Regional analysis of inflammation and contractile function in reperfused acute myocardial infarction by in vivo 19F cardiovascular magnetic resonance in pigs.

Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (19F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo 1H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by 19F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The 19F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The 19F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of 19F integral (19F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, 19F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling.

[Contrast medium-induced renal failure : Useful protective measures prior to contrast medium administration]. / Kontrastmittelinduziertes Nierenversagen : Sinnvolle Schutzmaßnahmen vor Kontrastmittelgabe.

BACKGROUND: Iodinated contrast is essential for diagnosis and treatment in contemporary interventional cardiology. An important complication of percutaneous intervention is contrast-induced nephropathy, which is associated with increased morbidity and mortality, while prolonged hospitalization is responsible for economic consequences. OBJECTIVES: This article reviews the definition of contrast-induced nephropathy, the role of biomarkers in early diagnosis to identify high-risk patients and potential therapeutic options for preventing acute nephropathy. CURRENT DATA: The optimization of patients' circulating volume remains the main aspect for preventing contrast-induced nephropathy, as recent studies confirm. Several medications are known to be nephrotoxic, whereas several are nephroprotective and the subject of recent research. CONCLUSION: Interventions to improve outcomes of established acute kidney injury have not been developed as yet. Prevention and early diagnosis are relevant factors in clinical management. It is important to identify patients at risk and to treat them preemptively.

CMR-guidance of passively tracked endomyocardial biopsy in an in vivo porcine model.

Endomyocardial biopsy (EMB) is considered to be the diagnostic gold-standard in detection of myocardial-inflammation. EMB is usually conducted under fluoroscopy without any specific target information. Specific target-information provided by cardiovascular magnetic resonance (CMR) may improve specificity of EMB. The aim was to investigate feasibility and safety of CMR-guided and targeted EMB in a preclinical-model using passively-tracked devices. Procedures were performed on a MRI-System equipped with an Interventional Software-Platform for real-time imaging. Ex vivo experiments were conducted to optimize visibility of the guide-sheath. In vivo experiments were conducted in 2 pigs for technical feasibility assessment and in 4 pigs after acute myocardial infarction to test feasibility of guided and lesion targeted EMB. For anatomical real-time imaging a single-shot-balanced-SSFP-sequence was applied. Myocardial targets were identified under real-time imaging (single-shot-T2 (sshT2) and single-shot Late-Gadolinium-Enhancement (sshLGE) sequences). Ex vivo experiments demonstrated best visibility of continuously labelled guide-sheath. CMR-guided EMB was feasible in all cases without major complications. Likewise, lesion-targeting endomyocardial biopsy was feasible in two cases. Biopsies exhibited appropriate sizes and qualities. Real-time lesion sequences revealed comparable CNR values to clinical-protocols. Real-time imaging of lesions showed following signal- and contrast-to-noise ratios (SNR/CNR): SNR of sshT2- and sshLGE was 124 ± 35 and 67 ± 51 respectively, whereas CNR was 81 ± 30 and 57 ± 44. This study demonstrates feasibility and safety of CMR-guided and basically targeted EMB with passively-tracked devices. Signal-to-noise ratios of real-time sequences is non-inferior to standard sequences for lesion detection. CMR-guidance may improve diagnostic accuracy of EMB since CMR can detect myocardial-targets under real-time-imaging.

T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy.

Aims: The aim of this study was to determine the value of T2 mapping for the non-invasive assessment of myocardial inflammation in different stages of systolic left ventricular dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy (EMB). Methods and results: A total of 132 subjects were enrolled between 2013 and 2016 (62 controls and 70 patients with DCM). All patients underwent CMR at 1.5 T and received coronary angiogram and EMB. CMR applied standard protocols including T2 mapping with Gradient And SpinEcho sequence (GRASE). Global T2 relaxation time was significantly increased in patients with DCM compared to the healthy controls (T2 time DCM vs. controls: 65.9 ± 6.2 vs. 60.0 ± 4.2 ms; P < 0.001). Of note, patients with the presence of inflammatory cells in EMB exhibited further elevation of T2 values (T2 time in patients with the presence of inflammatory cells vs. T2 time in patients without: 68.8 ± 5.8 vs. 64.7 ± 5.9 ms; P = 0.02). Receiver operating characteristic analysis of our data deciphered a global myocardial T2 time >65.3 ms as the best cut-off for distinction between the healthy controls and patients with myocardial inflammation [sensitivity 93%, specificity 90%, P < 0.01, area under the curve (AUC) 0.95]. In patients with DCM, this threshold identified patients with biopsy-proven inflammation with a sensitivity of 79% and specificity 58% (AUC 0.72). Conclusion: In patients with DCM and presence of inflammatory cells in the myocardium, myocardial T2 relaxation times may help to non-invasively detect myocardial inflammation. Although there is an overlap of T2 values between patients and healthy controls, T2 mapping may facilitate the identification of patients who may benefit from EMB for therapeutic decision-making.

[Dialysis and ultrafiltration therapy in patients with cardio-renal syndrome: recommendations of the working group "heart-kidney" of the German Cardiac Society and the German Society of Nephrology]. / Dialyse- und Ultrafiltrationsverfahren bei kardio-renalem Syndrom. Empfehlung der Arbeitsgemeinschaft "Herz--Niere" der Deutschen Gesellschaft für Kardiologie--Herz- und Kreislaufforschung e.V. und der Deutschen Gesellschaft für Nephrologie e.V.

Renal failure is common in patients with severe heart failure. This complex pathophysiological interaction has been classified as cardio-renal syndrome. In these patients hydropic decompensation is the main cause of hospitalization. In patients with refractory heart failure, characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In acute decompensated heart failure with worsening of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment specific advantages of peritoneal ultrafiltration. Prerequisite for an optimized care of patients with cardio-renal syndrome is the close collaboration among intensive care doctors, cardiologists and nephrologists.

Modulation of peripheral chemoreflex by neurohumoral adaptations after kidney transplantation.

BACKGROUND: Peripheral chemoreceptors residing predominantly in the carotid body monitor changes in arterial blood oxygen and are mechanistically linked to the cardiorespiratory control by the autonomic nervous system. Enhanced sympathetic activation is common in end-stage renal disease and kidney transplantation has been shown to improve cardiorespiratory reflex measures of autonomic function. OBJECTIVE: The aim of the present study was to test whether improvement in renal function following kidney transplantation is related to an improvement in chemosensory function. METHODS AND RESULTS: We compared hyperoxic chemoreflex sensitivity (CHRS) in patients after renal transplantation (RTX) to that in patients on maintenance hemodialysis (HD), and that of age- and gender-matched healthy controls. In addition, we investigated the impact of common confounding factors including pharmacological neurohumoral modulation and diabetes mellitus. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by 5-min inhalation of 7 L oxygen was calculated as the hyperoxic CHRS. Autonomic activity was characterized by 24-h time-domain heart rate variability (HRV) parameters. CHRS was improved in RTX patients as compared to HD patients being related to HRV. CHRS was related to the concomitant presence of diabetes and medication with cyclosporine. CONCLUSION: Our findings indicate that chemosensory activity following kidney transplantation is related to cardiac autonomic control, but functional testing might only be useful to characterize the time course and extent of sympathetic activation in selected patients due to existing co-morbidities and immunosuppressive medication in this population.

Cardiogenic shock due to tachycardiomyopathy after heart transplantation: successful treatment with ivabradine.

Tachycardia-induced cardiomyopathy refers to an impairment in left-ventricular function due to chronic or prolonged tachycardia. We describe a heart transplant patient who developed cardiogenic shock due to tachycardia-induced cardiomyopathy. Low-output failure was further aggravated by administration of a short-acting beta-blocker during invasive hemodynamic monitoring. In contrast, heart rate control by administration of increasing doses of ivabradine supported recovery from cardiogenic shock and led to an improvement in the patient's clinical condition as well as left-ventricular function during follow-up.

Sympathetic hyperactivity influences chemosensor function in patients with end-stage renal disease.

BACKGROUND: Autonomic neuropathy is common in patients suffering from end-stage renal disease (ESRD). This may in part explain the high cardiovascular mortality in these patients. Chemosensory function is involved in autonomic cardiovascular control and is mechanistically linked to the sympathetic tone. OBJECTIVE: The aim of the present study was to assess whether sympathetic hyperactivity contributes to an altered chemosensory function in ESRD. MATERIAL AND METHODS: In a randomized, double-masked, placebo controlled crossover design we studied the impact of chemosensory deactivation on heart rate, blood pressure and oxygen saturation in 10 ESRD patients and 10 age and gender matched controls. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by 5-min inhalation of 7 L oxygen was calculated as the hyperoxic chemoreflex sensitivity (CHRS). Placebo consisted of breathing room air. Baseline sympathetic activity was characterized by plasma catecholamine levels and 24-h time-domain heart rate variability (HRV) parameters. RESULTS: Plasma norepinephrine levels were increased (1.6 +/- 0.4 vs. 5.8 +/- 0.6; P<0.05) while the SDNN (standard deviation of all normal R-R intervals: 126.4 +/- 19 vs. 100.2 +/- 12 ms), the RMSSD (square root of the mean of the squared differences between adjacent normal R-R intervals: 27.1 +/- 8 vs. 15.7 +/- 2 ms), and the 24-h triangular index (33.6 +/- 4 vs. 25.7 +/- 3; each P<0.05) were decreased in ESRD patients as compared to controls. CHRS was impaired in ESRD patients (2.9 +/- 0.9 ms/mmHg, P<0.05) as compared to controls (7.9 +/- 1.4 ms/mmHg). On multiple regression analysis 24 h-Triangular index, RMSSD, and plasma norepinephrine levels were independent predictors of an impaired hyperoxic CHRS. CONCLUSION: Sympathetic hyperactivity influences chemosensory function in ESRD resulting in an impaired hyperoxic CHRS.

[Is there a correlation between C-reactive protein and calcification inhibitors with cardiovascular parameters and risk factors in hemodialysis patients?]. / Korrelieren C-reaktives Protein und Verkalkungsinhibitoren bei Hämodialyse-Patienten mit kardiovaskulären Parametern und Risikofaktoren?

BACKGROUND AND OBJECTIVE: Patients on hemodialysis exhibit a drastically increased cardiovascular mortality. Inflammation, hyperphosphatemia and lack of calcification inhibitors are uremia-associated risk factors for vascular calcification. Functional and morphological vascular parameters are used to assess cardiovascular risk. The aim of our study was to analyse the relation between pulse wave velocity (PWV) and intima-media-thickness (IMT) with calcification inhibitors. METHODS: A cohort of 97 hemodialysis patients was consecutively selected and investigated (age 56 +/- 9 years). Carotid-femoral PWV, carotid IMT, left ventricular ejection fraction and septum thickness were determined. These parameters were correlated with serum levels of CRP and calcification inhibitors (fetuin-A and osteoprotegerin [OPG]). RESULTS: Both PWV and IMT showed a positive correlation with age and systolic blood pressure and a negative correlation with Kt/V (dialysis efficiency). Additionally, fetuin-A was negatively associated with CRP and positively with cholesterol and triglycerides. Serum levels of the calcification inhibitors fetuin-A and OPG were not correlated to PWV or IMT. CONCLUSION: The lack of correlation of calcification inhibitors with PWV and IMT means that functional and morphological measurements of vascular properties can not necessarily be replaced by analysing "biomarkers".

Acute glomerular upregulation of ornithine decarboxylase is not essential for mesangial cell proliferation and matrix expansion in anti-Thy-1-nephritis.

BACKGROUND: Pathways of L-arginine metabolism including nitric oxide, agmatine and polyamine synthesis are upregulated during glomerular inflammation in experimental glomerulonephritis. In anti-Thy-1-glomerulonephritis L-arginine-deficient diets ameliorate the disease course in this model. However, it is unclear which metabolic pathway is affected by this substrate depletion. Since polyamines are important proproliferative molecules, we studied the effect of specific polyamine synthesis blockade in vivo on mesangial cell proliferation and glomerular fibrosis in this model. METHODS: Anti-Thy-1-glomerulonephritis was induced in male Sprague-Dawley rats by single-bolus injection of monoclonal ER4-antibodies. Rats were treated with difluoromethylornithine (0.5-2% in the drinking water), a selective inhibitor of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC). Mesangial cell proliferation and matrix expansion were evaluated in PAS-stained kidney tissues. Glomerular TGF-beta and biglycan-mRNA-expression were determined by Northern blot analysis and albuminuria was measured using a competitive ELISA. Data were compared to untreated controls. RESULTS: Though complete inhibition of ODC activity was achieved at any time point, difluoromethlornithine treatment had no significant effect on albuminuria, glomerular matrix protein expression and mesangial cell count in this model. CONCLUSIONS: The acute upregulation of glomerular ODC activity above baseline in anti-Thy1-glomerulonephritis is not pathophysiologically important for disease development however, biological effects of available polyamine pools cannot be excluded by our study.

[Nitric oxide, L-arginine and the kidney. Experimental studies of new therapy approaches]. / Stickstoffmonoxid, L-Arginin und die Niere. Experimentelle Studien zu neuen Therapieansätzen.

BACKGROUND: Nitric oxide (NO) is a small gaseous molecule with multiple biological effects. NO is produced from the semi-essential amino acid L-arginine by NO synthases (NOS). In the kidney, neuronal NOS (bNOS), which is localized in the macula densa, and endothelial NOS (ecNOS) are involved in the regulation of glomerular hemodynamics. Dysfunction of these enzymes may cause glomerular hypertension and increased intraglomerular platelet aggregation. NO production in high tissue concentrations can be achieved by activation of an inducible NOS isoform (iNOS) and may act as a potent mediator of inflammation in immune-mediated renal diseases. Selective inhibition of iNOS may, therefore, become a novel anti-inflammatory approach in the treatment of glomerulonephritis. Based on experimental data, the potential importance of NO and other metabolites of L-arginine in the pathophysiology and therapy of renal diseases is summarized in this article. CONCLUSION: Modulation of the renal L-arginine/NO-system represents a promising therapeutic target in the treatment of acute an chronic kidney diseases.