A new pharmacological approach for the treatment of congestiveheartfailure and myocardial fibrosis was recently suggested by our working group, i.e. inhibition of aldosterone biosynthesis with non steroidal, selective CYP11B2 inhibitors (Ehmer et al., 2002; Hartmann et al., 2003). By reducing the aldosterone secretion, these inhibitors could prevent or diminish fibrotic remodelling of the failing heart and facilitate its action due to their diuretic effects. The structure of the active site of the target enzyme is not yet elucidated, so a “key-lock” design of inhibitors is not possible. Unlike other P450 enzymes there are almost no CYP11B2 inhibitors known. Until now, only our working group described non steroidal CYP11B2 inhibitors, which are used i work as lead compo Ulmschneider et al., 2005a; Ulmschneider et al., 2005b). It is known that the concept of heme iron complexing compounds is appropriate to discover highly potent and selective inhibitors. These compounds interact with the substrate binding site in the apoprotein moiety and complex the heme iron which is located in the active site. This complexation mechanism does not only increase binding affinity of the in ts oxygen activation of the heme which is required for the catalytic process.
The atria are made vulnerable to AF by setting short refractive periods and by reducing the conduction velocity at the same time. The conduction velocity is reduced to 40 % its original value to 400 mm/s similar to the work by Moe et al. [188, 189] where the conduction velocity was re- duced to even 200 mm/s. For all simulations, the heart rate is set to the highest frequency which makes the cellular automaton select the short action potentials from memory when starting the simulation. Then, pulmonary vein firing is simulated by virtually exciting tissue at the veins ostia: Two stimuli cause a unidirectional block that leads to a rotor wave. The rotor wave is gained if the second stimulus is situated such that its excitation will meet cells in their absolute refractive phase and cells that are re-excitable again (see figure 9.1). While the excitation in the area of absolute refractoriness will not cause an excitation wave front, the excitation in the neighbouring area will kick off an action potential. Due to the slower conduction velocity and the relaxation of the excited cells, the excitation wave front will travel into the area that was previously non-excitable, creating a figure-of-eight re-entry that is quickly replaced by a rotor with its center at the position of the ectopic focus. This approach does not only model fast PV firing by two stimuli, it also represents the situation in which one single stimulus falls into an excitation wave front, e. g. the excitation wave front of a sinus rhythm. The difference between the latter and the simulation of two stimuli will only differ in the curvature of the wave front into which the second stimulus falls. The ad- vantage of using two stimuli with spatial and temporal offset is that the timing of the occurance of the ectopic beat can be better controlled. Also, the ectopic focus was modeled by a spherical stimulus which is advantagous in creating a rotor wave. It also approximates the measurements best. Using this approach, AF will be initiated by an arrhythmogenic excitation of a region in the pulmonary vein that falls in an excitation wave front and thus in areas of different refractive periods. A unidirectional block occurs resulting in a rotor wave.
for heartfailure. The risk for these endpoints is markedly increased in subjects with diabetes compared with those without diabetes. The Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study assessed the in ﬂuence of diabetes on the risk of death in 5491 patients hospitalized with congestiveheartfailure when followed up for 5 to 8 years. 12 In this study population 16% of patients had diabetes at baseline, and approximately 50% had an ejection fraction <35%, suggesting that both HFrEF and HFpEF were present in this subpopulation. 12 Crude mortality analyses suggested a 1-year mortality of 31%, much higher than in subjects without diabetes, and 50% of all heartfailure patients with diabetes died after 3 years. Additional data on the prognosis of patients with diabetes and established heartfailure came from large heartfailure trials, such as the Sur- vival And Ventricular Enlargement (SAVE) trial, 13,14 the Valsartan in Acute Myocardial Infarction Trial (VALIANT), 15 and the Candesartan in HeartFailure — Assessment of Reduction in Mortality and Morbidity (CHARM) trial. 16 All of these trials showed an increased risk of death in men and women with diabetes. For example, in CHARM, which analyzed the effect of candesartan versus placebo in a population with HFrEF and HFpEF, it was shown that both men and women with diabetes exhibited a higher risk of cardiovascular death or hospitalization for heartfailure compared with subjects without diabetes, with a cumulative incidence rate of approximately 40% over 3 years. 16 Further differentiated analyses in patients with or without diabetes and HFpEF or HFrEF showed that the highest mortality or hospitalization for heartfailure risk occurred in patients with diabetes and low ejection fraction (ie, HFrEF), followed by patients with diabetes and HFpEF. 16 The cumulative incidence rate of cardiovascular death and heartfailure hospitalization in subjects with dia- betes plus HFpEF was similar to that in subjects without diabetes but with HFrEF. A similar trend was true for all- cause mortality. In patients with diabetes, cardiovascular mortality was 58.6 per 1000 patient-years in those with HFpEF and 119.1 per 1000 patient-years in those with a low ejection fraction (ie, HFrEF). Similarly, in patients with diabetes, the risk for ﬁrst hospital admission for heartfailure was 116.6 per 1000 patient-years for those with HFpEF, whereas the rate was 155.4 per 1000 patient-years for those with HFrEF. 16 Compared with subjects without diabetes, the risk of hospitalization for heartfailure was almost doubled in patients with diabetes independent of HFpEF or HFrEF. 16 Consequently, among patients with HF, those with diabetes have a higher risk of mortality and hospitalization for HF than those without diabetes.
cases, congestiveheartfailure developed despite maximum surgical and medical care. At the time of cell therapy, three patients were on assist devices. Positive inotropic substances were used in four patients and a careful switch to anticongestive treat- ment was performed in two patients. Anticongestive treatment consisted of beta-1-selective beta-blockers, angiotensin converting enzyme-inhibitors, and spir- onolactone. Anticongestive treatment proved not to be sufficient, because both patients additionally required diuretics. In all, five patients were listed for heart transplantation; in one case, heart transplantation was not an option because the patient was from a non- European Union country.
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 congestiveheartfailure 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 congestiveheartfailure 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-induced heartfailure 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.
The excess of fluid in the HF is caused by excessive intake of fluids and sodium, due to non-adherence to nutritional therapy, causing overload of renal and water functions. Excess sodium in the diet causes multiple effects, particularly increased activity of the renin-angiotensin system. The excessive stimulation of this system by the high sodium intake results in water retention and has been associated with cardiac hypertrophy and congestiveheartfailure. Brazilian guidelines for the treatment of HF recommend the restriction of 1.0 to 1.5 liters/day for symptomatic patients at risk of fluid overload. 19
for heartfailure. The risk for these endpoints is markedly increased in subjects with diabetes compared with those without diabetes. The Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study assessed the inଏuence of diabetes on the risk of death in 5491 patients hospitalized with congestiveheartfailure when followed up for 5 to 8 years. 12 In this study population 16% of patients had diabetes at baseline, and approximately 50% had an ejection fraction <35%, suggesting that both HFrEF and HFpEF were present in this subpopulation. 12 Crude mortality analyses suggested a 1-year mortality of 31%, much higher than in subjects without diabetes, and 50% of all heartfailure patients with diabetes died after 3 years. Additional data on the prognosis of patients with diabetes and established heartfailure came from large heartfailure trials, such as the Sur- vival And Ventricular Enlargement (SAVE) trial, 13,14 the Valsartan in Acute Myocardial Infarction Trial (VALIANT), 15 and the Candesartan in HeartFailure— Assessment of Reduction in Mortality and Morbidity (CHARM) trial. 16 All of these trials showed an increased risk of death in men and women with diabetes. For example, in CHARM, which analyzed the effect of candesartan versus placebo in a population with HFrEF and HFpEF, it was shown that both men and women with diabetes exhibited a higher risk of cardiovascular death or hospitalization for heartfailure compared with subjects without diabetes, with a cumulative incidence rate of approximately 40% over 3 years. 16 Further differentiated analyses in patients with or without diabetes and HFpEF or HFrEF showed that the highest mortality or hospitalization for heartfailure risk occurred in patients with diabetes and low ejection fraction (ie, HFrEF), followed by patients with diabetes and HFpEF. 16 The cumulative incidence rate of cardiovascular death and heartfailure hospitalization in subjects with dia- betes plus HFpEF was similar to that in subjects without diabetes but with HFrEF. A similar trend was true for all- cause mortality. In patients with diabetes, cardiovascular mortality was 58.6 per 1000 patient-years in those with HFpEF and 119.1 per 1000 patient-years in those with a low ejection fraction (ie, HFrEF). Similarly, in patients with diabetes, the risk for ଏrst hospital admission for heartfailure was 116.6 per 1000 patient-years for those with HFpEF, whereas the rate was 155.4 per 1000 patient-years for those with HFrEF. 16 Compared with subjects without diabetes, the risk of hospitalization for heartfailure was almost doubled in patients with diabetes independent of HFpEF or HFrEF. 16 Consequently, among patients with HF, those with diabetes have a higher risk of mortality and hospitalization for HF than those without diabetes.
High heart rate (HR) predicts poor outcome in patients with HFpEF and sinus rhythm, but does not apply for those in atrial fibrillation, as shown in a post hoc analysis of the I-PRESERVE trial [ 72 ]. These findings were supported by a sub-analysis of the CHART-2 study, in which elevated HR was associated with a higher CV mortality in HFpEF patients [ 73 ]. The MAGICC registry confirmed the prog- nostic association of HR in sinus rhythm, but not in atrial fibrillation in 2285 HFrEF and 974 HFpEF patients [ 74 ]. Thus, several studies investigated whether beta-blockers induce positive prognostic effects in patients with HFpEF by helping to reduce HR. In a pre-specified sub-analysis of the SENIORS trial, no significant differences were observed regarding the prognostic impact of nebivolol, a β 1 -selective beta-blocker, in patients with impaired and preserved LV function (separation in this trial was LVEF > 35%) [ 75 ]. In the ELANDD study, 6 month treatment with nebivolol led to a reduction in HR, while it had no effect on exercise capacity in terms of 6MWTD and peak oxygen consumption (VO 2 ) in 116 HFpEF patients [ 76 ]. A large meta-analysis on the prog- nostic effects of beta-blockers in HFpEF showed a reduc- tion in mortality by 21%, but results were mainly influenced by findings from observational cohort studies [ 77 ]. In the pooled analysis of RCTs only, use of beta-blockers was asso- ciated with a reduced risk of mortality but without reach- ing statistical significance. The OPTIMIZE-HF registry, on the other hand, did not find a relevant prognostic effect of beta-blocker treatment in patients with HFpEF [ 17 ]. How- ever, both the mentioned meta-analysis [ 77 ] and the OPTI- MIZE-HF registry [ 17 ] did not assess potential differences in therapeutic efficacy between the different sub-classes of
antihyperglycemic drugs, requiring a cardiovascular outcome trial . This novel regulation has changed the landscape for clinical trials in the field of diabetes significantly and since 2008 more than 160,000 patients have been enrolled in cardiovascular outcome trials (Figure 1) . Augmenting data on potential cardiovascular side effects of antidiabetic drugs is very valuable since millions of people are treated over many years. In most of these patients, multiple cardiovascular risk factors are commonly present, so lowering the risk for macrovascular complications is one of the major tasks in current multifactorial diabetes management. Over the last years besides the classical primary ischemic endpoints, heartfailure has emerged as an increasingly important endpoint in
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.
20 the alveoles of the lung which results in pulmonary edema. Patients feel severe cardiac asthma and may experience cardiogenic shock if it worsens. If acute left-sided HF can’t be stopped from further progression, because of the congested pulmonary circulation the right heart gets damaged as well and it will also result in acute right-sided HF. (24) In patients with chronic left-sided HF pulmonary congestion, a milder subacute form of pulmonary edema, arises and therefore the cardiac output decreases. A consequence of that can be shortness of breath (dyspnea), shortness of breath at rest (orthopnea), bronchitis as a result of the congestion and cyanosis. The heart muscle gets hypertrophic and the blood volume increases because neurohormonal adaptions are started. Due to the deficient oxygen supply polyglobulia occurs, thus increasing the viscosity of the blood and therefore causing even more pressure on the heart. (24)
In chronic heartfailure (CHF), chronic kidney disease (CKD) is one of the most prevalent co-morbidities. 1 Patients with CHF and CKD show a worse prognosis than those without CKD. 2 The close interaction of the heart and the kidney was de- scribed by the term cardiorenal syndrome (CRS) depending on intra-renal haemodynamics, trans-renal perfusion pres- sures, and neurohormonal factors. 3 Associated with CRS is the problem of derailment of electrolytes especially a high in- cidence of hyperkalaemia. The risk of hyperkalaemia in HF is further increased by guideline-recommended drugs improv- ing mortality and morbidity like mineralocorticoid antagonists or renin –angiotensin system inhibitors (RASi). 4 New potas- sium binders, like patiromer 5 or ZS 9, 6 have been shown to be effective in the treatment of hyperkalaemia and will be assessed in HF to enable adequately dosed mineralocorticoid receptor antagonists (MRAs), RASi, and sacubitril/valsartan. 7
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 ].
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
In all study participants an invasive hemodynamic assessment was performed for definite diagnosis of PH-HFpEF. A coronary angiography was performed in all patients to exclude coronary heart disease. Patients received a 7F Swan-Ganz catheter (Edwards Lifescience, Irvine, California) via a femoral access. All pressures were recorded over eight-consecutive heart cycles and documented as average of eight measurements using CathCorLX (Siemens AG, Berlin and Munich, Germany). The mean PAWP was recorded as the average of eight time-pressure integral derivations resulting from wedging the inflated Swan-Ganz balloon catheter into a middle-sized pulmonary artery. Zero reference level was obtained at mid-thoracic level. The PA systolic, diastolic and mean pressures as well as the mean right atrial pressure were recorded. CO was measured by thermodilution and by the Fick method. TPG was computed by subtracting mean PAWP from mean PAP; DPG was calculated as the difference between diastolic PAP and mean PAWP during a pull-back; PVR was calculated by dividing TPG by CO; pulmonary pulse pressure was calculated as the difference between systolic PAP and diastolic PAP; pulmonary arterial compliance as the ratio of SV (CO/HR) to pulse pressure. 18 patients agreed to an endomyocardial biopsy taken from the LV utilizing a Bipal ® biopsy forceps (Cordis ® Corporation a Johnson & Johnson Company, New Jersey, USA). Patients who agreed to undergo all study investigations except for myocardial biopsy will not be excluded from the study.
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.
However, conflicting data exist in some forms of heart disease regarding the protection by PPAR α . Schupp et al. (2005) reported that in patients with dilated cardiomyopathy PPAR α expression is increased. There are several literary sources which suggest that the overexpression of PPAR α in heart results in the development of cardiomyopathy. It has been reported that hearts of mice with cardiac-restricted overexpression of PPAR α (MHC-PPAR α) exhibit signs of diabetic cardiomyopathy including ventricular hypertrophy and systolic dysfunction subsequent to increased myocardial fatty acids β -oxidation rates and decreased glucose oxidation rates (Finck et al. 2002). Furthermore, it seems that treatment of healthy WT mice with PPAR α agonists induces cardiomycocyte degeneration and necrosis, due to increased fatty acid oxidation and subsequent accumulation of oxidative stress intermediates, an effect not observed in PPAR α KO mice (Pruimboom-Brees et al. 2006). Sambandam et al. (2006) also showed a deterioration of cardiac recovery after ischaemia / reperfusion in isolated hearts from MHC-PPAR α mice.