Treatment Option For Heart Failure Research Articles

Targeting Macrophage Phenotype for Treating Heart Failure: A New Approach.

Heart failure (HF) is a disease with high morbidity and mortality rates worldwide and significantly affects human health. Currently, the treatment options for HF are limited, and there is an urgent need to discover new therapeutic targets and strategies. Macrophages are innate immune cells involved in the development of HF. They play a crucial role in maintaining cardiac homeostasis and regulating cardiac stress. Recently, macrophages have received increasing attention as potential targets for treating HF. With the improvement of technological means, the study of macrophages in HF has made great progress. This article discusses the biological functions of macrophage phagocytosis, immune response, and tissue repair. The polarization, pyroptosis, autophagy, and apoptosis are of macrophages, deeply involved in the pathogenesis of HF. Modulation of the phenotypic changes of macrophages can improve immune-inflammation, myocardial fibrosis, energy metabolism, apoptosis, and angiogenesis in HF.

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: Real-life data from the Swedish Heart Failure Registry 2013-2020

Abstract Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

Contemporary treatment options in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately half of the heart failure population, with its prevalence markedly increasing with older age and the presence of cardio-metabolic comorbidities. Although HFpEF is associated with a high symptom- and mortality burden, historically there have been few evidence-based treatment options for patients with HFpEF. Recent randomized clinical trials have expanded evidence on pharmacological treatment options, introducing new agents for managing HFpEF. Given the complex clinical phenotype with pathophysiological heterogeneity and evolving diagnostic standards, the evidence-based management of HFpEF remains challenging for clinicians. This review summarizes the latest evidence from contemporary randomized clinical trials and recent guideline recommendations to provide guidance for the treatment of patients with HFpEF.

Heart failure with reduced left ventricular ejection fraction (HFrEF, HFmrEF)

Heart failure is the final stage of most heart diseases and, with over 64 million people affected worldwide, is considered a global pandemic. The prevalence is expected to continue to rise. The prevention and treatment of cardiovascular diseases and the early detection of patients suffering from heart failure are essential. Different therapies are available depending on the extent of the reduction in left ventricular ejection fraction (LVEF). Optimal treatment prevents unnecessary admissions to hospital, reduces mortality and improves quality of life. In the following article, we discuss the diagnosis of heart failure and explain the various treatment options for heart failure with reduced LVEF (HFrEF, HFmrEF).

Study on the hemodynamic effects of different pulsatile working modes of a rotary blood pump using a microfluidic platform that realizes in vitro cell culture effectively.

Rotary blood pumps (RBPs) operating at a constant speed generate non-physiologic blood pressure and flow rate, which can cause endothelial dysfunction, leading to adverse clinical events in peripheral blood vessels and other organs. Notably, pulsatile working modes of the RBP can increase vascular pulsatility to improve arterial endothelial function. However, the laws and related mechanisms of differentially regulating arterial endothelial function under different pulsatile working modes are still unclear. This knowledge gap hinders the optimal selection of the RBP working modes. To address these issues, this study developed a multi-element in vitro endothelial cell culture system (ECCS), which could realize in vitro cell culture effectively and accurately reproduce blood pressure, shear stress, and circumferential strain in the arterial endothelial microenvironment. Performance of this proposed ECCS was validated with numerical simulation and flow experiments. Subsequently, this study investigated the effects of four different pulsation frequency modes that change once every 1-4-fold cardiac cycles (80, 40, 80/3, and 20 cycles per min, respectively) of the RBP on the expression of nitric oxide (NO) and reactive oxygen species (ROS) in endothelial cells. Results indicated that the 2-fold and 3-fold cardiac cycles significantly increased the production of NO and prevented the excessive generation of ROS, potentially minimizing the occurrence of endothelial dysfunction and related adverse events during the RBP support, and were consistent with animal study findings. In general, this study may provide a scientific basis for the optimal selection of the RBP working modes and potential treatment options for heart failure.

Preprocedural simulation of a mitral transcatheter edge-to-edge repair using computed tomography imaging

Abstract Mitral transcatheter edge-to-edge repairs (TEERs) are a widespread treatment option for heart failure complicated with mitral regurgitation. Although we generally use trans-oesophageal echocardiography (TOE) to understand structural heart disease conditions, TOE does not provide a complete view of the heart and surrounding structures. As the TEER device moves in complex ways during the procedure, it is difficult to imagine the actual behavior of the device only from the images obtained from TOE because of its restricted angle of view. Contrast-enhanced CT, on the other hand, is a modality that can capture the image of the heart as a whole, as if looking at a bird’s eye view. The purpose of our study was to create a TEER device simulator using ECG-gated computed tomography imaging. As the first step, we created a virtual inferior vena cava and fossa ovalis model. We obtained 192 possible CT image patterns of the TEER device with this model, and they all were extracted into an STL file format. As the second step, the ECG-gated cardiac CT images of the patients were segmented into each cardiac structure and also extracted into STL files. Finally, both STL file images were fused by some 3D software, and we made a simulation of the TEER procedure preoperatively. By piling up each knob operation and rotation, we could reproduce the serial movement of the TEER device. We could successfully reproduce the TEER device with each knob operation and rotation on a patient-specific cardiac CT image. The positional relationship between the heart and device were visualized, showing the entire trajectory of the device. It could also allow preoperative simulations to be tailored to each patient. Compared to some previous reports about TEER simulations using 3D printing models, our method could save time and cost 1)2). Another report demonstrated a simulator using a cardiac CT image, but that report did not mention how to obtain the device image 3). Our method would be more precise because our simulator was based on real TEER device images. We will apply this method for upcoming real cases and will then confirm whether a preoperative simulation of the ideal manipulation would enable optimal clipping. We successfully created a prototype of a TEER simulator using ECG-gated computed tomography imaging.en face view of the mitral valve (TOE)en face view (simulator)

Review of best treatment option in heart failure 2023

Congestive heart failure is a clinical condition in which the heart is unable to pump enough blood to meet the metabolic needs of the body because of pathological changes in the myocardium. The three main causes of CHF are coronary artery disease, diabetes mellitus, and hypertension. US hospitalizations for heart failure decreased up until 2012; however, from 2013 to 2017, an increase in HF hospitalizations was observed. In 2017, there were 1.2 million HF hospitalizations in the United States among 924 000 patients with HF. This represents a 26% increase in HF hospitalizations and number of patients hospitalized with HF. For this reason, as a team, we have decided to conduct a review of the best treatment options for heart failure based on multiple articles.

Which Factors Influence the Immensely Fluctuating CRT Implantation Rates in Europe? A Mixed Methods Approach Using Qualitative Content Analysis Based on Expert Interviews.

(1) Background: Cardiac resynchronisation therapy (CRT) is nowadays an indispensable treatment option for heart failure. Although the indication is subject to clear cross-national guidelines by the European Society of Cardiology (ESC), there is immense variation in the number of implantations per 100,000 inhabitants in Europe, especially in German-speaking countries (Germany, Austria and Switzerland). The aim of the present study was to identify possible factors for these differences using a qualitative research approach. (2) Methods: Semi-standardized interviews were conducted with 11 experts in the field of CRT therapy (3 experts from Germany, 4 from Austria and 4 from Switzerland) using a pre-prepared interview template and analysed according to Mayring's qualitative content analysis. (3) Results: The main factors identified were the costs of purchasing the devices and the financing systems of the respective healthcare systems, although cost pressure still seems to play a subordinate role in the German-speaking countries. Moreover, "lack of implementation of ESC guidelines", "insufficient training" and "lack of medical infrastructure" could be excluded as potential reasons. (4) Conclusions: Economic factors, but not a lack of adherence to ESC guidelines, seem to have a major influence on the fluctuating implantation figures in German-speaking countries, according to the unanimous assessment of renowned experts.

Plasma Extracellular Vesicles as Liquid Biopsy to Unravel the Molecular Mechanisms of Cardiac Reverse Remodeling Following Resynchronization Therapy?

Cardiac resynchronization therapy (CRT) has become a valuable addition to the treatment options for heart failure, in particular for patients with disturbances in electrical conduction that lead to regionally different contraction patterns (dyssynchrony). Dyssynchronous hearts show extensive molecular and cellular remodeling, which has primarily been investigated in experimental animals. Evidence showing that at least several miRNAs play a role in this remodeling is increasing. A comparison of results from measurements in plasma and myocardial tissue suggests that plasma levels of miRNAs may reflect the expression of these miRNAs in the heart. Because many miRNAs released in the plasma are included in extracellular vesicles (EVs), which protect them from degradation, measurement of myocardium-derived miRNAs in peripheral blood EVs may open new avenues to investigate and monitor (reverse) remodeling in dyssynchronous and resynchronized hearts of patients.

Polypharmacy in Older People With Heart Failure: Roles of the Geriatrician and Pharmacist.

Heart failure (HF) is a common health condition that typically affects older adults. Many people with HF are cared for on an inpatient basis, by noncardiologists, such as acute medical physicians, geriatricians and other physicians. Treatment options for HF are ever increasing, and adherence to guidelines for prognostic therapy contributes to polypharmacy, which is very familiar to clinicians who care for older people. This article explores the recent trials in both HF with reduced ejection fraction and HF with preserved ejection fraction and the limitations of international guidance in their management with respect to older people. In addition, this article discusses the challenge of managing polypharmacy in those with advanced age, and the importance of involving a geriatrician and pharmacist in the HF multidisciplinary team to provide a holistic and person-centred approach to optimisation of HF therapies.

Abstract 15482: Self-Adaptive Deep Learning-Based Segmentation for Uniform and Functional Preclinical and Clinical CT Image Analysis

Currently, effective treatment options for heart failure are lacking. Methods to monitor cardiac function longitudinally can accelerate preclinical and clinical research into disease progression and novel drugs. However, manual image analysis of cardiac substructures is resource-intensive and error-prone. While automated methods exist for clinical CT images, translating these to preclinical μCT data is challenging. We aimed at employing deep-learning to automatically extract quantitative data on cardiac functional parameters, developing a uniform method for both μCT and CT images. For this, we collected 110 contrast-enhanced μCT images of wild-type and accelerated aging (Ercc1 Δ/- ) mice, as well as a public dataset of 60 segmented cardiac CT images. Substructures, i.e., the left ventricle, left myocardium and right ventricle, were manually segmented in 24 μCT images to create a training set. After template-based heart detection, two separate segmentation neural network architectures were trained using the nnU-Net framework. Automatic and manual segmentations of the μCT training set were nearly identical (mean Dice score 0.983). The estimated median Dice score (0.940) of the test set results was comparable to existing methods for μCT image segmentation. Also, the automatic volume metrics were similar to manual observations by an expert. In Ercc1 Δ/- mice, ejection fractions had significantly decreased, and myocardial mass increased by age 24 weeks. The mean Dice score of the CT segmentation results (0.925 ± 0.019, n = 40) was superior to those achieved by state-of-the-art algorithms. While further optimization and validation of the models is recommended, automated data extraction expands the use application of (μ)CT imaging, while reducing subjectivity and workload. In conclusion, the proposed method offers a pipeline to efficiently monitor disease progression in animals and humans, allowing uniform translation from preclinical to clinical studies.

Impact of post-transplant diabetes on left ventricular function following heart transplantation

Abstract Background Orthotopic heart transplantation (OHT) is an end-stage treatment option for heart failure (HF). Although post-transplant diabetes (PTDM) is a well-described complication following immunosuppressive treatment, the impact on LV function post-OHT has not been evaluated. The purpose of this study was to analyse the influence of PTDM on LV function in OHT patients using conventional and speckle tracking echocardiography. Furthermore, we aimed to compare echocardiographic LV function parameters to HbA1c levels in OHT recipients with or without PTDM. Methods The study included 104 (n=77 male, mean age 51±15 years) consecutive OHT patients (PTDM n=36) examined at their routine 3-year follow-up. Blood pressure, heart rate, and HbA1c levels were recorded in conjunction with the echocardiographic examination. Results Participants with PTDM demonstrated impaired LV function measured by global longitudinal strain (p=0.002). Patients with PTDM also revealed increased septum diameter (p=0.008), and a lower diastolic EA-ratio (p=0.04) compared to the non-PTDM patients. A weak correlation between high HbA1c levels and poor LVGLS was detected (r=0.30, p<0.05). No correlation was found when comparing echocardiographic parameters to blood pressure and heart rate. Conclusion A subtle LV dysfunction, including remodelling of the heart (i.e., increased wall thickness), reduced longitudinal contractile function, and altered diastolic function, was present in OHT patients with PTDM. Our findings suggest that sub-clinical myocardial dysfunction is present in OHT patients with PTDM and may progress to clinical LV dysfunction and HF. Hence, analysing secondary cardiac effects of PTDM in OHT patients may have a therapeutic and prognostic value and could potentially influence long-term patient survival. Funding Acknowledgement Type of funding sources: None.

Biventricular versus conduction system pacing after atrioventricular node ablation in heart failure patients with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrioventricular node ablation (AVNA) with biventricular (BiV) pacing is an established treatment option for heart failure (HF) patients with drug refractory atrial fibrillation (AF) (1). However, compared to conduction system pacing (CSP) modalities, including His bundle pacing (HBP) and left bundle branch pacing (LBBP), BiV pacing delivers non-physiological ventricular activation (2). Purpose To compare clinical outcomes of BiV pacing and both CSP modalities in HF patients with symptomatic AF who underwent AVNA. Methods Consecutive AF patients with LV ejection fraction (LVEF <50%) who received either BiV pacing or CSP in conjunction with AVNA between May 2015 and July 2021 were retrospectively analysed. Procedural characteristics, electrocardiographic, echocardiographic, and clinical parameters were assessed at baseline and 6 months after the procedure. Results Fifty-five patients (male 43.6%, age 71 years (IQR 10), LVEF 39% (IQR 14)) were included. Thirteen patients (23.6%) received BiV pacing, 30 patients (54.5%) HBP and 12 patients (21.8%) LBBP. All groups had similar baseline characteristics, acute success rate and adverse events. Post-procedural QRS duration was significantly shorter (p<0.01) in CSP (118 ms (IQR 28)) than in BiV pacing (172 ms (IQR 18)). While NYHA class improved in both HBP (p<0.01) and LBBP (p=0.01), it did not improve in BiV group (p=0.1) At follow-up, end systolic volume (ESVi) decreased in both HBP (48±20 to 32±12 mL/m2, p<0.01) and LBBP (62±22 to 52±22 mL/m2, p=0.02), but did not differ in BiV pacing group (51±12 to 53±14 mL/m2, p=0.6). Similarly, LVEF increased in HBP (form 39% (IQR 16) to 53% (IQR 14), p<0.01) and LBBP (from 41% (IQR 23) to 40% (IQR 25), p=0.04), but did not change in BiV group (from 38% (IQR 5) to 37% (IQR 6), p=0.9). Significantly lower (p<0.01) pacing thresholds were achieved in LBBP (0.75 V at 0.5 ms (IQR 0.3)) than in HBP group (1.0 V at 0.5 ms (IQR 1)). Two patients in HBP group were switched to right ventricular pacing due to rise in HBP threshold. In the remaining patients threshold remained stable during follow-up. Conclusion Conduction system pacing modalities showed superior symptomatic and echocardiographic improvement compared to BiV pacing after AVNA. While LBBP offered lower and more stable pacing parameters, there were no differences in clinical outcomes and echocardiographic remodelling when compared to HBP.

Pharmacological treatment options for heart failure with reduced ejection fraction: A 2022 update

ABSTRACT Introduction Despite considerable advances in the treatment of heart failure with reduced ejection fraction (HFrEF) over the last 60 years, mortality and morbidity remains high. Fortunately, in the last years, further developments expanded the toolbox for HF treatment. Areas covered The authors provide an overview of recent developments in HF treatment and bring the recommendations in the HF guidelines of the European Society of Cardiology into perspective. Expert opinion Nowadays, basic pharmacological treatment of patients with HFrEF consists of a combination of angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and the SGLT2 inhibitors dapagliflozin or empagliflozin. Treatment initiation of all four drug classes should be fast and simultaneous. In some cases, the ARNI sacubitril/valsartan may be initiated even in ACE inhibitor-naïve patients. Further HF treatment has to be individualized. Another important point is that both SGLT2 inhibitors and vericiguat can be used in patients with severely reduced kidney function. Finally, an important piece in the HF management puzzle is the treatment of its comorbidities. For instance, patients hospitalized for acute HF decompensation should be systematically screened for iron deficiency, since HF patients with proven iron deficiency benefit from intravenous ferric carboxymaltose.

Growing role of SGLT2i in heart failure: evidence from clinical trials

ABSTRACT Introduction : There is an unmet need for therapies that improve overall mortality and morbidity for patients with preserved ejection fraction, who comprise roughly half of all heart failure (HF) cases. The growing role of sodium–glucose cotransporter-2 inhibitors (SGLT2is) in cardiovascular outcomes provides a paradigm shift in the treatment of HF. Areas covered : This review article provides a general overview of the growing role of SGLT2is and summarizes the mechanism of action, side effects, and contraindications for the treatment of HF. We also discuss recent clinical trials measuring the effects of different SGLT2is as possible treatment options for HF with reduced ejection fraction and HF with mid-range and preserved EF. We conducted a review of all the randomized, controlled studies with SGLT2is in patients with known heart failure with and without type-2 diabetes (T2DM). We performed a literature search in PubMed, Google Scholar, the Web of Science, and the Cochrane Library while screening results by the use of titles and abstracts. Expert opinion : The promising pathophysiological profile of SGLT2i and their role in cardioprotective effects demonstrate an invaluable discovery in the management of patients with HF irrespective of their diabetes status.

Heart Failure with Preserved Ejection Fraction: a Pharmacotherapeutic Update.

While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients.

Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction

ABSTRACT Introduction Sacubitril/valsartan is the first-in-class angiotensin-receptor neprilysin inhibitor approved in 2015 for the treatment of heart failure with reduced ejection fraction (HFrEF). On 16 February 2021, the Food and Drug Administration acknowledged that “Benefits are most clearly evident in patients with left ventricular ejection fraction below normal,” thus potentially extending the use in subjects with heart failure and preserved ejection fraction (HFpEF). Areas covered The authors outline the regulatory history, pharmacokinetics, pharmacodynamics, and risk-benefit profile of sacubitril/valsartan in HFrEF and HFpEF. A critical cross-trial comparison is presented, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), together with an insight into the latest European Society of Cardiology guidelines, where the new category of heart failure with mildly reduced ejection fraction is introduced. Expert opinion Sacubitril/valsartan is a foundation of the pharmacological armamentarium in HFrEF to counteract the neuro-hormonal changes and reverse cardiac remodeling, together with beta-blockers, SGLT2i and mineralocorticoid receptor antagonists. The optimal sequence algorithm is an evolving issue, and the authors provide the reader with their personal perspective. A multidisciplinary management is encouraged to minimize the therapeutic inertia and manage tolerability issues, thus supporting adherence. Pragmatic trials, pharmacovigilance, and high-quality real-world evidence are crucial toward personalized safe prescribing of sacubitril/valsartan.

Angiotensin receptor-neprilysin inhibition by sacubitril/valsartan attenuates doxorubicin-induced cardiotoxicity in a pretreatment mice model by interfering with oxidative stress, inflammation, and Caspase 3 apoptotic pathway.

Doxorubicin (DOX) is a well-known cardiotoxic agent, whereas sacubitril/valsartan (Sac/Val) is an effective treatment option in heart failure. In this study, we aimed to evaluate the effect of Sac/Val on DOX-induced cardiotoxicity in pretreatment mice model. A total of 24 mice were equally classified into 4 groups; control group, DOX (20 mg/kg; fifth day), Sac/Val (80 mg/kg), and Sac/Val+DOX (Sac/Val was given from day one of the study before doxorubicin administration). Electrocardiography parameters, including durations of QRS, ST, QT, PP segment, and QT/PQ index were measured. Total antioxidant status (TAS), total oxidant status (TOS), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, NT-proBNP concentrations, and Caspase 3 activity were evaluated. At the end of the 9-day study duration, QRS, ST, QT intervals, QT/PQ index and TAS, TOS, TNF-α, IL-1β, IL-6 levels were significantly higher in the DOX group than in the control group (p<0.001). Moreover, there were significant differences only in the PP interval when comparing the Sac/Val+DOX and control groups (p<0.001). QRS, ST, QT intervals, and QT/PQ index, TAS, TOS, TNF-α, IL-1β, IL-6 levels were significantly lower in the Sac/Val+ DOX group compared with the DOX group (p<0.001). Furthermore, NT-proBNP levels were lower in the Sac/Val+DOX group compared with the DOX group along with less Caspase 3 apoptosis. Sac/Val seems to be cardioprotective against DOX-induced cardiotoxicity in pretreatment mice model. These findings can be attributed to the antiarrhythmic, anti-inflammatory, antioxidant, and antiapoptotic effects of Sac/Val as shown in this study.

Pathophysiological Mechanisms for Heart Failure with Preserved Ejection Fraction (HF‐pEF): A Mathematical Modeling Analysis

While there are many treatment options for heart failure with reduced ejection fraction (HF-rEF), therapeutic improvements in long-term outcomes for patients with heart failure with preserved ejection fraction (HF-pEF) have proven elusive. Part of the challenge is the heterogeneous phenotype and poorly understood mechanisms responsible for HF-pEF. A wide range of pathophysiological mechanisms have been proposed to cause or contribute to HF-pEF such as cardiac interstitial fibrosis, cardiac hypertrophy, impaired cardiac metabolism and bioenergetics, impaired LV relaxation, endothelial dysfunction, impaired nitric oxide (NO) bioavailability, vascular stiffening, and systemic inflammation, among others. In this study, we used a mathematical modeling approach to evaluate the contribution of a subset of these hypothesized mechanisms in producing a hemodynamic phenotype of HF-pEF. Utilizing an existing model of cardiorenal function, we created a virtual reference patient with baseline hypertension and associated LV hypertrophy as a comorbidity, since a history of hypertension is highly prevalent in HF-pEF. We varied parameters associated with hypothesized HF-pEF mechanisms over a wide range, alone and in combination. Cardiac changes included increased myocardial stiffness (representing fibrosis), decreased myocardial contractility (representing impaired cardiac bioenergetics), and impaired LV relaxation. Vascular changes included increased arterial stiffness and increased arterial resistance. HF-pEF was defined as a state with elevated LV end diastolic pressure (LVEDP), increased interstitial fluid volume (IFV), and normal ejection fraction (EF). As expected, hypertension and LV hypertrophy alone were not sufficient to increase LV EDP or IFV. Our simulations predicted that increasing LV stiffness or decreasing LV contractility tended to increase LVEDP and IFV, while changing both stiffness and contractility together magnified their effects. However, substantial changes in these parameters also suppressed EF into the HF-rEF range. A range of parameter values was identified that elevated LVEDP and IFV while keeping EF above 50%. In addition, inducing delayed ventricular relaxation had minimal effect on LVEDP or EF, but did elevate mean pulmonary venous pressure. On the vascular side, decreases in systemic or pulmonary vascular compliance had minimal effects on LVEDP or EF, but increased IFV. In summary, increased LV stiffness and mild decreases in LV contractility, on top of existing hypertension and hypertrophy, are predicted to contribute to the shift toward elevated preload and volume retention characteristic of heart failure, without suppressing ejection fraction. Decreased vascular compliance may exacerbate fluid overload.

Right Heart Phenotype in Heart Failure With Preserved Ejection Fraction.

The health burden of heart failure with preserved ejection fraction is increasingly recognized. Despite improvements in diagnostic algorithms and established knowledge on the clinical trajectory, effective treatment options for heart failure with preserved ejection fraction remain limited, mainly because of the high mechanistic heterogeneity. Diagnostic scores, big data, and phenomapping categorization are proposed as key steps needed for progress. In the meantime, advancements in imaging techniques combined to high-fidelity pressure signaling analysis have uncovered right ventricular dysfunction as a mediator of heart failure with preserved ejection fraction progression and as major independent determinant of poor outcome. This review summarizes the current understanding of the pathophysiology of right ventricular dysfunction in heart failure with preserved ejection fraction covering the different right heart phenotypes and offering perspectives on new treatments targeting the right ventricle in its function and geometry.