Trigger-Associated Clinical Implications and Outcomes in Takotsubo Syndrome: Results From the Multicenter GEIST Registry.

Background Takotsubo syndrome is usually triggered by a stressful event. The type of trigger seems to influence the outcome and should therefore be considered separately. Methods and Results Patients included in the GEIST (German-Italian-Spanish Takotsubo) registry were categorized according to physical trigger (PT), emotional trigger (ET), and no trigger (NT) of Takotsubo syndrome. Clinical characteristics as well as outcome predictors were analyzed. Overall, 2482 patients were included. ET was detected in 910 patients (36.7%), PT in 885 patients (34.4%), and NT was observed in 717 patients (28.9%). Compared with patients with PT or NT, patients with ET were younger, less frequently men, and had a lower prevalence of comorbidities. Adverse in-hospital events (NT: 18.8% versus PT: 27.1% versus ET: 12.1%, P<0.001) and long-term mortality rates (NT: 14.4% versus PT: 21.6% versus ET: 8.5%, P<0.001) were significantly lower in patients with ET. Increasing age (P<0.001), male sex (P=0.007), diabetes (P<0.001), malignancy (P=0.002), and a neurological disorder (P<0.001) were associated with a higher risk of long-term mortality, while chest pain (P=0.035) and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P=0.027) were confirmed as independent predictors for a lower risk of long-term mortality. Conclusions Patients with ET have better clinical conditions and a lower mortality rate. Increasing age, male sex, malignancy, a neurological disorder, chest pain, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and diabetes were confirmed as predictors of long-term mortality.

Hemodynamic Assessment in Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome (TTS) is a reversible form of heart failure with incompletely understood pathophysiology. OBJECTIVES: This study analyzed altered cardiac hemodynamics during TTS to elucidate underlying disease mechanisms. METHODS: Left ventricular (LV) pressure-volume loops were recorded in 24 consecutive patients with TTS and a control population of 20 participants without cardiovascular diseases. RESULTS: TTS was associated with impaired LV contractility (end-systolic elastance 1.74 mm Hg/mL vs 2.35 mm Hg/mL [P = 0.024]; maximal rate of change in systolic pressure over time 1,533 mm Hg/s vs 1,763 mm Hg/s [P = 0.031]; end-systolic volume at a pressure of 150 mm Hg, 77.3 mL vs 46.4 mL [P = 0.002]); and a shortened systolic period (286 ms vs 343 ms [P < 0.001]). In response, the pressure-volume diagram was shifted rightward with significantly increased LV end-diastolic (P = 0.031) and end-systolic (P < 0.001) volumes, which preserved LV stroke volume (P = 0.370) despite a lower LV ejection fraction (P < 0.001). Diastolic function was characterized by prolonged active relaxation (relaxation constant 69.5 ms vs 45.9 ms [P < 0.001]; minimal rate of change in diastolic pressure -1,457 mm Hg/s vs -2,192 mm Hg/s [P < 0.001]), whereas diastolic stiffness (1/compliance) was not affected during TTS (end-diastolic volume at a pressure of 15 mm Hg, 96.7 mL vs 109.0 mL [P = 0.942]). Mechanical efficiency was significantly reduced in TTS (P < 0.001) considering reduced stroke work (P = 0.001), increased potential energy (P = 0.036), and a similar total pressure-volume area compared with that of control subjects (P = 0.357). CONCLUSIONS: TTS is characterized by reduced cardiac contractility, a shortened systolic period, inefficient energetics, and prolonged active relaxation but unaltered diastolic passive stiffness. These findings may suggest decreased phosphorylation of myofilament proteins, which represents a potential therapeutic target in TTS. (Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops [OCTOPUS]; NCT03726528).

Happy Heart Syndrome: Frequency, Characteristics, and Outcome of Takotsubo Syndrome Triggered by Positive Life Events.

BACKGROUND: The association with a preceding stressor is a characteristic feature of takotsubo syndrome (TTS). Negative emotions before TTS are common and led to the popular term "broken heart syndrome." In contrast, pleasant triggers ("happy heart syndrome") are rare and are scarcely investigated. OBJECTIVES: The authors analyzed the frequency, clinical characteristics, and prognostic implications of positive emotional stressors in the multicenter GEIST (GErman-Italian-Spanish Takotsubo) Registry. METHODS: Patients enrolled in the registry were categorized according to their stressors. This analysis compared patients with pleasant emotional events with patients with negative emotional events. RESULTS: Of 2,482 patients in the registry, 910 patients (36.7%) exhibited an emotional trigger consisting of 873 "broken hearts" (95.9%) and 37 "happy hearts" (4.1%). Consequently, the prevalence of pleasant emotional triggers was 1.5% of all TTS cases. Compared with patients with TTS with negative preceding events, patients with happy heart syndrome were more frequently male (18.9% vs 5.0%; P < 0.01) and had a higher prevalence of atypical ballooning patterns (27.0% vs 12.5%; P = 0.01), particularly midventricular ballooning. In-hospital complications, including death, pulmonary edema, cardiogenic shock, or stroke (8.1% vs 12.3%; P = 0.45), and long-term mortality rates (2.7% vs 8.8%; P = 0.20) were similar in "happy hearts" and "broken hearts." CONCLUSIONS: Happy heart syndrome is a rare type of TTS characterized by a higher prevalence of male patients and atypical, nonapical ballooning compared with patients with negative emotional stressors. Despite similar short- and long-term outcomes in our study, additional data are needed to explore whether numerically lower event rates in "happy hearts" would be statistically significant in a larger sample size. (GErman-Italian-Spanish Takotsubo Registry [GEIST Registry]; NCT04361994).

[Atrial fibrillation-Syndromic phenotype in HFpEF or primary disease?] / Vorhofflimmern ­ syndromaler Phänotyp bei HFpEF oder primäre Erkrankung?

Atrial fibrillation and heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) are of high importance in cardiology due to the increasing number of cases. Both diseases can mutually affect each other and important cardiovascular risk factors, e.g. arterial hypertension, diabetes mellitus, obesity and chronic renal insufficiency can be observed with increasing frequency. Currently proven treatment concepts for patients with heart failure and reduced ejection fraction (HFrEF) do not appear to have a comparable prognostic or symptomatic benefit for patients with HFpEF. In addition, there are indications that de novo manifestation of atrial fibrillation in HFpEF patients has been linked to reduced survival. Also, heart and kidney function are negatively affected by atrial fibrillation. Retrospective analyses of patients with HFpEF and atrial fibrillation who had been treated by pulmonary vein isolation could show that interventional treatment of the atrial fibrillation led to an improvement in the New York Heart Association (NYHA) stage and diastolic function. Currently running prospective randomized clinical trials, such as the AMPERE study including patients with HFpEF and atrial fibrillation undergoing pulmonary vein isolation, will hopefully provide reliable prospective randomized data and possibly show an improved symptom control and perhaps also prognostically relevant treatment for HFpEF patients with atrial fibrillation.

The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets.

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1-/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.

Distinct pressure half-time values by transthoracic echocardiography for grading of paravalvular regurgitation after transcatheter aortic valve replacement.

Postprocedural aortic regurgitation (AR) has negative impact on patient outcome after transcatheter aortic valve replacement (TAVR). Standard assessment of AR severity by echocardiography is hampered after TAVR. Measurement of pressure half-time (PHT) by echocardiography is not limited in these patients but it may be affected by concomitant left ventricular hypertrophy (LVH). This study sought to evaluate distinct cut-off values of PHT differentiating between patients without and with more than mild LVH for grading of AR after TAVR with cardiac magnetic resonance (CMR) as the reference method for comparison. 71 patients (age 81 ± 6 years) with severe aortic stenosis undergoing TAVR were included into the study. Transthoracic echocardiography (TTE) and CMR were performed after TAVR. Left ventricular mass index was calculated by TTE. PHT was measured by continuous-wave Doppler echocardiography of aortic regurgitation jet. In 18 patients (25%) PHT could not be obtained due to no or very faint Doppler signal. Aortic regurgitant volume and regurgitant fraction were calculated by CMR by flow analysis of the ascending aorta. In 14 of 53 patients (26%) AR after TAVR was moderate or severe as categorized by CMR analysis. More than mild LVH was present in 27 of 53 patients (51%). PHT correlated inversely less to regurgitant fraction by CMR analysis in patients with LVH (r = -0.293; p = 0.138) than in patients without LVH (r = -0.455; p = 0.020). In patients without relevant LVH accuracy of PHT to predict moderate or severe paravalvular regurgitation AUC was 0.813 using a cut-off value of 347 ms and AUC was 0.729 in patients with more than mild LVH using a cut-off value of 420 ms. Analysis of PHT by TTE with distinct cut-off values for patients without and with more than mild LVH allows detection of moderate or severe AR after TAVR as defined by CMR. In none of the patients in which PHT could not be measured AR was categorized as more than trace by CMR analysis.

Conventional echocardiographic parameters or three-dimensional echocardiography to evaluate right ventricular function in percutaneous edge-to-edge mitral valve repair (PMVR).

INTRODUCTION: In this study, we evaluated right ventricular (RV) function before and after percutaneous mitral valve repair (PMVR) using conventional echocardiographic parameters and novel 3DE data sets acquired prior to and directly after the procedure. PATIENTS AND METHODS: Observational study on 45 patients undergoing PMVR at an university hospital. RESULTS: In the overall collective, the 3D RV-EF before and after PMVR showed no significant change (p = 0.16). While there was a significant increase of the fractional area change (FAC, from 23 [19-29] % to 28 [24-33] %, p = 0.001), no significant change of the tricuspid annular plane systolic excursion (TAPSE, from 17 ±â€¯6 mm to 18 ±â€¯5 mm (standard deviation), p = 0.33) was observed. Regarding patients with a reduced RV-EF (< 35%), a significant RV-EF improvement was observed (from 27 [23-34] % to 32.5 [30-39] % (p = 0.001). 71.4% of patients had an improved clinical outcome (improvement in 6-minute walk test and/or improvement in NYHA class of more than one grade), whereas clinical outcome did not improve in 28.6% of patients. Using univariate logistic regression analysis, the post-PMVR RV-EF (OR 1.15: 95% CI 1.02-1.29; p = 0.02) and the change in RV-EF (OR 1.13: 95% CI 1.02-1.25; p = 0.02) were significant predictors for improved clinical outcome at 6 months follow up. CONCLUSION: Thus, RV function may be an important non-invasive parameter to add to the predictive parameters indicating a potential clinical benefit from treatment of severe mitral regurgitation using PMVR.

Platelets and Immune Responses During Thromboinflammation.

Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases. FXII of the intrinsic pathway connects platelet activation with the coagulation cascade during immune reactions. It can activate the contact system thereby either creating an inflammatory state or accelerating inflammation. Recent insights into platelet biology could show that platelets are equipped with complement receptors. Platelets are important for tissue remodeling after injury has been inflicted to the endothelial barrier and to the subendothelial tissue. Thus, platelets are increasingly recognized as more than just cells relevant for bleeding arrest. Future insights into platelet biology are to be expected. This research will potentially offer novel opportunities for therapeutic intervention in diseases featuring platelet abundance.

Elevated Mitral Valve Pressure Gradient Is Predictive of Long-Term Outcome After Percutaneous Edge-to-Edge Mitral Valve Repair in Patients With Degenerative Mitral Regurgitation ( MR ), But Not in Functional MR.

Background This study analyzed the effects on long-term outcome of residual mitral regurgitation ( MR ) and mean mitral valve pressure gradient ( MVPG ) after percutaneous edge-to-edge mitral valve repair using the MitraClip system. Methods and Results Two hundred fifty-five patients who underwent percutaneous edge-to-edge mitral valve repair were analyzed. Kaplan-Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome. A combined clinical end point (all-cause mortality, MV surgery, redo procedure, implantation of a left ventricular assist device) was used. After percutaneous edge-to-edge mitral valve repair, mean MVPG increased from 1.6±1.0 to 3.1±1.5 mm Hg ( P<0.001). Reduction of MR severity to ≤2+ postintervention was achieved in 98.4% of all patients. In the overall patient cohort, residual MR was predictive of the combined end point while elevated MVPG >4.4 mm Hg was not according to Kaplan-Meier and Cox regression analyses. We then analyzed the cohort with degenerative and that with functional MR separately to account for these different entities. In the cohort with degenerative MR , elevated MVPG was associated with increased occurrence of the primary end point, whereas this was not observed in the cohort with functional MR . Conclusions MVPG >4.4 mm Hg after MitraClip implantation was predictive of clinical outcome in the patient cohort with degenerative MR . In the patient cohort with functional MR , MVPG >4.4 mm Hg was not associated with increased clinical events.