or studies using pulmonary catheterization [1, 22, 23]. This might be based on the difference in the evaluation of the EF primarily when using non-enhanced 2D echocardiog- raphy . For example, Navarri et al. showed significant changes after levosimendan infusion in LVEF with echocar- diography, but, at the same time, nonsignificant changes in LV systolic and LV diastolic values . These finding are in contrast to ours and may be based on the methodology used for assessing LV volumes and LV EF. Imaging reports showed significantly lower EF values in echocardiography when comparing unenhanced echocardiography to CMR, and, despite a good correlation between the modalities, a wide limit of agreement in heartfailure patients, especially with regard to LV volumes [25, 26]. This might favor the use of CMR in heartfailure cohorts with severely dilated LVs. Furthermore, we were not able to exactly compare our study cohort to others published in the literature in terms of LV volumes, as most of the studies used invasive pulmonary artery catheterization to report on SV or solely reported on outcomes.
4.3 Pathophysiology of low natriuretic peptide levels and findings in GHS This large study cohort showed the inverse relationship of natriuretic peptides with BMI like many studies in the past (18,66-69,70-77). Obese individuals had lower NT-proBNP levels than individuals with a BMI<30kg/m², particularly in obese individuals with heartfailure we could describe significantly lower NT- proBNP levels compared to none obese individuals with heartfailure. This could be especially noticed by the results of the male participants. The BASEL study examined especially the BNP levels in women and showed significantly differences between men and women (84). There are various theories that try to explain why the relationship of NT-proBNP with BMI is as described. Some studies discussed an increased clearance of NT-proBNP (73,74) but the Suita Study refuted this (75). Sugisawa et al. showed an inverse relationship of NT- proBNP with BMI after adjusting their multivariable regression analysis for the serum creatinine (75). Others debated about a higher expression of natriuretic peptide clearance receptor-C (NPR-C) on the adipocytes (18,76,77), which could be disproved by the Dallas Heart Study (66). Das et al. argued against this, because they could find low NT-proBNP levels in obese individuals and that these low levels were unrelated to the NPR-C levels (66).
(2010), the prevalence of ID in the anaemic patients was 57 ± 10% vs. 32 ± 4% in non-anaemic patients. Thus the prevalence of iron deficiency in the anaemic and non-anaemic subgroup in the present study was significantly higher than in the study of Jankowska et al. At this point it is important to again underline the different inclusion criteria, which result in a much more ailing population studied. The prevalence of ID in the anaemic population studied by Nanas et al. was estimated on the basis of different anaemia criteria (haemoglobin <11.5 g/dl in women and <12 g/dl in men). Using these criteria we estimated an anaemia prevalence of 11% (n=11; 95% CI, 5-18%) and an ID prevalence of 91% in this small anaemia group (n=10; 95% CI, 59-100%), which is in concordance with the ID prevalence of 73% (95% CI, 56-86%) of the study of Nanas et al. In the study of Nanas et al. the mean LVEF was 22.5 ± 5.9% and thus not significantly different from the anaemic population of this thesis, which exhibited a mean LVEF of 19.5 ± 4.5%. These findings support our thesis that the prevalence of ID is determined by the severity of heartfailure.
Heartfailure in diabetes represents a multifactorial problem resulting from a variety of cardiotoxic factors, such as coro- nary artery disease, hypertension, and direct harmful effects of glucose on the myocardium . Besides well character- ized macrovascular effects leading to coronary heart disease and corresponding clinical events, there is increasing data suggesting that there are direct associations between diabetes and heartfailure. A 2-fold higher risk of heartfailure in male diabetics and a 5-fold increase in risk in female patients with diabetes have already been demonstrated in the Framingham study  and this association is of particular importance in younger patients . The underlying mechanisms include but are not limited to increased interstitial and perivascular fibro- sis. This histological pattern was considered the basis for the term “diabetic cardiomyopathy” in the early 1970s . This type of fibrosis is independent of coronary artery disease or hypertension . Nonetheless, diabetic cardiomyopathy remains only moderately understood. Advanced glycation end products (AGE)  and increased content crosslink- ing of collagen seem to play a significant role [12–14]. Besides histological findings, calcium homeostasis is proba- bly affected directly as indicated by lower activity levels of the
Heartfailure (HF) is a complex clinical syndrome, in which the heart is unable to deliver enough blood to the metabolizing body tissue with the consequence that organs do not receive enough nutrients and oxygen to work properly. 1 This failure can result from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood. 1 HF is a major public health problem with a considerable social burden to the health care system, with high rates of hospitalizations, readmissions and outpatient visits. 2 In the last three decades a steep increase of the elderly population older than 65 years has been recognized. This finding in combination with a prolonged life expectancy has lead to the rising prevalence of HF. 1 In the western world the prevalence of HF ranges between 1 and 2% in the adult population with an incidence of HF about 5- 10 per 1000 persons per year. 1 Every year over 650 000 individuals are newly diagnosed with HF in the USA. 3 HF in persons younger than 50 years of age is hardly found, whereas in developed countries the prevalence rises up to 10% among persons 70 years of age or older. 4 The diagnosis of HF carries a substantial risk of mortality and morbidity, even though advances in medical treatment were done in the last decades. The rate of hospitalizations for HF in Europe is clearly declining 5 with an improved survival observed in the past 30 years. 6 However, the 5-year mortality is still approximately 50% worse than that of many cancer types. 7 In a long-term outcome study the 10-year survival was 26.7% in HF patients compared to 75% for study participants without HF. 8
Abstract: The prevalence of heartfailure with preserved ejection fraction (HFpEF) is constantly increasing and no evidence-based pharmacological treatment option is available. While exercise training (ET) improves diastolic function, its metabolic mechanisms in HFpEF are unclear. We assessed the metabolic response to 12 weeks of ET in patients with HFpEF by performing a post hoc analysis of the EX-DHF-P trial (ISRCTN86879094). Plasma concentrations of 188 endogenous metabolites were measured in 44 ET and 20 usual care (UC) patients at baseline and 3-months follow-up. Metabolic differences between ET and UC from baseline to follow-up were compared and differential responses to ET were examined by random forest feature selection. ET prevented the increase of acetylornithine and carnitine as well as the decrease of three glycerophospholipids. After ET, two opposite metabolic response clusters were identified. Cluster belonging was associated with perceived well-being at baseline and changes in low-density lipoprotein but not with cardiorespiratory, ventilatory or echocardiographic parameters. These two ET-induced metabolic response patterns illustrate the heterogeneity of the HFpEF patient population. Our results suggest that other biological parameters might be helpful besides clinical variables to improve HFpEF patient stratification. Whether this approach improves response prediction regarding ET and other treatments should be explored. Keywords: exercise; heartfailure with preserved ejection fraction; metabolomics
have been found to be best associated with clinical measures of heartfailure in UVH patients using microarray analysis. However, after validation by RT-qPCR, miR-150-5p only turned out to be significantly related to a higher NYHA class or the occurrence of overt heartfailure ( Table 2 ). Moreover, miR-150-5p was significantly down-regulated in UVH patients prior to the occurrence of overt heartfailure ( Fig 2 ) indicating its pathophysiological relevance of downregulation for heartfailure progression or even acute worsening of heartfailure. Our results are in line with those found in patients with left heartfailure in whom miR-150-5p turned out to be significantly downregulated in those patients with advanced left heartfailure or in patients with chronic systolic left heartfailure and atrial fibrillation reflecting disease pro- gression and a poor outcome in those patients [ 28 , 29 ]. Moreover, initial studies have demon- strated that low levels of miR-150-5p predict adverse left ventricular remodeling in patients after acute myocardial infarction [ 30 , 31 ].
Endothelial cells are, by number, one of the most abundant cell types in the heart and active players in cardiac physiology and pathology. Coronary angiogenesis plays a vital role in maintaining cardiac vascularization and perfusion during physiological and pathological hypertrophy. On the other hand, a reduction in cardiac capillary density with subsequent tissue hypoxia, cell death and interstitial fibrosis contributes to the development of contractile dysfunction and heartfailure, as suggested by clinical as well as experimental evidence. Although the molecular causes underlying the inadequate (with respect to the increased oxygen and energy demands of the hypertrophied cardiomyocyte) cardiac vascularization developing during pathological hypertrophy are incompletely understood. Research efforts over the past years have discovered interesting mediators and potential candidates involved in this process. In this review article, we will focus on the vascular changes occurring during cardiac hypertrophy and the transition toward heartfailure both in human disease and preclinical models. We will summarize recent findings in transgenic mice and experimental models of cardiac hypertrophy on factors expressed and released from cardiomyocytes, pericytes and inflammatory cells involved in the paracrine (dys)regulation of cardiac angiogenesis. Moreover, we will discuss major signaling events of critical angiogenic ligands in endothelial cells and their possible disturbance by hypoxia or oxidative stress. In this regard, we will particularly highlight findings on negative regulators of angiogenesis, including protein tyrosine phosphatase-1B and tumor suppressor p53, and how they link signaling involved in cell growth and metabolic control to cardiac angiogenesis. Besides endothelial cell death, phenotypic conversion and acquisition of myofibroblast-like characteristics may also contribute to the development of cardiac fibrosis, the structural correlate of cardiac dysfunction. Factors secreted by (dysfunctional) endothelial cells and their effects on cardiomyocytes including hypertrophy, contractility and fibrosis, close the vicious circle of reciprocal cell-cell interactions within the heart during pathological hypertrophy remodeling.
Figure 1 A 69-year old female patient presented with acute kidney failure with increased serum creatinine and serum urea and decreased serum cre- atinine –eGFR. Under ongoing heartfailure medication and patiromer, serum potassium values could be kept stable. At acute hospitalization, serum creatinine (A) was at 3.2 mg/dL, serum creatinine –eGFR (B) at 14 mL/min/1.73 m 2 , elevated serum urea (C) at 237 mg/dL, and serum sodium at 146 mmol/L (E). Under ﬂuid therapy in the next 3 days, these values improved and reached output value. Potassium value (D) could be kept stable at output value throughout the acute kidney failure accompanied with stable blood pressure values during acute hospitalization (F). At Day 5, even up-titration of spironolactone was possible. Big blue circles indicate value at index event when patiromer was started; small blue circles, average value under patiromer before acute hospitalization; green circles, values before taking of patiromer; yellow circles, value after 3 months ’ control. DBP, dia- stolic blood pressure; eGFR, estimated glomerular ﬁltration rate; SBP, systolic blood pressure.
In contrast to the wealth of proven therapies for heartfailure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heartfailure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heartfailure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF. Keywords Heartfailure · Preserved ejection fraction · Pharmacotherapy in HFpEF · LCZ696 · Device therapy
Skeletal muscle wasting affects about 20% of ambulatory patients with chronic heartfailure and has serious implications for their activities of daily living. The assessment of muscle wasting is technically challenging. C-terminal agrin-fragment (CAF), a breakdown product of the synaptically located protein agrin, has shown early promise as biomarker for the detection of muscle wasting. We sought to investigate the diagnostic properties of CAF in the detection of muscle wasting among patients with heartfailure.
The result of this work is the development of a stochastic simulation model, which allows to compare health and cost outcomes of different integrated care concepts for the treatment of heartfailure patients. Additionally to the simulation of standard outpatient and inpatient care procedures in Austria the approach of a telemedical moni- toring system for heartfailure patients was implemented in this economic model. Model parameters can be directly modified via input masks on the simulation screen to set, for example, mortality rates, hospitalizations, costs for visits to the ambulance, amount and type of individual medical procedures and class changes to conduct specific simulation runs. In total 3 input masks allow the adjust- ment of the event-probabilities, which then influence the patient’s treatment procedure, but do not interfere with the general model structure. As a first step for each simulation the amount and the distribution of patients under investigation can be adjusted for each NYHA class. In a second step the probabilities for events occurring in the outpatient and inpatient care can be specified. This refers to the parameters previously described in the methods section, for example the distribution of home visits, doctor and specialist visits, in-hospital length of stay, mortality, intensive care unit treatment and so on. Finally the model allows the separate adjustment of expenses for standard care events, telemedical procedure and hospitalization as described above (see Figure 5). In addition the amount of Euros per procedure-oriented diagnosis-related case group point is adjustable for pos- sible future adaptations.
The inability of the left ventricle to fill properly with blood at normal pressures is largely due to left ventricular hypertrophy 48 and cardiomyocytes stiffness as a result of lowered NO-cGMP- PKG signaling. 41 Concentric hypertrophy, defined as an increase in relative wall-thickness and normal internal diameter, plays a predominant role, being present in approximately 3/5 of HFpEF cases. 33 Titin provides passive elasticity to cardiomyocytes by acting as a “molecular spring”, 49 which is able to adapt to stretching or refolding of the protein. 50 In cardiomyocytes, two isomers of this protein are present. One, called N2BA, is highly stretchable and provides elasticity to the muscle cell. The other one, N2B, is shorter and stiffer, reducing the cells ability to dilate. 49 In healthy adults, the stiffer N2B makes up 70% and with a higher share, the passive stiffness increases. Unfortunately, a relation that is very common in end-stage heartfailure. 51 Another characteristic of Titin is its decreased resting-tension, when being phosphorylated post- translational. 43 With increased oxidative stress, cGMP levels fall low, which decreases PKG activity and enhances titin hypophosphorylation and cardiomyocyte stiffness. 44 Oxidative stress impairs not only cGMP/PKG signaling, 52 but induces oxidation and mechanical unfolding of titin´s Ig-domain, as well, which is crucial for providing elasticity. 53
Assessment of HeartFailure
The Gothenburg score[ 17 , 18 , 19 ] is a validated HF screening tool for epidemiological studies composed of three components: a cardiac score (positive if one or more of the following is pres- ent: coronary heart disease (CHD), angina pectoris, edema, dyspnea at night, pulmonary rales or atrial fibrillation), dyspnea on exertion, and the intake of HF medication. The presence of manifest HF defined as Gothenburg stage 2 (presence of a positive cardiac score with either dyspnea on exertion or HF medication) or stage 3 (presence of all three components) was eval- uated. Pulmonary rales were not included since auscultation was not part of the physical exam. Developed in 1987, the original Gothenburg score defined digitalis or loop diuretics as typical HF medication. To allow for changes in treatment regimens over time, we included additional HF medication and established a modified definition that was used for the analyses in this re- port and was evaluated in several validation analyses (see below). HF according to the Gothen- burg definition was compared to self-reported HF, which was assessed by asking the patients “Are you suffering from heartfailure/weakness of the heart?”.
Background: The underlying reasons for the highly inconsistent clinical outcome data for omega ‐3‐polyunsaturated fatty acids (n3‐PUFAs) supplementation in patients with cardiac disease have not been understood yet. The aim of this prospective, randomized, double ‐blind, placebo controlled study was to determine the effects of oral treatment with n3 ‐PUFAs on the anti‐oxidant capacity of HDL in heartfailure (HF) patients.
Standard transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and chronic heartfailure (Fliegner et al., 2010; Kararigas et al., 2014). Briefly: mice were anesthetized by injecting an intraperitoneal (i.p.) ketamine hydrochloride/xylazine hydrochloride/acepromazine (80 mg/ml; 12 mg/ml; 10mg/ml) solution with a dose of 1 mg/kg (Fliegner et al., 2010; Grune et al., 2016). Then, mice were placed in a supine position on top of a heating pad. After anesthesia mice were intubated using the plastic tube of an intravenous catheter and ventilated using a Mouse Minivent Type 845 (Hugo Sachs Elektronik). All mice were ventilated with a breathing volume of 200 µL and 200 breaths per minute. Fur was removed by using Veet hair removal cream and Rimadyl (5.0 mg/kg per kg BW) was injected i.p. as analgesia during surgery. Partial thoracotomy was performed until the second rip, before thymus was gently separated. Aorta and carotid arteries were then exposed. The transverse aorta was ligated between innominate artery and common carotid artery. Hereby a 6.0 non-sterile silk suture (FST) was ligated against a 26.0 Gauge needle. The needle was quickly removed, leaving a narrowing of the aorta of 0.46 mm in diameter (Tarnavski et al., 2004). Rip cage was closed using 6.0 sterile PERMA-HAND Silk Suture (Ethicon). The skin was sutured using a 6.0 sterile Polyester Suture (Ethicon). The surgery lasted for approximately 30 minutes. Mice recovered from anesthesia under normal conditions and normal ventilation using an infrared light lamp. For analgesia after TAC mice were given Metamizole by drinking water for seven days. To evaluate the narrowing of the transverse aorta, animals underwent echocardiography one week after TAC.
It has been previously reported that impaired cardiac output causes impaired renal perfusion and increased venous pressure leading to reduced glomerular filtration rate and acute kidney injury (Ronco et al., 2008). Under chronic conditions of heartfailure, excessive sympathetic activation, increased oxidative stress to kidney, and impaired nitric oxide function on the renal vascular endothelium may lead to severe kidney injury (Ronco et al., 2008). However, there is scant evidence regarding the precise histomorphological alterations and their putative mechanisms of heartfailure-induced kidney injury. This study aimed to assess the histo- morphological evidence for the heartfailure-induced kidney damage.
Figure 2 Cardiac metabolic alterations in heartfailure. In heartfailure, increased uptake of free fatty acids and glucose into the cytosol is uncoupled from mitochondrial uptake and oxidation of free fatty acid and pyruvate, respectively. This provokes accumulation of metabolic intermediates in the cytosol which can trigger lipo- and glucotoxicity. Instead, utilization of ketone bodies is increased in heartfailure. Impaired overall substrate oxidation reduces Krebs cycle (TCA) activity, oxidizing electron donors NADH and FADH2 for the electron transport chain (ETC). This reduces metabolic flux through creatine kinase (CK), thereby the phosphocreatine (PCr) to ATP ratio. b-Ox., b-oxidation; CPT-1/2, carnitine palmitoyltransferase type 1/2; FA-CoA, fatty acyl-coenzyme A; FACS, fatty acyl-coenzyme A synthetase; FAT/CD36, fatty acid translocase; GLUT 1/4, glucose transporters 1/ 4; G6P, glucose-6-phosphate; PDH, pyruvate dehydrogenase complex; PPP, pentose phosphate pathway; Polyol P., Polyol pathway; TAG, triacylgly- cerol; UDPGlcNac, UDP-glycnacylation. Red arrows (#") indicate the changes in heartfailure.
The results of our studies add to several previous publications, showing increased sensitivity to heartfailure in PPAR α KO compared to WT mice. It has been showed in an ischaemia / reperfusion study, that hearts from PPAR α KO mice were more susceptible for myocardial dysfunctions (longer time of recovery and lower developed force) than those from WT mice and that the beneficial effects of fenofibrate treatment were lost in KO mice (Tabernero et al. 2002). Similarly, Yue et al. (2003) demonstrated greater infarct sizes in PPAR α KO mice hearts after ischaemia / reperfusion than in WT mice hearts. It also seems that PPAR α KO mice had reduced systolic performance in echocardiographic measurements without changes in heart rate and blood pressure (Loichot et al. 2006). Furthermore, isolated perfused hearts from these mice had reduced developed force at basal levels and after β -adrenergic stimulation compared to WT mice and these effects were associated with myocardial fibrosis. Finally, it has been reported that PPAR α KO mice had reduced systolic performance without ventricular dilatation in echocardiography and significant cardiomyocyte hypertrophy in histological investigations (Guellich et al. 2007). Markers of oxidative damage were increased in PPAR α KO mice hearts. These data indicate that functional PPAR α seems to be required to protect and preserves contractile function in cardiac muscle.