Phasic left atrial strain to predict worsening of diastolic function: Results from the prospective Berlin Female Risk Evaluation follow-up trial

Purpose: The predictive value of maximum left atrial volume index (LAVI), phasic left atrial strain (LAS) and other standard echocardiographic parameters assessing left ventricular (LV) diastolic function to discriminate a future worsening of diastolic function (DD) in patients at risk is unclear. We aimed to prospectively assess and compare the clinical impact of these parameters in a randomly selected study sample of the general urban female population. Methods and results: A comprehensive clinical and echocardiographic evaluation was performed in 256 participants of the Berlin Female Risk Evaluation (BEFRI) trial after a mean follow up time of 6.8 years. After an assessment of participants' current DD status, the predictive impact of an impaired LAS on the course of DD was assessed and compared with LAVI and other DD parameters using receiver operating characteristic (ROC) curve and multivariate logistic regression analyses. Subjects with no DD (DD0) who showed a decline of diastolic function by the time of follow-up showed a reduced LA reservoir (LASr) and conduit strain (LAScd) compared to subjects who remained in the healthy range (LASr 28.0% +/- 7.0 vs. 41.9% +/- 8.5; LAScd -13.2% +/- 5.1 vs. -25.4% +/- 9.1; p < 0.001). With an area under the curve (AUC) of 0.88 (95%CI 0.82-0.94) and 0.84 (95%CI 0.79-0.89), LASr and LAScd exhibited the highest discriminative value in predicting worsening of diastolic function, whereas LAVI was only of limited prognostic value [AUC 0.63 (95%CI 0.54-0.73)]. In logistic regression analyses, LAS remained a significant predictor for a decline of diastolic function after controlling for clinical and standard echocardiographic DD parameters, indicating its incremental predictive value. Conclusion: The analysis of phasic LAS may be useful to predict worsening of LV diastolic function in DD0 patients at risk for a future DD development.GRAPHICAL ABSTRAC

Phasic left atrial strain to predict worsening of diastolic function: Results from the prospective Berlin Female Risk Evaluation follow-up trial

Purpose: The predictive value of maximum left atrial volume index (LAVI), phasic left atrial strain (LAS) and other standard echocardiographic parameters assessing left ventricular (LV) diastolic function to discriminate a future worsening of diastolic function (DD) in patients at risk is unclear. We aimed to prospectively assess and compare the clinical impact of these parameters in a randomly selected study sample of the general urban female population. Methods and results: A comprehensive clinical and echocardiographic evaluation was performed in 256 participants of the Berlin Female Risk Evaluation (BEFRI) trial after a mean follow up time of 6.8 years. After an assessment of participants’ current DD status, the predictive impact of an impaired LAS on the course of DD was assessed and compared with LAVI and other DD parameters using receiver operating characteristic (ROC) curve and multivariate logistic regression analyses. Subjects with no DD (DD0) who showed a decline of diastolic function by the time of follow-up showed a reduced LA reservoir (LASr) and conduit strain (LAScd) compared to subjects who remained in the healthy range (LASr 28.0% ± 7.0 vs. 41.9% ± 8.5; LAScd −13.2% ± 5.1 vs. −25.4% ± 9.1; p < 0.001). With an area under the curve (AUC) of 0.88 (95%CI 0.82–0.94) and 0.84 (95%CI 0.79–0.89), LASr and LAScd exhibited the highest discriminative value in predicting worsening of diastolic function, whereas LAVI was only of limited prognostic value [AUC 0.63 (95%CI 0.54–0.73)]. In logistic regression analyses, LAS remained a significant predictor for a decline of diastolic function after controlling for clinical and standard echocardiographic DD parameters, indicating its incremental predictive value. Conclusion: The analysis of phasic LAS may be useful to predict worsening of LV diastolic function in DD0 patients at risk for a future DD development. GRAPHICAL ABSTRAC

Impact of body mass index on worsening of diastolic function and impairment of left atrial strain in the general female urban population: a subanalysis of the Berlin female risk evaluation echocardiography follow-up study

Background: The association of body mass index (BMI) with diastolic dysfunction (DD) is well described in the literature. However, there is conflicting evidence and long-term follow-up data regarding effects of BMI on preclinical DD and left atrial (LA) function are scarce, highlighting the importance of early detection tools, such as myocardial strain. Purpose: The aim of our study was to prospectively analyze the impact of clinical and demographic parameters, especially of BMI, on worsening of diastolic function and left atrial strain (LAS) in an urban population of women with a low prevalence of cardiovascular risk factors. Methods and Results: An extensive clinical and echocardiographic assessment comprising the analysis of phasic LAS using two-dimensional speckle-tracking echocardiography (2D STE) was performed in 258 participants of the Berlin Female Risk Evaluation (BEFRI) trial between October 2019 and December 2020 after a mean follow-up period of 6.8 years. We compared clinical and echocardiographic parameters stratifying women by BMI < or ≥25 kg/m2, and we analyzed the impact of demographic characteristics on the worsening of DD and LA mechanics in the longer-term follow-up using univariate and multivariate regression analyses. 248 women were suitable for echocardiographic analysis of LAS using 2D STE. After a mean follow-up time of 6.8 years, LA reservoir strain (LASr) and LA conduit strain (LAScd) were significantly reduced in participants with a BMI ≥25 kg/m2 compared with women with a BMI <25 kg/m2 at baseline (30 ± 8% vs. 38 ± 9%, p < 0.0001; −14 ± 7% vs. −22 ± 8%, p < 0.0001). 28% of the overweighted women presented a deterioration of diastolic function at the time of follow-up in contrast with only 7% of the group with a BMI <25 kg/m2 (p < 0.0001). BMI remained significantly associated with LAS reductions after adjustment for other risk factors in multivariate regression analyses. Conclusion: Overweight and obesity are related to impaired LAS and to a worsening of diastolic function after a long-term follow-up in a cohort of randomly selected women

Impact of body mass index on worsening of diastolic function and impairment of left atrial strain in the general female urban population: a subanalysis of the Berlin female risk evaluation echocardiography follow-up study

BackgroundThe association of body mass index (BMI) with diastolic dysfunction (DD) is well described in the literature. However, there is conflicting evidence and long-term follow-up data regarding effects of BMI on preclinical DD and left atrial (LA) function are scarce, highlighting the importance of early detection tools, such as myocardial strain.PurposeThe aim of our study was to prospectively analyze the impact of clinical and demographic parameters, especially of BMI, on worsening of diastolic function and left atrial strain (LAS) in an urban population of women with a low prevalence of cardiovascular risk factors.Methods and ResultsAn extensive clinical and echocardiographic assessment comprising the analysis of phasic LAS using two-dimensional speckle-tracking echocardiography (2D STE) was performed in 258 participants of the Berlin Female Risk Evaluation (BEFRI) trial between October 2019 and December 2020 after a mean follow-up period of 6.8 years. We compared clinical and echocardiographic parameters stratifying women by BMI &lt; or ≥25 kg/m2, and we analyzed the impact of demographic characteristics on the worsening of DD and LA mechanics in the longer-term follow-up using univariate and multivariate regression analyses. 248 women were suitable for echocardiographic analysis of LAS using 2D STE. After a mean follow-up time of 6.8 years, LA reservoir strain (LASr) and LA conduit strain (LAScd) were significantly reduced in participants with a BMI ≥25 kg/m2 compared with women with a BMI &lt;25 kg/m2 at baseline (30 ± 8% vs. 38 ± 9%, p &lt; 0.0001; −14 ± 7% vs. −22 ± 8%, p &lt; 0.0001). 28% of the overweighted women presented a deterioration of diastolic function at the time of follow-up in contrast with only 7% of the group with a BMI &lt;25 kg/m2 (p &lt; 0.0001). BMI remained significantly associated with LAS reductions after adjustment for other risk factors in multivariate regression analyses.ConclusionOverweight and obesity are related to impaired LAS and to a worsening of diastolic function after a long-term follow-up in a cohort of randomly selected women

Effects of diadenosine heptaphosphate (Ap7A) and diadenosine octaphosphate (Ap8A) on regulation of vascular tone in isolated perfused rat kidney

Titel und Inhaltsverzeichnis 1. Einleitung 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Bedeutung der arteriellen Hypertonie / Gegenstand dieser Arbeit Folgeerkrankungen der arteriellen Hypertonie Definition / Epidemiologie der arteriellen Hypertonie Klinik der arteriellen Hypertonie Ätiologie der arteriellen Hypertonie Dinukleosidpolyphosphate / Purinrezeptoren Fragestellung 1 2 4 5 6 7 14 2. Material und Methoden 15 2.1 2.2 2.3 2.4 2.5 2.6 Präparationen zur Isolierung und Perfusion der Rattenniere Verwendete Chemikalien Das Nierenperfusionssystem Äquilibrierung des Systems und Überprüfung auf Funktionstüchtigkeit Durchführung der Nierenversuche Statistik 15 16 17 18 19 20 3. Ergebnisse 21 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Veränderungen des MPD bei Dauerperfusion mit Tyrodelösung, Suramin, PPADS, NF023, , -meATP, ATP S, MRS 2179, RB-2 und CPDPX Untersuchung der dosisabhängigen ED50 von Ang II, , -meATP, Ap7A und Ap8A Untersuchung der dosisabhängigen ED50 von Ap7A und AP8A unter Dauerperfusion mit Suramin, PPADS, , -meATP und NF023 Untersuchung der dosisabhängigen ED50 von Ap7A und Ap8A unter Dauerperfusion mit MRS 2179, RB-2 und ATP S Untersuchung der dosisabhängigen ED50 von Ap7A und Ap8A unter Dauerperfusion mit CPDPX Untersuchung der dosisabhängigen ED50 von Ang II unter Dauerperfusion mit , -meATP und Suramin Bestimmung der beteiligten Purin-Rezeptoren Desensitisierungsexperimente 21 21 23 25 27 29 30 31 4. Diskussion 32 5. Zusammenfassung 36 8. Literaturverzeichnis 37In menschlichen Thrombozyten sind kürzlich weitere neue Dinukleosidpolyphosphate, genauer Diadenosinpolyphosphate, entdeckt worden. Es handelt sich hierbei um Diadenosinheptaphosphat (Ap7A) und Diadenosinoctaphosphat (Ap8A). Wie auch andere Substanzen dieser Gruppe könnten sie eine bedeutende Rolle in der Regulation des Gefäßtonus und der Thrombozytenaggregation spielen. In der hier vorliegenden Arbeit sollten Ap7A und Ap8A auf eine mögliche Vasoaktivität am Modell der isolierten perfundierten Rattenniere untersucht und die korrespondierenden Rezeptoren bestimmt werden. Ap7A und Ap8A werden in vivo mit Hilfe der Thrombin- induzierten Thrombozytenaggregation aus Thrombozyten in den Extrazellulärraum freigesetzt. In unseren Experimenten konnten wir zeigen, daß Ap7A und Ap8A potente Vasokonstriktoren sind. Nach Applikation eines 10 nmol/l Bolus kam es unter Ap7A und Ap8A zu einem signifikanten Anstieg des Perfusionsdruckes. Bei Ap7A betrug dieser 74 mmHg ? 5 und bei AP8A 38 mmHg ? 3. Der vasokonstriktive Effekt konnte durch Suramin, PPADS und NF023 aufgehoben werden (je p < 0,05), was auf eine Aktivierung von P2X-Rezeptoren hindeutet. Unter Suramin ließ sich der Perfusionsdruckanstieg bei Ap7A auf 2 mmHg ? 1 und bei Ap8A auf 0 mmHg ? 1 senken. Unter PPADS minimierte sich der Perfusionsdruckanstieg bei Ap7A auf 3 mmHg ? 2 und bei Ap8A auf 4 mmHg ? 2. Auch unter kontinuierlicher Perfusion mit ?,?-meATP kam es zu einer vollständigen Inhibierung der Wirkung von Ap7A und Ap8A, was ebenfalls für eine P2X-Rezeptoraktivierung spricht. Die Substanz ist dafür bekannt, daß sie als P2X-Rezeptoragonist den P2X-Rezeptor für weitere Aktivierung blockiert (desensitisiert). Der Perfusionsdruckanstieg ließ sich unter ?,?-meATP bei AP7A und AP8A fast vollständig inhibieren. Außerdem konnten wir nachweisen, daß es unter Dauerperfusion mit MRS 2179, RB-2 und ATP?S im Vergleich zu den Versuchen mit Dauerperfusion von P2X- Rezeptoragonisten und -antagonisten zu keiner signifikanten Hemmung der kontraktilen Potenz von Ap7A und Ap8A kommt. Damit kommt ein P2Y- Rezeptorsubtyp, über den Ap7A und Ap8A ihre Wirkung vermitteln, nicht in Frage. Auch unter Dauerperfusion mit CPDPX konnte die vasokonstriktive Eigenschaft von Ap7A und Ap8A nicht signifikant unterdrückt werden, was damit gegen eine Aktivierung von P1-Rezeptoren spricht. Ap7A und Ap8A hemmen ferner die ADP-induzierte Plättchenaggregation. Mit den hier aufgeführten Daten bestätigt sich die Vermutung, dass Ap7A und Ap8A eine wichtige Rolle in der Regulation des Gefäßtonus und damit in der Pathogenese der essentiellen arteriellen Hypertonie wie auch der Hämostase spielen könnten.Recently, diadenosine heptaphosphate and diadenosine octaphosphate have been isolated in human platelets. With thrombin-induced platelet aggregation, Ap7A and Ap8A are released from the platelets into the extracellular space. Like other dinucleoside polyphosphates, maybe they play an important role in the control of vascular tone and platelet aggregation. Here we describe the effects on regulation of vascular tone of Ap7A and Ap8A in isolated perfused rat kidney. Our experiments demonstrate that Ap7A and Ap8A are potent vasoconstrictive substances. The vasoconstrictive action of Ap8A on the vasculature of the isolated perfused rat kidney was slightly less than that of Ap7A. The vasoconstrictive effect of Ap7A and Ap8A was abolished by ?,?-meATP and also suramin, NF023 and pyridoxal phosphate 6-azophenyl-2', 4'-disulfonic acid, suggesting an activation of P2x receptors. In contrast, the vasoconstrictive action was not abolished by ATP?S and MRS 2179, RB-2 and also CPDPX. Therefore an activation of P2y receptor or P1 receptor by Ap7A and Ap8A is improbable. Furthermore, Ap7A and Ap8A inhibit ADP-induced platelet aggregation. Thus, the potent vasoconstrictor Ap7A and Ap8A derived from human platelets, like other diadenosine polyphosphates, may play a role in the regulation of vascular tone and hemostasis

Usefulness of an implantable loop recorder to detect clinically relevant arrhythmias in patients with advanced fabry cardiomyopathy

Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder

Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant

Background: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. Methods: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/c.427G>A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. Results: p.A143T patients suffering from stroke/transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (similar to 50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. Conclusions: We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option