Case report: "A healthy woman with exertional dyspnea: Indication of a pacemaker or not?"

The selection of patients with chronotropic incompetence (CI) for cardiac pacing therapy remains challenging. Here, we present a case of a 40-year-old woman with severe exertional dyspnea. The exercise test revealed a blunted increase in the heart rate (HR) (maximum of 110 bpm). Her exercise capacity significantly improved under atrial stimulation at 170 bpm using a temporary pacing lead. Therefore, we implanted a rate-adaptive dual-chamber pacemaker with a blended sensor. During follow-up exercise capacity normalized, and she had no residual exertional dyspnea at 6 months. This case highlights the potential value for individual assessments of CI to identify clear indications for pacemaker implantation.

Acute reverse annular remodeling during MitraClip® therapy predicts improved clinical outcome in heart failure patients: a 3D echocardiography study.

BACKGROUND: Transcatheter mitral valve repair (TMVR) has been shown to have acute effects on mitral valve geometry in patients with functional mitral regurgitation (FMR). This study investigates the impact of MitraClip® therapy-induced annular remodeling on clinical outcome and mitral regurgitation in heart failure patients. METHODS: TMVR was performed successfully in 45 patients with FMR. In this study, mitral valve datasets were obtained before and directly after MitraClip® implantation using three-dimensional (3D) transesophageal echocardiography, and were analyzed offline retrospectively using dedicated 3D reconstruction software. Patients underwent clinical and echocardiographic evaluation at baseline and after 6 months. At follow-up, the patients were allocated into two groups according to their improvement in New York Heart Association (NYHA) functional class: a Low Responder group with ΔNYHA <1.5 (n = 25); and a High Responder group with ΔNYHA ≥1.5 (n = 20). RESULTS: At 6-month follow-up, data analysis revealed that while mitral regurgitation was reduced significantly in both groups, only the High Responder group had experienced significant downsizing of the 3D circumference (137 ± 14 mm to 126 ± 13 mm; p < 0.01) and the anterior-to-posterior diameter (33 ± 5 mm to 29 ± 4 mm; p < 0.01) of the mitral annulus during the intervention. Furthermore, only the High Responder group with reverse annular remodeling as shown had substantial advances in quality of life (Minnesota living with heart failure questionnaire: 55 ± 10 to 34 ± 14 points; p < 0.01) and functional status (6-min walk distance: 290 ± 104 m to 462 ± 111 m; p = 0.07). CONCLUSION: Our study demonstrates that instantaneous left ventricular annular remodeling during MitraClip® implantation is associated with improved clinical outcome of heart failure patients with functional mitral regurgitation. Trial registration The study was approved by the local ethics committee (Study Number 4497R, Registration ID: 2013121585). TRIAL REGISTRATION: NCT02033811 Retrospectively registered January 9, 2014.

Diagnostic value of the six-minute walk test (6MWT) in grown-up congenital heart disease (GUCH): Comparison with clinical status and functional exercise capacity.

BACKGROUND: Exercise testing for the assessment of functional capacity plays an important role in long-term follow-up of GUCH patients. CPX is the favored modality for decision-making recommended in the current guidelines. In contrast to this complex method, the 6 MWT is a simple, easy-to-perform, safe, and commonly available exercise test. Although well-established in various cardiopulmonary diseases, the diagnostic impact of the 6 MWT in GUCH patients is not known so far. METHODS: 102 GUCH patients were evaluated by 6 MWT and CPX simultaneously. Clinical symptoms were assessed, according to the NYHA classification. Additionally, an echocardiography study, and selected cardiac blood tests (N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive Troponin T) were performed. RESULTS: Ranges of six-minute walk distance (6 MWD) and peak oxygen consumption (peakVO2) were 116-765 m and 6.4-36.2 ml/kg/min, respectively. 6 MWD and peakVO2 showed a close correlation (r=0.72, 95% CI, 0.63 to 0.79). Patients with a peakVO2 of ≤ 15.5 ml/kg/min were excellently identified by 6 MWT (c-value=0.82). A cut-off value of 482 m was optimal to predict reduced peakVO2. In multivariate regression analysis, 6 MWD and NYHA class were identified as relevant predictors of peakVO2. In subgroup analysis, Eisenmenger patients achieved the shortest 6 MWD (280, SD 178 m). CONCLUSION: In our study population of GUCH patients, the 6 MWD shows a close correlation to peakVO2, and an excellent prediction of reduced peakVO2. Thus, it seems to be an easy-to-perform and reliable screening parameter to evaluate functional capacity of these patients (Controlled Clinical Trials number, NCT02193243).

Left Atrial Appendage Closure Guided by Integrated Echocardiography and Fluoroscopy Imaging Reduces Radiation Exposure.

AIMS: To investigate whether percutaneous left atrial appendage (LAA) closure guided by automated real-time integration of 2D-/3D-transesophageal echocardiography (TEE) and fluoroscopy imaging results in decreased radiation exposure. METHODS AND RESULTS: In this open-label single-center study LAA closure (AmplatzerTM Cardiac Plug) was performed in 34 consecutive patients (8 women; 73.1±8.5 years) with (n = 17, EN+) or without (n = 17, EN-) integrated echocardiography/fluoroscopy imaging guidance (EchoNavigator® [EN]; Philips Healthcare). There were no significant differences in baseline characteristics between both groups. Successful LAA closure was documented in all patients. Radiation dose was reduced in the EN+ group about 52% (EN+: 48.5±30.7 vs. EN-: 93.9±64.4 Gy/cm2; p = 0.01). Corresponding to the radiation dose fluoroscopy time was reduced (EN+: 16.7±7 vs. EN-: 24.0±11.4 min; p = 0.035). These advantages were not at the cost of increased procedure time (89.6±28.8 vs. 90.1±30.2 min; p = 0.96) or periprocedural complications. Contrast media amount was comparable between both groups (172.3±92.7 vs. 197.5±127.8 ml; p = 0.53). During short-term follow-up of at least 3 months (mean: 8.1±5.9 months) no device-related events occurred. CONCLUSIONS: Automated real-time integration of echocardiography and fluoroscopy can be incorporated into procedural work-flow of percutaneous left atrial appendage closure without prolonging procedure time. This approach results in a relevant reduction of radiation exposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT01262508.

[Congenital heart disease in adults]. / Angeborene Herzfehler im Erwachsenenalter.

Adult congenital heart diseases are common, and nowadays treatable with convincing success. Interventional occlusion of septal defects, and percutaneous valve implantation become widely accepted. Considering trend analysis, surgical repair of malfunctioning valves is favored over valve replacement. Endocarditis prophylaxis is reserved for high risk situations.

Initial clinical experience using the EchoNavigator(®)-system during structural heart disease interventions.

AIM: To present our initial clinical experience using this innovative software solution for guidance of percutaneous structural heart disease interventions. METHODS: Left atrial appendage, atrial septal defect and paravalvular leak closure, transaortic valve repair and MitraClip(®) procedures were performed in the catheter laboratory under fluoroscopic and echocardiographic guidance. The two-dimensional and three-dimensional images generated by the transesophageal echocardiography probe were interfaced with the fluoroscopic images in real-time using the EchoNavigator(®)-system. RESULTS: The application of the novel image fusion technology was safe and led to a better appreciation of multimodality imaging guidance due to improved visualization of the complex relationship between catheter devices and anatomical structures. CONCLUSION: The EchoNavigator(®)-system is a feasible and safe tool for guidance of interventional procedures in structural heart disease. This innovative technology may improve confidence of interventional cardiologists in targeting and positioning interventional devices in order to increase safety, accuracy, and efficacy of percutaneous interventions in the catheter laboratory.

Left atrial appendage morphology is closely associated with specific echocardiographic flow pattern in patients with atrial fibrillation.

AIMS: To assess the relation between left atrial appendage (LAA) morphology and echocardiographic flow pattern of the LAA by means of two- and three-dimensional transoesophageal echocardiography (3D-TEE). METHODS AND RESULTS: In a total of 131 patients with atrial fibrillation, LAA morphology was analyzed by 3D-TEE and classified into four types (Chicken Wing, Windsock, Cactus, Cauliflower). Left atrial appendage flow pattern as maximal LAA emptying flow velocity and spontaneous echo contrast (SEC) were retrieved from 2D-TEE imaging in all patients. In patients with atrial fibrillation (AF), Chicken Wing morphology was associated with a higher LAA emptying flow velocity (difference of means = -11.7, 95% CI 4.6-19.3, P = 0.003) and a reduced prevalence of SEC (OR 3.2, 95% CI 1.1-9.3, P = 0.025) compared with all other LAA types (so-called 'Non-Chicken Wing' LAA). These alterations were irrespective of the underlying type of AF. CONCLUSION: Non-Chicken Wing LAA morphologies are associated with a specific echocardiographic flow pattern in patients with AF. Since evidence exists that LAA flow pattern are indicative of an enhanced risk of thrombus formation, 3D-TEE might be a valuable tool warranting future studies to test whether these morphological and functional characteristics permit risk stratification in AF.

TNF-α, myocardial perfusion and function in patients with ST-segment elevation myocardial infarction and primary percutaneous coronary intervention.

AIMS: To characterize the time course of tumor necrosis factor-α (TNF-α) serum levels along with myocardial perfusion and contractile function in patients with ST-segment elevation myocardial infarction (STEMI) and successful primary percutaneous coronary intervention (PCI). METHODS: Serum levels of TNF-α, interleukin 6 (IL-6), and C-reactive protein (CRP) were measured in 42 patients with STEMI before, one and 6 days after successful PCI. Myocardial perfusion was assessed by contrast-enhanced echocardiography (ceEcho), contractile function by unenhanced two-dimensional (2DE) and real-time three-dimensional echocardiography. In a subset of 18 patients, infarct size was quantified by late gadolinium enhancement cardiovascular magnetic resonance imaging (LGE-CMR) on day six. RESULTS: TNF-α serum levels were in the upper normal range within the first 12 h from symptom onset and increased continuously until day six, while IL-6 and CRP increased subsequently with a peak on day one after STEMI. Serum TNF-α on day one after PCI correlated with perfusion defects, wall motion abnormalities, and infarct size (ceEcho: r = 0.52, p = 0.005; 2DE: r = 0.56, p = 0.002; LGE-CMR: r = 0.83-0.86; p < 0.0001). Using multiple regression linear analysis, infarct size on day six was predicted by serum TNF-α 1 day after PCI (p = 0.006, adjusted R (2) 0.638). CONCLUSION: Our data reflect the clinical significance of early TNF-α elevation in patients with STEMI and primary PCI (Controlled Clinical Trials number, NCT00529607).

Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function.

OBJECTIVES: This study sought to characterize the impact of hemodialysis (HD)-induced release of hemoglobin on the bioavailability of nitric oxide (NO) and endothelial function. BACKGROUND: Patients on chronic HD suffer from endothelial dysfunction and a massively increased risk for cardiovascular events. Although dialysis-dependent and -independent factors are discussed, the exact mechanisms are not fully understood. METHODS: In 14 HD patients (56+/-15 years of age), endothelial function was determined by measuring flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound before and after treatment. The NO consumption activity of plasma isolated from patients before and after hemodialysis was studied with an NO-sensitive electrode. RESULTS: HD impaired FMD (3.5+/-2.6% to 1.7+/-1.4%, p=0.04) without affecting brachial artery diameter (4.7+/-0.6 mm vs. 4.4+/-0.9 mm, p=0.27). This was accompanied by an increase in cell-free plasma hemoglobin (196+/-43 mg/l to 285+/-109 mg/l, p=0.01), which led to a decrease in the bioavailability of free NO by more than 70%. Oxidation of the released plasma ferrous hemoglobin prevented the consumption of NO. The amount of decompartmentalized hemoglobin after HD correlated inversely with the change in FMD (r=-0.65, p=0.041). CONCLUSIONS: Our data support a role of HD-induced release of hemoglobin in the pathogenesis of endothelial dysfunction in patients with end-stage renal disease. Approaches that oxidize free plasma hemoglobin may restore NO bioavailability and may have potential beneficial effects on vascular function. (Influence of Hemodialysis on Endothel-Depending Dilatation of Peripheral Arteries; NCT00764192).

Serial measurements of whole blood nitrite in an intensive care setting.

Nitrite plays an eminent role in cardiovascular physiology and pathology, mediating hypoxic vasodilation, reducing ischemia-reperfusion injury, and regulating cardiac energetics and function. The role of circulating nitrite in critically ill patients has not been examined so far. To investigate whether whole blood nitrite can be determined reproducibly in an intensive care setting, 30 patients from a cardiology intensive care unit were enrolled in this study, no matter what the underlying disease. Blood was drawn from an arterial catheter and whole blood nitrite was determined, using a tri-iodide/ozone-based chemiluminescence assay after incubation with a ferricyanide-containing stabilization solution. Whole blood nitrite levels ranged from 35 to 1193 nmol/L (mean+/-SEM: 220+/-20 nmol/L). Myocardial infarction was associated with lower whole blood nitrite levels (200+/-53 nmol/L for elevated serum CK MB levels vs 432+/-95 nmol/L in the normal CK MB range, p=0.039). Neither impaired kidney function nor an inflammatory state was associated with higher or lower whole blood nitrite levels. In conclusion, whole blood nitrite can be measured easily and reproducibly in critically ill patients, regardless of renal function and inflammation. The origin of decreased nitrite levels in myocardial infarction is currently unclear and needs to be further elucidated.

Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise.

Age-dependent alterations of the vessel wall may predispose older individuals to increased cardiovascular pathology. Aging is associated with an impaired bioactivity of nitric oxide (NO). Plasma nitrite reflects NO-synthase activity under fasting conditions and is an important storage pool of NO. To test the hypothesis that aging is associated with an impaired capacity of the vasculature to increase plasma nitrite during exercise, 29 young and 28 old healthy individuals (25 +/- 1 years and 58 +/- 2 years; P < 0.001) without major cardiovascular risk factors were enrolled. Exercise stress was similar in both groups. Baseline nitrite did not differ (107 +/- 8 vs. 82 +/- 10 nmol/l, young vs. old; n.s.) although a trend toward higher nitrite levels in young individuals was seen. In young subjects, exercise increased plasma nitrite by 38 +/- 7% (P < 0.001) compared to only 13 +/- 8% (P = n.s.) in older subjects. L-NMMA blocked increases of nitrite. Endothelial function, as defined by flow-mediated-dilation (FMD) of the brachial artery via ultrasound, was impaired in older subjects (5.4 +/- 0.4% vs. 6.7 +/- 0.3%; P < 0.01). Multivariate analysis showed that age (P = 0.007), BMI (P = 0.010), and LDL (P = 0.021) were independent predictors of nitrite increase. The fact that aging is associated with an impaired capacity of the vasculature to adequately increase nitrite to physiological stimuli may contribute to attenuated maintenance and further deterioration of vascular homeostasis with aging.

Cellular steady-state levels of "high risk" but not "low risk" human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53- and E6AP-binding capabilities.

The group of mucosal epithelia-infecting human papillomaviruses (HPV) can be subdivided in "low" and "high risk" HPV types. Both types induce benign neoplasia (condyloma), but only the infection with a "high risk" HPV type is causally associated with an increased risk of developing anogenital tumors. The oncogenic potential of high risk HPVs resides at least partially in the viral E6 protein. The E6 protein targets the cellular p53 protein for proteasome-dependent degradation, which is associated with the immortalizing and transforming functions of these viruses. Recently the E6-dependent proteasome-mediated destabilization of additional cellular proteins (E6TP1, c-myc, Bak, hMCM7, human scribble, E6AP, MAGI-1) has been described, but the cellular mechanisms controlling the viral E6 protein stability itself have been so far not analyzed. In this study, we transiently expressed the E6 genes of the high risk HPV type 16, the low risk HPV types 6a and 11, and the cutaneous epithelia-infecting HPV types 5 and 8 from a eucaryotic expression vector and compared the cellular steady-state levels of the expressed E6 proteins. We demonstrated that the high risk HPV 16 E6 protein possesses the lowest steady-state level in comparison to the low risk HPV type E6 proteins and the cutaneous epithelia-infecting HPV type E6 proteins. Inhibition of cellular proteasome-dependent protein degradation led to an increase in steady-state levels of high risk but not of low risk E6 proteins. Analysis of functionally deficient HPV 16 E6 proteins in p53 null- and p53 wild-type-expressing cell lines revealed that the cellular steady-state level of this protein is influenced neither by its p53- nor its E6AP-binding abilities.