Takotsubo syndrome in New Zealand: current knowledge and future challenges.

Takotsubo syndrome (TS), also known as apical ballooning syndrome, is a transient stress-related cardiomyopathy characterised by acute but reversible left ventricular dysfunction. The condition tends to occur in postmenopausal women after a stressful event. At presentation, TS typically mimics acute myocardial infarction (MI) and the incidence of TS has been increasing worldwide. This is likely a consequence of an improved awareness of the existence of this syndrome and easier access to early echocardiography and coronary angiography. However, its aetiology remains poorly understood and it is probably still underdiagnosed. Similar to other countries, TS is being increasingly recognised in New Zealand. In this review, we discuss the demographics, clinical features and outcomes of patients with TS in New Zealand. Doing so informs us not only of the pattern of disease in New Zealand but it also provides insights into the condition itself.

Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome: Insights From the International Takotsubo Registry.

OBJECTIVE: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0-38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×103 cells/µL emerged as independent predictors for thrombus formation or embolism. CONCLUSIONS: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.

The effects of beta-blockers in patients with stress cardiomyopathy.

Beta-blockers are often used in the treatment of patients with stress cardiomyopathy without firm evidence of benefit. We conducted a retrospective case note review investigating the effects of beta-blockers on QT interval and heart rate in patients with stress cardiomyopathy over 3 days of hospital admission. We found no evidence of effects on QT interval from beta-blocker treatment in this condition.

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. METHODS AND RESULTS: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. CONCLUSIONS: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01947621.

The fifth takotsubo variant.

We document the fifth pattern of takotsubo cardiomyopathy, in which the mid-LV is hyperdynamic but the apex and base are akinetic or hypokinetic. This is a reverse mid-ventricular takotsubo. The patient is a 79-year-old woman admitted with chest pain and initially a normal EKG. Her troponin I rose to 5.4 µg/L (0.02-0.03 µg/L) and she developed QT prolongation and widespread T-wave inversion. Coronary angiography showed only very mild atheroma. Follow-up echocardiogram six weeks later showed normal left ventricular function.

Nonmuscle myosin II is a critical regulator of clathrin-mediated endocytosis.

Variable requirements for actin during clathrin-mediated endocytosis (CME) may be related to regional or cellular differences in membrane tension. To compensate, local regulation of force generation may be needed to facilitate membrane curving and vesicle budding. Force generation is assumed to occur primarily through actin polymerization. Here we examine the role of myosin II using loss of function experiments. Our results indicate that myosin II acts on cortical actin scaffolds primarily in the plane of the plasma membrane (bottom arrow) to generate changes that are critical for enhancing CME progression.

Frailty in acute cardiology: comparison of a quick clinical assessment against a validated frailty assessment tool.

BACKGROUND: Increasingly frail patients are being to be referred for invasive cardiac interventions and cardiac surgery. We aimed to evaluate the utility of a quick clinical assessment of frailty against a validated frailty assessment tool in an acute cardiology setting. METHODS: Forty-seven cardiology in-patients ≥70 years were recruited in this prospective study. All patients were first assessed by a senior cardiology registrar as either not-frail or frail. This was based on general observation and brief discussions. Following this, patients were administered the Reported Edmonton Frail Scale (REFS) questionnaire. After a registrar assessment, the foot-of-the bed frailty assessment was independently repeated by one or two consultant cardiologists. RESULTS: None of the three clinicians showed satisfactory similarity to the REFS score. When the two consultants were compared with the registrar, and with each other, the Cohen's kappa was only above 0.7 for the comparison between Consultant 1 and the registrar. Consultant 1 and the registrar were also significantly more likely to disagree at higher REFS score with a mean REFS score of 8.8. CONCLUSION: A quick foot-of-the-bed clinical assessment is not a reliable way to determine frailty.

Myosin II regulates activity dependent compensatory endocytosis at central synapses.

Recent evidence suggests that endocytosis, not exocytosis, can be rate limiting for neurotransmitter release at excitatory CNS synapses during sustained activity and therefore may be a principal determinant of synaptic fatigue. At low stimulation frequencies, the probability of synaptic release is linked to the probability of synaptic retrieval such that evoked release results in proportional retrieval even for release of single synaptic vesicles. The exact mechanism by which the retrieval rates are coupled to release rates, known as compensatory endocytosis, remains unknown. Here we show that inactivation of presynaptic myosin II (MII) decreases the probability of synaptic retrieval. To be able to differentiate between the presynaptic and postsynaptic functions of MII, we developed a live cell substrate patterning technique to create defined neural circuits composed of small numbers of embryonic mouse hippocampal neurons and physically isolated from the surrounding culture. Acute application of blebbistatin to inactivate MII in circuits strongly inhibited evoked release but not spontaneous release. In circuits incorporating both control and MIIB knock-out cells, loss of presynaptic MIIB function correlated with a large decrease in the amplitude of evoked release. Using activity-dependent markers FM1-43 and horseradish peroxidase, we found that MII inactivation greatly slowed vesicular replenishment of the recycling pool but did not impede synaptic release. These results indicate that MII-driven tension or actin dynamics regulate the major pathway for synaptic vesicle retrieval. Changes in retrieval rates determine the size of the recycling pool. The resulting effect on release rates, in turn, brings about changes in synaptic strength.

A case of recurrent earthquake stress cardiomyopathy with a differing wall motion abnormality.

We present the case of a Caucasian woman who survived two major earthquakes, presenting on each occasion with stress cardiomyopathy, but with a different pattern of regional wall motion abnormality on the second occasion. The first Christchurch earthquake struck on September 4, 2010. At 7.1 on the Richter scale, it was larger than the major Haiti quake, but miraculously there were no direct fatalities. In the week following, eight women meeting modified Mayo criteria for stress cardiomyopathy presented to Christchurch Hospital. The second Christchurch earthquake was on February 22, 2011. It measured 6.4 on the Richter scale and caused 180 direct fatalities. In the week following this earthquake, 24 women were admitted with stress cardiomyopathy. One patient presented after both earthquakes. This 76-year-old woman first presented on September 4 with 10 hours of chest pain. Electrocardiogram showed inferolateral deep T-wave inversion and QT prolongation. TnI peaked at 0.81 µg/L. Coronary angiography demonstrated diffuse atheroma with a moderate mid LAD lesion that was stented at the time. Echocardiography showed a classic takotsubo pattern. Her follow-up echocardiogram on September 28 was normal and she was completely well at that point. However, during the second earthquake of February 22, she again developed chest pain and shortness of breath. TnI peaked at 1.3 µg/L. Echocardiogram showed a midwall variant takotsubo with apical sparing. She was discharged from hospital on the 25th, planning to leave Christchurch for a new home in another city, but returned for follow-up echocardiogram on July 27. This was normal.

Successful management of a large air embolus during an extended right hepatectomy with an emergency cardiopulmonary bypass.

BACKGROUND: An air embolus is a recognized but rare complication of a partial hepatectomy. The aim of this report was to describe the diagnosis and management of a large paradoxical air embolus during hepatic resection. METHODS: Case report. RESULTS: A single patient report of a massive paradoxical air embolus during an extended right hepatectomy is described. The diagnosis was confirmed by trans-oesophageal echo (video provided). After failed conservative management an emergency cardiopulmonary bypass was instituted with a successful outcome. CONCLUSION: Surgeons and anaesthetists involved in hepatic surgery should be aware of signs, investigations and management of this life-threatening intra-operative complication.

A randomised cross-over trial of QT response to hyperventilation-induced anxiety and diaphragmatic breathing in patients with stress cardiomyopathy and in control patients.

OBJECTIVES: The most perfect example of the mind-body interaction in all of medicine is provided by stress cardiomyopathy. In stress cardiomyopathy, what is initially a purely emotional event may become rapidly fatal. Prolongation of the QT interval is a cardinal feature of the condition, but the mechanism of the prolongation is unknown. We undertook a randomised controlled trial of stress with a cross-over design, comparing the cardiac response of women with a history of stress cardiomyopathy to age-matched controls to explore the mind-body interaction. Our hypothesis is that the hearts of women with a history of stress cardiomyopathy will respond differently to emotional stress than those of the controls. METHOD: This is a randomised cross-over study. Each patient underwent two separate 24-hour Holter monitors performed at least 5 days apart. Baseline recording was followed by either the stress intervention (hyperventilation) or control (diaphragmatic breathing). Our primary endpoint is change in QTc interval over the first hour. Secondary endpoints were change in QTc over 24 hours, and change in SDNN, a measure of heart rate variability. As a secondary stressor, each participant was telephoned four times during their stressed recording and asked to complete a questionnaire. RESULTS: Twelve stress cardiomyopathy patients and twelve control patients were recruited. Baseline characteristics did not differ between cases and controls. With hyperventilation, there was a significant initial difference in anxiety (p<0.001), heart rate response (p<0.0001), and QTc (p<0.0002) compared to diaphragmatic breathing, but no differences between the cases and controls. Only first phone call caused an increase in QTc in cases and controls (p = 0.0098). SDNN increased with hyperventilation (p<0.0001) but did not differ between cases and controls. CONCLUSIONS: QTc response in women with a history of stress cardiomyopathy does not differ from controls. The relevance of QT prolongation and sensitivity in the autonomic response to the pathogenesis of stress cardiomyopathy remains uncertain.

Impact of Atrial Fibrillation on Outcome in Takotsubo Syndrome: Data From the International Takotsubo Registry.

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (P<0.001), and there were fewer women (P=0.046) in the AF than in the non-AF group. Left ventricular ejection fraction was significantly lower (P=0.001), and cardiogenic shock was more often observed (P<0.001) in the AF group. Both in-hospital (P<0.001) and long-term mortality (P<0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long-term mortality (hazard ratio, 2.31; 95% CI, 1.50-3.55; P<0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in-hospital and long-term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in-hospital and long-term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01947621.

Yeast actin patches are networks of branched actin filaments.

Cortical actin patches are the most prominent actin structure in budding and fission yeast. Patches assemble, move, and disassemble rapidly. We investigated the mechanisms underlying patch actin assembly and motility by studying actin filament ultrastructure within a patch. Actin patches were partially purified from Saccharomyces cerevisiae and examined by negative-stain electron microscopy (EM). To identify patches in the EM, we correlated fluorescence and EM images of GFP-labeled patches. Patches contained a network of actin filaments with branches characteristic of Arp2/3 complex. An average patch contained 85 filaments. The average filament was only 50-nm (20 actin subunits) long, and the filament to branch ratio was 3:1. Patches lacking Sac6/fimbrin were unstable, and patches lacking capping protein were relatively normal. Our results are consistent with Arp2/3 complex-mediated actin polymerization driving yeast actin patch assembly and motility, as described by a variation of the dendritic nucleation model.

Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density.

The identification of molecular motors that modulate the neuronal cytoskeleton has been elusive. Here, we show that a molecular motor protein, myosin Va, is present in high proportions in the cytoskeleton of mouse CNS and peripheral nerves. Immunoelectron microscopy, coimmunoprecipitation, and blot overlay analyses demonstrate that myosin Va in axons associates with neurofilaments, and that the NF-L subunit is its major ligand. A physiological association is indicated by observations that the level of myosin Va is reduced in axons of NF-L-null mice lacking neurofilaments and increased in mice overexpressing NF-L, but unchanged in NF-H-null mice. In vivo pulse-labeled myosin Va advances along axons at slow transport rates overlapping with those of neurofilament proteins and actin, both of which coimmunoprecipitate with myosin Va. Eliminating neurofilaments from mice selectively accelerates myosin Va translocation and redistributes myosin Va to the actin-rich subaxolemma and membranous organelles. Finally, peripheral axons of dilute-lethal mice, lacking functional myosin Va, display selectively increased neurofilament number and levels of neurofilament proteins without altering axon caliber. These results identify myosin Va as a neurofilament-associated protein, and show that this association is essential to establish the normal distribution, axonal transport, and content of myosin Va, and the proper numbers of neurofilaments in axons.

Laminin stimulates and guides axonal outgrowth via growth cone myosin II activity.

Guidance cues and signal transduction mechanisms acting at the nerve growth cone are fairly well understood, but the intracellular mechanisms operating to change the direction of axon outgrowth remain unknown. We now show that growth cones integrate myosin II-dependent contraction for rapid, coordinated turning at borders of laminin stripes in response to signals from laminin-activated integrin receptors; in the absence of myosin II activity, outgrowth continues across the borders.

Comparing the variants of takotsubo syndrome: an observational study of the ECG and structural changes from a New Zealand tertiary hospital.

OBJECTIVES: In takotsubo syndrome, QTc prolongation is a measure of risk of potentially fatal arrhythmia. It is not known how this risk, or derangement of other markers, differs across the echo variants of takotsubo syndrome. Therefore, we sought to explore whether apical takotsubo syndrome differs from the variants of the syndrome in more ways than just regional wall motion pattern. As the region of affected myocardium is usually larger, we hypothesised that patients with the classic apical ballooning form of takotsubo syndrome would have more severe derangement of their markers. DESIGN: Observational study of patients gathered from a prospective database (2010-2018) and by retrospective review (2006-2009). SETTING: The sole tertiary hospital from a New Zealand region in which case clusters of takotsubo syndrome were precipitated by large earthquakes in 2010, 2011 and 2016. PARTICIPANTS: A total of 222 patients who met a modified version of the Mayo criteria for takotsubo syndrome were included. All patients had digitally archived echocardiograms that were over-read by a second echocardiologist blinded to the clinical report. PRIMARY OUTCOME MEASURES: Ejection fraction, peak troponin and QTc interval. RESULTS: Patients with the apical form were older (p=0.011), had a lower initial left ventricular ejection fraction (35% vs 44%, p<0.0001) and a higher peak high-sensitivity troponin I (hsTnI) (p=0.01) than those with variant forms. There was no difference in the electrical abnormalities between the variants (QTc interval, heart rate, PR interval, QRS duration or T-wave axis). There was also no correlation between any of peak hsTnI, peak QTc and ejection fraction. QTc interval increased on day 2 and peaked on day 3 before falling steeply (p<0.0001). CONCLUSIONS: The variants of takotsubo syndrome differ in more ways than just their echo pattern but do not differ in their electrical abnormalities. There is a dissociation between the structural and electrical abnormalities. QTc peaks on day 3 and then falls steeply.

Clinical Predictors and Prognostic Impact of Recovery of Wall Motion Abnormalities in Takotsubo Syndrome: Results From the International Takotsubo Registry.

Background Left ventricular (LV) recovery in takotsubo syndrome (TTS) occurs over a wide-ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut-off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In-hospital outcomes and 1-year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; P=0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, P=0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1-year outcome compared with patients with early recovery (P=0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1-year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.

Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction.

After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-beta is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-beta receptor 1 (SD-208) in an experimental model of MI. Mice underwent ligation of the left coronary artery to induce MI and were subsequently treated for 30 d after infarction with either SD-208 or a vehicle control. Blockade of TGF-beta signaling reduced mean arterial pressure in all groups. SD-208 treatment after MI resulted in a trend for reduced ventricular and renal gene expression of TGF-beta-activated kinase-1 (a downstream modulator of TGF-beta signaling) and a significant decrease in collagen 1, in association with a marked decrease in cardiac mass. Post-MI SD-208 treatment significantly reduced circulating levels of plasma renin activity as well as down-regulating the components of the cardiac and renal renin-angiotensin system (angiotensinogen, angiotensin converting enzyme, and angiotensin II type I receptor). Our findings indicate that blockade of the TGF-beta signaling pathway results in significant amelioration of deleterious cardiac remodeling after infarction.

Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy.

The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition.