Cardiopulmonary function during exercise in heart failure with reduced ejection fraction following baroreflex activation therapy.

PURPOSE: Baroreflex activation therapy has favorable effects in heart failure patients. We report the results of a single-center study of baroreflex activation therapy in heart failure with reduced ejection fraction including cardiopulmonary exercise testing for the first time to show the effect on exercise capacity. METHODS: A total of 17 patients were treated with baroreflex activation therapy. Eligibility criteria were the New York Heart Association class ⩾III and ejection fraction ⩽35% on guideline-directed medical and device therapy. The New York Heart Association class, quality of life, and 6-min hall walk distance were assessed in all patients. Twelve patients underwent cardiopulmonary exercise testing before and 8.9 ± 6.4 months after initiation of baroreflex activation therapy. RESULTS: The New York Heart Association class and 6-min hall walk distance improved after baroreflex activation therapy, while quality of life remained stable. Weight-adapted peak oxygen uptake increased significantly from 10.1 (8.2-12.9) ml/min/kg to 12.1 (10.4-14.6) ml/min/kg (p = 0.041). Maximal heart rate was stable. Maximal oxygen pulse increased from 9.7 (5.5-11.3) to 9.9 (7.1-12.1) ml/heartbeat (p = 0.047) in 10 patients with low maximal oxygen pulse at baseline (<16.5 ml/heartbeat). There was no significant change in maximal oxygen pulse in the whole cohort. Ventilatory efficiency remained stable. CONCLUSION: Weight-adapted peak oxygen uptake improved after baroreflex activation therapy, pointing to an enhanced exercise capacity. Ventilatory efficiency and heart rate did not change, while oxygen pulse increased in patients with low oxygen pulse at baseline, indicating an improvement in circulatory efficiency, that is, a beneficial effect on stroke volume and peripheral oxygen extraction.

Ferric carboxymaltose in patients with pulmonary arterial hypertension and iron deficiency: a long-term study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation. METHODS: We retrospectively analysed the long-term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin < 100 µg/L or ferritin 100-300 µg/L and transferrin saturation (TSAT) < 20%] who were on stable targeted PAH therapy, compared with matched controls without ID. Patients with ID received a single infusion of FCM (500 to 1000 mg). Clinical measures monitored included exercise capacity, World Health Organization (WHO) functional class, ESC/ERS risk status, and hospitalizations. The observation period was up to 18 months. RESULTS: One hundred and seventeen patients (mean age 60.9 ± 16.1 years; 64.1% females) with confirmed PAH and on stable targeted therapy for ≥3 months were included (58 with and 59 patients without ID who did not receive FCM). In patients with ID, iron supplementation with FCM resulted in an immediate and sustained improvement of iron status for up to 18 months (serum iron, ferritin, TSAT, all P < 0.01). Fourteen patients in the FCM group received a second FCM infusion after 9.6 ± 4.8 months due to recurrent ID. At 6 and 18 months after FCM infusion, 6 min walk distance improved from 377.5 ± 15.9 at baseline to 412.5 ± 15.1 and 400.8 ± 14.5 m, respectively (both P < 0.05). WHO functional class (P < 0.05) and ESC/ERS risk status also improved, and there was a reduction of hospitalizations for worsening PAH in the 12 months post vs. prior to iron repletion (P = 0.029). No significant changes were observed in the control group. FCM was well tolerated in all patients, with no severe adverse events. CONCLUSIONS: In addition to targeted therapy, correction of ID by parenteral iron supplementation with FCM appears feasible and safe, has sustained effects on iron status, and may improve the clinical status and hospitalization rates in patients with PAH. Larger controlled studies are required to confirm this finding.

Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp-/-) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp-/- mice both in vivo and in vitro. Mlp-/- mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp-/- mice exhibited enhanced TGFß signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp-/- mice. In vitro studies of TGFß-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGFß downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGFß signaling.

Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis.

Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT). Accordingly, epicardial mapping revealed a markedly enhanced homogeneity in ventricular conduction. NO2-OA treatment of isolated cardiomyocytes lowered the number of spontaneous contractions upon adrenergic isoproterenol stimulation and nearly abolished ryanodine receptor type 2 (RyR2)-dependent sarcoplasmic Ca2+ leak. NO2-OA also significantly reduced RyR2-phosphorylation by inhibition of increased CaMKII activity. Thus, NO2-OA might be a novel pharmacological option for the prevention of VT development.

A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.

BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

Non-Vitamin K Oral Anticoagulants in Comparison to Phenprocoumon in Geriatric and Non-Geriatric Patients with Non-Valvular Atrial Fibrillation.

Geriatric characteristics such as high age, multi-morbidity, polypharmacy and frailty are common in patients with atrial fibrillation (AF). In a retrospective study using a German claims database, effectiveness (ischaemic stroke/systemic embolism) and safety (intracerebral, gastrointestinal and major extracranial bleeding) were compared in patients with non-valvular AF starting non-vitamin K oral antagonists (NOACs) (apixaban, dabigatran and rivaroxaban) and phenprocoumon. Cox proportional hazards models were used to calculate adjusted hazard ratios, and interaction terms of the treatment group and geriatric status (defined by age ≥75 years, frailty, ≥ 4 co-morbidities and polypharmacy) were entered into the model. A total of 42,562 and 27,939 patients initiated NOAC and phenprocoumon treatment (mean age 74 years ± 11, 51% male) with a follow-up time of 147,785 person-years. Note that 52.9% of patients were elderly, 50.8% were frail, 37.0% were co-morbid and 46.5% had polypharmacy. NOAC use was not associated with effectiveness and gastrointestinal bleeding, neither in geriatric nor in non-geriatric patients. The hazard of major extracranial and intracranial bleeding was significantly decreased for NOAC use, with similar risk reduction in geriatric and non-geriatric patients: major extracranial bleeding 0.70 (95% confidence interval [CI], 0.56-0.87) to 0.73 (95% CI, 0.60-0.89) for the geriatric groups and 0.71 (95% CI, 0.56-0.93) to 0.76 (0.59-0.98) for the non-geriatric groups (p-values for interaction > 0.6); and intracranial bleeding 0.52 (95% CI, 0.39-0.69) to 0.59 (95% CI, 0.47-0.73) for the geriatric groups and 0.54 (95% CI, 0.37-0.79) to 0.65 (95% CI, 0.49-0.86) for the non-geriatric groups (p-values for interaction > 0.2). Hence, NOACs showed similar effectiveness and superior safety in geriatric and non-geriatric patients.

Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: a pilot study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency. METHODS: 20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤1000 mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose. RESULTS: In iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7±0.4 to 11.1±1.1 µmol/L, ferritin 29.3±6.3 to 145.2±25.4 µg/L, transferrin saturation 7.5±0.7 to 19.3±2.3%, all p≤0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5±28.3 to 374.0±25.5 m (p=0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9±25.3 to 379.6±26.2 m; n.s.), resulting in a net increase in the 6MWD of 37.8m (p=0.003). This was associated with an improvement in QoL (SF-36 score from 44.3±3.7 to 50.6±3.6; p=0.01). Only minimal side-effects were reported. CONCLUSIONS: These data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.

Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins.

BACKGROUND: Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF. METHODS AND RESULTS: C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF. CONCLUSIONS: The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.

Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.

BACKGROUND: Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. METHODS AND RESULTS: Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls. CONCLUSIONS: Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.

Failure in downregulation of intratumoral survivin expression following neoadjuvant chemoradiation in esophageal cancer.

INTRODUCTION: Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis associated with locally advanced esophageal cancer. However, only patients with a major histopathologic response to neoadjuvant therapy will have a significant survival benefit. Predictive markers to allow individualization of multimodality treatment could be very helpful. We aimed to examine the association of survivin protein expression, an inhibitor of apoptosis, with histopathologic response to neoadjuvant chemoradiation and prognosis in patients with esophageal cancer. PATIENTS & METHODS: A total of 59 patients with esophageal cancer (clinical tumor stage 2-4, N(x), M(0)) received neoadjuvant chemoradiation followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% vital tumor cells. Intratumoral survivin expression was determined by immunohistochemistry in pretherapeutic biopsies and post-therapeutic resection specimens and correlated with clinicopathologic parameters. RESULTS: The pretherapeutic intratumoral survivin protein expression was not associated with any clinicopathologic factor. Survivin protein expression decreased significantly during neoadjuvant therapy, showing lower levels in post-therapeutic tumor samples (p < 0.01). Elevated postoperative survivin levels were significantly associated with a higher pathologic tumor stage after neoadjuvant therapy (ypT) category (p < 0.01), a poorer histopathologic response (p < 0.01) and a shorter overall survival (p < 0.028). CONCLUSION: Intratumoral survivin protein expression was significantly downregulated during neoadjuvant therapy of esophageal cancers. Elevated survivin levels after preoperative therapy were significantly associated with a minor histopathologic response and prognosis. Therefore, failure in downregulation of intratumoral survivin expression following neoadjuvant chemoradiation in esophageal cancer needs therapeutic strategies to reduce survivin expression or block survivin-mediated pathways to increase the histopathologic response rate and prognosis.

Reduced incidence of nodal micrometastasis after major response to neoadjuvant chemoradiation in locally advanced esophageal cancer.

BACKGROUND: Neoadjuvant treatment modalities for esophageal cancer were developed to improve local tumor control as well as to reduce lymph node metastases and distant metastases in patients with locally advanced esophageal cancer. The influence on nodal micrometastasis has not yet been evaluated. METHODS: This study includes 52 patients with localized (cT2-4, Nx, M0) esophageal cancers (21 adenocarcinomas, 31 squamous cell cancers) who received neoadjuvant chemoradiation (36Gy, 5-FU, cisplatin) followed by transthoracic en bloc esophagectomy with two field lymphadenectomy. The extent of histomorphologic regression was categorized into major (< 10%) and minor response (>10% vital residual tumor cells) as recently reported. A total of 1186 lymph nodes were diagnosed as negative for metastases by routine histopathological analysis and were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3. RESULTS: Twenty-two tumors (42.3%) showed a major histopathologic response whereas in 30 tumors (57.7%) only a minor response was present. Of 32 patients with a pN0 category, major response was present in 19 (59.4%) tumors, whereas 13 (40.6%) tumors showed minor response. Nine (69%) out of 13 patients with minor response had AE1/AE3-positive cells in their lymph nodes, whereas only four (21%) out of 19 pN0-patients with major response showed nodal micrometastasis (P = 0.013, chi(2)-test). CONCLUSIONS: If tumors show a major histomorphologic response following neoadjuvant chemoradiation, the presence of nodal micrometastasis is significantly reduced compared to those with minor response.

High cyclooxygenase-2 expression following neoadjuvant radiochemotherapy is associated with minor histopathologic response and poor prognosis in esophageal cancer.

PURPOSE: High expression of cyclooxygenase-2 (COX-2) was shown to inhibit chemotherapy- and radiotherapy-induced apoptosis. We analyzed the association of COX-2 mRNA and protein expression with histomorphologic response to neoadjuvant radiochemotherapy in esophageal cancer. EXPERIMENTAL DESIGN: Fifty-two patients with resectable esophageal cancers (cT2-4, Nx, and M0) received neoadjuvant radiochemotherapy (cisplatin, 5-5-fluorouracil, 36 Gy) followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% of residual vital tumor cells. RNA was isolated from endoscopic biopsies (paired tumor and normal tissue) before neoadjuvant treatment and quantitative real-time reverse transcriptase-PCR (Taqman) assays were done to determine COX-2 mRNA expression levels standardized for beta-actin. COX-2 protein expression in pretreatment biopsies and post-therapeutic resection specimens was analyzed by immunostaining of tumor cells. RESULTS: Median COX-2 mRNA expression levels were significantly (P < 0.0001) different between paired tumor (median, 2.2) and normal tissues (median, 0.159). Comparison of pre-therapeutic and posttherapeutic specimens showed a significant difference (P < 0.006) in COX-2 protein expression. Twelve of 52 tumors showed down-regulation and 3 of 52 showed up-regulation of COX-2 protein expression during neoadjuvant radiochemotherapy. High COX-2 protein expression in post-therapeutic resection specimens was significantly associated with minor histopathologic response (P < 0.04) and poor prognosis (5-year survival probabilities: 26.3 +/- 8.2% for minor and 58.6% +/- 12.9% for major histopathologic response; P < 0.01). CONCLUSION: High COX-2 protein expression following neoadjuvant radiochemotherapy in resection specimens is significantly associated with minor histopathologic response to neoadjuvant therapy and very poor prognosis.

Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells.

OBJECTIVE: Nebivolol, in contrast to other selective beta1-adrenergic receptor antagonists like atenolol, improves endothelial function in patients with oxidative stress within vascular tissue. With the present studies we sought to determine whether beta receptor blockade with nebivolol may improve endothelial function in hyperlipidemia and whether this is attributable to reductions in vascular oxidative stress. METHODS AND RESULTS: Watanabe heritable hyperlipidemic rabbits (WHHL) were treated with nebivolol (10 mg/kg per day for 8 weeks). New Zealand white rabbits (NZWR) served as controls. Nebivolol improved endothelial function, reduced vascular superoxide and vascular macrophage infiltration, and prevented NO synthase uncoupling in WHHL. Nebivolol treatment did not modify the expression of sGC or cGK-I but improved cGK-I activity (assessed by the phosphorylation state of the VAsodilator Stimulated Phosphoprotein at serine239, P-VASP). NAD(P)H oxidase activity in whole blood and isolated neutrophils was dose-dependently inhibited by nebivolol, whereas atenolol, metoprolol, and carvedilol were markedly less effective. CONCLUSIONS: Nebivolol therapy effectively prevents NO synthase III uncoupling and prevents activation of the neutrophil NAD(P)H oxidase and infiltration of inflammatory cells. These novel antioxidative stress actions of this compound may explain partly the beneficial effects on endothelial function in patients with enhanced vascular oxidative stress.