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but more recent data have shown that a significant rate of in-hospital complications may be seen&#44; and that the short- and medium-term prognosis may be less favorable than previously thought&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Data from studies in Portugal&#44; including registries&#44; have certainly contributed to a better understanding of this condition&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;5</span></a> The initial results published from the International Takotsubo &#40;InterTAK&#41; Registry showed that more than half of the patients with TTS &#40;55&#46;8&#37;&#41; had a history or an acute episode of a neurologic or psychiatric disorder&#44; conditions that were evident in only 25&#46;7&#37; of patients with an acute coronary syndrome&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The spectrum of TTS was wide&#44; with low to very high risk in the acute phase&#46; The physical triggers and acute neurologic or psychiatric diseases were among the factors associated with an increased incidence of acute complications&#46; Also&#44; patients had substantial rates of death and complications after the acute phase&#46; Regarding medical therapy&#44; the use of angiotensin converting enzyme &#40;ACE&#41; inhibitors or angiotensin receptor blockers &#40;ARB&#41;&#44; but not of beta-blockers&#44; was associated with improved survival at one year&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Another observational&#44; retrospective study&#44; that evaluated the use of beta-blockers in the acute phase&#44; found neither a beneficial nor harmful association between early beta-blocker use and in-hospital mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In this edition of the Portuguese Journal of Cardiology&#44; Raposeiras-Roub&#237;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> present an interesting study which aims to assess the impact of beta-blocker therapy &#40;patients that have received beta-blockers at discharge&#41; in long-term mortality and TTS recurrence&#46; The cohort used was from the national Spanish Registry on TTS &#40;RETAKO Registry&#41;&#46; It is a partially retrospective and prospective &#40;since 2012&#41; observational study from 38 centers in Spain&#46; Considering the exclusion criteria&#44; 970 &#40;from 1095&#41; patients were included and divided into groups according to the types of preceding stressors &#40;emotional stress&#44; physical stress and no identifiable trigger&#41;&#59; the pattern of LV dysfunction was classified in apical and non-apical type&#46; The considered follow-up outcomes&#44; after hospital discharge&#44; were defined as the first non-fatal TTS recurrence or the occurrence of all-cause of death &#40;mean follow-up of 2&#46;5&#177;3&#46;3 years&#41;&#46; The main results were&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;a&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">60&#37; of the patients were treated with beta-blockers&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;b&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall">there were 87 deaths &#40;3&#46;6 per 100 patients&#47;year&#41; and 29 TTS recurrences &#40;1&#46;2 per 100 patients&#47;year&#41;&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#40;c&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">even after multivariate adjustment&#44; no significant differences in the composite outcome of mortality or TTS recurrence between patients treated and untreated with beta-blockers were found &#40;the same result in a propensity score analysis&#41;&#59;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#40;d&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">no benefit of beta-blockers in follow-up mortality and&#47;or TTS recurrence&#44; across all TTS types&#59;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#40;e&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall">regarding the trigger&#44; beta-blocker therapy was most frequently prescribed in the TTS group related to emotional stress&#44; but no significant differences in the follow-up outcomes were found&#59;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#40;f&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">in a subgroup analysis &#40;considering age&#44; gender&#44; coronary artery disease&#44; atrial fibrillation&#44; chronic obstructive pulmonary disease &#40;COPD&#41;&#44; Killip class&#44; cardiogenic shock&#44; ACE inhibitors&#47;ARB at discharge&#41; no benefit of beta-blockers was found in any subgroup&#44; with an increase in mortality and recurrence rates of TTS in COPD&#46;</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">The results presented by Raposeiras-Roub&#237;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> are in line with other earlier studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;6</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The several study limitations are addressed by the authors and consist of&#44; among others&#44; the heterogeneity of beta-blocker therapy &#40;dose and type&#41;&#44; and rates of discontinuation or new prescriptions during follow-up&#46; These data were not collected and might have affected the outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">There are very few studies that have evaluated the impact of the type of beta-blocker on clinical outcomes in TTS&#44; but beta-blockers that activate &#946;2 adrenoceptor &#40;to inhibitory G protein signaling&#41; may be deleterious&#44; as they might exacerbate the epinephrine-induced negative inotropic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Although there have been no randomized trials to define the optimal management in this syndrome&#44; beta-blockers are one of the most frequently prescribed therapies at discharge&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding this problematic&#44; studies like the one presented by Raposeiras-Roub&#237;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> also alert the clinician to the need for more investigation and trials&#44; for a better understanding of the pathophysiology and therapeutic management of TTS&#44; in order to use a more appropriate approach&#44; with possible implications for its course&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">TTS is heterogeneous&#44; not only with different clinical profiles&#44; triggers&#44; and anatomical shapes but also with different recovery times&#46; Another study from InterTAK Registry addresses this issue&#46; In-hospital outcomes and one-year mortality were compared for patients with versus without early recovery of LV wall motion abnormalities &#40;the cut off for early recovery was defined as 10 days after the acute event&#41;&#46; The authors found that 53&#37; of the patients presented late LV improvement&#46; The absence of an early recovery showed unfavorable one-year outcomes compared with an early recovery&#46; Male sex&#44; lower LV ejection fraction and acute neurologic disorders were among the factors associated with the absence of an early recovery&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Besides the issue of the therapeutic approach&#44; maybe we should ask a broader question&#58; how can we improve the management of such a complex entity&#63; We certainly still have some way to go&#46; One of the gaps is in the knowledge of the pathogenic mechanisms&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A recent position paper on pathophysiology of TTS mentioned that all the complex mechanisms and changes that can happen within the heart need to be integrated at a systems biology level&#44; with peripheral vasculature&#44; the brain&#44; and autonomic and peripheral nervous system&#46; Given this&#44; the recognition of key pathways in the heart&#44; vasculature and brain could be future targets for new treatments&#44; with possible diagnostic and therapeutic impact in TTS&#44; in the acute phase and subsequently&#46; A correct and earlier diagnosis may also be of relevance to the better management of this syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">More data from prospective studies&#44; randomized and controlled trials are warranted to better identify the mechanisms underlying this syndrome&#44; its treatment and follow-up&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">It is of special interest whether medical treatment influences the outcome&#44; especially after the acute phase&#46; This will also require a better understanding of this complex heart&#8211;brain duality in order to clarify the pathophysiology and&#44; consequently&#44; the therapy and prevention in this syndrome&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Takotsubo syndrome is as complex and challenging as it is fascinating&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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Takotsubo syndrome: We are still “halfway”. A complex heart-brain duality?
Síndrome de Takotsubo: ainda estamos a «meio do caminho» … Uma complexa dualidade coração-cérebro?
Catarina Ferreiraa,b,c
a Cardiology Department, Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal
b Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal
c Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal
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but more recent data have shown that a significant rate of in-hospital complications may be seen&#44; and that the short- and medium-term prognosis may be less favorable than previously thought&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Data from studies in Portugal&#44; including registries&#44; have certainly contributed to a better understanding of this condition&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;5</span></a> The initial results published from the International Takotsubo &#40;InterTAK&#41; Registry showed that more than half of the patients with TTS &#40;55&#46;8&#37;&#41; had a history or an acute episode of a neurologic or psychiatric disorder&#44; conditions that were evident in only 25&#46;7&#37; of patients with an acute coronary syndrome&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The spectrum of TTS was wide&#44; with low to very high risk in the acute phase&#46; The physical triggers and acute neurologic or psychiatric diseases were among the factors associated with an increased incidence of acute complications&#46; Also&#44; patients had substantial rates of death and complications after the acute phase&#46; Regarding medical therapy&#44; the use of angiotensin converting enzyme &#40;ACE&#41; inhibitors or angiotensin receptor blockers &#40;ARB&#41;&#44; but not of beta-blockers&#44; was associated with improved survival at one year&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Another observational&#44; retrospective study&#44; that evaluated the use of beta-blockers in the acute phase&#44; found neither a beneficial nor harmful association between early beta-blocker use and in-hospital mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In this edition of the Portuguese Journal of Cardiology&#44; Raposeiras-Roub&#237;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> present an interesting study which aims to assess the impact of beta-blocker therapy &#40;patients that have received beta-blockers at discharge&#41; in long-term mortality and TTS recurrence&#46; The cohort used was from the national Spanish Registry on TTS &#40;RETAKO Registry&#41;&#46; It is a partially retrospective and prospective &#40;since 2012&#41; observational study from 38 centers in Spain&#46; Considering the exclusion criteria&#44; 970 &#40;from 1095&#41; patients were included and divided into groups according to the types of preceding stressors &#40;emotional stress&#44; physical stress and no identifiable trigger&#41;&#59; the pattern of LV dysfunction was classified in apical and non-apical type&#46; The considered follow-up outcomes&#44; after hospital discharge&#44; were defined as the first non-fatal TTS recurrence or the occurrence of all-cause of death &#40;mean follow-up of 2&#46;5&#177;3&#46;3 years&#41;&#46; The main results were&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;a&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">60&#37; of the patients were treated with beta-blockers&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;b&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall">there were 87 deaths &#40;3&#46;6 per 100 patients&#47;year&#41; and 29 TTS recurrences &#40;1&#46;2 per 100 patients&#47;year&#41;&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#40;c&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">even after multivariate adjustment&#44; no significant differences in the composite outcome of mortality or TTS recurrence between patients treated and untreated with beta-blockers were found &#40;the same result in a propensity score analysis&#41;&#59;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#40;d&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">no benefit of beta-blockers in follow-up mortality and&#47;or TTS recurrence&#44; across all TTS types&#59;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#40;e&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall">regarding the trigger&#44; beta-blocker therapy was most frequently prescribed in the TTS group related to emotional stress&#44; but no significant differences in the follow-up outcomes were found&#59;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#40;f&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">in a subgroup analysis &#40;considering age&#44; gender&#44; coronary artery disease&#44; atrial fibrillation&#44; chronic obstructive pulmonary disease &#40;COPD&#41;&#44; Killip class&#44; cardiogenic shock&#44; ACE inhibitors&#47;ARB at discharge&#41; no benefit of beta-blockers was found in any subgroup&#44; with an increase in mortality and recurrence rates of TTS in COPD&#46;</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">The results presented by Raposeiras-Roub&#237;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> are in line with other earlier studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3&#44;6</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The several study limitations are addressed by the authors and consist of&#44; among others&#44; the heterogeneity of beta-blocker therapy &#40;dose and type&#41;&#44; and rates of discontinuation or new prescriptions during follow-up&#46; These data were not collected and might have affected the outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">There are very few studies that have evaluated the impact of the type of beta-blocker on clinical outcomes in TTS&#44; but beta-blockers that activate &#946;2 adrenoceptor &#40;to inhibitory G protein signaling&#41; may be deleterious&#44; as they might exacerbate the epinephrine-induced negative inotropic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Although there have been no randomized trials to define the optimal management in this syndrome&#44; beta-blockers are one of the most frequently prescribed therapies at discharge&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding this problematic&#44; studies like the one presented by Raposeiras-Roub&#237;n et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> also alert the clinician to the need for more investigation and trials&#44; for a better understanding of the pathophysiology and therapeutic management of TTS&#44; in order to use a more appropriate approach&#44; with possible implications for its course&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">TTS is heterogeneous&#44; not only with different clinical profiles&#44; triggers&#44; and anatomical shapes but also with different recovery times&#46; Another study from InterTAK Registry addresses this issue&#46; In-hospital outcomes and one-year mortality were compared for patients with versus without early recovery of LV wall motion abnormalities &#40;the cut off for early recovery was defined as 10 days after the acute event&#41;&#46; The authors found that 53&#37; of the patients presented late LV improvement&#46; The absence of an early recovery showed unfavorable one-year outcomes compared with an early recovery&#46; Male sex&#44; lower LV ejection fraction and acute neurologic disorders were among the factors associated with the absence of an early recovery&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Besides the issue of the therapeutic approach&#44; maybe we should ask a broader question&#58; how can we improve the management of such a complex entity&#63; We certainly still have some way to go&#46; One of the gaps is in the knowledge of the pathogenic mechanisms&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A recent position paper on pathophysiology of TTS mentioned that all the complex mechanisms and changes that can happen within the heart need to be integrated at a systems biology level&#44; with peripheral vasculature&#44; the brain&#44; and autonomic and peripheral nervous system&#46; Given this&#44; the recognition of key pathways in the heart&#44; vasculature and brain could be future targets for new treatments&#44; with possible diagnostic and therapeutic impact in TTS&#44; in the acute phase and subsequently&#46; A correct and earlier diagnosis may also be of relevance to the better management of this syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">More data from prospective studies&#44; randomized and controlled trials are warranted to better identify the mechanisms underlying this syndrome&#44; its treatment and follow-up&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">It is of special interest whether medical treatment influences the outcome&#44; especially after the acute phase&#46; This will also require a better understanding of this complex heart&#8211;brain duality in order to clarify the pathophysiology and&#44; consequently&#44; the therapy and prevention in this syndrome&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Takotsubo syndrome is as complex and challenging as it is fascinating&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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