Rethinking Tako-tsubo Cardiomyopathy: The Contribution of Myocardial Pathology and Molecular Imaging.

BACKGROUND: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive. OBJECTIVE: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. METHODS: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. RESULTS: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determinant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardial perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. CONCLUSION: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamineinduced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.

Clinical characteristics of interim-PET negative patients with a positive end PET from the prospective HD08-01 FIL study.

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18-4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.

Complete response after rechallenge with trabectedin in a patient with previously responding high-grade undifferentiated sarcoma.

Evidence supporting rechallenge in patients responding to first exposure to trabectedin is limited. We report on a 39-year-old woman with advanced high-grade undifferentiated sarcoma (US) retreated twice with trabectedin after first response. The patient presented in June 2006 with an abdominal mass originating from the rear fascia of the rectus abdominis. Staging examinations did not indicate metastases and she underwent surgery; pathology showed a high-grade (FNCLCC G3) US. Subsequently, the patient received five cycles of adjuvant chemotherapy with epirubicin and ifosfamide. In February 2009 a computed tomography (CT) scan showed an abdominal mass involving the transverse mesocolon. R0 surgery was performed. In September 2009, peritoneal lesions appeared. Trabectedin was initiated at a dose of 1.5 mg/m by a 24 h intravenous infusion every 3 weeks, without relevant toxicity. After six cycles (March 2010), CT and PET-CT scans showed complete disappearance of metastases. In February 2012, new secondary lesions in the subdiaphragmatic region and a peritoneal lesion appeared. We rechallenged the patient with the same schedule of trabectedin; a complete response was achieved after two cycles. In October 2013, new secondary lesions in the subdiaphragmatic region and a retroperitoneal lesion were found. We rechallenged with the same schedule of trabectedin; PET-CT scans after two cycles showed complete response on the subdiaphragmatic lesion. Radiotherapy on the retroperitoneal lesion was performed. The patient underwent a total of 18 cycles and remains free from radiologically detectable disease. We report complete radiological remission after two rechallenges with trabectedin in a patient with previously responding high-grade US.

Prognostic implications of post-stress ejection fraction decrease detected by gated SPECT in the absence of stress-induced perfusion abnormalities.

PURPOSE: The prognostic meaning of a post-stress ejection fraction (EF) decrease detected by perfusion gated SPECT is still unclear.We therefore followed up patients with post-stress EF decrease in the absence of stress-induced perfusion abnormalities. METHODS: We prospectively enrolled 57 consecutive patients with post-stress EF drop ≥ 5 EF units and summed difference score (SDS) ≤ 1. They were followed up for more than 1 year and their outcome was compared with a group of sex- and age-matched controls with the same SDS but without EF decrease. RESULTS: During follow-up there were 13 events (1 cardiac death, 1 non-fatal myocardial infarction, 1 congestive heart failure and 10 late revascularizations). In the control group we registered six events. There was a significant difference (p<0.0001) between the event-free survival curves of the two groups. CONCLUSION: The event rate of patients with post-stress EF decrease ≥ 5 EF units is relatively high and is significantly worse than that of a control group of patients with similarly normal SDS but without EF changes. Therefore, a post-stress EF decrease without stress-induced perfusion abnormalities should be cautiously interpreted.

Feasibility of an accurate assessment of myocardial salvage by comparing functional and perfusion abnormalities in post-reperfusion gated SPECT.

BACKGROUND: Because of persistent stunning, post-treatment functional abnormalities could identify the initial risk area. The study aims to detect myocardial salvage using post-revascularization gated SPECT in acute myocardial infarction (AMI) treated by reperfusion therapy. METHODS: In 36 AMI patients, we performed a first gated SPECT injecting (99m)Tc-sestamibi before primary percutaneous coronary intervention (PCI), and a second 5 days later. The salvage index defined by the two perfusion images was compared with the value obtained by subtracting in the second gated SPECT the extent of perfusion defect from the extent of wall thickening abnormalities. RESULTS: The wall thickening salvage index correlated with the reference perfusion salvage index (Spearman's ρ = .92, P < .0001), with a 95% limit of agreement = ±.25. The agreement between the classifications in salvage index tertiles of the reference and of the wall thickening salvage index was good (kappa = .75). All patients with optimal PCI result and 18/24 of those with intermediate or poor outcome were correctly classified. CONCLUSIONS: Comparing function and perfusion in a single post-PCI (99m)Tc-sestamibi gated SPECT it is possible to estimate myocardial salvage. This could have useful implications in studies comparing different treatment strategies for AMI.

Is 16-frame really superior to 8-frame gated SPECT for the assessment of left ventricular volumes and ejection fraction? Comparison of two simultaneously acquired gated SPECT studies.

PURPOSE: Conflicting data exist about the difference between 8- and 16-frame gated single-photon emission computed tomography (SPECT) left ventricular volumes and ejection fraction (EF); moreover, the influence of framing on detection of stress-induced functional changes is unknown. METHODS: In 133 patients, two separate gated SPECT studies, one with 8 and one with 16 frames, were simultaneously acquired during a single gantry orbit using dedicated software. In 33 of 133 patients, two additional studies (with 8 and 16 frames, respectively) were acquired using arrhythmia rejection. Left ventricular EF and volumes were calculated using the QGS software. Stress-induced ischemia was identified on summed perfusion images. RESULTS: Arrhythmia-rejection did not influence volumes and EF independently of framing rate. Using data without arrhythmia-rejection, there was a significant difference in volumes and EF between 8 and 16 frames both in resting and post-stress gated SPECT. However, the difference was small: 2.6% for resting and 2.8% for post-stress EF. Both using 8 and 16 frames, there were significantly larger volumes and lower EF in patients with than without stress-induced ischemia. A stress-induced decrease >5 EF units was observed in 26 of 133 patients using 8 and in 23 of 133 using 16 frames, respectively, with finding agreement in 19 patients. CONCLUSIONS: Comparing two simultaneously acquired studies, the use of 16 instead of 8 frames has minor and predictable influence on functional data. Furthermore, there are no differences in the detection of stress-induced functional changes. The advantage of 16 over 8 frames in the daily clinical practice appears questionable.

Influence of the postexercise acquisition delay on the detection of functional abnormalities in sestamibi-gated SPECT.

BACKGROUND: Gated single photon emission computed tomography (SPECT) identifies functional changes produced by ischemia, but the influence of acquisition delay on their detection is not established. METHODS AND RESULTS: In 80 patients with known or suspected coronary artery disease, gated SPECT was acquired twice: first, less than 30 minutes after peak exercise (stress 1), and second, more than 45 minutes after peak exercise (stress 2). End-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were compared with perfusion. The relationship between the DeltaEF (stress EF - resting EF) and the summed difference score (SDS) was -0.443 (P < .0001) for stress 1 and -0.416 (P < .0001) for stress 2. In stress 1, EF increased in patients without inducible ischemia (SDS = 0) (57% +/- 10% vs 54% +/- 9% at rest, P < .02) and decreased in those with an SDS of 1 or greater (53% +/- 10.8% vs 55% +/- 9.6% at rest, P < .05). In stress 2, EF was unchanged in patients without ischemia (55.8% +/- 9.7%, P = .06) and decreased in the other patients (52.8% +/- 10.2%, P < .01). In patients without ischemia, both the EDV and ESV decreased significantly in stress 1 and were unchanged in stress 2. In patients with an SDS of 1 or greater, the EDV remained unchanged and the ESV minimally decreased in stress 1, whereas both volumes clearly and significantly increased in stress 2. CONCLUSIONS: The early acquisition of postexercise gated SPECT is slightly more effective in detecting ischemia-related functional changes; however, a delayed acquisition within 60 minutes still permits the detection of functional abnormalities in most patients.