A systematic review on focal takotsubo syndrome: a not-so-small matter.

A focal contraction pattern in takotsubo syndrome (TTS) is considered rare. Due to its peculiar presentation, which includes segmental left ventricular (LV) regional wall motion abnormalities (RWMA), the focal TTS pattern may be hardly differentiable from other entities, such as myocarditis or myocardial infarction. We performed a comprehensive systematic literature review researching for works in English published in Journals indexed in Embase, available online for consultation, using the following keywords (in Title and/or Abstract): ("takotsubo" OR "broken heart" OR "apical ballooning" OR "stress cardiomyopathy") AND ("focal" OR "atypical" OR "variant" OR "segments"). Thirty-three papers were retrieved: 17 case reports, 6 case series, and 10 population studies-with a total of 166 focal TTS patients. Prevalence of focal TTS ranged between 0.1% and 14% (pooled mean: 2.8%). Mean age of onset (58 years), gender distribution (80% of females), and type of triggers appeared similar to those reported in typical TTS. RWMA more frequently involved the interventricular septum and the anterolateral LV segments, with often preserved LV ejection fraction. In the majority of focal TTS reports that included adequate ECG information (n = 13), abnormalities were localized and not diffuse, always matching RWMA, and in 3 cases, reciprocal changes were observed. No in-hospital nor long-term deaths were reported. The focal TTS contraction pattern may be more prevalent than currently reported. Though possibly presenting with similar demographic background compared with typical TTS, the focal variant might be characterized by peculiar ECG modifications and better prognosis.

Long-term management of Takotsubo syndrome: a not-so-benign condition.

Takotsubo syndrome (TTS) is an intriguing clinical entity, characterized by usually transient and reversible abnormalities of the left ventricular systolic function, mimicking the myocardial infarction with non-obstructive coronary arteries. TTS was initially regarded as a benign condition, however recent studies have unveiled adverse outcomes in the short- and long-term, with rates of morbidity and mortality comparable to those experienced after an acute myocardial infarction. Given the usual transient nature of TTS, this is an unexpected finding. Moreover, long-term mortality seems to be mainly driven by non-cardiovascular causes. The uncertain long-term prognosis of TTS warrants a comprehensive outpatient follow-up after the acute event, although there are currently no robust data indicating its modality and timing. The aim of the present review is to summarize recent available evidence regarding long-term prognosis in TTS. Moreover methods, timing and findings of the long-term management of TTS will be discussed.

Risk stratification in transthyretin-related cardiac amyloidosis.

Transthyretin related cardiac amyloidosis (TTR-CA) is an infiltrative cardiomyopathy that cause heart failure with preserved ejection fraction, mainly in aging people. Due to the introduction of a non invasive diagnostic algorithm, this disease, previously considered to be rare, is increasingly recognized. The natural history of TTR-CA includes two different stages: a presymptomatic and a symptomatic stage. Due to the availability of new disease-modifying therapies, the need to reach a diagnosis in the first stage has become impelling. While in variant TTR-CA an early identification of the disease may be obtained with a genetic screening in proband's relatives, in the wild-type form it represents a challenging issue. Once the diagnosis has been made, in order to identifying patients with a higher risk of cardiovascular events and death it is necessary to focus on risk stratification. Two prognostic scores have been proposed both based on biomarkers and laboratory findings. However, a multiparametric approach combining information from electrocardiogram, echocardiogram, cardiopulmonary exercise test and cardiac magnetic resonance may be warranted for a more comprehensive risk prediction. In this review, we aim at evaluating a step by step risk stratification, providing a clinical diagnostic and prognostic approach for the management of patients with TTR-CA.

A contemporary update on cancer and takotsubo syndrome.

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved.

Myocardial oedema contributes to interstitial expansion and associates with mechanical and electrocardiographic changes in takotsubo syndrome: a CMR T1 and T2 mapping study.

AIMS: myocardial oedema is largely represented in takotsubo syndrome (TTS) and may contribute to alter the myocardium morphology and function. The aim of the study is to describe relationships between oedema, mechanical, and electrical abnormalities in TTS. METHODS AND RESULTS: the study included n = 32 hospitalized TTS patients and n = 23 controls. Cardiac magnetic resonance (CMR) with tissue mapping and feature tracking was performed with concomitant 12-lead electrocardiogram (ECG) recording. Mean age of TTS was 72 ± 12 years old, 94% women. Compared with controls, patients had higher left ventricular (LV) mass, worse systolic function, higher septal native T1 (1116 ± 73 msec vs. 970 ± 23 msec, P < 0.001), T2 (56 ± 5 msec vs. 46 ± 2 msec, P < 0.001), and extracellular volume (ECV) fraction (32 ± 5% vs. 24 ± 1%, P < 0.001). TTS patients had higher apicobasal gradient of T2 values (12 ± 6 msec vs. 2 ± 6 msec, P < 0.001); basal LV wall displayed higher native T1, T2, and ECV (all P < 0.002) but similar circumferential strain against controls (-23 ± 3% vs. -24 ± 4%, P = 0.351). In the TTS cohort, septal T2 values showed significant correlations with native T1 (r = 0.609, P < 0.001), ECV (r = 0.689, P < 0.001), left ventricular ejection fraction (r = -0.459, P = 0.008) and aVR voltage (r = -0.478, P = 0.009). Negative T-wave voltage and QTc length correlated with apicobasal T2 mapping gradient (r = 0.499, P = 0.007 and r = 0.372, P = 0.047, respectively) but not with other tissue mapping measurements. CONCLUSIONS: CMR T1 and T2 mapping demonstrated increased myocardial water content conditioning interstitial expansion in acute TTS, detected even outside areas of abnormal wall motion. Oedema burden and distribution associated with mechanical and electrocardiographic changes, making it a potential prognostic marker and therapeutic target in TTS.

Incidence and determinants of atrial fibrillation in patients with wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening. METHODS: Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes. RESULTS: Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008). CONCLUSIONS: At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Prognostic implications of different clinical profiles in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a myocardial genetic disease relatively common in the general population with heterogenous clinical presentation, natural history and prognosis. About 60% of HCM patients have a stable clinical course, while others may experience a variety of HCM-related complications which follows relatively independent pathways, and that can be distinguished in different subgroups. These subgroups are represented by patients with left ventricular outflow tract obstruction; patients with end-stage disease and reduced or preserved systolic function; patients with apical hypertrophy; patients with apical aneurysm; patients with atrial fibrillation, patients at high risk of sudden death and patients with preclinical HCM. The purpose of this review was to describe each of these clinical profiles with its prognostic implications.

Exploring the influence of takotsubo syndrome on oncologic patients' mortality.

It has been reported that patients affected by takotsubo syndrome (TTS) with a concurrent diagnosis of cancer suffer from greater mortality as compared to their non-cancer counterpart. It remains unclear whether TTS worsens the prognosis of cancer patients as well. Aim of this study was to compare outcomes of cancer patients with and without TTS. We combined data from two independent cohorts: one consisted of a prospective multicentre TTS registry; the second cohort consisted of all oncologic patients from two Cardio-Oncology Outpatient Clinics, who did not have cardiovascular conditions at the time of the cardio-oncologic visit. From the TTS registry, we selected patients with cancer (cancer-TTS patients). Next, we matched these patients with those from the cardio-oncologic cohort (cancer non-TTS patients) in a 1:2 fashion by age, sex, and type and cancer staging. Study endpoint was all-cause mortality. Among 318 TTS patients, 42 (13%) had a concurrent diagnosis of cancer. Characteristics of cancer-TTS patients and of the 84 matched cancer non-TTS subjects were comparable with the exception of diabetes mellitus, which was more common in cancer non-TTS patients. All-cause mortality was similar between cancer-TTS and cancer non-TTS patients. At Cox regression analysis TTS was not associated with mortality (OR 1.4, 95% CI 0.6-3.3, p = 0.43). Our findings show that even in the presence of acute heart failure due to TTS, the prognosis of oncologic patients is driven by the malignancy itself. Our results may prove useful for integrated management of cardio-oncologic patients.

Exercise oxygen pulse kinetics in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Reduced cardiac output (CO) has been considered crucial in symptoms' genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O2-pulse (oxygen uptake/heart rate (VO2/HR)), and the VO2/work relationship during exercise reflect closely stroke volume (SV) and CO changes, respectively. We hypothesise that adding O2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM. METHODS: CPETs were performed in 3 HCM dedicated clinical units. We retrospectively enrolled non-end-stage consecutive patients with HCM, grouped according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuvre (72% of patients with LVOTO <30; 10% between 30 and 49 and 18% ≥50 mm Hg). We evaluated the CPET response in HCM focusing on parameters strongly associated with SV and CO, such as O2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise. RESULTS: We included 312 patients (70% males, age 49±18 years). Peak VO2 (percentage of predicted), O2-pulse and ventilation to carbon dioxide production (VE/VCO2) slope did not change across LVOTO groups. Ninety-six (31%) patients with HCM presented an abnormal O2-pulse temporal behaviour, irrespective of LVOTO values. These patients showed lower peak systolic pressure, workload (106±45 vs 130±49 W), VO2 (21.3±6.6 vs 24.1±7.7 mL/min/kg; 74%±17% vs 80%±20%) and O2-pulse (12 (9-14) vs 14 (11-17) mL/beat), with higher VE/VCO2 slope (28 (25-31) vs 27 (24-31)) (p<0.005 for all). Only 2 patients had an abnormal VO2/work slope. CONCLUSION: None of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, identifying more advanced disease irrespectively of LVOTO.

Gender Differences in Takotsubo Syndrome.

BACKGROUND: Male sex in takotsubo syndrome (TTS) has a low incidence and it is still not well characterized. OBJECTIVES: The aim of the present study is to describe TTS sex differences. METHODS: TTS patients enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry were analyzed. Comparisons between sexes were performed within the overall cohort and using an adjusted analysis with 1:1 propensity score matching for age, comorbidities, and kind of trigger. RESULTS: In total, 286 (11%) of 2,492 TTS patients were men. Male patients were younger (age 69 ± 13 years vs 71 ± 11 years; P = 0.005), with higher prevalence of comorbid conditions (diabetes mellitus 25% vs 19%; P = 0.01; pulmonary diseases 21% vs 15%; P = 0.006; malignancies 25% vs 13%; P < 0.001) and physical trigger (55 vs 32% P < 0.01). Propensity-score matching yielded 207 patients from each group. After 1:1 propensity matching, male patients had higher rates of cardiogenic shock and in-hospital mortality (16% vs 6% and 8% vs 3%, respectively; both P < 0.05). Long-term mortality rate was 4.3% per patient-year (men 10%, women 3.8%). Survival analysis showed higher mortality rate in men during the acute phase in both cohorts (overall: P < 0.001; matched: P = 0.001); mortality rate after 60 days was higher in men in the overall (P = 0.002) but not in the matched cohort (P = 0.541). Within the overall population, male sex remained independently associated with both in-hospital (OR: 2.26; 95% CI: 1.16-4.40) and long-term mortality (HR: 1.83; 95% CI: 1.32-2.52). CONCLUSIONS: Male TTS is featured by a distinct high-risk phenotype requiring close in-hospital monitoring and long-term follow-up.

Clinical characteristics of patients with takotsubo syndrome recurrence: An observational study with long-term follow-up.

BACKGROUND: Research investigating takotsubo syndrome (TTS) recurrence yielded conflicting results. Aim of the present study is to describe clinical characteristics of patients with TTS recurrence in a cohort with available long-term follow-up. METHODS: The study population included 234 TTS patients enrolled in a prospective multicenter registry, median follow-up of 1328 (407, 2526) days. To investigate factors associated with TTS recurrence, we analyzed patients with recurrence (Group A) in comparison with a subgroup of TTS patients within the whole population (group B) who had similar age, sex and median follow-up length (Group A 2280 days vs Group B 2361 days). RESULTS: We observed 9 TTS recurrences affecting 8 patients, all women, with a rate of 0.9% patients/year. Median time to first recurrence was 1593 days (interquartile range: 950, 2516). We detected no significant differences between patients with and without recurrences regarding cardiovascular risk factors, symptoms, ECG and echocardiographic findings at presentation, discharge therapy. Physical trigger and chronic obstructive pulmonary disease (COPD) were more prevalent in patients who experienced a recurrence (75% vs 27% and 50% vs 14% with p = 0.01 and p = 0.022 respectively). Univariable Cox regression analysis identified physical trigger and history of COPD to be both associated with TTS recurrence [hazard ratio (HR) 11.4, 95% confidence interval (CI) 2.29-56.8, p = 0.003 and HR 4.94, 95% CI 1.16-20.99 p = 0.031 respectively]. CONCLUSION: TTS recurrence is relatively uncommon. Association with physical trigger and COPD would suggest a closer follow-up in this subgroup of patients.

Left Ventricular Remodeling in Hypertrophic Cardiomyopathy: An Overview of Current Knowledge.

While most patients with hypertrophic cardiomyopathy (HCM) show a relatively stable morphologic and clinical phenotype, in some others, progressive changes in the left ventricular (LV) wall thickness, cavity size, and function, defined, overall, as "LV remodeling", may occur. The interplay of multiple pathophysiologic mechanisms, from genetic background to myocardial ischemia and fibrosis, is implicated in this process. Different patterns of LV remodeling have been recognized and are associated with a specific impact on the clinical course and management of the disease. These findings underline the need for and the importance of serial multimodal clinical and instrumental evaluations to identify and further characterize the LV remodeling phenomenon. A more complete definition of the stages of the disease may present a chance to improve the management of HCM patients.

Novel Imaging and Genetic Risk Markers in Takotsubo Syndrome.

Takotsubo syndrome (TTS) is an increasingly recognized condition burdened by significant acute and long-term adverse events. The availability of novel techniques expanded the knowledge on TTS and allowed a more accurate risk-stratification, potentially guiding clinical management. The present review aims to summarize the recent advances in TTS prognostic evaluation with a specific focus on novel imaging and genetic markers. Parametric deformation analysis by speckle-tracking echocardiography, as well as tissue characterization by cardiac magnetic resonance imaging T1 and T2 mapping techniques, currently appear the most clinically valuable applications. Notwithstanding, computed tomography and nuclear imaging studies provided limited but promising data. A genetic predisposition to TTS has been hypothesized, though available evidence is still not sufficient. Although a genetic predisposition appears likely, further studies are needed to fully characterize the genetic background of TTS, in order to identify genetic markers that could assist in predicting disease recurrences and help in familial screening.

Admission heart rate and in-hospital course of patients with Takotsubo syndrome.

BACKGROUND: In-hospital course of patients with Takotsubo syndrome (TS) is quite heterogeneous and life-threatening complications are not uncommon in the acute phase. The role of heart rate (HR) as a predictor of prognosis has not been sufficiently investigated in this setting. The study aims to assess the impact of HR at presentation on in-hospital course of patients with TS. METHODS: The study population included 221 patients with TS enrolled in a multicentric registry. HR at admission was evaluated on the first electrocardiogram. According to tertile distribution of HR at presentation, 3 groups were identified: Group A (HR ≤ 76 beats per minute (bpm), n = 76), Group B (HR 77-95 bpm, n = 74) and Group C (HR > 95 bpm, n = 71). Acute in-hospital complications were defined as occurrence of severe pump failure and major arrhythmias. RESULTS: 32 (14.4%) patients experienced complicated in-hospital course. HR on admission was significantly higher (108 bpm vs. 85 bpm; p < 0.001) and ejection fraction (EF) lower (35% vs. 40%; p = 0.009) in patients with complications than in those without. Patients in Group C experienced a 5-fold higher rate of complications compared to group A and B. After multivariate analysis, higher HR (odds ratio 1.34 per 10 bpm increase, 95% confidence interval (CI) 1.12-1.59; p = 0.001) and lower EF (odds ratio 1.24 per 5% decrease, 95% CI 1.01-1.54; p = 0.049) remained independently associated with a worse outcome. CONCLUSION: In a large population with TS, high HR on admission independently predicted complicated in-hospital course.