Acute heart failure : An unmet medical need.

Despite recent advances in the management of heart failure with reduced ejection fraction (HFrEF), the burden of acute heart failure (AHF) remains significant with a high morbidity and mortality that has not been improved by any treatment modality. A meta-analysis summarized the study results on the effects of tolvaptan on AHF, which failed to demonstrate an improvement in short-term and long-term mortality, length of hospital stay and reduced frequency of worsening heart failure (WHF). Similar trial results were also reported in other AHF studies, such as the ASCEND-HF and the RELAX-AHF-2 trials. In view of these inconclusive studies it is evident that improving the prognosis of AHF patients remains an unmet medical need. Further efforts should focus on organ damage protection, individualized treatment, patient benefits and standardized management programs, including immediate identification and management of cardiogenic shock and establishment of HF networks for close monitoring of AHF patients.

In-hospital mortality after acute STEMI in patients undergoing primary PCI.

BACKGROUND: Acute myocardial infarction (AMI) is the main cause of global and in-hospital mortality in patients with cardiovascular diseases. We aimed to examine the association between the coronary artery involved and the in-hospital mortality in patients who underwent primary percutaneous coronary intervention (pPCI) after ST segment elevation myocardial infarction (STEMI). METHODS: The in-hospital mortality of STEMI patients who underwent pPCI was assessed at the Department of Cardiology, Harzklinik Goslar, Germany, which has no access to immediate mechanical circulatory support (MCS), between 2013 and 2017. RESULTS: We enrolled 312 STEMI patients, with a mean age of 67.1 ± 13.4 years, of whom 211 (68%) were male. In-hospital mortality was documented in 31 patients (10%). In-hospital mortality was associated with pre-hospital cardiopulmonary resuscitation (CPR; n = 39/12.5%), older age, lower systolic blood pressure, Killip class > 1, triple-vessel disease (each p < 0.0001), female gender (p = 0.0158), and with the localization of the treated culprit lesion in the left main coronary artery (LMCA; p = 0.0083) and in the ramus circumflexus (RCX; p = 0.0141). CONCLUSION: In this monocentric cohort, all-cause in-hospital mortality of STEMI patients after pPCI was significantly higher in those patients with culprit lesions in the LMCA and in the RCX, which may prove to be a substantial novel risk factor for STEMI-related mortality. Increasing age and female gender may be interdependent risk factors for mortality in this patient population. Furthermore, our data highlight the importance of the availability of MCS options in pPCI centers for patients after CPR.

Specific localization, gamma camera imaging, and intracellular trafficking of radiolabelled chimeric anti-G(D3) ganglioside monoclonal antibody KM871 in SK-MEL-28 melanoma xenografts.

The chimeric monoclonal antibody KM871, directed against the G(D3) antigen, is under evaluation for its potential to target melanoma. To facilitate the in vivo evaluation of biodistribution properties and measurement of pharmacokinetics, KM871 was radiolabeled with (125)I via tyrosine residues and with (111)In via the bifunctional metal ion chelator C-functionalized trans-cyclohexyl diethylenetriaminepentaacetic acid (CHX-A"-DTPA) to lysine residues. Using antigen-positive SK-MEL-28 melanoma cells, immunoreactivities of 42 and 40% cell binding were obtained, respectively, for the two radioconjugates. Binding was enhanced in the presence of added unlabeled antibody. A humanized A33 antibody was similarly labeled with the two isotopes and used as a control. To determine and compare in vivo biodistribution characteristics of KM871 radiolabeled with (111)In or (125)I, mixtures of the radioconjugates were injected i.v. into BALB/c nude mice bearing G(D3)-positive-SK-MEL-28 melanoma xenografts. Gamma camera images were acquired; groups of five mice were sacrificed at various time intervals, and tumors, blood, and tissues were analyzed. (111)In-labeled CHX-A"-DTPA-KM871 showed a maximum tumor uptake of 41.9 +/- 7.0% injected dose/g at 72 h with prolonged retention over a 15-day period. The tumor:blood ratio was 3:1 by 72 h, and higher ratios were observed at later time points. No abnormal accumulation of (111)In-labeled conjugate was found in normal tissues. In contrast, there was little accumulation of (125)I-labeled KM871 in the same tumors. The specificity of antibody localization was confirmed by the low tumor uptake values for radiolabeled control antibody. Gamma camera imaging demonstrated excellent uptake of (111)In-labeled CHX-A"-DTPA-KM871 in the xenografts. Chromatographic analyses of xenograft cytosolic extracts demonstrated tumor internalization and catabolism of radiolabeled KM871 with the formation of small molecular weight metabolites. Laser scanning confocal microscopy demonstrated that the majority of intracellular KM871 is localized to lysosomes. Despite the catabolism of the radioconjugate, a dose-dependent increase in KM871 tumor localization was shown through immunohistochemical examination of xenograft biopsies. This study demonstrates for the first time the in vivo localization of a radiolabeled anti-G(D3) monoclonal antibody to G(D3)-expressing xenografts using gamma camera scanning techniques and tumor cell internalization of KM871 tagged with a green fluorescent dye, Alexa Fluor 488, through confocal microscopy. KM871 has potential for targeting tumors in patients with melanoma.

Immuno-PET of human colon xenograft- bearing BALB/c nude mice using 124I-CDR-grafted humanized A33 monoclonal antibody.

UNLABELLED: Radiolabeling monoclonal antibodies (mAbs) allows the evaluation of biodistribution of constructs in vivo through gamma camera imaging and also permits quantitation of mAb uptake in tumors through biopsy-based counting techniques. The quantitation of radiolabeled mAb uptake in cancer patients is complicated by the attenuation of gamma emissions of routinely used isotopes (e.g., 131I and 111In) and the spatial resolution and sensitivity of gamma cameras. METHODS: We used the positron-emitting isotope 124I (half-life [T1/2] = 4.2 d) to label the recombinant humanized anti-colorectal cancer A33 antibody (huA33) and evaluated its biodistribution properties and PET imaging characteristics in BALB/c nude mice bearing SW1222 colorectal xenografts and control colon tumors. RESULTS: The immunoreactivity of radioconjugate was 78% as determined using the cell-binding Lindmo assay. The apparent association constant was found to be 2.2 x 10(9) M(-1), and the number of antibody binding sites per cell was 371,000. The radioconjugate was found to be stable in serum obtained from mice at various times after injection. Assuming a two-compartment model with a four-parameter fit of mean blood levels, the T1/2alpha was 1.5 h and the T1/2beta was 38.2 h. Excellent tumor uptake was obtained, with maximal uptake reaching 50.0 +/- 7.0 percentage injected dose per gram of tumor by 4 d after injection. Specificity of localization was shown by lack of uptake in control tumor. PET imaging detected antigen-positive tumor by 4 h after injection, and high-resolution images were obtained by 24 h after injection. CONCLUSION: In clinical trials using PET, huA33 labeled with 124I has potential for imaging and staging colon tumors and quantifying antibody uptake in colon tumors in vivo.

Usefulness of noninvasive detection of left ventricular diastolic abnormalities during isometric stress in hypertrophic cardiomyopathy and in athletes.

We showed previously that the handgrip apexcardiographic test (HAT) is a useful method for detecting left ventricular (LV) diastolic abnormalities in patients with coronary artery disease and systemic hypertension. This study evaluates the use of HAT for assessing the prevalence and types of exercise-induced diastolic abnormalities in patients with obstructive (n = 31) and nonobstructive (n = 35) hypertrophic cardiomyopathy (HC) as well as its potential value for separating healthy subjects and athletes from patients with HC. We obtained a HAT in 66 consecutive patients with HC and in 72 controls (52 healthy volunteers and 20 athletes). A positive HAT was defined by the presence of one of the following: (1) relative A wave to total height (A/H) during or after handgrip > 21% (compliance type), (2) total apexcardiographic relaxation time (TART) > 143 ms or the heart rate corrected TART (TARTI) during handgrip < 0.14, (relaxation type), (3) both types present (mixed type), and (4) diastolic amplitude time index (DATI = TARTI/[A/D]) during handgrip < 0.27. Of the controls, only 1 of 52 healthy subjects and 1 of 20 athletes showed a positive HAT, whereas of the total HC cohort 63 of 66 patients (95%) had a positive result. There was no significant difference in the distribution of these types between obstructive and nonobstructive HC. Further, no LV diastolic abnormalities were present in 10 of 35 patients (29%) with nonobstructive HC at rest and in 3 of 35 patients (9%) during handgrip, whereas of the patients with obstructive HC only 1 of 31 (3%) had no LV diastolic abnormalities at rest and none during handgrip. Based on HAT data, our study demonstrates that in HC (1) LV diastolic abnormalities are very frequent during handgrip; (2) patients with nonobstructive HC show significantly fewer LV diastolic abnormalities at rest than those with obstructive HC; and (3) no significant difference exists between obstructive and nonobstructive HC in the prevalence of types of handgrip-induced LV diastolic abnormalities. Consequently, HAT appears to be of clinical value as an additional tool for separating normal patients and athletes from patients with HC.

Irinotecan and vinorelbine in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. A phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: To evaluate the efficacy and tolerability of irinotecan plus vinorelbine every 2 weeks in patients with advanced non-small cell lung cancer (NSCLC), previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Forty-one patients with advanced NSCLC, refractory or resistant to platinum derivatives, were treated on an out-patient basis with irinotecan 150 mg/m2 intravenous (i.v.) and vinorelbine 25 mg/m2 on days 1 and 15. Chemotherapy was repeated every 4 weeks. The response was evaluated every two cycles. RESULTS: On an intent-to-treat analysis, 6 patients (14.6%) [95% confidence interval (CI) 5.57% to 29.17%] achieved partial response (PR), 15 (36.6%) stable disease (SD) and 20 (48.8%) progressive disease (PD). The median time to tumor progression (TTP) was 4.9 months (range 0.17-15.5 months), the median survival time was 7.8 months (range 0.9 to 19.6 months) and the 1-year survival rate was 37%. Symptomatic benefit response including improvement of performance status (PS), dyspnea, anorexia and fatigue, cessation of hemoptysis, fever and reduction of cough and pain was seen in 10 to 42% of patients. No patient experienced grade 3/4 anemia. Grade 3/4 thrombocytopenia occurred in 2 (5%) patients. Five patients (12%) developed grade 3/4 neutropenia and 5 (12%) had neutropenic fever that required hospitalization, but was successfully treated with antibiotics and G-CSF support. One patient (2%) developed grade 4 fatigue and was withdrawn. Other grade 3/4 adverse events included diarrhea (n = 3; 2 required hospitalization), alopecia (n = 5) and neurotoxicity (n = 1). Six patients required a dose reduction. CONCLUSION: The combination of irinotecan plus vinorelbine administered every 2 weeks demonstrated rather low activity in advanced NSCLC patients who had previously failed platinum-based chemotherapy, but it was well-tolerated and was associated with increased 1-year survival rate and improvement in cancer related symptoms.

[Myocardial contrast echocardiography guided alcohol septal ablation in hypertrophic obstructive cardiomyopathy with a new echocardiographic contrast agent]. / Echokontrastmittelgesteuerte Alkoholablation bei hypertropher obstruktiver Kardiomyopathie mit neuem Echokontrastmittel.

HISTORY AND ADMISSION FINDINGS: Myocardial contrast echocardiography guided alcohol septal ablation (PTSMA) is an established treatment for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). Most important properties of the optimal echocardiographic contrast agent are good contrast imaging and sufficient stability without fast washing out. HOCM was diagnosed in a 49-year-old female patient 4 years before first admission. Despite optimal medical treatment the patient was highly symptomatic with angina pectoris and dyspnoea NYHA II-III.Investigations, treatment and course: ECG showed signs of left ventricular hypertrophy. Echocardiography revealed asymmetric septal hypertrophy, dynamic LVOT obstruction with pronounced SAM and associated moderate mitral valve regurgitation. Coronary angiography performed in the catheterization laboratory showed coronary atherosclerosis and haemodynamic measurements verified a significant LVOT obstruction. An atypical septal branch, originating from the intermediate artery, was regarded as target branch and was occluded with a balloon catheter. For the contrast echocardiography guided septal ablation cold, agitated Gelafundin® was used. This led to a good subaortic septal contrast demarcation with confirmation of the correct choice of target branch. No arrhythmias were recorded during the administration of contrast medium. Injection of Levovist® in the same septal branch for comparison resulted in opacification of the same myocardial area without any sign of misplacement. After alcohol injection in the balloon-occluded septal branch, an effective elimination of the LVOT gradient could be haemodynamically documented. CONCLUSION: For contrast echocardiography guided PTSMA a good myocardial opacification with an appropriate contrast agent is essential, not only to recognize the obstruction dependent region but also to identify any possible misplacement. Gelafundin® seems to offer similarly sufficient contrast potential as Levovist®, so that Gelafundin® could be a possible alternative.

A critical Evaluation of Surgical Treatment of Perforated Ulcer.

The treatment of perforated ulcer disease continues to evolve because of recent advances in pharmacology, bacteriology, and operative techniques. Despite antisecretory medication and Helicobacter pylori eradication, it is still the most common indication for emergency gastric surgery associated with high morbidity and mortality. A clinical study was carried out on patients with perforated gastric or duodenal ulcer, admitted in the 1st Surgery Department between 2002 and 2008. During the 7 years of study there were admitted 256 patients with perforated ulcer - 212 cases of duodenal and 44 cases of gastric perforated ulcer. The main surgical treatment option was simple closure with Graham patch, followed by ulcer excision and vagotomy with pyloroplasty. The second major objective was the topical treatment of peritonitis and consisted in the lavage of the peritoneal cavity and drainage. Distal gastric resection has now very limited indications. We recorded no complications postoperatively. In the modern treatment of ulcer, surgery is reserved for the acute (perforation and bleeding) and chronic complications (stenosis / penetration) and exceptionally or the patients with a prolonged history of uncomplicated ulcers with lack of response to conservative therapy.

Hypertension and paroxysmal atrial fibrillation: a novel predictive role of high sensitivity C-reactive protein in cardioversion and long-term recurrence.

The role of inflammation in maintenance of paroxysmal atrial fibrillation (PAF) in patients with hypertension and no other heart disease has not been fully elucidated yet. We investigated the association of various inflammatory markers with cardioversion and recurrence of PAF in patients with hypertension. We studied 75 patients (44 male, mean age 67.9+/-9.9 years) with PAF (duration from onset of symptoms<24 h) secondary to hypertension. None had heart failure or any other ongoing inflammatory process. All patients received anticoagulation and intravenous amiodarone for cardioversion. High sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and tumour necrosis factor (TNF)-alpha were measured on admission and 48 h later. By 48 h from admission 61/75 patients (81.3%) regained sinus rhythm (cardioverted), whereas 14/75(18.7%) remained in AF (non-cardioverted). hsCRP, IL-6 and TNF-alpha serum levels on admission were similar between groups. hsCRP at 48 h was the most significant factor correlated with cardioversion outcome (OR: 0.06, 95% CI: 0.01-0.47, P=0.008). During a 1-year follow-up, AF recurred in 28/61(45.9%) patients. The strongest factor associated with AF recurrence was hsCRP at 48 h > or =2.27 mg l(-1) (hazard ratio: 6.2, 95% CI: 2.2-17.6, P=0.001). hsCRP at 48 h after admission correlates with cardioversion outcome and may predict long-term AF recurrence.

Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study.

OBJECTIVE: We sought to quantify left atrial longitudinal function by tissue Doppler (TDI) and two-dimensional (2D) strain in patients with hypertrophic cardiomyopathy (HCM). DESIGN: Case-control study. SETTING: Tertiary university hospital. PATIENTS: 43 consecutive patients with familial HCM, aged 49 (SD 18) years, along with 21 patients with non-HCM left ventricular hypertrophy (LVH, aged 52 (12) years) and 27 healthy volunteers (aged 42 (13) years). INTERVENTIONS: Subjects were studied by both TDI and 2D left atrial strain during all three atrial phases (reservoir, conduit, contractile), as well as by left ventricular systolic strain; total atrial deformation (TAD) was defined as the sum of maximum positive and maximum negative strain during a cardiac cycle. MAIN OUTCOME MEASURES: Left atrial longitudinal function. RESULTS: Both TDI and 2D atrial strain and TAD were significantly reduced in HCM, compared to the other two groups in all atrial phases (p<0.001 in most cases); left ventricular systolic strain was also significantly reduced in HCM (p<0.001). Adding 2D contractile atrial strain to a model of conventional echo measurements (including left atrial diameter and volume index, interventricular septal thickness and E/A ratio and E/e' ratios) increased its prognostic value in differentiating HCM from non-HCM LVH (p value of the change <0.001), while addition of TDI atrial strain or left ventricular strain did not. A cut-off for 2D contractile strain of -10.82% discriminated HCM from non-HCM LVH with a sensitivity of 82% and a specificity of 81%. Intra-observer and inter-observer variabilities for atrial strain in HCM were 16% and 17.5% for TDI and 8% and 9.5% for 2D, respectively. Processing time per case in HCM was 12.5 (2.6) minutes for TDI versus 3.8 (1.2) minutes for 2D strain (p<0.001). CONCLUSION: Left atrial longitudinal function is reduced in HCM compared to non-HCM LVH and healthy controls. In addition, 2D atrial strain has an additive value in differentiating HCM from non-HCM LVH and it is more reproducible and less time consuming than TDI strain.

Molecular diagnosis of the viral component in cardiomyopathies: pathophysiological, clinical and therapeutic implications.

BACKGROUND: Myocarditis is defined as the inflammation of myocardium associated with cardiac dysfunction. Despite this clear-cut definition, diagnosis and etiologic treatment continue to create considerable debate. Viral infections are frequent causes of myocarditis and there is evidence that persistent viral infection is associated with poor prognosis in different subtypes of cardiomyopathy. OBJECTIVE: To review methods for diagnosis of viral myocarditis and present the use of polymerase chain reaction (PCR)-based protocols for evaluating viral infection in myocarditis/cardiomyopathies. METHODS: A review of published literature. RESULTS/CONCLUSION: There is increasing evidence that PCR-based protocols can provide reliable molecular evidence for the presence of viral infection in myocardium. Thus application of molecular techniques will allow collection and analysis of more information on the epidemiology of viral cardiomyopathies, patient risk stratification and appropriate medical treatment.

Long-term follow-up after percutaneous septal ablation in hypertrophic obstructive cardiomyopathy.

OBJECTIVES: The aim of this study was to evaluate the longterm follow-up results of percutaneous transluminal septal myocardial ablation (PTSMA) in a large patient cohort. BACKGROUND: PTSMA by alcohol injection into septal branches has shown good acute and short-term results in symptomatic patients with hypertrophic obstructive cardiomyopathy. METHODS: A total of 100 consecutive symptomatic (NYHA class 2.8 +/- 0.6) patients underwent PTSMA. All patients had clinical and non-invasive follow-up at 3 months, 1 year, and annually up to 8 years. RESULTS: One patient died at day 2 after intervention due to fulminant pulmonary embolism following deep venous thrombosis, and eight patients required a permanent DDD-pacemaker due to post-interventional complete heart block. Acute reduction of the left ventricular outflow tract gradient was achieved from 76 +/- 37 to 19 +/- 21 mmHg at rest, from 104 +/- 34 to 43 +/- 31 mmHg during Valsalva maneuver, and from 146 +/- 45 to 59 +/- 42 mmHg post extrasystole (p < 0.0001, each). During follow-up (mean follow-up time: 58 +/- 14 months), three additional patients died (sudden death at 48 months, non-cardiac death at 49 months and stroke-related death at 60 months after the index procedure). All living patients showed clinical improvement to NYHA-class 1.4 +/- 0.6 (after 3 months, n = 99), 1.5 +/- 0.6 (after 1 year, n = 99), and 1.6 +/- 0.7 at final follow-up (n = 96; p < 0.0001, each). Non-invasive follow-up studies documented ongoing outflow tract gradient reduction, decrease of septal and left ventricular posterior wall thickness, and improvement of exercise capacity. CONCLUSIONS: PTSMA is an effective treatment for symptomatic patients with hypertrophic obstructive cardiomyopathy. Follow-up showed ongoing hemodynamic and clinical improvement without increased mortality and morbidity.

Lipid peroxides in type 2 diabetic patients with neuropathy.

Diabetes and its metabolic changes in peripheral nerves contribute to cause a decrease of nitric oxide production and diminished nerve blood flow. Since lipid peroxides are thought to be formed by free radicals and may play an important role in the development of vascular disease, we have investigated the possible relationship between lipid peroxides (measured as thiobarbitouric acid reacting substances (TBARS) in diabetic patients with peripheral neuropathy. Seventy-seven patients with Type 2 diabetes (39 neuropathic and 38 non-neuropathic) and 38 control subjects were studied. The neuropathy study group had significantly lower levels of TBARS, 3.5micromol/l (2.2-5.6, 95% confidence limits) compared to controls 4.5microm/l (3.08-6.8), p < 0.001 and to diabetics without neuropathy 4.9micromol/l (3.09-8.05), p < 0.001. No differences were found in metabolic control between the two diabetic groups. In the neuropathy group there was a negative correlation between the score for nerve dysfunction with the TBARS levels (r = - 0.42, p < 0.01). In conclusion, in diabetic patients with neuropathy there are abnormalities of TBARS levels.

Hematological malignancies are associated with a lower interferon-a blocking activity than solid tumors.

UNLABELLED: Interferon (IFN) and especially IFN-alpha exhibit clinical anti-tumor activity against various types of malignant diseases. Natural inhibitors to various cytokines and IFNs have been documented in vitro as well as in vivo. IFN inhibitors have been implicated for the ineffectiveness of IFN treatment in malignant neoplasias. The aim of this study was to investigate the incidence of the IFN inhibiting activity in serum from patients with haematological malignancies versus patients with solid tumours, as an effort to explain, just in part, the different response of these patients to IFN treatment. PATIENTS AND METHODS: Ninety patients with a clinically evident solid tumour and forty-six patients with haematological malignancies were included in the study. Serum samples from all patients were collected before any treatment and stored at -70 degrees until use. Controls sera were selected from 50 apparently healthy blood donors. Interferon-inhibiting activity as well as endogenous IFN-like activity were determined in all serum samples in a cell line highly sensitive to IFN. RESULTS: There was no endogenous IFN-like activity in any of the patients' group or controls' group. Sera from patients with haematological malignancies exhibited IFN-blocking activity at a lower percentage (21.7%) in comparison to sera from patients with solid tumours (56.6%, P<0.001), but at a significantly higher percentage in comparison to sera from controls (P<0.01). CONCLUSIONS: The fact that IFN inhibitors were detected at a significantly lower percentage in sera from patients with haematological malignancies versus patients with solid tumours, could explain in part the better response of the haematological malignancies to IFN treatment.

Electromyographic evidence of subclinical myopathy in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is due to a number of mutations of contractile protein genes such as beta-cardiac myosin, myosin binding protein-C, and troponin-T. Unlike troponin-T, beta-myosin is a constituent of slow skeletal muscle and its mutations generally have a better prognosis. In order to investigate the usefulness of electromyography in detecting skeletal muscle involvement in HCM, 46 patients were examined using both conventional electromyography (EMG) and quantitative electromyography (QEMG) methods. The QEMG involved motor unit potential (MUP) analysis, turns/amplitude (TAA) analysis, and power spectrum analysis of the interference pattern. Using conventional EMG, myopathic findings were demonstrated in 13 patients (28%). Receiver operating characteristic (ROC) analysis of the results of a discriminant function extracted using QEMG values, identified correctly 10 out of 11 normal controls and all 9 myopathic control patients, and displayed a 15% presence of myopathy (7 patients) among the cardiomyopathy group. The duration of MUPs was the most sensitive among the quantitative parameters in differentiating normal from myopathic subjects. Since skeletal muscle involvement may be due to distinct gene mutations, normal and myopathic EMG findings may reflect HCM subpopulations with a different genetic substrate.