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Aimsl: A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischaemia/reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stresses in vivo. Methods and results:Transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild-type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodelling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure-volume loop analysis. Histological indices of remodelling, including cardiomyocyte cross-sectional diameter, capillary density, and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 min of ischaemia followed by 24 h of reperfusion, AKIP1-TG mice displayed a significant two-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signalling molecules NF-kB, protein kinase A, or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium-induced swelling, indicative of reduced MPT pore formation. Conclusions: In contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodelling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Aims Differences in clinical characteristics and outcome of patients with established heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are well established. Data on epidemiology and prediction of new onset HFpEF, compared with HFrEF, have not been described. Methods and results In 8592 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND), a community-based, middle-aged cohort study, we performed cause-specific hazard analyses to study the predictive value of risk factors and established cardiovascular biomarkers on new onset HFrEF vs. HFpEF (left ventricular ejection fraction ≤40 and ≥50%, respectively). A P-value for competing risk (Pcr) <0.10 between HFrEF and HFpEF was considered statistically significant. All potential new onset heart failure cases were reviewed and adjudicated to HFrEF or HFpEF by an independent committee. During a median follow-up of 11.5 years, 374 (4.4%) subjects were diagnosed with heart failure, of which 125 (34%) with HFpEF and 241 (66%) with HFrEF. The average time to diagnosis of new onset HFrEF was 6.6 ± 3.6 years; it was 8.3 ± 3.3 years for HFpEF (P < 0.001). Male gender was associated with new onset HFrEF, whereas female gender with new onset HFpEF (Pcr < 0.001). Higher age and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased the risk for both HFpEF and HFrEF, although for age this was stronger for HFpEF (Pcr = 0.018), whereas NT-proBNP was stronger associated with risk for HFrEF (Pcr = 0.083). Current smokers, increased highly sensitive troponin T, and previous myocardial infarction conferred a significantly increased risk for HFrEF, but not for HFpEF (Pcr = 0.093, 0.091, and 0.061, respectively). Conversely, a history of atrial fibrillation, increased urinary albumin excretion (UAE), and cystatin C were significantly more associated with the risk for HFpEF, but not for HFrEF (Pcr < 0.001, 0.061, and 0.033, respectively). The presence of obesity at baseline was associated with comparable prognostic information for both HFpEF and HFrEF. Conclusion Higher age, UAE, cystatin C, and history of atrial fibrillation are strong risk factors for new onset HFpEF. This underscores differential pathophysiological mechanisms for both subtypes of heart failure. [ABSTRACT FROM PUBLISHER]

Aims Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage and exposure of phosphatidylserine (PS) residues at the cell surface. Excessive eryptosis may lead to anaemia. We aimed to study the role of eryptosis in heart failure (HF)-associated anaemia. Methods and results We measured eryptosis in rodent models of HF. Typical measures of eryptosis including PS-exposure, increased intracellular Ca2+ levels, and decreased cell volume were determined by flow cytometry. Transgenic REN2 rats displayed mild anaemia which was associated with a two-fold increase in erythrocyte PS-exposure when compared with Sprague Dawley (SD) control rats (P < 0.01). Upon stimulation with eryptotic triggers such as oxidative stress, hyperosmotic shock and energy depletion, eryptosis was more prominent in REN2 as shown by increased PS-exposure, cytosolic Ca2+ influx, and cell shrinkage (P < 0.05 vs. SD). Increasing cytosolic Ca2+ levels resulted in a stronger increase in PS-exposure in REN2 erythrocytes (P < 0.01 vs. SD). Accordingly, inhibition of Ca2+ entry blunted the increased PS-exposure upon oxidative stress. The REN2 rats had significantly higher reticulocytes (REN2: 10.6 ± 2.3%; SD: 5.4 ± 0.1%; P < 0.05) and erythrocyte turnover was increased, indicated by increased clearance of eryptotic erythrocytes. Eryptosis was also increased in a rat model of hypertensive cardiac remodelling (uninephrectomized rats implanted with deoxycorticosterone acetate pellets), in mice after transverse aortic constriction, as well as in a small proof-of-concept study in human HF patients. Conclusion Eryptosis is increased during HF development and could contribute to HF-associated anaemia. Eryptosis may therefore become a novel target for therapy in HF-associated anaemia. [ABSTRACT FROM PUBLISHER]

Aims The renin–angiotensin system plays a central role in patients with established cardiovascular (CV) disease, but the prognostic effect of plasma renin in the community is unclear. Methods and results The relationship between plasma renin concentration and CV events was studied in 6228 subjects who were enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, and who were not using antihypertensive medication. Plasma renin concentration was measured using a direct automated immunochemiluminescent assay. The mean (±SD) age was 47(±12) years, 49% were male; the mean follow-up was 10.5 years. The median (Q1–Q3) plasma renin was 17.6 (10.9–27.2) µIU/mL, and plasma aldosterone was 119 (93–153) ng/L. The primary outcome was a composite of fatal (n = 27) and non-fatal (n = 408) CV events. Adjusted for age and sex each doubling of plasma renin was associated with a hazard ratio (HR) for the primary outcome of 1.22 (95% CI: 1.04–1.43; P= 0.015). In a multivariable model, plasma renin showed a positive correlation with heart rate and male sex and a negative correlation with blood pressure, urinary sodium, glucose, and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (adjusted R2: 0.167, P< 0.001). After adjustment for covariates associated with plasma renin, the HR for reaching the primary outcome was 1.28 (95% CI: 1.09–1.49, P= 0.002). Plasma renin was associated with CV events regardless of blood pressure, but in subjects using antihypertensive medication this association was absent. Conclusion Plasma renin concentration is associated with an increased risk for CV events in a community-based cohort not on antihypertensive medication. [ABSTRACT FROM PUBLISHER]

Structural remodelling occurring before, due to the underlying heart disease, and during atrial fibrillation (AF) sets the stage for permanent AF. Current therapy in AF aims to maintain sinus rhythm in symptomatic patients, but outcome is unfortunately poor. Stretch of the atria is a main contributor to atrial remodelling. In this review, we describe different aspects of structural remodelling as seen in animal models and in patients with AF, including atrial enlargement, cellular hypertrophy, dedifferentiation, fibrosis, apoptosis, and loss of contractile elements. In the second part, we describe downstream signals of mechanical stretch and their contribution to AF and structural remodelling. Ultimately, knowledge of mechanisms underlying structural remodelling may help to identify new pharmacological targets for AF prevention. [ABSTRACT FROM AUTHOR]

Aims Cardioprotective effects of erythropoietin (EPO) have been shown in experimental and smaller clinical studies. We performed a prospective, multicentre, randomized trial to assess the effects of a single high dose of EPO after primary coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods and results Patients with a successful PCI for a first STEMI were randomized to receive either standard medical care alone, or in combination with a single bolus with 60 000IU i.v. of epoetin alfa within 3 h after PCI. Primary endpoint was left ventricular ejection fraction (LVEF) after 6 weeks, assessed by planar radionuclide ventriculography. Pre-specified secondary endpoints included enzymatic infarct size and major adverse cardiovascular events. Conclusion A single high dose of EPO after a successful PCI for a STEMI did not improve LVEF after 6 weeks. However, the use of EPO was related to less major adverse cardiovascular events and a favourable clinical safety profile. Clinical Trial Registration Information: NCT00449488; http://www.clinicaltrials.gov/ct2/show/NCT00449488?term=voors&rank=2. [ABSTRACT FROM PUBLISHER]

Aims: We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. [ABSTRACT FROM PUBLISHER]

Background: psychological stress and depressive symptoms have been implicated with accelerated ageing and increased progression of diseases. Shorter telomere length indicates a more advanced biological age. It is unknown whether psychological well-being is associated with telomere length in patients with the somatic condition of chronic heart failure (CHF). [ABSTRACT FROM PUBLISHER]

Aims: Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV. [ABSTRACT FROM PUBLISHER]

Background: The association of renin-angiotensin system (RAS) polymorphisms and left-ventricular hypertrophy (LVH) may depend on the presence of risk factors for LVH, such as renal dysfunction. We studied whether renal function modulates the association between RAS polymorphisms and LVH in a cross-sectional study of 8592 inhabitants of Groningen. Methods: Left-ventricular hypertrophy was determined with electrocardiograms, using the Cornell voltage-duration product. The following RAS polymorphisms were determined: angiotensin II type-1 receptor (AGTR1 A1166C), angiotensin-converting enzyme (ACE) insertion/deletion (I/D), and angiotensinogen (AGT G-6A). The AGTR1 A1166C and ACE I/D polymorphisms were in Hardy-Weinberg equilibrium. Results: Electrocardiographic LVH was present in 417 (5.0%) subjects. Subjects with LVH were older (53 v 49 years) and overall had more cardiovascular risk factors. Using logistic regression, creatinine clearance interacted with the relationship between the AGTR1 A1166C polymorphism and LVH (β, −0.19; P = .033). In subjects with the CC genotype, in contrast to carriers of an A allele, the prevalence of LVH increased with more pronounced renal dysfunction. Creatinine clearance also interacted with the relationship between the ACE I/D polymorphism and LVH (β, 0.12; P = .037), although less strongly, and the other way around. Creatinine clearance did not influence the association between the AGT G-6A polymorphism and LVH (β, −0.006; P = .491). Conclusions: In this population-based study, the AGTR1 A1166C polymorphism was associated with LVH, dependent on concomitant renal dysfunction. A weaker renal function dependent association between the ACE I/D polymorphism and LVH was also observed. Renal function should be taken into account as a relevant environmental factor for the pathogenetic effects of RAS polymorphisms. [Copyright &y& Elsevier]

Aims Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients. [ABSTRACT FROM PUBLISHER]

Background. Statins improve cardiovascular outcome, but less is known on the renal outcome. We, therefore, studied the relationship between the use of statins and urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in two settings: a randomized controlled trial (RCT) and an observational cohort study, in which patients were included to study the impact of an elevated UAE on renal and cardiovascular prognosis. [ABSTRACT FROM PUBLISHER]

Abstract: Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients. [Copyright &y& Elsevier]

Aims Non-compliance in patients with heart failure (HF) contributes to worsening HF symptoms and may lead to hospitalization. Several smaller studies have examined compliance in HF, but all were limited as they only studied either the individual components of compliance and its related factors or several aspects of compliance without studying the related factors. The aims of this study were to examine all dimensions of compliance and its related factors in one HF population. [ABSTRACT FROM PUBLISHER]

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin–angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients. [ABSTRACT FROM PUBLISHER]

Aims Microalbuminuria frequently clusters with the metabolic syndrome and may identify subjects at increased coronary risk. Statin treatment may reduce the incidence of major adverse cardiac events in subjects with the metabolic syndrome, but evidence is limited. We evaluated the impact of pravastatin treatment on the incidence of major adverse cardiac events in microalbuminuric subjects with the metabolic syndrome. [ABSTRACT FROM PUBLISHER]

Background: Both renal dysfunction and left ventricular hypertrophy (LVH) are signs of end-organ damage, risk markers of cardiovascular (CV) disease and chronic heart failure. In selected populations such as those with diabetes or hypertension, renal dysfunction was found to be related to LVH. We studied the relation between renal dysfunction and LVH in a cross-sectional study in 8592 inhabitants from Groningen, The Netherlands. Methods: Standard 12-lead electrocardiograms were recorded, and LVH was classified using the Cornell voltage duration product. Renal dysfunction was defined as creatinine clearance <60 mL/min/1.73 m2 or microalbuminuria (30 to 300 mg/24 h). Results: Electrocardiographic signs of LVH were present in 396 of subjects (5.3%). Subjects with LVH were older and had a more extensive CV risk profile. We found that LVH was more prevalent in subjects with renal dysfunction than in those without (8% v 4%, P < .001). Multivariate regression analysis demonstrated that renal dysfunction was independently related to a 1.47-fold increased risk of the presence of LVH (95% CI = 1.15 to 1.88, P = .009). In addition, both creatinine clearance (OR = 1.56, 95% CI = 1.07 to 2.2, P = .044) and microalbuminuria (OR = 1.37, 95% CI = 1.04 to 1.80, P = .024) were independently associated with the presence of LVH. Conclusion: Subjects with mild renal dysfunction have a substantially higher risk of LVH on electrocardiography than those without renal dysfunction. [Copyright &y& Elsevier]

Several studies showed that anaemia is commonly observed in patients with Chronic Heart Failure (CHF) and is associated with worsened symptoms and survival. When anaemia in these patients is treated with erythropoietin (EPO), a significant improvement in cardiac function and symptoms was observed. Although it was originally believed that EPO specifically acted on haematopoietical cells, recent evidence demonstrated several non-haematopoietical effects. Ischaemia/reperfusion experiments in rat heart and brain showed large infarct reduction when treated with EPO. Other effects of EPO are related to its pro-angiogenic effects on endothelial cells, which could be of potential value in patients with ischaemic heart disease. These preclinical findings suggest that EPO may have potential effects in cardiovascular disease beyond correction of haemoglobin levels. [ABSTRACT FROM PUBLISHER]

Objective: Different components of the renin–angiotensin system (RAS) have been demonstrated in atherosclerotic plaques. However, the involvement of the RAS in in-stent restenosis is not clear. We studied the differential immunolocalisation of angiotensin converting enzyme (ACE) and the angiotensin II type 1 (AT1) receptor in de-novo stenotic lesions and in-stent restenotic lesions in human coronary arteries. Methods: Using a pullback atherectomy catheter, biopsies from de-novo coronary lesions (n=19) and in-stent restenotic lesions (n=19) were obtained. The biopsies were immunostained for vascular smooth muscle cells (VSMCs), macrophages, ACE and the AT1 receptor. Results: In biopsies from de-novo stenotic lesions ACE-positive macrophages were more numerous than in in-stent restenotic lesions (P=0.002). Moreover, in the latter lesions, ACE-positive macrophages decreased when the time interval of stent implantation was longer. On the other hand, in-stent restenotic lesions contained predominantly young VSMCs, which abundantly expressed AT1 receptors. Conclusions: Lesional ACE expression is not a prominent feature of in-stent restenotic lesions. In contrast, AT1 receptors are abundantly expressed on young VSMCs. In de-novo lesions ACE and AT1 receptors were found on macrophages and VSMCs, which were present in all specimens. [Copyright &y& Elsevier]

Objective: To study the effects of increased levels of myocardial angiotensin II type 1 (AT1) receptor on microvascular growth following myocardial infarction (MI). Methods: MI was created in transgenic rats (TGR) with a cardioselective overexpression of the AT1 receptor. We used Sprague–Dawley (SD) rats as controls. Some of the rats were treated with the selective AT1 receptor blocker losartan (Los). Rats were sacrificed after 3 weeks. Results: MI caused left ventricular (LV) hypertrophy and LV dysfunction in both SD and TGR, which was prevented by AT1 receptor blockade. Furthermore, MI decreased microvessel density in the non-infarcted myocardium (SD MI: 1653±37/mm2, P<0.01 vs. sham-operated controls), however, microvessel density decreased significantly more in TGR with MI (1298±33/mm2, P<0.01 vs. SD MI). AT1 receptor blockade restored microvessel density (SD MI Los: 2046±195/mm2; TGR MI Los: 1742±47/mm2; P<0.01 vs. untreated). The differences in microvessel density were still present after correction for LV hypertrophy. The increase in microvessel density after AT1 receptor blockade was not accompanied by increased myocardial vascular endothelial growth factor (VEGF) levels. Microvessel density correlated with parameters of myocardial stretch, such as LV end-diastolic pressure (−0.681, P<0.001) and N-ANP (−0.424, P=0.01). Conclusions: Microvessel density after MI is decreased when the AT1 receptor is overexpressed, and this is amenable to AT1 receptor blockade. This suggests that efficacy of AT1 receptor blockers post-MI may not only be due to attenuation of LV remodeling, but also to a stimulatory effect on angiogenesis. [Copyright &y& Elsevier]

Objective: Atrial fibrillation (AF) is accompanied by electrical, structural and ion-channel protein remodeling. We tested if proteolysis by calpain and proteasome is activated during AF, and studied the relation with the remodeling processes. Methods: Right atrial appendages were obtained from patients with paroxysmal (n=7) or persistent (n=10) lone AF and compared to controls (n=10) in sinus rhythm undergoing coronary artery bypass grafting (CABG). Proteolysis was measured using Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl-coumarin. Protein expression of calpain I and II was assessed by Western-blot and calpain I localization by immunohistochemistry. Structural changes were quantified by counting atrial myocytes with contraction bands or hibernation. Results: Calpain activity was significantly increased in paroxysmal AF (2-fold, P<0.001) and persistent AF (3-fold, P<0.001), mainly due to calpain I activation. Increased calpain I protein expression was found in AF with Western blot and immunohistochemistry. Myocytes from all AF groups showed increased contraction bands, whereas hibernation was only found in persistent AF. Calpain activity correlated with L-type Ca2+ channel and Kv1.5 protein amounts (r=−0.80, P<0.001 and r=−0.72, P<0.001, respectively), degree of structural changes (r=0.90, P<0.001), shortening of atrial effective refractory period (AERP) (basic cycle length 500 ms, r=−0.60, P<0.001) and AERP rate adaptation (r=−0.80, P<0.001). Conclusions: Calpain activity is induced during AF and correlates with parameters of ion-channel protein, structural and electrical remodeling. The results suggest that calpain activation represents an important mechanism linking calcium overload to cellular adaptation mechanisms in human AF. [Copyright &y& Elsevier]

Objective: Persistent atrial fibrillation (AF) results in an impairment of atrial function. In order to elucidate the mechanism behind this phenomenon, we investigated the gene expression of proteins influencing calcium handling. Methods: Right atrial appendages were obtained from eight patients with paroxysmal AF, ten with persistent AF (>8 months) and 18 matched controls in sinus rhythm. All controls underwent coronary artery bypass grafting, whereas most AF patients underwent Cox’s MAZE surgery (n=12). All patients had a normal left ventricular function. Total RNA was isolated and reversely transcribed into cDNA. In a semi-quantitative polymerase chain reaction the cDNA of interest and of glyceraldehyde-3-phosphate dehydrogenase were coamplified and separated by ethidium bromide-stained gel electrophoresis. Slot blot analysis was performed to study protein expression. Results: L-type calcium channel α1 and sarcoplasmic reticulum Ca2+-ATPase mRNA (−57%, p=0.01 and −28%, p=0.04, respectively) and protein contents (−43%, p=0.02 and −28%, p=0.04, respectively) were reduced in patients with persistent AF compared to the controls. mRNA contents of phospholamban, ryanodine receptor type 2 and sodium/calcium exchanger were comparable. No changes were observed in patients with paroxysmal AF. Conclusions: Alterations in gene expression of proteins involved in the calcium homeostasis occur only in patients with long-term persistent AF. In the absence of underlying heart disease, the changes are rather secondary than primary to AF. [ABSTRACT FROM PUBLISHER]

Objective: Treatment with the β-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of β-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on β-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized β-adrenergic signal transduction. Methods: Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 μg/kg) or held under control conditions and were compared with Sprague-Dawley rats. Myocardial β-adrenoceptors (125I-labeled iodocyanopindolol binding), Giα (pertussis toxin labeling), Gsα-activity (reconstitution into cyc−S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined. Results: β-Adrenoceptors were downregulated and Giα-protein levels were significantly increased, producing a desensitization of basal, isoprenaline- and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced β-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac β-adrenergic receptors similar to isoprenaline but different from metoprolol. Conclusions: Carvedilol did not restore β-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with β-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of β-adrenergic receptors. [ABSTRACT FROM PUBLISHER]

Objective: Replication-deficient, recombinant adenovirus is used as a carrier for gene transfer, but it is unspecific and the onset of transgene expression is relatively late. Here, we evaluated the efficiency and selectivity of gene transfer mediated by recombinant Semliki Forest virus (SFV). Methods: We compared the efficiency of a SFV-based vector with an adenoviral vector, using LacZ as a reporter gene. Firstly, the affinity for vascular smooth muscle cells, endothelial cells and cardiac myocytes was assessed. Secondly, we compared the time course of LacZ expression and cytotoxicity in vascular smooth muscle cells. Results: The SFV-based vector infects vascular smooth muscle cells and cardiomyocytes as efficiently as adenovirus. In contrast to adenovirus, SFV hardly transfers LacZ to endothelial cells (2.6% or less). SFV-mediated expression was visible after 1 h, reaching a maximum after 6 h. In contrast, adenovirus-mediated expression became visible after 6 h, and reached a maximum after 48–72 h. Both vectors were cytotoxic. Conclusions: We demonstrate that SFV efficiently transfers LacZ to vascular smooth muscle cells and cardiomyocytes, but not to endothelial cells. In contrast, adenovirus causes efficient transgene expression in all cell types tested. Furthermore, SFV-mediated expression is faster than adenovirus-mediated expression. Therefore, SFV-mediated gene transfer may be a suitable alternative to adenovirus, providing a fast expression in non-endothelial cardiovascular cell types. [ABSTRACT FROM PUBLISHER]

Objective:Impairment of endothelium-dependent relaxation is related to dyslipidemia and may be an early marker for atherosclerosis in angiographically smooth arteries. The aim of the present study was to relate preoperative serum lipids to endothelium-dependent relaxation in internal mammary arteries of patients undergoing coronary bypass surgery. Methods: The study group consisted of 37 patients, from whom segments of the internal mammary artery were obtained during surgery. Measurements of endothelium-dependent relaxation were performed in organ baths by adding methacholine (10 nM–10 μM). Results: All internal mammary arteries dilated in response to methacholine, ranging from 4 to 112% of the precontraction to 10 μmol phenylephrine. In a multiple regression model, increased total serum cholesterol appeared to be the best predictor for impaired endothelium-dependent relaxation. A 1 mmol increase of total cholesterol was associated with a 11.2% decrease of endothelium-dependent relaxation (P=0.006). When total cholesterol was omitted from the model, LDL-cholesterol became the best predictor of endothelium-dependent relaxation (regression coefficient 10.3%/mmol; P=0.02). No other variable was significantly associated with endothelium-dependent relaxation, and none of the preoperative variables was associated with endothelium-independent relaxation, expressed as the response to sodium nitrite (10 mM). Conclusion: Our study showed that endothelium-dependent relaxation in apparently non-diseased internal mammary arteries used for coronary bypass surgery was independently related to preoperative (LDL)-cholesterol levels. [ABSTRACT FROM PUBLISHER]

Objectives: The purpose of this study was to investigate the changes in β-adrenoceptor density (Bmax) and distribution in a model of chronic myocardial infarction in rats, and to relate possible changes to hemodynamic and neurohumoral abnormalities. In addition, we examined the effects of 8 weeks treatment with ibopamine and captopril. Methods: There were 3 experiments: (1) Bmax and plasma catecholamines were examined (n = 46), (2) Bmax was compared in infarcted and non-infarcted tissue (n = 13), and (3) contractile function was evaluated by isolated heart perfusion (n = 40). Of rats in Expts. (1) and (3), 50% had myocardial infarction induced by coronary ligation and 50% were controls. Each group was divided between ibopamine, ibopamine and captopril, or standard (no drug) treatment. Results:Bmax was not decreased in rats with myocardial infarction (10.8 ± 0.8 fmol/mg protein), compared to normal rats (11.4 ± 0.6 fmol/mg protein), and the ratio β1/β2 was also unaffected. In infarcted tissue, Bmax was significantly (P = 0.03) lower than in non-infarcted tissue. Baseline left ventricular pressure, systolic and diastolic dP/dT were all impaired (P < 0.001), and plasma norepinephrine levels were elevated in rats with myocardial infarction (16.03 ± 230 vs. 1287 ± 83 pg/ml; P < 0.05), compared to normals. Both ibopamine alone and in combination with captopril reduced the elevated plasma norepinephrine levels in infarcted rats (P < 0.001), but only the combination of the 2 drugs significantly increased Bmax in infarcted rats (14.7 ± 0.8 fmol/mg protein; P = 0.03 vs. untreated myocardial infarction), while ibopamine alone had no significant effect (13.1 ±1.1 fmol/mg protein; p = ns). Also, active drug treatment had no significant effect on the hemodynamic changes. Conclusions: In this coronary artery ligation model of myocardial infarction in rats, no β-adrenoceptor down-regulation is observed, despite marked abnormalities in baseline left ventricular function and plasma norepinephrine levels. The combination of ibopamine and captopril significantly increases Bmax in infarcted rats, which is accompanied by a reduction in plasma norepinephrine levels, but not by an improvement in hemodynamic parameters. [ABSTRACT FROM PUBLISHER]

Objective: The cardiac renin-angiotensin system is activated in experimental heart failure, but it is unknown at what stage of heart failure it becomes activated, and whether activation is related to ventricular dysfunction and dilatation. Changes in activity of cardiac, renal, and plasma angiotensin converting enzyme (ACE) were therefore examined at different stages of experimental heart failure, with simultaneous measurements of left ventricular pressure, systolic dP/dt, and inner ventricular radius. Methods: Heart failure was induced by experimental infarction in 17 normotensive male Wistar rats; 14 rats were sham operated. Rats were killed 3, 5, or 80 d after infarction. In an isolated heart perfusion, left ventricular pressure and systolic dP/dT were measured. ACE activity was determined in samples of the left and right cardiac ventricle, kidney, and plasma. Radius of the ventricular cavity was planimetrically determined in transverse sections of the left ventricle. Results: At the different stages both left ventricular pressure and systolic dP/dT progressively decreased and inner radius of the left ventricle increased in all heart failure groups. ACE activity in the left ventricle increased significantly in all heart failure groups and correlated inversely with left ventricular pressure (R=−0.81; p < 0.001) and dP/dt (R=−0.85; p < 0.001). ACE activity in the kidney was only increased 80 d after the induction of heart failure [17(SEM 1) v 11.2(0.5) nM His-Leu generated per min·mg−1, p < 0.01], while plasma ACE activity was not increased in any heart failure group. Conclusions: Cardiac ACE is activated in the early stage after induction of heart failure and is related to the amount of dysfunction. ACE in the kidney is activated only in the chronic stage. The cardiac renin-angiotensin system therefore already appears to be an important neurohumoral adjustment in the early stage of heart failure and is thereby a suitable target for early intervention by ACE inhibitors.Cardiovascular Research 1993;27:1933-1938 [ABSTRACT FROM PUBLISHER]