Tricuspid Valve Surgery in Patients Receiving Left Ventricular Assist Devices.

BACKGROUND: Tricuspid regurgitation (TR) is common and related to poor prognosis in patients after left ventricular assist device (LVAD) implantation. The concomitant tricuspid valve surgery (TVS) at the time of LVAD implantation on short and long-term outcomes are controversial in current evidence. METHODS: This is a single-center, observational, retrospective study. We enrolled patients with moderate-to-severe TR who received LVAD implantations from 2009 to 2020. Postoperative right ventricular failure (RVF), right ventricular assist device (RVAD) use, hospital mortality, new-onset renal replacement therapy (RRT), and acute kidney injury (AKI) were evaluated retrospectively. RESULTS: Sixty-eight patients were included, 36 with and 32 without concomitant TVS. Baseline characteristics did not differ between the two groups. Patients receiving TVS had significantly increased incidences of postoperative RVF (52.8 vs. 25.0%, p = 0.019), RVAD implantation (41.7 vs. 18.8%, p = 0.041), and new-onset RRT (22.2 vs. 0%, p = 0.004). No difference in the incidence of AKI and hospital mortality was detected. Besides, these associations remained consistent in patients who underwent LVAD implantation via median sternotomy. During a median follow-up of 2.76 years, Kaplan-Meier analysis and competing-risk analysis showed that TVS was not associated with better overall survival in patients after LVAD implantation compared with the no-TVS group. CONCLUSION: Our study suggests that concomitant TVS failed to show benefits in patients receiving LVAD implantation. Even worse, concomitant TVS is associated with significantly increased incidences of RVF, RVAD use, and new-onset of RRT. Considering the small sample size and short follow-up, these findings warrant further study.

Inpatient Cardiac Rehabilitation of LVAD Patients-Updated Recommendations from the Working Group of the German Society for Prevention and Rehabilitation of Cardiovascular Diseases.

Cardiac rehabilitation physicians are faced to an increasing number of heart failure patients supported by left ventricular assist devices (LVAD). Many of these patients have complex medical issues and prolonged hospitalizations and therefore need special cardiac rehabilitation strategies including psychological, social, and educational support which are actually poorly implemented.Cardiac rehabilitation with clear guidance and more evidence should be considered as an essential component of the patient care plan especially regarding the increasing number of destination patients and their long-term follow-up.In this article the working group for postimplant treatment and rehabilitation of LVAD patients of the German Society for Prevention and Rehabilitation of Cardiovascular Diseases has summarized and updated the recommendations for the cardiac rehabilitation of LVAD patients considering the latest literature.

Improved aftercare in LVAD patients: Development and feasibility of a smartphone application as a first step for telemonitoring.

For the success of the treatment with a left ventricular assist device (LVAD), both adequate self-management by the patient and an optimum level of support from the implanting hospital are crucial. A smartphone application has recently been developed within the framework of a European research project for the close monitoring of LVAD patients in order to improve upon their current aftercare situation. Using this new tool, different relevant parameters (eg, weight, international normalized ratio [INR], medication, LVAD parameters, symptoms, and photos of the driveline exit) can be sent daily or as required to a corresponding clinical application at the hospital for evaluation. The objective of this study was to monitor the functionality, acceptance, and usability of this smartphone application in LVAD patients. Prospective single-center study: in total, 13 patients (60 ± 7 years, 92% male, 1027 ± 653 days after LVAD implantation) were requested to test the application for approx. 4 weeks. At the end of the study, all entered data were evaluated and the patients were questioned regarding the acceptance and the usability. During the study period of mean 34 ± 8 days, a total of 453 data records (mean 35 ± 7 per patient) arrived at the hospital. In addition, a total of 19 photos of the driveline exit site were also sent via smartphone. The clinical application registered a total of 160 conspicuities. These comprised 126 INR deviations (target range 2.3-2.8) and 34 symptoms (mainly nosebleeds). The smartphone application functioned reliably, was well received by the patients and was graded highly for acceptance and usability. The results show that smartphone applications can definitely be used to improve aftercare in LVAD therapy in selected patients. Long-term studies are now needed to investigate the extent to which complications can be prevented, healthcare costs reduced, and quality of life increased.

Postoperative Complications and Long-Term Results after Primary Cardiac Sarcoma Resection.

BACKGROUND: Primary malignant cardiac tumors rarely occur in clinical care. Little is known about the impact of a parameter on postoperative survival. METHODS: From May 1991 to May 2014, a total of 24 patients underwent surgical treatment of a primary cardiac sarcoma in our center. We analyzed our clinical database retrospectively for information on patient characteristics and treatment data. The follow-up could be completed to 91.7%. RESULTS: Angiosarcoma and non-otherwise-specified sarcoma were the most common tumor entities. R0 resection was achieved in most cases. Postoperative mortality within the first 30 days was 20.8% (n = 5). In four of these five cases, postoperative low-output cardiac failure was the leading cause of death. The cumulative survival rate was 77.3% after 30 days, 68.2% after 3 months, 50.0% after 6 months, 45.0% after 12 months, and 18.0% after 24 months. The mean survival time in the whole group was 47.0 months. A low tumor differentiation was associated with low mean survival, but this was not statistically significant. Mean survival of sarcoma was higher after R0 resection. There was no significant rate of survival difference regarding the adjuvant therapy concept. CONCLUSION: Extended surgery alone or in combination with chemo- and/or radiotherapy may be successful in certain cases and may offer a satisfactory quality of life. The establishment of a multicenter heart tumor register in Germany is necessary to increase the number of cases in studies, get more remarkable study results, and standardize the diagnosis and therapy.

Metabolic volume performs better than SUVmax in the detection of left ventricular assist device driveline infection.

PURPOSE: A continuous-flow left ventricular assist device (LVAD) is a new and highly promising therapy in supporting end-stage heart failure patients, either bridging them to heart transplantation or as a destination therapy. Infection is one of the major complications associated with LVAD implants. 18F-FDG PET/CT has already been shown to be useful in the detection of LVAD infection. The goal of this study was to compare the diagnostic accuracy of different PET analysis techniques (visual grading versus SUVmax and metabolic volume). METHODS: We retrospectively analyzed 48 patients with implanted LVAD who underwent an 18F-FDG PET/CT that were either suspected to have a driveline or device infection or inflammation of unknown origin. PET/CT was analyzed qualitatively (visual grading) and quantitatively (SUVmax and metabolic volume) and matched to the final clinical diagnosis concerning driveline infection. The final diagnosis (standard of reference) was made at the end of clinically recorded follow-up or transplantation and included microbiological cultures of the driveline exit site and/or surgical samples, and clinical signs of infection despite negative cultures as well as recurrence of symptoms. RESULTS: Sensitivity, specificity, positive and negative predictive value were 87.5%, 79%, 81% and 86% for visual score, 87.5%, 87.5%, 87.5% and 87.5% for SUVmax and 96%, 87.5%, 88.5%, 95.5% for metabolic volume, respectively. ROC analysis revealed an AUC of .929 for SUVmax and .969 for metabolic volume. Both SUVmax and metabolic volume had a high detection rate of patients with driveline infection (21/24 = 91.5% true positive vs. 23/26 = 88.5% true positive, respectively). However, metabolic volume detected more patients without any infection correctly (1/22 = 4.5% false negative vs. 3/24 = 12.5% false negative). CONCLUSIONS: 18F-FDG PET/CT is a valuable tool for the diagnosis of LVAD driveline infection with high diagnostic accuracy. Particularly the use of the metabolic volume yields very high accuracy and performs slightly better than SUVmax.

Left Ventricular Assist Devices as Bridge to Cardiac Recovery in Nonischemic Heart Failure: Keeping Weaning from the Device in Mind.

A minority of patients on left ventricular assist devices (LVADs) display myocardial recovery raising the question of device explantation. We report a series of seven LVAD patients with nonischemic cardiomyopathy allowing explantation of the VAD. In case of four patients we overview follow-up periods of 4 to 10 years. Remarkably, in three cases device explantation was considered beyond 1 year of LVAD support. Explantation was finally performed after 20 months and more on the device. In light of the scarcity of donor organs we conclude that patients on LVAD support should be evaluated for possible weaning from the device on a regular basis.

Pulmonary Bleeding During Right Ventricular Support After Left Ventricular Assist Device Implantation.

OBJECTIVES: Right heart failure still occurs in up to 20% of patients after implantation of a left ventricular assist device (LVAD). One treatment option for these patients is the implantation of a temporary right ventricular assist device (RVAD). Experimental data suggest that non-pulsatile perfusion of the lungs is associated with an increased rate of pulmonary hemorrhage. The aim of this study was to determine the incidence of pulmonary bleeding complications in these patients. DESIGN: Observational study. SETTING: Single center, university hospital. PARTICIPANTS: This study included patients undergoing LVAD implantation for end-stage heart failure and subsequent implantation of a temporary right ventricular support system. INTERVENTIONS: In this study, 25 patients who underwent LVAD and additional temporary RVAD implantation were screened for pulmonary bleeding complications. MEASUREMENTS AND MAIN RESULTS: The mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level at the time of LVAD implantation was 2.84. All patients experienced severe right ventricular failure (tricuspid annular plane systolic excursion [TAPSE], 10.16±26.3 mm) and severe pulmonary hypertension (right atrial [RA] pressure, 56.21±15.58 mmHg). Average duration of right ventricular support was 11.12±7.20 days, with right ventricular support being administered to 14 patients for more than 7 days. Seventeen patients were weaned successfully from right ventricular support after a mean support duration of 5 days. Five patients developed pulmonary bleeding complications, diagnosed using computed tomography scan and bronchoscopy. All bleeding occurred after postoperative day 7 and was associated with RVAD flow of more than 4 L/min within 24 hours before bleeding occurred. CONCLUSIONS: The data presented in this study suggested that right ventricular support for more than 7 days and a blood flow greater than 4 L/min were associated with pulmonary bleeding complications. This should be taken into consideration when temporary right ventricular support after LVAD implantation is planned.

Can Perioperative Right Ventricular Support Prevent Postoperative Right Heart Failure in Patients With Biventricular Dysfunction Undergoing Left Ventricular Assist Device Implantation?

OBJECTIVES: Depending on the pre-existing condition of the right ventricle (RV), left ventricular assist device (LVAD) implantation may have a detrimental effect on RV function, subsequently leading to right heart failure. This study details the authors' experience with perioperative mechanical RV support in patients with biventricular impairment but primarily scheduled for isolated LVAD implantation. DESIGN: Retrospective study. SETTING: Two center study, university hospital. PARTICIPANTS: This study included LVAD recipients with preoperative biventricular impairment who received an additional right ventricular assist device (RVAD) after a failed weaning attempt from cardiopulmonary bypass due to acute RV failure. INTERVENTIONS: Outcomes of 25 patients who underwent LVAD and unplanned temporary RVAD implantation were analyzed. MEASUREMENTS AND MAIN RESULTS: All patients experienced significant preoperative RV impairment (tricuspid annular plane systolic excursion: 10.2±26.3 mm; right atrium pressure: 17.9±10.4 mmHg) and pulmonary hypertension (pulmonary artery pressure: 54.8±25.7 mmHg). In 15 patients, additional tricuspid valve annuloplasty was performed. Mean duration of temporary RVAD support was 11.1±7.2 days. In 23 patients (92%), the RVAD was removed successfully. None of the patients developed RV failure after RVAD removal. Hospital survival and the 1-year survival rate of the study group were 68% and 56%, respectively. CONCLUSIONS: The results of perioperative RVAD support in LVAD recipients with biventricular dysfunction are encouraging. Temporary RVAD support allows an already compromised RV to become attuned to the hemodynamic conditions after LVAD implantation. This strategy provides patients with preoperative impaired RV function a high likelihood to permanently undergo LVAD support only.

Is Implantation of a Left Ventricular Assist Device in Patients With Critical or Impending Cardiogenic Shock an Absolute Contraindication? Looking Back at Our Past Experience Trying to Identify Contraindicative Risk Factors.

Poor survival has been demonstrated after ventricular assist device (VAD) implantation for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 and 2 patients compared with more stable levels. However, risk factors within this high-risk cohort have not been determined so far. The aim of the present study was to identify risk factors associated with this very high mortality rate. Between February 1993 and January 2013, 298 patients underwent VAD implantation in our institution. One hundred nine patients were in INTERMACS level 1 and 49 patients were in INTERMACS level 2 and were therefore defined as hemodynamically critical (overall 158 patients). Assist devices implanted were: HVAD HeartWare n = 18; Incor n = 11; VentrAssist n = 2; DeBakey n = 22; and pulsatile systems n = 105. After cumulative support duration of 815.35 months, Kaplan-Meier analysis revealed a survival of 63.9, 48.8, and 40.3% at 1, 6, and 12 months, respectively. Cox regression analyses identified age > 50 (P = 0.001, odds ratio [OR] 2.48), white blood cell count > 13.000/µL (P = 0.01, OR 2.06), preoperative renal replacement therapy (P = 0.001, OR 2.63), and postcardiotomy failure (P < 0.001, OR 2.79) as independent predictors of mortality. Of note, last generation VADs were not associated with significantly better 6-month survival (P = 0.59). Patients without the aforementioned risk factors could yield a survival of 79.2% at 6 months. This single-center experience shows that VAD implantation in hemodynamically unstable patients generally results in poor early outcome, even in third-generation pumps. However, avoiding the aforementioned risk factors could result in improved outcome.

Survival results after implantation of intrapericardial third-generation centrifugal assist device: an INTERMACS-matched comparison analysis.

Reports on third-generation centrifugal intrapericardial pumps (HeartWare International, Inc., Framingham, MA, USA) have shown better survival results than the previous-generation devices. However, outcomes depending on the preoperative level of stability can substantially differ, resulting in a limited analysis of potentialities and drawbacks of a given device. In the present study we sought to compare in our single-center experience the survival results of this third-generation device with previous left ventricular systems taking into account the different preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels. Between February 1993 and March 2012, 287 patients underwent assist device implantation in our university hospital (INTERMACS Level 1-2 = 158 patients; INTERMACS Level 3-4-5 = 129 patients). Assist devices implanted were: Group A (HVAD HeartWare, n = 52), group B (previous continuous-flow ventricular assist device [VAD], InCor [Berlin Heart, Berlin, Germany], n = 37; VentrAssist [VentraCor, Inc., Chatswood, NSW, Australia], n = 7; DeBakey [MicroMed Cardiovascular, Inc., Houston, TX, USA], n = 32), and group C (pulsatile systems, n = 159). After cumulative support duration of 54 436 days and a mean follow-up of 6.21 ± 7.46 months (range 0-45.21 months), log-rank analysis revealed a survival for group A of 82.0%, 70.4%, and 70.4%; for group B of 84.0%, 48.2%, 33.7%; and for group C of 71.6%, 46.1%, 33.8%, at 1, 12, and 24 months respectively, with a significantly (P = 0.013) better outcome for group A. When stratifying the survival on the basis of INTERMACS level, no significant survival improvement was observed among all patients who underwent VAD implantation in INTERMACS 1-2 (P = 0.47). However, among patients who underwent elective VAD implantation (INTERMACS 3-4-5), group A had a significantly better outcome (P = 0.005) compared with the other INTERMACS-matched groups (B,C) with a survival rate of 88.8% in group A versus 34.2% in group B and 45.6% in group C at 24 months, respectively. Elective HVAD system implantation shows improved survival benefit over the other INTERMACS-matched devices. Moreover, preoperative unstable hemodynamics resulted in a poor prognosis independently from the pump generation.

BMI-Stratified Exploration of the 'Obesity Paradox': Heart Failure Perspectives from a Large German Insurance Database.

Background: The global rise of obesity and its association with cardiovascular risk factors (CVRF) have highlighted its connection to chronic heart failure (CHF). Paradoxically, obese CHF patients often experience better outcomes, a phenomenon known as the 'obesity paradox'. This study evaluated the 'obesity paradox' within a large cohort in Germany and explored how varying degrees of obesity affect HF outcome. Methods: Anonymized health claims data from the largest German insurer (AOK) for the years 2014-2015 were utilized to analyze 88,247 patients hospitalized for myocardial infarction. This analysis encompassed baseline characteristics, comorbidities, interventions, complications, and long-term outcomes, including overall survival, freedom from CHF, and CHF-related rehospitalization. Patients were categorized based on body mass index. Results: Obese patients encompassed 21.3% of our cohort (median age 68.69 years); they exhibited a higher prevalence of CVRF (p < 0.001) and comorbidities than non-obese patients (median age 70.69 years). Short-term outcomes revealed lower complication rates and mortality (p < 0.001) in obese compared to non-obese patients. Kaplan-Meier estimations for long-term analysis illustrated increased incidences of CHF and rehospitalization rates among the obese, yet with lower overall mortality. Multivariable Cox regression analysis indicated that obese individuals faced a higher risk of developing CHF and being rehospitalized due to CHF but demonstrated better overall survival for those classified as having low-level obesity (p < 0.001). Conclusions: This study underscores favorable short-term outcomes among obese individuals. The 'obesity paradox' was confirmed, with more frequent CHF cases and rehospitalizations in the long term, alongside better overall survival for certain degrees of obesity.

Efficacy and safety of sacubitril/valsartan in an outpatient setting: A single-center real-world retrospective study in HFrEF patients with focus on possible predictors of clinical outcome.

BACKGROUND: Currently, data on sacubitril/valsartan therapy from the real-world settings are scarce and the predictors of a good clinical responsiveness to this drug are unknown. OBJECTIVES: To assess efficacy and safety profile of sacubitril/valsartan and to identify predictors for a better clinical outcome. MATERIAL AND METHODS: Clinical, laboratory and echocardiographic data of 95 chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) were retrospectively analyzed. A good efficacy of sacubitril/valsartan was defined as the fulfilment of at least 2 of the following criteria: improvement of left ventricular ejection fraction (LVEF) or functional status, and reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels or hospitalization rates. RESULTS: Under sacubitril/valsartan, major improvements were observed in LVEF, the New York Heart Association (NYHA) class, NT-proBNP levels, and hospitalization rates. Patients with a good efficacy of sacubitril/valsartan were characterized by initially worse LVEF (median (interquartile range (IQR)): 29.0% (23.0-33.0%) compared to 32.0% (28.5-38.0%) with more frequent nonischemic etiology (65.4% compared to 41.9%) and hospitalizations for CHF/month (0.016 (0.004-0.057) compared to 0.000 (0.000-0.012)), lower cholesterol (42.3% compared to 65.1%), higher C-reactive protein (CRP) levels at baseline (0.5 mg/L (0.5-1.0 mg/L) compared to 0.5 mg/L (0.5-0.5 mg/L)), and a shorter timespan between CHF diagnosis and the start of sacubitril/valsartan treatment (66.0 (11.0-127.0) compared to 111 (73.0-211.0) months) (p < 0.05 each). In a multivariate Cox analysis, only the last 2 parameters were shown to be independent predictors of good clinical responsiveness to sacubitril/valsartan (hazard ratio (HR) = 1.263, 95% confidence interval (95% CI) = [1.048; 1.521]; HR = 0.992, 95% CI = [0.987; 0.997], p < 0.05, respectively). CONCLUSIONS: Sacubitril/valsartan improved LVEF, NYHA class, NT-proBNP levels, and hospitalization rates, mostly without relevant side effects. The independent predictors of a good clinical efficacy were higher CRP levels at baseline and a shorter delay between CHF diagnosis and the initialization of sacubitril/valsartan therapy.

An external validation study of the Utah Bleeding Risk Score.

OBJECTIVES: Gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices (CF-LVAD) impairs quality of life and increases hospitalization rate. The Utah Bleeding Risk Score (UBRS) has been created to predict gastrointestinal bleeding (GIB) in patients on left ventricular assist device. We here aimed to externally validate UBRS on our cohort of CF-LVAD patients. METHODS: Utah Bleeding Risk Score was calculated, GIB events summarized on follow-up and patients stratified into 3 risk groups. Predictive ability of UBRS was examined at 3 years and during whole support time and person time incidence rates correlated to UBRS. In a sub-analysis, single effects of UBRS variables on freedom from GIB were assessed. RESULTS: A total of 111 CF-LVAD patients were included. The median UBRS was 2 (3-1). Receiver operating characteristic curve analysis showed an area under the curve of 0.519 (P = 0.758, 95% confidence interval = 0.422-0.615) at 3 years and an area under the curve of 0.515 (P = 0.797, 95% confidence interval = 0.418-0.611) during whole support time. No significant difference was observed in UBRS between bleeders and non-bleeders (P = 0.80). No significant difference in freedom from GIB was observed (P3 years = 0.7; Psupport-time = 0.816) and no independent significance regarding the freedom from bleeding at 3 years for any variable was observed. Coronary artery disease was associated with higher risk of GIB beyond the 3rd year (P = 0.048). CONCLUSIONS: UBRS was not able to predict GIB and therefore not applicable in our cohort of patients. Coronary artery disease could lead to a higher risk for GIB during support time. An additional validation in a larger cohort is advisable.

Protein phosphatase 2A affects myofilament contractility in non-failing but not in failing human myocardium.

Protein phosphatase (PP) type 2A is a multifunctional serine/threonine phosphatase that is involved in cardiac excitation-contraction coupling. The PP2A core enzyme is a dimer, consisting of a catalytic C and a scaffolding A subunit, which is targeted to several cardiac proteins by a regulatory B subunit. At present, it is controversial whether PP2A and its subunits play a critical role in end-stage human heart failure. Here we report that the application of purified PP2AC significantly increased the Ca2+-sensitivity (ΔpCa50=0.05±0.01) of the contractile apparatus in isolated skinned myocytes of non-failing (NF) hearts. A higher phosphorylation of troponin I (cTnI) was found at protein kinase A sites (Ser23/24) in NF compared to failing myocardium. The basal Ca2+-responsiveness of myofilaments was enhanced in myocytes of ischemic (ICM, ΔpCa50=0.10±0.03) and dilated (DCM, ΔpCa50=0.06±0.04) cardiomyopathy compared to NF. However, in contrast to NF myocytes the treatment with PP2AC did not shift force-pCa relationships in failing myocytes. The higher basal Ca2+-sensitivity in failing myocytes coincided with a reduced protein expression of PP2AC in left ventricular tissue from patients suffering from ICM and DCM (by 50 and 56% compared to NF, respectively). However, PP2A activity was unchanged in failing hearts despite an increase of both total PP and PP1 activity. The expression of PP2AB56α was also decreased by 51 and 62% in ICM and DCM compared to NF, respectively. The phosphorylation of cTnI at Ser23/24 was reduced by 66 and 49% in ICM and DCM compared to NF hearts, respectively. Our results demonstrate that PP2A increases myofilament Ca2+-sensitivity in NF human hearts, most likely via cTnI dephosphorylation. This effect is not present in failing hearts, probably due to the lower baseline cTnI phosphorylation in failing compared to non-failing hearts.

Granulocyte macrophage colony-stimulating factor deficiency affects vascular elastin production and integrity of elastic lamellae.

BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) deficiency affects the production and fiber assembly/organization of the vascular collagenous matrix; structural alterations to the elastic system were observed. The present study elaborates the effect of GM-CSF deficiency on the vascular elastin system. METHODS AND RESULTS: Histological examination of the aorta of GM-CSF-deficient mice revealed structurally altered elastic fibers. The elastic fiber area was significantly enhanced, whereas the remaining medial area was not affected. Aortic size was significantly increased. Reverse transcription polymerase chain reaction demonstrated decreased expression levels of tropoelastin, lysyl oxidase and bone morphogenetic protein 1 (BMP-1). Cell culture studies on vascular smooth muscle cells showed that after clearance of GM-CSF with GM-CSF antibodies, the tropoelastin mRNA expression was markedly reduced. Concomitantly, lysyl oxidase and BMP-1 mRNA levels were decreased. Treatment with GM-CSF stimulated the expression of these mRNAs. CONCLUSIONS: Our studies demonstrate that disorganization of elastic lamellae as induced by GM-CSF deficiency is associated with adaptive vascular remodeling. The decreased tropoelastin expression observed is associated with elastic fiber hypertrophy. This paradox effect may be explained by decreased expression levels of lysyl oxidase and BMP-1, both mediating cross-linkage and thus assembly and organization of elastic fibers. From our data, we conclude that GM-CSF is a prerequisite for the maintenance of structural integrity of the vessel wall.

Transgenic model of smooth muscle cell cycle reentry: expression pattern of the collageneous matrix.

BACKGROUND: We have previously shown that genetically induced smooth muscle cell (SMC) cycle reentry in transgenic mouse models expressing the SV40 T antigen (TAg) resulted in adaptive arterial remodeling. The present investigation targeted the in vitro expression pattern of the collageneous matrix associated with TAg-induced SMC cycle modulation. METHODS: SMC cultures were established from the transgenic model expressing temperature-sensitive TAg. This allowed inducible transgene expression at the permissive temperature of 33 degrees C compared with the restrictive temperature of 39.5 degrees C. To distinguish a transgene effect from a temperature effect, SMCs with constitutively expressed TAg were used as controls. Data were obtained using array technology, Northern blotting, reverse transcription polymerase chain reaction, and zymography. RESULTS: TAg-induced SMC cycle reentry resulted in significant down-regulation of matrix metalloproteinase (MMP)-3, whereas MMP-2, -9, and -11 were not influenced. In addition, SMC cycle reentry resulted in significantly increased RNA levels of procollagen alpha2(IV), procollagen alpha2(V), and procollagen alpha1(XI), whereas procollagen alpha1(III) and procollagen alpha1(VIII) were down-regulated. Studies of the RNA expression levels of granulocyte-macrophage colony-stimulating factor revealed an up-regulation of this proinflammatory and matrix-modulating cytokine. CONCLUSIONS: This transgenic model provides evidence that TAg-induced cell cycle reentry is associated with a complex modulation of the collageneous matrix. Factors identified in this in vitro study reveal a comprehensive expression pattern of candidates, which might allow the vessel to undergo adaptive arterial remodeling under in vivo conditions. Our results will give rise to further investigations to elaborate on this hypothesis and to improve understanding of the role of such factors in vascular diseases.

Low-energy electromagnetic fields promote proliferation of vascular smooth muscle cells.

The rationale was to investigate the effects of low-energy electromagnetic fields (EMF) on the proliferation of bovine coronary and murine aortic smooth muscle cells (SMC). EMF were applied to SMC at field frequencies of 25, 50, or 100 Hz, and exposure time was set to 5, 15, or 30 minutes. Significant increases in SMC-counts compared with sham exposed controls were found for all EMF-frequencies tested. The effect was most pronounced for 50 Hz fields with maximum increases of 1.2-fold over controls. Sequential double exposure of mouse aortic SMC to 50 Hz fields revealed significantly enhanced cell proliferation by 1.2 fold compared with single exposure (p < 0.05). Experiments performed on bovine SMC also revealed significant increases in cell proliferation. The results demonstrate that EMF are capable of significantly enhancing the proliferation of vascular SMC. These results rise the question whether EMF would qualify as supportive means to angio-/arteriogenic approaches.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography for improving diagnosis of infection in patients on CF-LVAD: longing for more 'insights'.

Aim: Presence and consequent extent of infection in patients on continuous-flow left ventricular assist devices (CF-LVADs) can be challenging with the current diagnostic tools. The present study sought to demonstrate the diagnostic power of 18F-Fluorodeoxyglucose-Positron-Emission Tomography/Computed Tomography (18F-FDG PET/CT) in detecting infection in patients supported with CF-LVAD. Background: The present study sought to demonstrate the diagnostic power of 18F-fluorodeoxyglucose-positron-emission tomography/computed tomography (18F-FDG PET/CT) in detecting infection in patients supported with CF-LVAD. Methods and results: Between July 2009 and April 2016, 61 PET/CT examinations were performed in 47 patients (median age 64.13 years, IQR 18.77) supported with a CF-LVAD. PET/CT assessments were performed qualitatively and quantitatively at three different levels: at the piercing site of driveline (first level), along the intracorporeal course of driveline (second level), and around the device (third level). Final diagnosis of LVAD infection was prospectively performed and was based upon microbiological samples taken at hospital admission, during the surgical revision/transplantation and recurrence of symptoms on long-term follow-up. At last follow-up a total of 40 (65.57%) final diagnoses of LVAD-infection could be ascertained. Matching the final diagnosis with the PET/CT assessments the sensitivity, specificity, and positive and negative predictive value were 90.0, 71.4, 85.71, and 78.94%, respectively. Level sub-analyses of SUV max showed an optimal discriminator power for levels 1 and 2 (AUC of level 1-0.824, P < 0.001; AUC of level 2-0.849, P < 0.001, respectively). At the third level semi-quantitative analysis showed poor discriminator power (AUC 0.589, P = 0.33). Qualitative visual analysis instead indicated a trend toward significance (P = 0.07). Conclusions: Quantitative 18F-FDG PET/CT is an optimal diagnostic tool in detecting superficial and deep driveline infections. However, diagnostic accuracy with regard to the diagnosis of pump housing infection is limited. Here, clinical and qualitative PET/CT analyses must be better considered.

Supporting imaging modalities for improving diagnosis of prosthesis endocarditis: preliminary results of a single-center experience with 18F-FDG-PET/CT.

BACKGROUND: The aim of the current study was to evaluate the role of PET-CT in the diagnosis of prosthetic valve endocarditis (PVE). METHODS: This is a single-center study including 13 PET/CT examinations performed between February 2009 and March 2016 in 13 patients (76.9% men, mean age 68.1 years, IQR 11.1) because of suspect of PVE. Median interval time between first operation and PET/CT examination was 19.02 months (IQR 85.5). Final diagnosis was made according to pathological criteria (histological and microbiological) of the Duke classification. RESULTS: Eleven patients (84.6%) presented at the hospital admission positive blood cultures. Eight patients (61.5%) had inconclusive transesophageal echocardiography (TEE). Abnormal 18F-FDG uptake suggestive of active PVE was observed in 10 patients (76.9%), whereas in 3 patients (23.1%) PET/CT did not show any pathological tracer uptake at the level of the previous implanted prostheses. PET/CT revealed 15 (115.4%) new extracardiac findings and one (7.7%) new cardiac focus not previously detected in TEE. All patients underwent redo surgery. Matching the intraoperative findings with those of PET/CT, a total of 10 true positives, 2 true negatives, no false positive and 1 false negative finding was reported. Sensitivity, specificity, and positive and negative predictive values of PET/CT were 90.9%, 100%, 100% and 50% whereas for TEE they were 81.82%, 50%, 81.82%, and 50% respectively. In 61.63% of patients (N. 8) PET/CT and echo findings were concordant. In those cases the diagnosis of endocarditis was confirmed in all. CONCLUSIONS: This study highlights the potential advantages of PET-CT in patients with suspected prosthesis endocarditis. Further prospective evaluations are needed to confirm those preliminary results.

PKC delta-induced activation of MAPK pathway is required for bFGF-stimulated proliferation of coronary smooth muscle cells.

OBJECTIVE: Basic fibroblast growth factor (bFGF)-stimulated proliferation of coronary smooth muscle cells (cSMC) contributes to the pathogenesis of arteriosclerosis and restenosis. However, the molecular mechanisms involved are not fully understood. We have shown previously that protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) are required for the bFGF-stimulated mitogenic process in bovine cSMC. In this study, we determined the PKC isoform(s) involved and investigated their functional role in the bFGF-stimulated signaling and cell cycle progression in human and bovine cSMC. METHODS AND RESULTS: Downregulation of PKC by phorbol 12-myristate 13-acetate (PMA) inhibited bFGF-induced DNA synthesis, the activation of MAPK, and the expression of c-myc, demonstrating the involvement of PMA-sensitive PKC isoforms in growth factor-induced proliferation and the MAPK pathway. The PMA-sensitive classical PKC isoforms alpha, beta, gamma and novel PKC isoforms delta and epsilon were found in human cSMC. Whereas blocking of the classical PKC isoforms had no influence, the suppression of PKC delta by genetic and pharmacological approaches inhibited the bFGF-stimulated c-Raf1-MEK-MAPK-c-myc signaling and DNA synthesis in cSMC. In contrast to PKC epsilon, our results showed that bFGF activated PKC delta by phosphorylation in a time-dependent manner. In addition, inhibition of PKC delta induced a hypophosphorylation of the retinoblastoma protein and suppression of the cyclins D1 and A, demonstrating the importance of PKC delta for bFGF-induced cell cycle progression through the G1 phase in cSMC. CONCLUSIONS: Our results show that PKC delta is required for the bFGF-stimulated c-Raf1-MEK-MAPK-c-myc signaling pathway involved in the proliferation of cSMC. Therefore, it may be an interesting therapeutic target for preventing proliferative vascular disorders.