investigated whether an adequately introduced LA acceleration factor derived from magnetic resonance (MR) four-dimensional (4D) flow imaging could provide an estimate of PAWP in patients with known or suspected PH.ClinicalTrials.gov identifier: NCT00575692) were retrospectively analyzed. Early diastolic LA peak outflow velocity (vE) as well as systolic (vS) and early diastolic (vD) LA peak inflow velocities were determined with prototype software to calculate the LA acceleration factor (α) defined as α = vE/[(vS + vD)/2]. Correlation, regression and Bland-Altman analysis were employed to investigate the relationship between α and PAWP, α-based diagnosis of elevated PAWP (>15 mmHg) was analyzed by receiver operating characteristic curve analysis.LA 4D flow data of 62 patients with known or suspected PH who underwent RHC and near-term 1.5 T cardiac MR (r = 0.94). Standard deviation of differences between RHC-derived PAWP and PAWP estimated from linear regression model (α = 0.61 + 0.10·PAWP) was 2.0 mmHg. Employing the linear-regression-derived cut-off α = 2.10, the α-based diagnosis of elevated PAWP revealed the area under the curve 0.97 with sensitivity/specificity 93%/92%.α correlated very strongly with PAWP (The very close relationship between the LA acceleration factor α and RHC-derived PAWP suggests α as potential non-invasive parameter for the estimation of PAWP and the distinction between pre- and post-capillary PH. Mean pulmonary artery wedge pressure (PAWP) represents a surrogate for mean left atrial (LA) pressure , 2, and If there is one, then a flow-based correlate for PAWP is likely to be encoded in LA blood flow patterns. MR 4D flow imaging of the LA has mainly been employed to study vortical blood flow and stasis within the LA –9. The LWe therefore hypothesized that PAWP should correlate closely with a LA acceleration factor—defined as an adequate ratio of 4D flow-derived LA peak outflow to peak inflow velocities. The purpose of the present study was to investigate the relationship between the LA acceleration factor and PAWP in patients with known or suspected PH.ClinicalTrials.gov identifier, NCT00575692) complied with the Declaration of Helsinki, was approved by the local ethical review board and all subjects gave written informed consent. 4D flow in the right ventricular outflow tract of the subjects was explored previously  using the transjugular approach. Zero reference level was set to anterior axillary line. All intrathoracic pressures—including PAWP—were averaged over 3–4 respiratory cycles during normal respiration. No triggering on any respirator or cardiac waves was employed . RHC parElectrocardiographically (ECG)-gated cardiac MR imaging, including functional imaging and 4D flow imaging of the left atrium, was performed on a 1.5 T MR scanner  using a 6-channel cardiac-array coil together with a spine array coil. Subjects were investigated in the supine position.3 in long-axis and 2.2 × 1.4 × 8.0 mm3 in short-axis view; imaging time per slice, 12–15 heart beats in long-axis and 6–8 heart beats in short-axis view.For functional assessment, retrospectively ECG-gated, balanced steady state free precession (bSSFP) cine series were obtained in 2-chamber and 4-chamber views as well as in contiguous gapless short-axis slices covering the ventricles. Imaging parameters were as follows: temporal resolution, 32–41 ms in long-axis and 48–54 ms in short-axis view; interpolated cardiac phases, 30; echo time, 1.2 ms; flip angle, 60°; bandwidth, 930 Hz/pixel; voxel size, 1.7–1.9 × 1.4 × 6.0 mm3; imaging time per slice, 22–24 heart beats.4D flow imaging data were acquired employing a retrospectively ECG-gated, segmented, two-dimensional (2D) spoiled gradient-echo-based cine phase-contrast sequence with three-directional velocity encoding by a simple four-point velocity encoding scheme. The LA was covered by gapless slices in 4-chamber orientation containing the orifices of the right and left inferior pulmonary veins as well as the mitral valve. Velocity encoding (VENC) was set to 90 cm/s in all directions and was adapted—if necessary—to prevent aliasing in regions close to the mitral valve. Further protocol parameters were as follows: temporal resolution, 89 ms; interpolated cardiac phases, 20; echo time, 4.1 ms; flip angle, 15°; bandwidth, 455 Hz/pixel; GRAPPA  factor, 2; voxel size, 2.4 × 1.8 × 6.0 mmFunctional and 4D flow imaging were performed during multiple breath holding. For patients who were unable to hold their breath, three-fold averaging was used to suppress breathing artifacts.max) was calculated from cine bSSFP 2-chamber and 4-chamber images employing the bi-planar area-length method (Quantification of left ventricular (LV) and right ventricular (RV) end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), stroke volume (SV) and muscle mass (MM) was performed with standard software  by manual segmentation of myocardial end-diastolic and end-systolic epicardial and endocardial borders in the stack of bSSFP short-axis images including papillary muscles and trabeculae to the myocardium. Cardiac output (CO) was calculated from SV multiplied by the average heart rate during the short-axis scans. Additionally to ventricular volumetry, maximal LA volume (LAVh method . All nonvE) and late diastolic (vA) LA peak outflow velocities were defined as early and late diastolic peaks of the transmitral maximal velocity-time curve; systolic (vS) and diastolic (vD) LA peak inflow velocities were defined as systolic and early diastolic peaks of the left or right pulmonary venous maximal velocity-time curve, whichever exhibited higher velocities  velocities across the time-varying planes of the atrio-ventricular junction and the atrial junctions of the left and right inferior pulmonary veins were determined from 4D flow data employing dedicated prototype software . Early diastolic .Statistical analysis was performed using NCSS software . NCSS, LLC. Kaysville, Utah, USA) employing a significance level of 0.05 for statistical tests. Mean values are given together with standard deviations and diagnostic measures are specified together with 95%-confidence intervals. The nomenclature 0.3–0.5 = weak, 0.5–0.7 = moderate, 0.7–0.9 = strong, and 0.9–1.0 = very strong is employed for classifying the strength of a correlation by the Pearson's correlation coefficient  and Tukey-Kramer multiple comparison procedure. Relationships between these parameters were investigated by means of correlation and linear regression analysis. The dependency of slopes and intercepts of the linear regression models on binary variables was analyzed by adding them (with and without interaction) separately to the respective linear regression model and performing partial vE, vA, vS and vD was employed to motivate the definition of the LA acceleration factor α as linear correlate to PAWP among all general ratios  of linear combinations of LA peak outflow velocities to linear combinations of LA peak inflow velocities: Up to a multiplicative constant such a general ratio can be written asNon-linear regression of PAWP on cout and cin are constants and where vE+A, vE−A, vS+D, and vS−D represent short notations for (vE + vA)/2, (vE – vA)/2, (vS + vD)/2, and (vS – vD)/2, respectively. A specific choice of αgeneral was interpreted as optimal if the choices for cout and cin were contained within the large sample 95%-confidence intervals of the non-linear regression of PAWP on vE, vA, vS and vD.where calc from α and to compare PAWPcalc and PAWP by Bland-Altman analysis. The diagnostic performance of α in predicting PAWP > 15 mmHg was investigated by means of receiver operating characteristic curve (ROC) analysis.The linear regression equation of α on PAWP was inverted to derive calculated mean pulmonary arterial wedge pressure values PAWPt-test was employed to test if differences of quantities from velocity measurements at different locations differed from zero. Pearson correlation coefficients between PAWP and LA acceleration factors derived from velocity measurements at different locations were compared by means of Williams-Hotelling test.One-sample n = 15), PH due to lung diseases (n = 2), chronic thromboembolic PH (n = 2) and PH with unclear multifactorial mechanisms (n = 2). Demographic, RHC-derived hemodynamic and volumetric cardiac parameters of the study population derived from RHC are summarized in max demonstrated the strongest correlation to PAWP (r = 0.49). After omission of one severe outlier in the pre-capillary PH group the correlation increased to r = 0.60; the significance of differences in LAVImax between non-PH, pre-capillary PH and post-capillary PH subjects remained unaltered.PH was diagnosed in 34 of the analyzed 62 patients; nine patients demonstrated mPAP between 21 and 24 mmHg, one of them with PAWP > 15 mmHg. Nineteen patients had normal mPAP <21 mmHg. Thirteen PH patients with PAWP > 15 mmHg were classified as having post-capillary PH. The remaining 21 pre-capillary PH patients suffered from pulmonary arterial hypertension .LA peak inflow velocities were determined from the left inferior pulmonary vein's inflow in 25 subjects and from the right inferior pulmonary vein's inflow in 37 subjects. vS correlated moderately negatively (r = −0.57) and vE moderately positively (r = 0.59) with PAWP, whereas vD and vA did not show significant correlations with PAWP. The linear regression results of LA peak in- and outflow velocities are shown in vS when added to PAWP.general, regression of PAWP on vE, vA, vS and vD for all patients with biphasic transmitral flow profile (n = 56) resulted in a non-linear correlation coefficient r = 0.94 and 95%-confidence intervals 0.53–1.14 and −0.06 to 0.33 for the constants cout and cin, respectively. Fixing cout = 1 and performing regression of PAWP on vE, vS and vD for all patients resulted in r = 0.94 and the 95%-confidence interval −0.05 to 0.26 for cin. Consequently, cout = 1 and cin = 0 or, equivalently, omission of vA- and vS−D-terms in α were optimal when searching for a linear correlate to PAWP. Notably cin = 1  was not in the derived 95%-confidence intervals, although vE/vS correlated strongly with PAWP (r = 0.85).Assuming a linear relationship between PAWP and αp < 0.0001).Mean α for all patients was 1.69 ± 0.57. While mean α for patients without PH (1.46 ± 0.42) and for patients with pre-capillary PH (1.51 ± 0.40) did not differ significantly, both differed significantly from mean α in the post-capillary PH group , even when restricted to the non-PH (r = 0.90), the pre-capillary PH (r = 0.91) and the post-capillary PH (r = 0.80) groups. The linear regression equation α = 0.61 + 0.10·PAWP (PAWP in mmHg) is shown in r2 and prediction sum of squares (PRESS) R2 was small (0.01). Inversion of the linear regression equation to calculate PAWP from α  resulted in a standard deviation of differences of SD = 2.0 mmHg between PAWP and PAWPcalc; the corresponding Bland-Altman plot is presented in α correlated very strongly with PAWP  for the prediction of PAWP > 15 mmHg employing α was 0.97 with a 95%-confidence interval of 0.90–0.99 . The cutThe AUC for the diagnosis of post-capillary PH in PH patients was 0.95 with the 95%-confidence interval 0.83–0.99. Sensitivity and specificity for the cut-off value α = 2.10 were 92 and 86%, with 95%-confidence intervals of 64–100 and 64–97%, respectively, whereas the sum of sensitivity and specificity was maximized for the cut-off value α = 1.90 with sensitivity and specificity of 100 and 86% , respectively.vE, tip was the only velocity exhibiting a significant bias to vE. vD, vein correlated, however, only weakly with vD. In contrast to measurements at the atrial junction, the means of vD, vein in the non-PH (30 ± 8 cm·s−1), the pre-capillary PH (37 ± 8 cm·s−1) and the post-capillary PH (40 ± 12 cm·s−1) groups differed significantly between non-PH and PH subjects (p = 0.0026). Moreover, vD, vein correlated significantly with sPAP (r = 0.44), mPAP (r = 0.33), dPAP (r = 0.31), PVR (r = 0.31), and TPG (r = 0.27).tip, αvein and αtip/vein on PAWP are shown in r = 0.85, p = 0.0004 for the correlation between PAWP and αtip, r = 0.69, p < 0.0001 for the correlation between PAWP and αvein, and r = 0.61, p < 0.0001 for the correlation between PAWP and αtip/vein). Notably, intercepts of the linear regression lines of αvein and αtip/vein on PAWP depended significantly on the presence of PH .Linear regressions of αvE and vA to linear combinations of vS and vD, (2) correlated very strongly with PAWP, (3) allowed an accurate prediction of PAWP > 15 mmHg, and (4) depended significantly on the location of measurement of vE, vS and vD.The main results of the study were that the LA acceleration factor α (1) represented an optimal linear correlate to PAWP among all ratios of linear combination of vE, a decrease of vS and non-significant changes of vA and vD with PAWP, are in line with the common interpretation of mean LA pressure as a major determinant of pulmonary venous and early diastolic transmitral blood flow velocities .Author GR is an employee of Siemens Healthcare Diagnostics GmbH. The remaining 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.


We report an autopsy case of a 69-year-old female with cervical cancer. She was given bevacizumab-containing chemotherapy for 4 months. After two years of chemotherapy, she developed congestive heart failure (CHF) with left ventricular dysfunction. Cardiac magnetic resonance (CMR) imaging revealed late gadolinium enhancement (LGE) of linear mid-wall delayed enhancement located in the basal to the mid-septal wall, suggesting bevacizumab-related cardiotoxicity. Although she was treated with cardioprotective medications and discharged, she eventually died from worsening CHF a year later, and we conducted an autopsy. Histopathological examination revealed diffuse fibrosis in the myocardium, and the area where LGE was present on CMR showed thinning and wavy changes in cardiomyocytes with diffuse interstitial fibrosis and edema. Cancer treatment at present employs a combination of chemotherapy, radiotherapy, and surgery to prolong life and provide a cure. However, many of these treatments can cause cardiovascular complications such as heart failure, hypertension, thromboembolism, myocardial ischemia, and arrhythmias . These cA 69-year-old woman with cervical cancer presented with acute decompensated heart failure. Two years before heart failure development, she was diagnosed with cervical cancer and underwent chemotherapy combined with bevacizumab (4.9 mg/kg/week) and paclitaxel (1.0 mg/kg/week) for 4 months. Before chemotherapy, she had no history of cardiovascular disease including hypertension; electrocardiography (ECG) showed a sinus rhythm and narrow QRS morphology with nonspecific T wave abnormalities , and echOn admission, her breathing was rapid, and she had tachycardia, jugular venous distension, and lower-extremity edema. Her blood pressure was 96/59 mmHg, with a heart rate of 125/min. ECG demonstrated sinus tachycardia with a wide QRS complex in the pattern of left bundle branch block . Chest r1 antibody that targets vascular endothelial growth factor (VEGF), is widely used for the treatment of various solid tumors. Following the rapid introduction of VEGF signaling inhibitors (VEGFIs), a range of VEGFIs-associated cardiovascular toxicities has been reported. VEGFIs-associated hypertension has received the most attention, with an increase in blood pressure occurring in 80–90% of patients treated with VEGFIs. Moreover, VEGFIs are associated with a wider range of cardiovascular toxic effects, including left ventricular systolic dysfunction (LVSD), heart failure, arterial and venous thromboembolism, QT interval prolongation, and arrhythmia. The incidence of VEGFIs-associated LVSD may range from 10 to 20%, with the incidence of heart failure being approximately 1–5% [Bevacizumab, a humanized monoclonal immunoglobulin Gely 1–5% . Althougely 1–5% . VEGF inely 1–5% ,7. HowevA limitation of this case is that the patient had mild LV dysfunction before chemotherapy. The possibility that the patient had the organic cardiac disease before the chemotherapy cannot be completely ruled out. However, the patients certainly had no history of cardiovascular disease including hypertension and no cardiovascular family history and there was no evidence of LV hypertrophy, LV enlargement, LV asynergy, or valvular disease before chemotherapy. Considering the above and pathohistological findings, it is unlikely that organic myocardial injury had originally been present before chemotherapy.This is the first case report of bevacizumab-related cardiotoxicity based on CMR imaging and histopathological findings. The early detection of LV dysfunction using CMR-LGE may allow for one to adjust treatment with bevacizumab or cardioprotective treatment before the development of irreversible heart failure.


Compared to the 3-month assessment, individuals with c-SCI displayed structural, functional, and mechanical changes during the 6-month assessment, including significant reductions in end diastolic volume , stroke volume , myocardial contractile velocity (S') , and peak diastolic longitudinal strain rate , and increased early diastolic filling over early myocardial relaxation velocity (E/E') ratio . These indices did not significantly change in individuals with tl-SCI between time points. Ejection fraction was different between individuals with c-SCI and tl-SCI at 3  and 6 months , though values were considered normal. These results demonstrate that individuals with c-SCI exhibit significant reductions in cardiac function from 3 to 6 months post-injury, whereas individuals with tl-SCI do not, suggesting the need for early rehabilitation to minimize cardiac consequences in this specific population.Individuals with cervical spinal cord injury (SCI) experience deleterious changes in cardiac structure and function. However, knowledge on when cardiac alterations occur and whether this is dependent upon neurological level of injury remains to be determined. Transthoracic echocardiography was used to assess left ventricular structure, function, and mechanics in 10 male individuals  with cervical ( Left ventricular (LV) atrophy and decreased volumes are well documented in individuals with chronic spinal cord injury (SCI) . DecreasSimilar to SCI, microgravity exposure during spaceflight has been associated with an overall physiological decline, providing a potential model to better understand the alterations in these specific populations over time . While tNo study to date has examined the longitudinal changes in cardiac function post-SCI in the sub-acute setting , stratifying for neurological level of injury (NLI). Thus, the aim of this present longitudinal case series was to investigate changes in LV structure, function, and mechanics, in individuals with cervical SCI and thoracolumbar SCI at 3- and 6-months post-injury using transthoracic echocardiography (TTE) .Clinical protocols were approved by the University of British Columbia Clinical Research Ethics Board (H13-03072) and conducted in accordance with the second Helsinki Declaration. The participants provided written informed consent prior to data collection. The NLI and the severity of SCI were classified according to the International Standards for Neurological Classification of SCI (ISNCSCI) by a trained physician  . ParticiTTE was performed on a commercially available ultrasound  and stored for offline analysis using specialized computer software  according to the recommendations of the American Society for Echocardiography (ASE) , by a siThe average of three cardiac cycles was used to determine LV structure and functional indices. Measures of LV structure at end-diastole and end-systole were reported from the parasternal long-axis views, and used to derive relative wall thickness . VolumetIndices of LV mechanics were derived from apical four-chamber and parasternal short-axis images at the level of the mitral valve , papillary muscle (mid), and apex . Images were analyzed using 2D speckle-tracking software in accordance with recommended guidelines . Raw speP ≤ 0.05. Wilcoxon signed rank test were used to analyze outcomes between time points within groups. Group differences were analyzed using the Mann Whitney U-test. Results are presented as median with upper and lower quartiles . Graphical representations were made in Prism , SPSS, and Adobe Illustrator .Data are presented as raw values and percentages. Statistical analyses were performed using Statistical Package for Social Science software  with statistical significance set at n = 5) or thoracolumbar SCI (n = 5) were included. TTE was conducted 79 days (65–108) and 204 (191–218) post-injury. Demographics are highlighted in A total of 10 male participants  with motor-complete (AIS A/B) cervical SCI  , end-systolic volume (ESV) , SV , S' , and increased E/E' ratio  for individuals with cervical SCI. For LV diastolic mechanics, longitudinal strain rate was lower in the cervical group at three compared to 6 months    . These iP < 0.01), which was still within the normal range of 52–72% for males as per ASE guidelines . While a recent meta-analysis demonstrated that structural and functional changes are apparent for individuals with chronic SCI compared to non-injured individuals , these cReductions in LV structural and functional cardiac indices were found for individuals with cervical SCI between 3- and 6-months post-injury, whereas these changes were not apparent for individuals with thoracolumbar SCI. As the LTPA measures were highly variable but somewhat comparable amongst the cervical SCI and thoracolumbar SCI participants, the most likely explanation for the differences between groups can be attributed to the disrupted supraspinal regulation of sympathetic activity to the heart following cervical SCI . To suppDespite reductions in LV structure and global function in the cervical SCI group, indices of LV systolic mechanics were similar over time. Perhaps this can be attributed to a mechanical compensation post-SCI to maintain systolic function in the cervical SCI group. The observation of preserved systolic mechanics and reduced SV has been previously reported , and is . Therefore, self-reported minutes of moderate-to-vigorous-intensity physical activity do not reflect actual time spent performing activities at higher intensities as measured objectively via a heart rate monitor. Therefore, In-keeping with other results, it could be implied that individuals with SCI do not reach an effective cardiovascular training threshold to improve neurologic, cardiovascular, or musculoskeletal health during inpatient therapy . The patients/participants provided their written informed consent to participate in this study.MW and AK had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SB, TN, MW, KC, and AK contributed to conception and experimental design. SB acquired the data. SB, TN, and MW analyzed the data. SB, TN, KC, CW, TT, MW, and AK interpreted the data. SB and TN drafted the manuscript. SB, MW, TN, KC, CW, TT, and AK contributed to editing the final version of the manuscript. AK is the principle investigator of the project. TN and MW co-supervised the project. All authors contributed to the article and approved the submitted version.This work was supported by a grant  from the Craig H. Neilsen Foundation (Grant H13-03072), the Canadian Foundation of Innovation , and the BC Knowledge Development Fund . SB was supported by The Robert H.N. Ho Scholarship, UBC President's Academic Excellence Award, and Peter McLardie Award (Sonography Canada). TN was supported by a Postdoctoral Research Trainee Award from the Michael Smith Foundation for Health Research (MSFHR) in partnership with the International Collaboration on Repair Discoveries, (Grant Number: 17767). KC was supported by a Craig H. Neilsen Foundation Postdoctoral Fellowship (Grant Number: 281863). MW was supported by a Postdoctoral Research Trainee Award from MSFHR in partnership with the Rick Hansen Foundation (Grant Number: 17110). AK holds the Endowed Chair in Rehabilitation Medicine.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.