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.

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.

Acute effect of nitroglycerin on cyclosporine-induced hypertension after cardiac transplantation.

BACKGROUND: Cyclosporine represents a milestone in immunosuppression following organ transplantation. Its use, however, comes at the cost of significant side effects, such as arterial hypertension which is rarely controllable by currently available anti-hypertensive drugs. The aim was to investigate the effect of acute administration of nitroglycerin in heart-transplanted patients with cyclosporine-induced hypertension. METHODS: The sample included 18 cyclosporine-induced hypertensive patients (HTX group) scheduled for elective cardiac catheterization following heart transplantation, as well as 6-matched essential hypertensive patients (HT group). The blood pressure (BP) in the aorta and pulmonary artery, before and after administration of nitroglycerin, was measured simultaneously. RESULTS: After injection of 50 µg and 100 µg nitroglycerin, BP significantly decreased both in HTX (systolic (s) BP p = 0.0001; diastolic (d) BP p = 0.0001) and in controls (sBP p = 0.006; dBP p = 0.05). This reduction was more pronounced in HTX (sBP p = 0.022; dBP p = 0.018 for group-comparison). Following analysis of the data in relation to its individual baseline, a significantly higher reduction of the BP induced by 100 µg nitroglycerin was observed in the HTX group compared to the HT group (p = 0.02 for sBP and p = 0.03 for dBP). 8 +/- 3 minutes after the last nitrate infusion, BP remained significantly reduced compared to baseline in HTX (p <0.001), whereas it came back to baseline in controls. The reduction in sBP was correlated to cyclosporine A levels (p = 0.04 after 50µg nitroglycerin; p = 0.05 after 100 µg nitroglycerin). CONCLUSION: After application of nitroglycerin, sBP is reduced immediately in HTX with uncontrolled cyclosporine-induced hypertension. Further studies are needed to evaluate the long-term effect of nitrates in these patients.

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.

[Diagnostic yield of the implantable loop recorder to detect the mechanism of syncope--a single center long term experience of a tertiary care center]. / Synkopenabklärung mittels implantierbarem Loop Recorder--Langzeiterfahrung eines Zentrumspitals.

AIM: The aim of this study was to investigate the usefulness in providing diagnostic information about syncope by implantation of a loop recorder (ILR). METHODS AND RESULTS: The study population consisted of 48 consecutive patients (23 male, 25 female, mean age 42 +/- 17) with unexplained syncope who presented between 1998 and 2002 and underwent extensive cardiological screening and were followed with an implantable loop recorder (Reveal or Reveal Plus). The mean follow-up duration was 9 +/- 6 months. During this follow-up in 17 (35%) patients syncope recurred. Arrhythmia correlating with syncope was documented in 15 (88%) of these patients, in 2 (12%) patients an arrhythmia could be excluded. Of these 15 patients with arrhythmogenic cause of syncope 5 (33%) patients revealed higher degree AV-Block, 7 (47%) patients sinus bradycardia or sinus pauses, 4 (27%) due to sick sinus syndrome and 3 (20%) due to neurally mediated syncope, 3 (20%) patients had atrial tachycardias or atrial fibrillation with rapid AV-conduction. As a result of ILR findings 12 pacemakers were implanted and 2 radiofrequency ablations were performed. CONCLUSION: The ILR is a valuable and effective tool to establish an arrhythmic cause for unexplained syncope. In these cases they have an impact on subsequent clinical decision making. ILR can also be useful in ruling out arrhythmias as cause of syncope and presyncope.

Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events.

Endothelial cells are a rich source of a variety of vasoactive substances, which either cause vasodilation or vasoconstriction. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin. nitric oxide exerts potent anti-atherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. Endothelium-derived contracting factors include the 21 amino acid peptide endothelin (ET). vasoconstrictor prostanoids such as thromboxane A2 and prostaglandin H2, as well as free radicals and components of the renin angiotensin system. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modem therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Angiotensin converting enzyme (ACE) inhibitors are a primary candidate for that concept as they inhibit the circulating and local renin angiotensin system. Angiotensin converting enzyme is an endothelial enzyme which converts angiotensin-I (A-I) into angiotensin-II (A-II). This effect of the ACE inhibitor prevents direct effects of angiotensin-II such as vasoconstriction and proliferation in the vessel wall but also prevents activation of the ET system and of plasminogen activator inhibitor. Furthermore, inhibition of ACE prolongs the half-life of bradykinin and stabilizes bradykinin receptors linked to the formation of nitric oxide and prostacyclin. In isolated arteries ACE inhibitors prevent the contractions induced by angiotensin II and enhance relaxation induced by bradykinin. Chronic treatment of experimental hypertension with ACE inhibitors normalizes endothelium-dependent relaxation to acetylcholine and other agonists. In addition, the dilator effects of exogenous nitric oxide donors are enhanced, at least in certain models of hypertension. In humans with essential hypertension ACE inhibitors augment endothelium-dependent relaxation to bradykinin, while those to acetylcholine remain unaffected, at least in the time frame of the published studies, i.e. 3-6 months. In patients with coronary artery disease, however, paradoxical vasoconstriction to acetylcholine is markedly reduced after 6 months of ACE inhibition. After myocardial infarction ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death in hypertensive patients. These effects have also been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial. Thus, in summary, ACE inhibitors are an important class of drugs providing cardiovascular protection in patients with increased cardiovascular risk.

Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide.

BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined. METHODS AND RESULTS: lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids. CONCLUSIONS: Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity.

Coexpression of inducible NO synthase and soluble guanylyl cyclase in colonic enterocytes: a pathophysiologic signaling pathway for the initiation of diarrhea by gram-negative bacteria?

Infectious diarrhea is often caused by the exotoxins of gram-negative bacteria such as Escherichia coli. However, these organisms also contain lipopolysaccharide (LPS) endotoxin. LPS induces nitric oxide synthase II (NOS II, inducible NOS) in various types of cells. We now demonstrate by RNase protection analysis, Western blot, and immunohistochemistry that the expression of NOS II mRNA and protein is markedly induced in colonic enterocytes of mice that ingest LPS with their drinking water. Using the same techniques, significant levels of soluble guanylyl cyclase (GC-S), the effector enzyme of NO, were found constitutively expressed in the mucosa. This creates a pathophysiologic autocrine pathway producing increased levels of cyclic GMP and leading to hypersecretion and diarrhea. In fact, the LPS-induced diarrhea developed in parallel with the NOS II induction. Diarrhea could be controlled with orally administered dexamethasone, which prevented the LPS-stimulated induction of NOS II (RNase protection analysis and Western blot). Diarrhea was also blocked by oral aminoguanidine, an inhibitor of NOS II activity. These data suggest that in addition to the known heat-labile and heat-stable exotoxins, gram-negative bacteria may induce diarrhea through the release of endotoxins that induce a NOS II-GC-S autocrine pathway in mucosal epithelium.