Long-Term Results of Patch Repair in Destructive Valve Endocarditis.

OBJECTIVES: Treatment of destructive endocarditis with abscess formation is a surgical challenge and associated with significant morbidity and mortality. A root replacement is often performed in case of an annular abscess. This retrospective study was designed to assess the long-term outcome of extensive debridement and patch reconstruction as an alternative approach. METHODS: Between November 2007 and November 2016, a selected group of 79 patients (29.6% of all surgical endocarditis cases) with native valve endocarditis (NVE, 53.2%) or prosthetic valve endocarditis (PVE, 46.8%) valve endocarditis underwent surgical therapy with extensive annular debridement and patch reconstruction. Their postoperative course, freedom from recurrent endocarditis, and survival at 1, 5, and 7 years were evaluated. RESULTS: About two-thirds of patients were in a stable condition, one-third of patients were in a critical state. The median logistic EuroSCORE I was 17%. Infected tissue was removed, and defect closure was performed, either with autologous pericardium for small defects, or with bovine pericardium for larger defects. Overall, in-hospital mortality was 11.3% (NVE: 9.7%, PVE: 13.2%; p = 0.412). In single valve endocarditis survival at 1, 5, and 7 years was 81, 72, 72%, respectively for NVE, and 80, 57, 57%, respectively for PVE (p = 0.589), whereas in multiple valve endocarditis survival at 1, 5, and 7 years was 82, 82, 82% for NVE, and 61, 61, and 31%, respectively for PVE (p = 0.132). Confirmed late reinfection was very low. CONCLUSION: Surgical treatment of destructive endocarditis with abscess formation using patch repair techniques offers acceptable early and long-term results. The relapse rate was low. PVE and involvement of multiple valves were associated with worse outcomes.

How arrhythmias weaken the ventricle: an often underestimated vicious cycle.

Arrhythmia-induced cardiomyopathy (AIC) is classified as a form of dilated cardiomyopathy in which left ventricular systolic dysfunction (LVSD) is triggered by tachycardic or arrhythmic heart rates. On the one hand AIC can develop in patients without cardiac disease and on the other hand it can appear in patients with pre-existing LVSD, leading to a further reduction in left ventricular (LV) ejection fraction. A special aspect of AIC is the potential termination or partial reversibility of LVSD; thus, AIC is curatively treatable by the elimination of the underlying arrhythmia. Since arrhythmias are often seen merely as a consequence than as an underlying cause of LVSD, and due to the fact that the diagnosis of AIC can be made only after recovery of LV function, the prevalence of AIC is probably underestimated in clinical practice. Pathophysiologically, animal models have shown that continuous tachycardic pacing induces consecutive changes such as the occurrence of LVSD, increased filling pressures, LV dilatation, and decreased cardiac output. After termination of tachycardia, reversibility of the described pathologies can usually be observed. Studies in human ventricular myocardium have recently demonstrated that various cellular structural and functional mechanisms are activated even by normofrequent atrial fibrillation, which may help to explain the clinical AIC phenotype.

Reduction of radiation exposure during transcatheter edge-to-edge mitral valve repair.

BACKGROUND: Transcatheter mitral valve repair is an increasingly used therapy for mitral regurgitation which requires fluoroscopic guidance. Limiting radiation exposure during lengthy procedures is important for both patient and operator safety. This study aimed to investigate radiation dose during contemporary use of MitraClip implantation and the effects of a dose reduction program. METHODS: A total of 115 patients who underwent MitraClip implantation were prospectively enrolled in a single-center observational study. During the inclusion period, our institution adopted a radiation dose reduction program, comprising lowering of fluoroscopy pulse rate and image target dose. The first 58 patients were treated with conventional fluoroscopy settings, while the following 57 patients underwent the procedure with the newly implemented low dose protocol. RESULTS: Radiation dose area product significantly decreased after introduction of the low dose protocol (693 [366-1231] vs. 2265 [1517-3914] cGy·cm2 , p < 0.001). After correcting for fluoroscopy time, gender and body mass index, the low dose protocol emerged as a strong negative predictor of radiation dose (p < 0.001), reducing dose area product by 64% (95% confidence interval [57-70]). Device time, device success, and procedural safety did not differ between the normal dose and low dose group. Furthermore, the low dose protocol was not associated with an increased incidence of a combined endpoint consisting of death, repeat intervention, or heart surgery during 12 months follow-up. CONCLUSION: Reduction of radiation exposure during transcatheter mitral valve repair by 64% is feasible without affecting procedural success or safety.

Reduced store-operated Ca2+ entry impairs mesenteric artery function in response to high external glucose in type 2 diabetic ZDF rats.

Diabetes is a major risk factor for cardiovascular disease, affecting both endothelial and smooth muscle cells. Store-operated Ca2+ channels (SOCCs) have been implicated in many diabetic complications. Vascular dysfunction is common in patients with diabetes, but the role of SOCCs in diabetic vasculopathy is still unclear. Our research aimed to investigate the effects of high glucose (HG) on store-operated Ca2+ entry (SOCE) in small arteries. Small mesenteric arteries from type 2 diabetic Zucker fatty rats (ZDF) versus their non-diabetic controls (Zucker lean, ZL) were examined in a pressurized myograph. Vascular smooth muscle cells (VSMC) were isolated and intracellular Ca2+ was measured (Fura 2-AM). A specific protocol to deplete intracellular Ca2+ stores and thereby open SOCCs, as well as pharmacological SOCE inhibitors (SKF-96365, BTP-2), were used to artificially activate and inhibit SOCE, respectively. High glucose (40 mmol/L) relaxed arteries in a SKF-sensitive manner. Diabetic arteries exhibited reduced HG-induced relaxation, as well as reduced contraction after Ca2+ replenishment. Further, the rise in intracellular Ca2+ on account of SOCE is diminished in diabetic versus non-diabetic VSMCs and was insensitive to HG in diabetic VSMCs. The expression of SOCC proteins was measured, detecting a downregulation of Orai1 in diabetes. In conclusion, diabetes leads to a reduction of SOCE and SOCE-induced contraction, which is unresponsive to HG-mediated inhibition. The reduced expression of Orai1 in diabetic arteries could account for the observed reduction in SOCE.

Simplified Method for Insertion of Steerable Guide into the Left Atrium Using a Pigtail Guide Wire During the MitraClip(®) Procedure: A Technical Tip.

BACKGROUND: To assess whether a new floppy pigtail guidewire provides sufficient support for introduction of the 22F-steerable guide catheter (SG) into the left atrium and is less time-consuming during the MitraClip(®) -procedure without necessity of probing and inserting a stiff wire into the pulmonary vein. METHODS: In group 1, traditional probing of the left upper pulmonary vein and insertion of a standard stiff wire was used. In group 2, direct insertion of the floppy pigtail guidewire directly after transseptal puncture was used. RESULTS: Patients in group 1 (n = 18) and group 2 (n = 21) did not differ significantly with respect to mitral regurgitation severity (3.2 ± 0.4 vs 3.2 ± 0.4; P = 0.814) and etiology (functional 78% vs 71%, P = 0.651). Comparing both methods, a significant reduction in time-to-SG was observed in group 2 versus group 1 (17 ± 7 minutes vs 30 ± 11 minutes; P = 0.001). The rate of crossing failures was 0% with use of the floppy pigtail guidewire as well as with the traditional technique. No complications were observed with use of the floppy pigtail guidewire. CONCLUSIONS: Utilization of a thin, floppy pigtail guidewire for left atrium access is safe and markedly accelerates insertion of the SG for the MitraClip(®) -procedure without crossing failures of the atrial septum.

Type 2 diabetes: increased expression and contribution of IKCa channels to vasodilation in small mesenteric arteries of ZDF rats.

Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the experimental models in our study. Third-order mesenteric arteries were dissected and mounted on a pressure myograph; mRNA was quantified by RT-PCR and channel proteins by Western blotting. Under nitric oxide (NO) synthase and cyclooxygenase inhibition, endothelial stimulation with ACh fully relaxes control but not diabetic arteries. In contrast, when small-conductance calcium-activated potassium (KCa) channels and intermediate- and large-conductance KCa (I/BKCa) are inhibited with apamin and charybdotoxin, NO is able to compensate for ACh-induced relaxation in control but not in diabetic vessels. After replacement of charybdotoxin with 1-[(2-chlorophenyl)diphenylmethyl]-(1)H-pyrazole (TRAM-34; IKCa inhibitor), ACh-induced relaxation in diabetic animals is attenuated. Specific inhibition with TRAM-34 or charybdotoxin attenuates ACh relaxation in diabetes. Stimulation with 1-ethyl-2-benzimidazolinone (IKCa activator) shows a reduced relaxation in diabetes. Activation of BKCa with 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-(2)H-benzimidazol-2-one NS619 leads to similar relaxations of control and diabetic arteries. RT-PCR and Western blot analysis demonstrate elevated mRNA and protein expression levels of IKCa in diabetes. Our results suggest that the compensatory effect of NO and EDH-associated, endothelium-dependent relaxation is reduced in ZDF rats. Specific blockade of IKCa with TRAM-34 reduces NO and EDH-type relaxation in diabetic rats, indicating an elevated contribution of IKCa in diabetic small mesenteric artery relaxation. This finding correlates with increased IKCa mRNA and protein expression in this vessel.

Time to Recovery from Systolic Dysfunction Correlates with Left Ventricular Fibrosis in Arrhythmia-Induced Cardiomyopathy.

BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is characterized by the reversibility of left ventricular (LV) systolic dysfunction (LVSD) after rhythm restoration. This study is a cardiac magnetic resonance tomography substudy of our AIC trial with the purpose to investigate whether left ventricular fibrosis affects the time to recovery (TTR) in patients with AIC. METHOD: Patients with newly diagnosed and otherwise unexplainable LVSD and tachyarrhythmia were prospectively recruited. LV ejection fraction (LVEF) was measured by echocardiography at baseline and 2, 4, and 6 months after rhythm control, and stress markers were assessed. After initial rhythm control, LV fibrosis was assessed through late gadolinium enhancement (LGE). Patients were diagnosed with AIC if their LVEF improved by ≥15% (or ≥10% when LVEF reached ≥50%). Non-responders served as controls (non-AIC). RESULTS: The LGE analysis included 39 patients, 31 of whom recovered (AIC). LV end-systolic diameters decreased and LVEF increased during follow-up. LV LGE content correlated positively with TTR (r = 0.63, p = 0.003), with less LGE favoring faster recovery, and negatively with ΔLVEF (i.e., LVEF at month 2 compared to baseline) as a marker of fast recovery (r = -0.55, p = 0.012), suggesting that LV fibrosis affects the speed of recovery. CONCLUSION: LV fibrosis correlated positively with the time to recovery in patients with AIC. This correlation may help in the estimation of the recovery period and in the optimization of diagnostic and therapeutic strategies for patients with AIC.

Clinical Characterization of Arrhythmia-Induced Cardiomyopathy in Patients With Tachyarrhythmia and Idiopathic Heart Failure.

BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is a known entity, but prospective evidence for its characterization is limited. OBJECTIVES: This study aimed to: 1) determine the relative frequency of the pure form of AIC in the clinically relevant cohort of patients with newly diagnosed, otherwise unexplained left ventricular systolic dysfunction (LVSD) and tachyarrhythmia; 2) assess the time to recovery from LVSD; and 3) identify parameters for an early diagnosis of AIC. METHODS: Patients were prospectively included, underwent effective rhythm restoration, and were followed-up at 2, 4, and 6 months to evaluate clinical characteristics, biomarkers, and cardiac imaging including cardiac magnetic resonance imaging. Patients with recurred arrhythmia were excluded from analysis. RESULTS: 41 of 50 patients were diagnosed with AIC 6 months after rhythm restoration. Left ventricular (LV) ejection fraction increased 2 months after rhythm restoration from 35.4% ± 8.2% to 52.7% ± 8.0% in AIC patients vs 37.0% ± 9.5% to 43.3% ± 7.0% in non-AIC patients. From month 2 to 6, LV ejection fraction continued to increase in AIC patients (57.2% ± 6.1%; P < 0.001) but remained stable in non-AIC patients (44.0% ± 7.8%; P = 0.628). Multivariable logistic regression analysis revealed that lower LV end-diastolic diameter at baseline could be used for early diagnosis of AIC, whereas biomarkers and other morphological or functional parameters, including late LV gadolinium enhancement, did not show suitability for early diagnosis. CONCLUSIONS: We observed a high prevalence of AIC in patients with otherwise unexplained LVSD and concomitant tachyarrhythmia, suggesting that this condition may be underdiagnosed in clinical practice. Most patients recovered fast, within months, from LVSD. A low initial LV end-diastolic diameter may constitute an early marker for diagnosis of AIC.

Antidiabetic treatment restores adiponectin serum levels and APPL1 expression, but does not improve adiponectin-induced vasodilation and endothelial dysfunction in Zucker diabetic fatty rats.

BACKGROUND: Adiponectin is able to induce NO-dependent vasodilation in Zucker lean (ZL) rats, but this effect is clearly alleviated in their diabetic littermates, the Zucker diabetic fatty (ZDF) rats. ZDF rats also exhibit hypoadiponectinemia and a suppressed expression of APPL1, an adaptor protein of the adiponectin receptors, in mesenteric resistance arteries. Whether an antidiabetic treatment can restore the vasodilatory effect of adiponectin and improve endothelial function in diabetes mellitus type 2 is not known. METHODS: During our animal experiment from week 11 to 22 in each case seven ZDF rats received an antidiabetic treatment with either insulin (ZDF+I) or metformin (ZDF+M). Six normoglycemic ZL and six untreated ZDF rats served as controls. Blood glucose was measured at least weekly and serum adiponectin levels were quantified via ELISA in week 11 and 22. The direct vasodilatory response of their isolated mesenteric resistance arteries to adiponectin as well as the endothelium-dependent and -independent function was evaluated in a small vessel myograph. Additionally, the expression of different components of the adiponectin signaling pathway in the resistance arteries was quantified by real-time RT-PCR. RESULTS: In ZDF rats a sufficient blood glucose control could only be reached by treatment with insulin, but both treatments restored the serum levels of adiponectin and the expression of APPL1 in small resistance arteries. Nevertheless, both therapies were not able to improve the vasodilatory response to adiponectin as well as endothelial function in ZDF rats. Concurrently, a downregulation of the adiponectin receptors 1 and 2 as well as endothelial NO-synthase expression was detected in insulin-treated ZDF rats. Metformin-treated ZDF rats showed a reduced expression of adiponectin receptor 2. CONCLUSIONS: An antidiabetic treatment with either insulin or metformin in ZDF rats inhibits the development of hypoadiponectinemia and downregulation of APPL1 in mesenteric resistance arteries, but is not able to improve adiponectin induced vasodilation and endothelial dysfunction. This is possibly due to alterations in the expression of adiponectin receptors and eNOS.

Less major bleeding and higher hemoglobin after left atrial appendage closure in high-risk patients: Data from a long-term, longitudinal, two-center observational study.

BACKGROUND: Left atrial appendage closure (LAAC) is a mechanical alternative for stroke prevention in patients at risk who cannot tolerate oral anticoagulation (OAC). HYPOTHESIS: Our hypothesis was that the reduction of anticoagulation following LAAC results in a decrease of bleeding events and a rise in serum hemoglobin in a high-risk collective of patients with atrial fibrillation (AF). METHODS: Bleeding events, use of erythrocyte concentrates, anticoagulation, embolic events, and serum hemoglobin levels before and following LAAC were compared over more than 4 years. RESULTS: Seventy-five patients (CHA2DS2-VASc score 4.4 ± 1.7, HAS-BLED score 4.6 ± 1.1) were analyzed. Before LAAC (observation period 1.8 ± 1.8 years), 67 patients experienced 1.8 ± 1.4 bleeding events (0.9 ± 1.3 major) per year resulting in 0.7 ± 1.3 transfusions per year. After LAAC (2.6 ± 2.0 years), 26 patients (p < .0001 vs. before) had 0.6 ± 2.1 bleeding events (p < .0001), 0.2 ± 0.6 major bleedings (p < .0001) and received 0.6 ± 1.9 transfusions per year (p = .671). Fourteen patients had stroke before and 3 after LAAC (p = .008). Serum hemoglobin increased from initially 9.9 ± 3.0 to 11.9 ± 2.3 g/dL until the end of follow-up (p = .0005). Adverse embolic events did not differ before and after LAAC in our collective. CONCLUSION: In this clinical relevant cohort of AF patients with high risk for stroke and intolerance to OAC, we show that LAAC was able to reduce the rate of stroke and bleeding events, which translated into a rising serum hemoglobin concentration.

Impact of transcatheter edge-to-edge mitral valve repair on central sleep apnoea.

AIMS: Sleep-disordered breathing (SDB) and its subtype central sleep apnoea (CSA) are highly prevalent in patients with heart failure and associated with worse prognosis. Whereas pharmacological therapy of heart failure has been shown to ameliorate CSA, results from previous studies on the effect of mitral regurgitation therapy on SDB are contradicting. The aim of this study was to assess the impact of transcatheter edge-to-edge mitral valve repair (TEER) on prevalence and severity of CSA. METHODS AND RESULTS: We enrolled 47 patients undergoing TEER for symptomatic mitral regurgitation in a prospective study. Secondary mitral regurgitation and left ventricular ejection fraction < 50% were present in 79% and 68% of patients, respectively. Respiratory polygraphy was performed before TEER in a compensated condition and four weeks after the procedure. 34 patients completed the follow-up. At baseline, 19 (56%) patients showed moderate-to-severe SDB, of whom 13 (68%) were classified as CSA. Both apnoea-hypopnoea index and percentage of recorded time spent in Cheyne-Stokes respiration strongly decreased from baseline to follow-up (median [IQR] 16 [7-30] vs. 7 [4-15] /h, p = 0.007; 6 [0-34] vs. 0 [0-8] %, p = 0.008). Median relative reduction of central apnoea index was 75% (p = 0.023), while obstructive apnoea index did not change significantly. Increase in stroke volume after TEER and high systolic pulmonary artery pressure at baseline predicted a > 50% reduction of both Apnoea-hypopnoea index and Cheyne-Stokes respiration. CONCLUSION: TEER is associated with a significant short-term reduction of CSA and Cheyne-Stokes respiration in high-risk patients, strengthening its value as an effective treatment option for advanced heart failure.

A Pilot Trial to Compare the Long-Term Efficacy of Pulmonary Vein Isolation with High-Power Short-Duration Radiofrequency Versus Laser Energy with Rapid Ablation Mode.

BACKGROUND: Pulmonary vein (PV) reconnection is the major cause of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). The probability of reconnection is higher if the primary lesion is not sufficiently effective, which can be unmasked with an adenosine provocation test (APT). High-power short-duration radiofrequency energy (HPSD) guided with ablation index (AI) and the third generation of the visually guided laser balloon (VGLB) are new methods for PVI. METHODS: A total of 70 participants (35 in each group) who underwent a PVI with either AI-guided HPSD (50 W; AI 500 for the anterior and 400 for the posterior wall, respectively) or VGLB ablation were included in this observational pilot trial. Twenty minutes after each PVI, an APT was performed. The primary endpoint was the event-free survival from AF after three years. RESULTS: A total of 137 (100%) PVs in the HPSD arm and 131 PVs (98.5%) in the VGLB arm were initially successfully isolated (p = 0.24). The overall procedure duration was similar in both arms (155 ± 39 in HPSD vs. 175 ± 58 min in VGLB, p = 0.191). Fluoroscopy time, left atrial dwelling time and duration from the first to the last ablation were longer in the VGLB arm (23 ± 8 vs. 12 ± 3 min, p < 0.001; 157 (111-185) vs. 134 (104-154) min, p = 0.049; 92(59-108) vs. 72 (43-85) min, p = 0.010). A total of 127 (93%) in the HPSD arm and 126 (95%) PVs in the VGLB arm remained isolated after APT (p = 0.34). The primary endpoint was met 1107 ± 68 days after ablation in 71% vs. 66% in the VGLB and HPSD arms, respectively (p = 0.65). CONCLUSIONS: HPSD and VGLB did not differ with respect to long-term outcome of PVI. A large, randomized study should be conducted to compare clinical outcomes with respect to these new ablation techniques.

Infective Endocarditis: Predictive Factors for Diagnosis and Mortality in Surgically Treated Patients.

Background: Diagnosis of infective endocarditis (IE) often is challenging, and mortality is high in such patients. Our goal was to characterize common diagnostic tools to enable a rapid and accurate diagnosis and to correlate these tools with mortality outcomes. Methods: Because of the possibility of including perioperative diagnostics, only surgically treated patients with suspected left-sided IE were included in this retrospective, monocentric study. A clinical committee confirmed the diagnosis of IE. Results: 201 consecutive patients (age 64 ± 13 years, 74% male) were finally diagnosed with IE, and 14 patients turned out IE-negative. Preoperative tests with the highest sensitivity for IE were positive blood cultures (89.0%) and transesophageal echocardiography (87.5%). In receiver operating characteristics, vegetation size revealed high predictive power for IE (AUC 0.800, p < 0.001) with an optimal cut-off value of 11.5 mm. Systemic embolism was associated with mortality, and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) had predictive power for mortality. Conclusion: If diagnostic standard tools remain inconclusive, we suggest employing novel cut-off values to increase diagnostic accuracy and accelerate diagnosis. Patients with embolism or elevated NT-proBNP deserve a closer follow-up.

Eplerenone prevents salt-induced vascular stiffness in Zucker diabetic fatty rats: a preliminary report.

BACKGROUND: Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet. METHODS: After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed. RESULTS: Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content. CONCLUSION: Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.

Echocardiographic Evaluation of LV Function in Patients with Tachyarrhythmia and Reduced Left Ventricular Function in Response to Rhythm Restoration.

AIMS: Tachyarrhythmia due to atrial fibrillation (AF) is often associated with reduced left ventricular (LV) function and has been proposed to cause arrhythmia-induced cardiomyopathy (AIC). However, the precise diagnostics of AIC and reversibility after rhythm restoration are poorly understood. Our aim was to investigate systolic LV function in tachycardic AF and to evaluate the direct effect of rhythm restoration. METHODS: We prospectively studied 24 patients (71% male, age 65 ± 9 years) with tachycardic AF and newly diagnosed reduced left ventricular ejection fraction (LVEF). Just before and immediately after electrical cardioversion (ECV), transthoracic echocardiography was performed. Geometric as well as functional data were assessed. RESULTS: Patients presented with a heart rate (HR) of 117.4 ± 21.6/min and a 2D-/3D-LVEF of 32 ± 9/31 ± 8%. ECV to sinus rhythm normalized HR to 77 ± 11/min with an increase of 2D-/3D-LVEF to 37 ± 9/37 ± 10% (p < 0.01 vs. baseline, each). Left ventricular geometry changed with an increase of end-diastolic volume (LVEDV) while end-systolic volume (LVESV) remained unchanged. Parameters concerning myocardial deformation (global longitudinal strain (GLS), strain rate (SR)) decreased whereas the RR interval-corrected GLS (GLSc) remained unchanged. In a simple linear regression model, GLS correlated with 2D- and 3D-LVEF not only before (pre) ECV, but also after (post) ECV. We demonstrate that the increase of LVEF and GLS (ratios pre/post) correlates with the change of HR (ΔHR; R2 = 0.20, 0.33 and 0.32, p < 0.05 each), whereas ratios of GLSc and SR do not significantly correlate with HR (R2 = 0.03 and 0.01, p = n.s. each). CONCLUSION: In patients with tachyarrhythmia and reduced ejection fraction, ECV leads to immediate improvement in EF and GLS while HR-corrected LV contractility remains unchanged. This suggests that the immediate effects of rhythm restoration are mostly related to changes in left ventricular volume, but not to an acute improvement of heart-rate independent contractility.

Acquired von Willebrand syndrome and factor VIII in patients with moderate to severe mitral regurgitation undergoing transcatheter mitral valve repair.

BACKGROUND AND HYPOTHESIS: The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR). METHODS AND RESULTS: 123 patients with moderate to severe MR were prospectively enrolled. Complete measurements of von Willebrand Factor activity (vWFAct), von Willebrand Factor antigen (vWFAg), and factor VIII expression before and 4 weeks after TMVR were available in 85 patients. At baseline, seven patients had a history of gastrointestinal bleeding, two patients suffered bleeding events during their hospital stay, and one patient had a bleeding 4 weeks after TMVR. Even though vWFAct, vWFAct/vWFAg ratio and vWFAg values did not change after TMVR, we observed a significantly lower vWFAct/vWFAg ratio in patients with primary MR as compared to patients with secondary MR both at baseline (p = 0.022) and 4 weeks following the TMVR procedure (p = 0.003). Additionally, patients with a mean mitral valve gradient ≥4 mmHg after TMVR had significantly lower vWFAct/vWFAg ratios as compared to patients with a mean mitral valve gradient <4 mmHg (p = 0.001). CONCLUSIONS: MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, morphological changes leading to postprocedural transmitral gradients ≥4 mmHg were related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Alterations of the vWFAct/vWFAg ratio in turn did not translate into a greater risk for bleeding events.

A novel mouse model of obstructive sleep apnea by bulking agent-induced tongue enlargement results in left ventricular contractile dysfunction.

AIMS: Obstructive sleep apnea (OSA) is a widespread disease with high global socio-economic impact. However, detailed pathomechanisms are still unclear, partly because current animal models of OSA do not simulate spontaneous airway obstruction. We tested whether polytetrafluoroethylene (PTFE) injection into the tongue induces spontaneous obstructive apneas. METHODS AND RESULTS: PTFE (100 µl) was injected into the tongue of 31 male C57BL/6 mice and 28 mice were used as control. Spontaneous apneas and inspiratory flow limitations were recorded by whole-body plethysmography and mRNA expression of the hypoxia marker KDM6A was quantified by qPCR. Left ventricular function was assessed by echocardiography and ventricular CaMKII expression was measured by Western blotting. After PTFE injection, mice showed features of OSA such as significantly increased tongue diameters that were associated with significantly and sustained increased frequencies of inspiratory flow limitations and apneas. Decreased KDM6A mRNA levels indicated chronic hypoxemia. 8 weeks after surgery, PTFE-treated mice showed a significantly reduced left ventricular ejection fraction. Moreover, the severity of diastolic dysfunction (measured as E/e') correlated significantly with the frequency of apneas. Accordingly, CaMKII expression was significantly increased in PTFE mice and correlated significantly with the frequency of apneas. CONCLUSIONS: We describe here the first mouse model of spontaneous inspiratory flow limitations, obstructive apneas, and hypoxia by tongue enlargement due to PTFE injection. These mice develop systolic and diastolic dysfunction and increased CaMKII expression. This mouse model offers great opportunities to investigate the effects of obstructive apneas.

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation.

BACKGROUND AND OBJECTIVES: MitraClip implantation is an established therapy for secondary mitral regurgitation (MR) in high-risk patients and has shown to improve several important outcome parameters such as functional capacity. Patient selection is both challenging and crucial for achieving therapeutic success. This study investigated baseline predictors of functional improvement as it was quantified by the six-minute walk distance (6MWD) after transcatheter mitral valve repair. METHODS AND RESULTS: We retrospectively analyzed 79 patients with secondary MR treated with MitraClip implantation at an academic tertiary care center. Before and four weeks after the procedure, all patients underwent comprehensive clinical assessment, six-minute walk tests and echocardiography. 6MWD significantly improved after MitraClip therapy (295 m vs. 265 m, p < 0.001). A linear regression model including seven clinical baseline variables significantly predicted the change in 6MWD (p = 0.002, R2 = 0.387). Female gender, diabetes mellitus and arterial hypertension were found to be significant negative predictors of 6MWD improvement. At baseline, female patients had significant higher left ventricular ejection fraction (49% vs. 42%, p = 0.019) and lower 6MWD (240 m vs. 288 m, p = 0.034) than male patients. CONCLUSION: MitraClip implantation in secondary MR significantly improves functional capacity in high-risk patients even in the short term of four weeks after the procedure. Female gender, diabetes mellitus and arterial hypertension are baseline predictors of a less favourable functional outcome. While further validation in a larger cohort is recommended, these parameters may improve patient selection for MitraClip therapy.

Glucocorticoid stimulation increases cardiac contractility by SGK1-dependent SOCE-activation in rat cardiac myocytes.

AIMS: Glucocorticoid (GC) stimulation has been shown to increase cardiac contractility by elevated intracellular [Ca] but the sources for Ca entry are unclear. This study aims to determine the role of store-operated Ca entry (SOCE) for GC-mediated inotropy. METHODS AND RESULTS: Dexamethasone (Dex) pretreatment significantly increased cardiac contractile force ex vivo in Langendorff-perfused Sprague-Dawley rat hearts (2 mg/kg BW i.p. Dex 24 h prior to experiment). Moreover, Ca transient amplitude as well as fractional shortening were significantly enhanced in Fura-2-loaded isolated rat ventricular myocytes exposed to Dex (1 mg/mL Dex, 24 h). Interestingly, these Dex-dependent effects could be abolished in the presence of SOCE-inhibitors SKF-96356 (SKF, 2 µM) and BTP2 (5 µM). Ca transient kinetics (time to peak, decay time) were not affected by SOCE stimulation. Direct SOCE measurements revealed a negligible magnitude in untreated myocytes but a dramatic increase in SOCE upon Dex-pretreatment. Importantly, the Dex-dependent stimulation of SOCE could be blocked by inhibition of serum and glucocorticoid-regulated kinase 1 (SGK1) using EMD638683 (EMD, 50 µM). Dex preincubation also resulted in increased mRNA expression of proteins involved in SOCE (stromal interaction molecule 2, STIM2, and transient receptor potential cation channels 3/6, TRPC 3/6), which were also prevented in the presence of EMD. CONCLUSION: Short-term GC-stimulation with Dex improves cardiac contractility by a SOCE-dependent mechanism, which appears to involve increased SGK1-dependent expression of the SOCE-related proteins. Since Ca transient kinetics were unaffected, SOCE appears to influence Ca cycling more by an integrated response across multiple cardiac cycles but not on a beat-to-beat basis.

Regulation of pulmonary vasoconstriction by agonists and caveolae.

Sustained pulmonary vasoconstriction contributes to the elevated pulmonary vascular resistance observed in pulmonary arterial hypertension. A rise in cytosolic Ca(2 +) in pulmonary artery smooth muscle cells (PASMCs) is major trigger for pulmonary vasoconstriction. One family of drugs currently being pursued as a potential treatment for pulmonary hypertension are the statins, which act by depleting cholesterol and reducing the number of caveolae. This study aimed at investigating the role of caveolae, membrane receptors, and ion channels (that are potentially located in the caveolae) in agonist-mediated pulmonary vasoconstriction in order to gain a greater understanding of the signaling mechanisms involved in the regulation of pulmonary vascular tone. Chronic treatment of PASMCs with the cholesterol-depleting agent, methyl-beta -cyclodextrin (Mbeta CD), significantly reduced the number of cholesterol rich caveolae regions in the membrane. This disruption of cholesterol in caveolae significantly inhibited pharmacomechanical (induced by phenylephrine), but not electromechanical (induced by elevated extracellular potassium concentration), rat pulmonary artery contraction. These results indicate that receptors may functionally colocalize in caveolae in PASMCs and coordinate to regulate pulmonary vascular tone.