Acute ischemic MR is a rare life-threatening condition requiring surgical and intensive care treatment. As a result of ischemia, damage to the papillary muscles (PM) occurs, which get stiff and shortened, and the mitral valve can no longer properly close. The PM is stretched during the isovolumic contraction and the ventricular ejection. Due to the shortening, the PM can no longer adapt to the contracting ventricular wall in the ejection phase. Since, most of the time only the posterior PM is affected, the anterior PM can continue to move normally. This results in a backflow from the LV into the LA. The LA is usually not enlarged and not stretchable at all, which leads to an increased volume load in both, the LV and LA. As a result, the pressure in the LA increases and the ejection fraction increases compensatory. Compared to the other heart cavities the LV has a very high systolic pressure and only a small opening area through the mitral valve, which leads to a massive reflux. Atrial emptying is not obstructed during diastole. The end-diastolic volume increases, and the volume overload causes muscle hypertrophy. This also increases the diastolic pressure in the LV and the effective ejection fraction decreases. Isometric chamber slackening is shortened due to the early opening of the valve induced by the increased pressure in the LA. As a result, the LA in the diastole empties very quickly resulting in rapid pressure drop. This is manifested by rapidly occurring pulmonary hypertension, which manifests itself in a pulmonary oedema. 17,21,22
The experimental model of heartfailure by volume overload via an aortocaval fistula was introduced first by Stumpe in 1971 (Stumpe et al., 1971). In this model an arteriovenous (AV) fistula between abdominal aorta and inferior vena cava is created by a longitudinal incision of both vessels and subsequent closure by use of a continuous Perlon suture No. 6 (MET). However, this model does take into account the knowledge that in the hands of a non-trained experimenter perioperative mortality is high and postoperative complications such as local haemorrhage is common and occurres quite often. Subsequently, the model of an aortocaval fistula was modified using a less invasive needle-technique in which an 18G needle was advanced from the aorta into the vena cava inferior at the site where both vessels appear to adhere to each other so that when the needle is withdrawn a shunt between aorta and vena cava remained (Garcia and Diebold et al., 1990). This modification resulted in congestive heartfailure with a much-reduced risk of local bleeding; however, the development of heartfailure lasted 8-10 weeks and was unpredictable (Garcia and Diebold et al., 1990; Brower GL, et al., 1996; Wang X et al., 2003). More recently, this model of infrarenal aortocaval fistula (ACF) was further improved by the use of 16G cannula, which had the advantage of producing congestive heartfailure in a shorter period (28±2 days) and in a more predictable way (Treskatsch et al., 2014). In contrast to other models of heartfailure (e.g. pressure overload) volume overload-inducedheartfailure leads to eccentric hypertrophy of the heart with an apparent dilation of the left ventricle with migration of various immune cells and apoptotic events as reported by Chen et al., 2011.
signiଏcantly reduced by intensive lifestyle intervention (HR 0.80; 95% CI, 0.61-1.04; P ¼ .10). Interestingly, a recent post hoc analysis reported a signiଏcant reduction of cardiovascular events in patients who lost at least 10% of their body weight during the ଏrst year (21% of all individuals from both inter- vention arms; adjusted HR 0.79; 95% CI, 0.64-0.98; P ¼ .034) in comparison with patients with stable body weight or weight gain. In addition, achievement of increased physical ଏtness (improvement by >2 metabolic equivalents reached by 13% of all individuals from both intervention arms) was associated with a signiଏcant reduction of the secondary composite endpoint that included heartfailure (adjusted HR 0.77; 95% CI, 0.61-0.96; P ¼ .023) but not of the original primary outcome of cardiovascular death, nonfatal myocardial infarc- tion, or nonfatal stroke (adjusted HR 0.78; 95% CI, 0.60-1.03; P ¼ .079). 49 These results highlight the difଏculty in per- forming lifestyle intervention trials, which largely depend on the motivation of individual study participants. Others have found that weight loss interventions reduce cardiac hypertro- phy, decrease left atrial volume, and improve diastolic func- tion in cohorts of obese individuals (approximately 30% of those experiencing weight loss had diabetes) with paroxysmal atrial ଏbrillation. 50,51 Metabolically induced left ventricular dysfunction can consequently be reversed by lifestyle inter- vention. 50,51 Importantly, both studies reported a potent reduction in atrial ଏbrillation as a primary endpoint, which gave weight loss management in obese patients a level IIa recommendation in the 2016 ESC guidelines on atrial ଏbrillation. 52
signi ﬁcantly reduced by intensive lifestyle intervention (HR 0.80; 95% CI, 0.61-1.04; P ¼ .10). Interestingly, a recent post hoc analysis reported a signi ﬁcant reduction of cardiovascular events in patients who lost at least 10% of their body weight during the ﬁrst year (21% of all individuals from both inter- vention arms; adjusted HR 0.79; 95% CI, 0.64-0.98; P ¼ .034) in comparison with patients with stable body weight or weight gain. In addition, achievement of increased physical ﬁtness (improvement by >2 metabolic equivalents reached by 13% of all individuals from both intervention arms) was associated with a signi ﬁcant reduction of the secondary composite endpoint that included heartfailure (adjusted HR 0.77; 95% CI, 0.61-0.96; P ¼ .023) but not of the original primary outcome of cardiovascular death, nonfatal myocardial infarc- tion, or nonfatal stroke (adjusted HR 0.78; 95% CI, 0.60-1.03; P ¼ .079). 49 These results highlight the dif ﬁculty in per- forming lifestyle intervention trials, which largely depend on the motivation of individual study participants. Others have found that weight loss interventions reduce cardiac hypertro- phy, decrease left atrial volume, and improve diastolic func- tion in cohorts of obese individuals (approximately 30% of those experiencing weight loss had diabetes) with paroxysmal atrial ﬁbrillation. 50,51 Metabolically induced left ventricular dysfunction can consequently be reversed by lifestyle inter- vention. 50,51 Importantly, both studies reported a potent reduction in atrial ﬁbrillation as a primary endpoint, which gave weight loss management in obese patients a level IIa recommendation in the 2016 ESC guidelines on atrial ﬁbrillation. 52
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
lower in ID patients compared to patients without ID (54. vs. 59.years ID). The relation was confirmed by univariate and multivariate analysis which demonstrated that lower age is an independent clinical predictor of ID (odds ratio 0.94). This might in part be a bias due to the exclusion criterion in this study. Patients with a history of bleeding, known to be the main cause of ID in the elderly (Mukhopadhyay and Mohanaruban 2002) were excluded. In our study, nine patients over 60 years where excluded from the study sample due to a history of haemorrhage or iron supplementation. Another explanation for the correlation between age and presence of ID is that with advancing age there is a progressive decrement of marrow haematopoesis and consecutive iron demand (Lipschitz et al. 1981). This could explain why all the patients under 40 years in our study belong to the iron deficiency group. The remaining clinical parameters showed no significant differences between the ID and no-ID groups and no association with iron deficiency in univariate and multivariate analysis. Jankowska et al. (2010) in a differently structured study found no correlation of age with ID; however, female gender and NYHA functional class showed an association with ID. The aetiology of heartfailure and the presence of diabetes were also of no significance.
Obese individuals have an increased risk for heartfailure. Although typical symptoms of heartfailure maybe present in obesity as well and may mask coincidence of heartfailure and obesity. The current gold standard represented by the natriuretic peptides have lower concentrations in obese subjects (66-69). In this background, the usefulness of the natriuretic peptides has been questioned because of the unequivocally observed inverse relationship with body mass index (BMI) (18,68). Even though obesity is related with cardiac pressure overload and volume expansion, which usually leads to an increased level of BNP, the BNP levels of obese people are in contrary lower (18,70-72). In some studies obesity is related to an elevated clearance of BNP (73,74). In contrast, the Suita Study disproved this theory, in which the multivariable regression analysis was adjusted for the serum creatinine but nevertheless showed the inverse relationship of natriuretic peptides with BMI (75). Another speculation related to the adipose tissue expansion in obesity. Since the adipocytes express their natriuretic peptide clearance receptor-C (NPR-C), this could lead to a low BNP level (18,76,77). But the Dallas Heart Study refuted this and also reported low BNP levels in obese subjects and that low levels were unrelated to NPR-C (66). Therefore it is necessary to evaluate new cut off values for natriuretic peptides in obese subjects
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 ].
access the subsidy, lack of time to make the application, or disinterest in organizing training may be factors resulting in the low uptake by smaller enterprises. 4
There is also the possibility that small firms are not interested in providing training, meaning that they offer less training not because they find it difficult or costly, but because they do not see the benefits for the firm. Because there is less available evidence linking training to outcomes in small firms than there is for large firms, owners may think there will be no impact (Hill 2004). The owner, who is also normally the manager and in micro firms may also be a member of the production staff, may have more pressing issues to address. As well, the enterprise may be engaged in nontechnical service activities (e.g., retailing) in which training is less important than it is for manufacturing or technical services. Even owners who appreciate the value of skilled workers may be reluctant to train because they fear that trained workers, especially those with certified skills, will be poached by other firms and the training investment would be lost. 5 If this is the case, then low levels of training among SMEs may not be the result of a market failure, and any efforts to make training cheaper or more available may have little impact on raising training levels.
„Ich, Steinbeck, Lisa, versichere an Eides statt durch meine eigenhändige Unterschrift, dass ich die vorgelegte Dissertation mit dem Thema: „Detection of muscle wasting in patients with chronic heartfailure using C-terminal agrin fragment: results from the Studies Investigating Co-morbidities Aggravating Heartfailure (SICA-HF)“ selbstständig und ohne nicht offengelegte Hilfe Dritter verfasst und keine anderen als die angegebenen Quellen und Hilfsmittel genutzt habe.
terminus. The critical phosphorylation site (Thr38) is present in the P-loop structure, in a cavity between helices (Ohki et al., 2001). CPI-17 was initially discovered in smooth muscle tissues (Eto et al., 1997), and the expression level is high in tonic muscles, but lower in phasic muscles. The PKC induced contraction depends on the expression level of CPI-17 in each tissue (Woodsome et al., 2001). The expression level of CPI-17 was also analyzed in embryonic smooth muscle tissues and arterial neointimal lesions. It is highly expressed in mature smooth muscle cells, but the expression level is different under pathological conditions (Kim et al., 2009). Moreover, undetectable level of CPI-17 was observed in arterial smooth muscle from chicken and it produces an insignificant level of the force through G-protein-mediated signals (Kitazawa et al., 2004). CPI-17 expression is also found in platelets (Watanabe et al., 2001) and brain tissues (Dubois et al., 2003). CPI-17 phosphorylation leads to pulmonary hypertension under hypoxia (Dakshinamurti et al., 2005). CPI-17 higher expression and activation has been observed in airway- hyper-responsiveness that is associated with heightened airway resistance and inflammation is a characteristic feature of asthma (Sakai et al., 2005). Thus, the expression level of CPI-17 is an essential determinant for MLC phosphorylation and smooth muscle contraction. Further, it was shown that upregulation of CPI-17 and Rho-kinase mediated Ca 2+ sensitization leads to high MLC phosphorylation level, slow relaxation in detrusor smooth muscle, and bladder dysfunction in diabetic animals (Chang et al., 2006).
endothelial cell survival represents a central mechanism during new vessel formation ( 225 ). Increased p53 expression and other components of apoptosis pathways have been observed in myocardial biopsies of patients with heart disease and were found to progressively increase during transition toward heartfailure ( 226 – 228 ), and similar findings were obtained in rats following TAC ( 229 ). Quantitative analysis revealed that a considerable number of endothelial cells undergo apoptotic cell death after TAC ( 230 ), and pressure overload in mice was found to be associated with increased endothelial expression of tumor suppressor p53, a central regulator of apoptosis and cell cycle arrest ( 231 ). In a rat and a canine model of left ventricular hypertrophy and heartfailure following chronic aortic banding, the overwhelming majority of apoptotic cells was identified as non-cardiomyocytes ( 232 ). In line with these observations, systemic caspase inhibition had no effect on the cardiomyocyte number, but enhanced angiogenesis to reduce cardiac fibrosis and to augment cardiac contractility following TAC injury in mice ( 233 ). We have demonstrated the importance of p53 expressed in endothelial cells for maintaining cardiac vessel density during hypertrophy, but also for angiogenesis in response to ischemia induced by unilateral femoral artery ligation ( 234 ). Previous studies had shown that global p53 deficiency ( 45 , 235 , 236 ) or pharmacological p53 inhibition ( 237 ) protect against cardiac injury, whereas activation of p53 following deletion of the p53 inhibitor mdm2 in cardiomyocytes accelerated left ventricular function deterioration in response to aortic banding or myocardial infarction ( 238 ). Similar cardioprotective effects were observed in mice with global deletion of Puma (p53-upregulated modulator of apoptosis), a proapoptotic Bcl-2 family protein that serves as general sensor of pathological apoptotic stimuli ( 239 ). Based on the above findings identifying p53 accumulation in the heart as essential mechanism and characteristic of cardiac decomponsation, AAV vectors containing the VEGF gene driven by a p53-responsive promoter have been tested in rats and were found to improve cardiac function, to reduce fibrosis and to reverse capillary rarefaction ( 240 ). Mice expressing heat shock transcription factor-1 (HSF-1) exhibiting reduced endothelial p53 expression were characterized by increased angiogenesis and cardiac HIF1α expression and protected against pressure overload-inducedheartfailure, whereas HSF1 deficient mice exhibit aggravated cardiac remodeling under pressure overload due to impaired, imbalanced angiogenesis ( 241 ).
Levosimendan improves cardiac function in heartfailure populations; however, its exact mechanism is not well defined. We analysed the short-term impact of levosimendan in heartfailure patients with ischemic and non-ischemic cardiomyopathy (CMP) using multiparametric cardiac magnetic resonance (CMR). We identified 33 patients with ischemic or non-ischemic CMP who received two consecutive CMR scans prior to and within one week after levosimendan administration. Changes in LV ejection fraction (LVEF) and LV volumes, as well as changes in strain rates, were measured prior to and within one week after levosimendan infusion. LV scarring, based on late gadolinium enhancement (LGE), was correlated to changes in LV size and strain rates. Both LV endiastolic (EDV) and endsystolic volumes (ESV) significantly decreased (EDV: p=0,001; ESV: p=0,002) after levosimendan administration, with no significant impact on LVEF (p=0.41), cardiac output (p=0.61), and strain rates. Subgroup analyses of ischemic or non-ischemic CMP showed no significant differences between the groups in terms of short-term LV reverse remodeling. The presence and extent of scarring in LGE did not correlate with changes in LV size and strain rates. CMR is able to monitor cardiac effects of levosimendan infusion. Short-term follow-up of a single levosimendan infusion using CMR shows a significant decrease in LV size, but no impact on LVEF or strain measurements. There was no difference between patients with ischemic or non-ischemic CMP. Quantification of LV scarring in CMR is not able to predict changes in LV size and strain rates in response to levosimendan.
Heartfailure is a progressive clinical syndrome which is characterized by the inability of the heart to pump or fill with a sufficient amount of blood through the systemic circulation. One receptor, which seems to be involved in the remodelling processes accompanying the progression of heartfailure, is the peroxisome proliferator- activated receptor alpha (PPAR α ). Indeed, it seems that PPAR α is downregulated in patients with heartfailure and has antihypertrophic and antifibrotic effects on the myocardium. Thus, the aim of this study was to investigate the role of PPAR α in the remodelling processes related to heartfailure, in models of ischaemia (chronic myocardial infarction model) and hypertension (deoxycorticosterone acetate / DOCA salt model) inducedheartfailure, the two most important causes of heartfailure development in patients. To this end, the effects of abrogation of PPAR α activity in knock-out (KO) mice were compared to normal activity in wild-type (WT) mice and activation of PPAR α by the PPAR α agonist fenofibrate (80 mg/kg/d) in the two aforementioned models. Furthermore the treatment with fenofibrate was compared to a standard therapy with the ACE inhibitor ramipril (10 mg/kg/d).
Glitazones, or TZD, are insulin-sensitizing agents that activate the nu- clear receptor PPAR-c, a transcription factor that regulates multiple genes implicated in several metabolic pathways related to insulin sen- sitivity. These drugs improve glucose metabolism by increasing insulin sensitivity (Figures 1 and 4 ), thereby reducing hyperglycaemia and hyperinsulinaemia. The main effect of TZD is to shift FFA towards adipose tissue and away from other tissues, hence inducing a ‘lipid- steal’ effect that, in turn, improves glucose utilization. In addition, PPAR-c agonists restore other metabolic derangements in insulin re- sistance and obesity by attenuating macrophage pro-inflammatory cytokine expression, adipocyte differentiation, and adipokine expres- sion in adipocytes. 77,78 Furthermore, PPAR-c activation abrogates vasoconstriction and atherogenic effects of angiotensin II and improves eNOS-dependent vasodilation (Figures 1 and 4 ). 79 Its activa- tion may also exert anti-remodelling effects by inhibiting glucose- induced induction of TGFb1 and TGFb1-mediated fibronectin ex- pression. 80,81 PPARy activation with pioglitazone may improve dia- stolic function, 82 and a recent meta-analysis suggests that TZD may protect against atrial fibrillation. 83 Furthermore, TZD exert beneficial effects on endothelial function, as rosiglitazone AMPK-dependently stimulates NO synthesis (Figure 4 ), and glitazones improve endothe- lial function in non-diabetic individuals with CAD. 84 However, PPAR- c agonism also confers some adverse effects, as it causes Na þ and fluid retention and oedema, body weight increase and bone fractures (Figure 1 ).
Currently, the only biomarkers who fit these standards are natriuretic peptides (BNP, ANP) (18). They are the only established biomarkers in clinical care, but there are a few more novel biomarkers, which are promising candidates. Recent ESC guidelines do not address this topic, but the American Heart Association (AHA) states that novel biomarkers may be useful for providing additional risk stratification and the prognosis of chronic HF (27).
Spermidine, a polyamine which induces autophagy, reduces the cardiometabolic risk in humans and is related with increased longevity in mice and rats [ 22 ]. Our results show that the baseline concentrations of spermidine and its derivative spermine are related to improvements in exercise capacity (i.e., VO 2 peak) and cardiac remodeling (i.e., LAVI and E/e’) (Figure S2). Autophagy is a cellular quality control mechanism essential for appropriate protein folding and maintenance of cell function. Constitutive autophagy in healthy hearts is a homeostatic mechanism for the preservation of cardiomyocyte size, global cardiac structure and function [ 23 ]. During heartfailure autophagy is upregulated to protect the cell from hemodynamic stress [ 23 ]. In addition, inhibiting autophagy by cardiomyocyte specific knockout of the autophagy-related 5 gene induces age-related cardiomyopathy [ 24 ]. Interestingly, not all subjects responded equally to ET with regards to spermine. Specifically, spermine concentration increased in subjects belonging to the metabolic cluster 1 but decreased in those in cluster 2. Currently, we cannot explain this observation and future studies need to explore the relation between exercise, autophagy and spermine signaling.