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Heart failure (HF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. Among the different types of HF, HF with preserved ejection fraction (HFpEF) is a highly prevalent, complex, and heterogeneous condition for which metabolic derangements seem to dictate disease progression. Changes in intermediate metabolism in cardiometabolic HFpEF—among the most prevalent forms of HFpEF—have a large impact both on energy provision and on a number of signalling pathways in the heart. This dual, metabolic vs. signalling, role is played in particular by long-chain fatty acids (LCFAs) and short-chain carbon sources [namely, short-chain fatty acids (SCFAs) and ketone bodies (KBs)]. LCFAs are key fuels for the heart, but their excess can be harmful, as in the case of toxic accumulation of lipid by-products (i.e. lipotoxicity). SCFAs and KBs have been proposed as a potential major, alternative source of energy in HFpEF. At the same time, both LCFAs and short-chain carbon sources are substrate for protein post-translational modifications and other forms of direct and indirect signalling of pivotal importance in HFpEF pathogenesis. An in-depth molecular understanding of the biological functions of energy substrates and their signalling role will be instrumental in the development of novel therapeutic approaches to HFpEF. Here, we summarize the current evidence on changes in energy metabolism in HFpEF, discuss the signalling role of intermediate metabolites through, at least in part, their fate as substrates for post-translational modifications, and highlight clinical and translational challenges around metabolic therapy in HFpEF.

Background In the DAPA-HF trial, SGLT inhibition reduces cardiovascular mortality in heart failure. However, the mechanism and a potential positive effect in HfpEF remain elusive. Introduction LA remodeling is a hallmark feature of HFpEF and commonly associated with LA enlargement and dysfunction. Previous studies of SGLT-2 inhibitor Empagliflozin suggest a utilization of alternative metabolites for energy consumption (i.e. ketone bodies). Additionally, alterations of sodium and calcium ion hemostasis have been reported. We investigated the effect of SGLT inhibition on mitochondrial (dys)function during atrial remodeling in HFpEF. Methods Rats (WT: Wistar Kyoto, HFpEF: ZFS-1 Obese (metabolic syndrome)) were obtained at ∼10w and fed Purina 5008 diet. At 17w, animals were randomized to treatment with either vehicle or Sota (30mg/kg/d) for 5w until primary adult cardiomyocytes were isolated for final experiments. Structural information of mitochondria was obtained with Mitotracker Red in either a glucose starved (1h incubation with mannitol) or saturated state. ROS production was assessed with H2-DCF in a starved and saturated condition. Mitochondrial calcium buffer capacity was imaged with Rhod-2 following perforation of the cellular membrane with saponin. Glycolytic dependency of calcium cycling was assessed upon glycolytic inhibition with 2-deoxyglucose during imaging of cytosolic calcium transients with Fura-2. Results In a glucose saturated state, LA cardiomyocytes in HFpEF showed increased mitochondrial density, which was ameliorated with Sota. Sota increased mitochondrial calcium buffer capacity in HFpEF, indicating a decrease in mitochondrial resting calcium. Differences in mitochondrial fission could not be detected. However, during glucose starvation cardiomyocytes showed a decrease in mitochondrial fission and ROS production with Sota. A difference in ROS production was not visible when cells were abruptly challenged with high glucose concentrations, but Sota decreased mitochondrial fission, indicating long term protective properties towards ROS. Glycolytic inhibition led to an increase of cytosolic diastolic calcium and calcium transient peak height in HFpEF vs. WT, indicating an increased glucose dependency of cytosolic calcium cycling, which was mitigated with Sota. Additionally, Sota negated an increase in diastolic calcium, when cardiomyocytes where challenged with high concentrations of glucose after starvation. Conclusion SGLT1/2 inhibition alters mitochondrial calcium uptake in HFpEF and positively affects mitochondrial structure with subsequent decreases of ROS production and enhanced calcium homeostasis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Else-Kröner-Fresenius-Stiftung, Deutsches Zentrum für Herz-Kreislaufforschung

Introduction Radiofrequency (RF) ablation is a commonly used tool in the invasive electrophysiology laboratory to treat a variety of rhythm disorders. Reliable creation of transmural ablation lesions is crucial for long-term success. Lesion size index (LSI) is a multiparametric index that incorporates time, power, contact force (CF), and impedance data recorded during RF ablation in a weighted formula and has been shown to predict the extent of myocardial tissue lesions. Whether the force stability of contact influences lesion size in LSI-guided ablations is unknown. Objectives The aim of this study was to analyze the influence of the force stability of contact on lesion size during LSI-guided ablations in an ex-vivo model. Methods and results A total of 267 RF lesions (n = 6 hearts) were created on porcine myocardial slabs by using an open-tip irrigated ablation catheter with the following settings: 35 W with either intermittent (varied between 0 and up to 20 g), variable (10 to 20 g), or constant tissue contact (15 g) in a perpendicular or parallel fashion (applied manually) up to a target LSI of either 5 or 6. Subsequently, lesion width and depth were determined. Lesion width was mainly influenced by catheter tip orientation and LSI, whereas lesion depth was mainly influenced by LSI alone. The force stability of catheter contact had no relevant impact on lesion width or depth. Conclusion The force stability of catheter contact has only little effect on lesion depth or width in LSI-guided catheter ablation while the catheter orientation primarily affects lesion width.

Aim Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF). Methods We assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)‐lean (control) and ZSF1‐obese rats, a metabolic risk‐related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo. Results At rest, mitochondrial Ca2+ concentration in ZSF1‐obese was larger than in ZSF1‐lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady‐state levels were larger in ZSF1‐obese. The half‐widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half‐times of the cytosolic Ca2+ transients were higher in ZSF1‐obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1‐obese. Conclusion The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.

Aims Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent. Methods and results Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca2+ transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca2+ release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca2+ and slowed Ca2+ removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca2+ content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca2+]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity. Conclusions Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.

In this article, we describe an optimized, Langendorff-based procedure for the isolation of single-cell atrial cardiomyocytes (ACMs) from a rat model of metabolic syndrome (MetS)-related heart failure with preserved ejection fraction (HFpEF). The prevalence of MetS-related HFpEF is rising, and atrial cardiomyopathies associated with atrial remodeling and atrial fibrillation are clinically highly relevant as atrial remodeling is an independent predictor of mortality. Studies with isolated single-cell cardiomyocytes are frequently used to corroborate and complement in vivo findings. Circulatory vessel rarefication and interstitial tissue fibrosis pose a potentially limiting factor for the successful single-cell isolation of ACMs from animal models of this disease. We have addressed this issue by employing a device capable of manually regulating the intraluminal pressure of cardiac cavities during the isolation procedure, substantially increasing the yield of morphologically and functionally intact ACMs. The acquired cells can be used in a variety of different experiments, such as cell culture and functional Calcium imaging (i.e., excitation-contraction-coupling). We provide the researcher with a step-by-step protocol, a list of optimized solutions, thorough instructions to prepare the necessary equipment, and a comprehensive troubleshooting guide. While the initial implementation of the procedure might be rather difficult, a successful adaptation will allow the reader to perform state-of-the-art ACM isolations in a rat model of MetS-related HFpEF for a broad spectrum of experiments.

Heart failure (HF) with preserved ejection fraction (HFpEF) is present in about 50% of HF patients. Atrial remodeling is common in HFpEF and associated with increased mortality. We postulate that atrial remodeling is associated with atrial dysfunction in vivo related to alterations in cardiomyocyte Calcium (Ca) signaling and remodeling. We examined atrial function in vivo and Ca transients (CaT) (Fluo4-AM, field stim) in atrial cardiomyocytes of ZSF-1 rats without (Ln; lean hypertensive) and with metabolic syndrome (Ob; obese, hypertensive, diabetic) and HFpEF. Results At 21 weeks Ln showed an increased left ventricular (LV) mass and left ventricular end-diastolic pressure (LVEDP), but unchanged left atrial (LA) size and preserved atrial ejection fraction vs. wild-type (WT). CaT amplitude in atrial cardiomyocytes was increased in Ln (2.9 ± 0.2 vs. 2.3 ± 0.2 F/F0 in WT; n = 22 cells/group; p Summary In hypertensive ZSF-1 rats, a possibly compensatory increase of cytosolic CaT amplitude and increased SR Ca leak precede atrial remodeling and HFpEF. Atrial remodeling in ZSF-1 HFpEF is associated with an altered tubular network in-vitro and atrial contractile dysfunction in vivo, indicating insufficient compensation. Atrial cardiomyocyte dysfunction in vitro is induced by the addition of angiotensin II.

Abstract A wireline retrievable coring system for use with conventional drilling equipment is described. The coring system was developed and tested by Amoco and Security DBS for application in evaluating coal bed methane prospects where a large quantity of core is required and it is essential that the core be processed soon after it is cut. A drill plug allows alternating between coring and drilling without tripping the drill string. The system is particularly advantageous where long intervals are cored, multiple zones relatively close together are cored, or the exact depth of the target zone is unknown. The system has been used to core more than 4940 m in Poland, Germany, and France, with a combined recovery of 94%. Introduction In 1994 Amoco obtained concessions in Poland covering 450+ sqkm for the exploration for coal-bed methane. The concession agreement included an obligation to drill fifteen wells within three years. These wells were of two fundamental types: "Core holes" were needed in order to provide core to evaluate both the quality and quantity of the coal bed methane resource and to better define the geological environment. Production test holes were required to test completion methods and production rates. A combination of Polish Mining laws and certification issues dictated that both the core holes and production holes were to be drilled with rigs that were already available, in Poland. The initial concept was to drill the core holes with a small coring rig that had been previously used by a local Polish company to core the coal seams in the same area as the Amoco concession. These wells would be drilled as "expendable" holes with no intention of completing them. The production test holes would be drilled with conventional Polish oil and gas drilling rigs with a minimum amount of core taken in these wells. There were numerous coal seams in the concession area that needed to be evaluated. The exact depth, thickness, and number of these seams varies considerably across the concession area. The overburden rock is quite diverse, ranging from very hard and abrasive siderite to very soft shales. Information available from previous coring operations conducted in the concession area in the mid-1980's indicated that slim hole core holes were drilled with a combination of roller cone core bits and natural diamond core bits. These wells, cored with conventional coring equipment, took 120 - 200+ days to core 800 - 1700 m in wells with depths ranging from 1500 - 1800+ m. The available information for drilling times and costs for drilling the core holes with the same technology as previously used by the local Polish contractor indicated that there were several fundamental problems to be overcome. First, the cost of the overall evaluation program appeared to be prohibitive unless a way of providing a significant cost reduction could be found. Secondly, it appeared that the coring technology used in Poland at the time would be inadequate to provide an accurate measurement of the methane saturation. P. 471

Hirsutism is excess terminal hair that commonly appears in a male pattern in women. Although hirsutism is generally associated with hyperandrogenemia, one-half of women with mild symptoms have normal androgen levels. The most common cause of hirsutism is polycystic ovary syndrome, accounting for three out of every four cases. Many medications can also cause hirsutism. In patients whose hirsutism is not related to medication use, evaluation is focused on testing for endocrinopathies and neoplasms, such as polycystic ovary syndrome, adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and androgen-secreting tumors. Symptoms and findings suggestive of neoplasm include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass. Patients without these findings who have mild symptoms and normal menses can be treated empirically. For patients with moderate or severe symptoms, an early morning total testosterone level should be obtained, and if moderately elevated, it should be followed by a plasma free testosterone level. A total testosterone level greater than 200 ng per dL (6.94 nmol per L) should prompt evaluation for an androgen-secreting tumor. Further workup is guided by history and physical examination, and may include thyroid function tests, prolactin level, 17-hydroxyprogesterone level, and corticotropin stimulation test. Treatment includes hair removal and pharmacologic measures. Shaving is effective but needs to be repeated often. Evidence for the effectiveness of electrolysis and laser therapy is limited. In patients who are not planning a pregnancy, first-line pharmacologic treatment should include oral contraceptives. Topical agents, such as eflornithine, may also be used. Treatment response should be monitored for at least six months before making adjustments.

There are approximately 300,000 survivors of childhood cancer in the United States, and most of them receive their medical care from primary care physicians. Adult survivors of childhood cancer are at considerable risk of long-term morbidity and mortality beyond the recurrence of their primary malignancy. Late adverse effects can impair organ function, stunt growth and development, and cause neurocognitive dysfunction and secondary malignancies. To address the need for systematic, comprehensive care of this expanding high-risk patient population, the Children's Oncology Group has developed long-term follow-up guidelines. Proper use of these guidelines will allow primary care physicians to understand a patient's individual risk, provide additional screening as needed, and identify late adverse effects of childhood cancer early. The foundation of the care of an adult survivor of a childhood cancer is a complete, accurate account of the patient's cancer and subsequent therapy in the form of a Summary of Cancer Treatment. A complete Summary of Cancer Treatment allows a primary care physician to use the longterm follow-up guidelines to create an individualized care plan. This article will review the late adverse effects of childhood cancer therapy and the transition of patients from pediatric oncologists to physicians in adulthood, and explain how primary care physicians can use these tools to provide appropriate care to adult survivors of childhood cancer.