Effect of intracoronary bone marrow-derived mononuclear cell injection early and late after myocardial infarction on CMR-derived myocardial strain.

BACKGROUND: Studies indicate no clear impact of intracoronary injection of bone-marrow unselected mononuclear cells (BM-MNC) after acute myocardial infarction (AMI) on left-ventricular function (LVEF). Strain parameters by cardiovascular magnetic resonance (CMR) have been proposed to be more sensitive to functional changes of the heart. The aim of the present study was to assess changes of global longitudinal (GLS) and circumferential strain (GCS) in a group of patients treated with BM-MNC after AMI. METHODS: One-hundred and forty-nine patients with successfully reperfused AMI and LV dysfunction (LVEF<45%) were retrospectively included into this sub-study of the SWISS-AMI multicentre trial. Patients were divided into control (N = 54), early (5-7 days after AMI, N = 51) and late BM-MNC treatment groups (3-4 weeks, N = 44). The endpoint was the change of GLS and GCS as obtained from cine sequences 4 and 12 months after AMI using feature tracking algorithm. RESULTS: In unadjusted analyses, the absolute change of GLS for the early treatment group from baseline to 4 months was 2.5 ± 4.3 (p < 0.01), to 12 months 2.7 ± 5.7% (p = 0.004). For late treatment, it was 1.5 ± 4.0% (p = 0.039, 4 months) and 2.5 ± 5.6% (p = 0.015, 12 months). For controls 0.7 ± 4.7% (p = 0.378), 0.8 ± 3.9% (p = 0.253) respectively. Adjusting for different baseline values, neither an overall treatment effect (both time-points) of BM-MNC nor a treatment time-related (only early or late) effect could be shown for all functional parameters. CONCLUSIONS: Among patients after AMI with successful reperfusion and LV dysfunction, intracoronary infusion of BM-MNC early or late after AMI did not improve global strain parameters at 4- or 12-months follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

Tumour Necrosis Factor-α Inhibition Improves Stroke Outcome in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

Comprehensive morphologic and functional imaging of heart transplant patients: first experience with dynamic perfusion CT.

OBJECTIVES: We aimed to assess the diagnostic performance of a combined protocol with coronary computed tomography angiography (CCTA) and stress CT perfusion imaging (CTP) in heart transplant patients for comprehensive morphological and functional imaging. METHODS: In this prospective study, 13 patients undergoing routine follow-up 8±6 years after heart transplantation underwent CCTA and dynamic adenosine stress CTP using a third-generation dual-source CT scanner, cardiac magnetic resonance (MR) adenosine stress perfusion imaging at 1.5 T, and catheter coronary angiography. In CCTA stenoses >50% luminal diameter narrowing were noted. Myocardial perfusion deficits were documented in CTP and MR. Quantitative myocardial blood flow (MBF) was calculated with CTP. Left ventricular ejection fraction was determined on cardiac MR cine images. Radiation doses of CT were determined. RESULTS: One of the 13 patients had to be excluded because of severe motion artifacts. CCTA identified three patients with stenosis >50%, which were confirmed with catheter coronary angiography. CTP showed four patients with stress-induced myocardial hypoperfusion, which were confirmed by MR stress perfusion imaging. Quantitative analysis of global MBF showed lower mean values as compared to known reference values (MBF under stress 125.5 ± 34.5 ml/100 ml/min). Average left ventricular ejection fraction was preserved (56 ± 5%). CONCLUSIONS: In heart transplant patients, a comprehensive CT protocol for the assessment of morphology and function including CCTA and CTP showed good concordance to results from MR perfusion imaging and catheter coronary angiography. KEY POINTS: • Stress CT perfusion imaging enables the detection of myocardial ischemia • CT myocardial perfusion imaging can be combined with coronary computed tomography angiography • Combining perfusion and coronary CT imaging is accurate in heart transplant patients • CT myocardial perfusion imaging can be performed at a reasonable radiation dose.

Impact of cardio-renal syndrome on adverse outcomes in patients with Fabry disease in a long-term follow-up.

AIMS: Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. METHODS AND RESULTS: A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CONCLUSIONS: CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial.

Unfavorable Donor Pretransplant APACHE II, SAPS II, and SOFA Scores Are Not Associated With Outcome: Implications for Heart Transplant Donor Selection.

BACKGROUND: The quality of the donor heart and the individual risk of the recipient awaiting heart transplantation are difficult to assess. We investigated whether routinely used intensive care scoring systems can provide additional prognostic information on outcomes after heart transplantation. METHODS: A total of 114 consecutive patients who underwent heart transplantation were included. The Acute Physiology and Chronic Health Evaluation II (APACHE II), the Simplified Acute Physiology Score (SAPS II), and the Sequential Organ Failure Assessment (SOFA) scores were calculated for donors and recipients. Risk factors such as the donor's cause of death, donor's catecholamine use, dialysis status of the recipient, and smoking pattern of the donor and the recipient were assessed. The association of these parameters with mortality, length of stay on the intensive care unit, and need for invasive ventilation was investigated. RESULTS: The median APACHE II score of the donors was 20 (confidence interval [CI], 19-20), the median SAPS II score was 46 (CI, 45-48), and the median SOFA score was 10 (CI, 9-10). In contrast, the median scores of the recipients were as follows: APACHE II, 7 (CI, 6-8); SAPS II, 13 (CI, 12-14); and SOFA, 1 (CI, 1-2). None of the scores as calculated significantly predicted clinical outcome after transplantation. CONCLUSIONS: This study detected no prognostic impact of donor-related risk factors on outcome after heart transplantation. Our findings support the growing practice of also considering organs from donors with high-risk scores for heart transplantation.

Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease. METHODS: In this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests. RESULTS: The study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4±2.4% vs. 4.8±1.9%, p=0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3±15.1 vs 24.7±12.8mm2, p=0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5±28.4 vs. 29.4±16.5 bursts/100 heart beats, p=0.09) with no significant differences in muscle sympathetic activity in response to stress. CONCLUSIONS: Our findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome. CLINICALTRIALS. GOV IDENTIFIER: NCT01249599.

The impact of pretransplantation urgency status and the presence of a ventricular assist device on outcome after heart transplantation.

INTRODUCTION: There are conflicting reports on the posttransplantation morbidity and mortality of patients listed urgently and/or supported by a ventricular assist device (VAD). The aim of this study was to analyze the outcomes with regard to pretransplantation condition (elective, urgent, VAD). METHODS: All adult recipients between January 1, 2005, and October 31, 2012, were included. Demographics; preoperative, operative, and postoperative data; outpatient follow-up; and donor characteristics were collected and analyzed. RESULTS: Of a total of 74 patients, 19 were listed urgently, 20 had a Berlin Heart EXCOR BVAD (biventricular assist device) (Berlin Heart, Berlin, Germany) (8 urgent), 7 had a Berlin Heart INCOR left VAD (Berlin Heart, Berlin, Germany) (2 urgent), and 2 had a HeartWare left VAD (HeartWare International, Framingham, Mass, USA) (none urgent). Mean age was 52 ± 12years. The overall 30-day, 1-year, and 3-year survival was 90% ± 3%, 79% ± 5%, and 66% ± 7%. There was no difference in survival when comparing urgently listed (95% ± 5%, 84% ± 8%, 74% ± 12%) and elective patients (89% ± 4%, 77% ± 6%, 63% ± 8%; P = .4), and VAD patients (86% ± 6%, 76% ± 8%, 63% ± 11%) and those without mechanical support (93% ± 4%, 81% ± 6%, 69% ± 9%; P = .6). In-hospital outcomes and long-term complications were also comparable. CONCLUSIONS: Our series suggests that urgent patients and patients on a VAD have a posttransplantation outcome comparable to elective patients and patients without a VAD. These data support the effectiveness of the current practice of listing for heart transplantation.

Fatal outcome after heart transplantation caused by Aspergillus lentulus.

Opportunistic invasive fungal infections are a major cause of mortality in immunocompromised patients. Early diagnosis of invasive aspergillosis and proper identification of the causative agent is crucial for guidance of therapy. Accurate differentiation of Aspergillus lentulus, a filamentous fungus often misidentified as atypical Aspergillus fumigatus, is of concern as multiple antifungal drugs show a reduced susceptibility. This is the first report, to our knowledge, of a proven pulmonary invasive fungal infection caused by A. lentulus after heart transplantation.

[Effect of paracetamol (acetaminophen) on blood pressure in patients with coronary heart disease]. / Effekt von Paracetamol auf den Blutdruck bei Patienten mit koronarer Herzkrankheit.

Analgesic drugs, non-steroidal anti-inflammatory drugs and paracetamol (acetaminophen) in particular, belong to the most widely prescribed therapeutic agents. Beside their efficacy in pain relief, these drugs were recently linked to increased cardiovascular risk. Indeed, epidemiological and clinical studies showed that non-selective non-steroidal anti-inflammatory drugs, as well as selective cyclooxygenase-2 inhibitors both may increase blood pressure and cardiovascular events. However, the effect of paracetamol (acetaminophen) on blood pressure and cardiovascular health should not be neglected, too. Unfortunately, long-term randomized controlled trials appropriately powered to evaluate cardiovascular outcomes are lacking. This review summarizes the available data about the effect of paracetamol in particular, on blood pressure and other cardiovascular outcomes.

Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial.

OBJECTIVE: Impaired endothelial function was demonstrated in HIV-infected persons on protease inhibitor (PI)-containing antiretroviral therapy, probably due to altered lipid metabolism. Atazanavir is a PI causing less atherogenic lipoprotein changes. This study determined whether endothelial function improves after switching from other PI to atazanavir. DESIGN: Randomised, observer-blind, treatment-controlled trial. SETTING: Three university-based outpatient clinics. PATIENTS: 39 HIV-infected persons with suppressed viral replication on PI-containing regimens and fasting low-density lipoprotein (LDL)-cholesterol greater than 3 mmol/l. INTERVENTION: Patients were randomly assigned to continue the current PI or change to unboosted atazanavir. MAIN OUTCOME MEASURES: Endpoints at week 24 were endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery, lipid profiles and serum inflammation and oxidative stress parameters. RESULTS: Baseline characteristics and mean FMD values of the two treatment groups were comparable (3.9% (SD 1.8) on atazanavir versus 4.0% (SD 1.5) in controls). After 24 weeks' treatment, FMD decreased to 3.3% (SD 1.4) and 3.4% (SD 1.7), respectively (all p = ns). Total cholesterol improved in both groups (p<0.0001 and p = 0.01, respectively) but changes were more pronounced on atazanavir (p = 0.05, changes between groups). High-density lipoprotein and triglyceride levels improved on atazanavir (p = 0.03 and p = 0.003, respectively) but not in controls. Serum inflammatory and oxidative stress parameters did not change; oxidised LDL improved significantly in the atazanavir group. CONCLUSIONS: The switch from another PI to atazanavir in treatment-experienced patients did not result in improvement of endothelial function despite significantly improved serum lipids. Atherogenic lipid profiles and direct effects of antiretroviral drugs on the endothelium may affect vascular function. TRIAL REGISTRATION NUMBER: NCT00447070.

Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia.

BACKGROUND: Reduced availability of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH(4) improves endothelial dysfunction, the effect of chronic BH(4) in humans is unknown. OBJECTIVE: To investigate the effect of chronic BH(4) supplementation on endothelial function and oxidative stress in hypercholesterolaemia. DESIGN: Randomised double-blind, placebo-controlled trial. SETTING: University Hospital. PATIENTS: 22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH(4) (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls. MAIN OUTCOME MEASURES: Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH(4) effect, NO release and superoxide anion (O(2)(-)) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l). RESULTS: BH(4) plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH(4). No effect of BH(4) on endothelium-independent vasodilatation was seen. Furthermore, 8-F(2 )isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH(4). In LDL-treated endothelial cells, BH(4) levels and NO release were reduced and O(2)(-) production increased compared with control cells. Exogenous BH(4) normalised NO and O(2)(-) production. CONCLUSIONS: In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH(4). Thus, BH(4) availability is essential for maintaining NO synthesis and low O(2)(-) production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.

Coxibs, non-steroidal anti-inflammatory drugs and cardiovascular risk.

The introduction of selective cyclooxygenase-2 inhibitors offered the promise of similar efficacy in pain control without the gastrointestinal effects associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs). By blocking prostacyclin formation but leaving platelet-derived thromboxane A2 generation unopposed, there is concern that the potential gastrointestinal benefit of cyclooxygenase-2-selective inhibitors may come at the cost of increased thrombotic risk. However, the differential effects of coxibs on blood pressure, endothelial function, oxidative stress, tissue factor expression, vascular smooth muscle proliferation and neointimal hyperplasia indicate a distinct heterogeneity among this class of drugs. Importantly, the observation of an excess cardiovascular risk with traditional NSAIDs in randomized clinical trials, meta-analysis and large-scale observational studies further highlights the need to scrutinize the entire class of anti-inflammatory drugs, including traditional NSAIDs, as rigorously as coxibs.

[The sweet secret of dark chocolate]. / Das süsse Geheimnis der dunklen Schokolade.

For centuries dark chocolate has been known for its taste as well as its beneficial effects on health. Mainly polyphenols, a heterogeneous group of molecules, have been associated with antioxidant and immunomodulatory properties. Furthermore they inhibit primary hemostasis and pathways associated with platelet activation and aggregation.

Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.