Recent hypotheses have suggested the pathophysiological role of catecholamines in the evolution of the Takotsubo syndrome (TTS). The extent of cardiac and circulatory compromise dictates the use of some form of supportive therapy. This study was designed to investigate the clinical outcomes associated with catecholamine use in TTS patients. Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The study-patients were subsequently classified into two groups based on the need for catecholamine support during hospital stay (catecholamine group n = 93; 81%, non-catecholamine group = 21; 19%). The primary end-point of our study was all-cause mortality. Patients receiving catecholamine support showed higher grades of circulatory and cardiac compromise (left ventricular ejection fraction (LVEF) 39.6% vs. 32.7%, p-value < 0.01) and the course of disease was often complicated by the occurrence of different TTS-associated complications. The in-hospital mortality (3.2% vs. 28.5%, p < 0.01), 30-day mortality (17.2% vs. 51.4%, p < 0.01) as well as long-term mortality (38.7% vs. 80.9%, p < 0.01) was significantly higher in the group of patients receiving catecholamine support. A multivariate Cox regression analysis attributed EF ≤ 35% (HR 3.6, 95% CI 1.6–8.1; p < 0.01) and use of positive inotropic agents (HR 2.2, 95% CI 1.0–4.8; p 0.04) as independent predictors of the adverse outcome. Rates of in-hospital events and short- as well as long-term mortality were significantly higher in TTS patients receiving catecholamine support as compared to the other study-patients. These results need further evaluation in pre-clinical and clinical trials to determine if external catecholamines contribute to an adverse clinical outcome already compromised by the initial insult.

The non-selective cation channel transient receptor potential vanilloid 1 (TRPV1) is expressed throughout the cardiovascular system. Recent evidence shows a role for TRPV1 in inflammatory processes. The role of TRPV1 for myocardial inflammation has not been established yet. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (hiPSC-CM) from 4 healthy donors were incubated with lipopolysaccharides (LPS, 6 h), TRPV1 agonist capsaicin (CAP, 20 min) or the antagonist capsazepine (CPZ, 20 min). TRPV1 expression was studied by PCR and western blotting. TRPV1 internalization was analyzed by immunofluorescence. Interleukin-6 (IL-6) secretion and phosphorylation of JNK, p38 and ERK were determined by ELISA. TRPV1-associated ion channel current was measured by patch clamp. TRPV1-mRNA and -protein were expressed in hiPSC-CM. TRPV1 was localized in the plasma membrane. LPS significantly increased secretion of IL-6 by 2.3-fold, which was prevented by pre-incubation with CPZ. LPS induced TRPV1 internalization. Phosphorylation levels of ERK, p38 or JNK were not altered by TRPV1 stimulation or inhibition. LPS and IL-6 significantly lowered TRPV1-mediated ion channel current. TRPV1 mediates the LPS-induced inflammation in cardiomyocytes, associated with changes of cellular electrophysiology. LPS-induced inflammation results in TRPV1 internalization. Further studies have to examine the underlying pathways and the clinical relevance of these findings.

Rationale: PCSK9 (proprotein convertase subtilisin/kexin type 9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and HDL (high-density lipoprotein) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance spectroscopy and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck study (n=656) revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein C3 (apoC3), an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk; n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 time points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apoC3 from HDL, and lower levels of small HDL as measured by nuclear magnetic resonance spectroscopy. Crosslinking mass spectrometry upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin, and apolipoprotein E within the HDL proteome that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalization and multimerization. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipemia as a driver of PCSK9 and apoC3 release from HDL. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03191513; URL: https://www.isrctn.com ; Unique identifier: ISRCTN20774126.

The pathophysiology of takotsubo syndrome (TTS) is unclear so far. There is strong association of the occurrence of TTS and malignant diseases. An association between malignant diseases and myocardial infarction (MI) was found recently and ascribed to common molecular and lifestyle mechanisms. To compare the outcome of patients with MI or TTS and malignant diseases in a matched cohort. Patients with TTS or with MI (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively. Occurrence of malignant diseases and clinical outcome was followed up over 4 years. At the time of the index event, 8 (5.8%) MI patients and 17 (12.3%) TTS patients were already diagnosed with cancer. During follow up, the rate of patients who developed cancer was significantly higher in the TTS group than in the MI group (log rank P = 0.01). Mortality was higher in the TTS group, but also in the subgroup of TTS patients with cancer (log rank P < 0.05). In the multivariate analysis, male gender, renal impairment and the history of cancer was associated with an increased risk for death. Patients with TTS have more often malignant diseases than patients with MI. Cancer patients with TTS have a worse clinical outcome. The underlying mechanism is unclear yet, but the results point at TTS being the syndrome of an extracardiac disease rather than a disease of cardiac origin. Longer and closer follow up of patients with TTS and further studies addressing the mechanism of TTS are needed.

Background: Left atrial appendage closure (LAAC) represents the interventional alternative to oral anticoagulation for stroke prevention in atrial fibrillation (AF). The metabolism of acylcarnitines was shown to affect cardiovascular diseases. This study evaluates the influence of successful LAAC on the metabolism of acylcarnitines. Methods: Patients undergoing successful LAAC were enrolled prospectively. Peripheral blood samples for metabolomics measurements were collected immediately before (i.e., index) and six months after LAAC (i.e., mid-term). A targeted metabolomics analysis based on electrospray ionization–liquid chromatography–mass spectrometry (ESI–LC–MS/MS) and MS/MS measurements was performed. Results: 44 patients with non-valvular AF (median CHA₂DS₂-VASc score 4, median HAS-BLED score 4) and successful LAAC were included. Significant changes in acylcarnitine levels were found in the total cohort, which were mainly attributed to patients with impaired left ventricular and renal function, elevated amino-terminal pro-brain natriuretic peptide (NT-proBNP) and diabetes mellitus. Adjusted multivariable regression models revealed significant changes of five metabolites over mid-term follow-up: C2, C14:1, C16, and C18:1 decreased significantly (each p < 0.05); short-chain C5 acylcarnitine plasma levels increased significantly (p < 0.05). Conclusion: This study demonstrates that successful LAAC affects the metabolism of acylcarnitines at mid-term follow-up. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02985463.