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Background Acute stress induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. Methods In a multi-centre study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age, sex and co-morbidity matched control subjects. During the index event and at 5 months follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched controls underwent investigation at a single time point. Results Subjects were predominantly middle aged (64±14years) women (90%). When compared to control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 versus 10.5±0.9 ms, p<0.001) and non-ballooning (12.9±0.6 versus 10.5±0.9 ms, p=0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 versus 6.5±5.8 pg/mL, p< 0.001) and chemokine (C-X-C motif) ligand 1 (1903±168 versus 1272±177 pg/mL, p=0.01) concentrations, and classical CD14++CD16- monocytes (90±0.5 versus 87±0.9%, p=0.01) were also increased whilst intermediate CD14++CD16+ (5.4±0.3 versus 6.9±0.6%, p=0.01) and non-classical CD14+CD16++ (2.7±0.3% versus 4.2±0.5%, p=0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium although there remained persistent elevations in serum interleukin-6 concentrations (p=0.009) and reductions in intermediate CD14++CD16+ monocytes (5.6±0.4 versus 6.9±0.6%, p=0.01). Conclusions We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets and an increase in systemic pro-inflammatory cytokines. Many of these changes persisted for at least 5 months suggesting a low-grade chronic inflammatory state.

These data indicate that a relatively high daily consumption of tomato-based products (equivalent to 32-50 mg lycopene/d) or lycopene supplements (10 mg/d) is ineffective at reducing conventional CVD risk markers in moderately overweight, healthy, middle-aged individuals. This trial was registered at isrctn.org as ISRCTN34203810.

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Background: Takotsubo syndrome is an increasingly recognized cause of chest pain and occasionally of cardiogenic shock. Despite rapid improvement of the Left Ventricular Ejection Fraction (LV EF), recent registry data raises concerns about long term prognosis. We hypothesized that restoration of normal EF after acute tako-tsubo is not equivalent to full functional recovery. Methods: We prospectively recruited 52 takotsubo patients [according to the Mayo criteria plus cardiac magnetic resonance imaging (CMR) to exclude myocardial infarction] and 44 healthy controls of the same age, gender and cardiovascular co-morbidity distribution. We focused the investigation on takotsubo patients presenting with ST-elevation type ECG or malignant arrhythmias and with LV apical ballooning variant and examined a 4 months recovery end-point. Patients underwent Echocardiography assessment of LV myocardial deformation (Global longitudinal, radial and circumferential strain, LV twist, torsion, untwist, time to peak twist and untwist) and assessment of LV myocardial structure by pre and post contrast-enhanced CMR by T1 mapping acutely and at 4 months follow-up. Controls had a single time-point investigation. Data were analyzed using paired or unpaired tests, as appropriate for their distribution and corrected for multiple comparisons. Results: The patients' mean age was 66 years (range 28-87) and 92% were women. All abnormal echocardiographic indices observed acutely in takotsubo patients improved (but not necessarily normalized) at followup. Significant mechano-temporal alterations characterizing both systole (global longitudinal strain, apical circumferential strain, both p<0.01; left ventricular twist, twist rate and torsion, all p<0.0001) and diastole (untwist rate and time to peak untwisting, all p<0.001) persisted at 4 months follow-up when compared with controls, despite normalization of LV ejection fraction and volumes. Whilst native T1 (which demonstrates edema) normalized at 4 months follow-up only in segments contracting normally during the acute phase [T1=1180± 40.6ms (normally contracting, p=0.2 vs control values of 1189±16 ms) and 1208± 60.3 ms (dysfunctional segments, p<0.05 vs control)], the extracellular volume fraction (ECV, which demonstrates diffuse fibrosis) remained significantly abnormal in all LV segments (whether normally contracting, 0.328±0.043, p<0.001 or ballooning during acute presentation, 0.320±0.044, p<0.001, both vs control values of 0.273±0.045). Conclusion: In patients with the most clinically severe spectrum of takotsubo cardiomyopathy, regional LV systolic and diastolic deformation abnormalities persist beyond the acute event, despite normalization of global LV EF and size. In addition, although myocardial edema partly subsides, a process of global microscopic fibrosis develops in its place, detected as early as 4 months.Suggested Reviewers:Opposed Reviewers: 1 24 th March, 2017 Dear Dr Pearlman, Thank you once again for your comments and those of the associate editors. I think it i...

Both GLS and ECV are able to independently discriminate between hypertensive heart disease and HFpEF and identify patients with prognostically significant functional limitation. ECV is the best diagnostic discriminatory marker of HFpEF and could be used as a surrogate endpoint for therapeutic studies.

Background Exercise‐induced pulmonary hypertension is common in heart failure with preserved ejection fraction ( HF p EF ). We hypothesized that this could result in pericardial constraint and diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HF p EF patients, 17 hypertensive controls, and 17 normotensive controls (healthy). Cardiac volumes, and normalized radius of curvature ( NRC ) of the interventricular septum at end‐diastole and end‐systole, were measured at rest and peak‐exercise, and compared between the groups. The septum was circular at rest in all 3 groups at end‐diastole. At peak‐exercise, end‐systolic NRC increased to 1.47±0.05 ( P <0.001) in HF p EF patients, confirming development of pulmonary hypertension. End‐diastolic NRC also increased to 1.54±0.07 ( P <0.001) in HF p EF patients, indicating septal flattening, and this correlated significantly with end‐systolic NRC (ρ=0.51, P =0.007). In hypertensive controls and healthy controls, peak‐exercise end‐systolic NRC increased, but this was significantly less than observed in HF p EF patients ( HF p EF , P =0.02 versus hypertensive controls; P <0.001 versus healthy). There were also small, non‐significant increases in end‐diastolic NRC in both groups (hypertensive controls, +0.17±0.05, P =0.38; healthy, +0.06±0.03, P =0.93). In HF p EF patients, peak‐exercise end‐diastolic NRC also negatively correlated ( r =−0.40, P <0.05) with the change in left ventricular end‐diastolic volume with exercise (ie, the Frank‐Starling mechanism), and a trend was noted towards a negative correlation with change in stroke volume ( r =−0.36, P =0.08). Conclusions Exercise pulmonary hypertension causes substantial diastolic ventricular interaction on exercise in some patients with HF p EF , and this restriction to left ventricular filling by the right ventricle exacerbates the pre‐existing impaired Frank‐Starling response in these patients.

Acute stress-induced (Tako-tsubo) cardiomyopathy is an increasingly recognized but insufficiently characterized syndrome. Here, we investigate the pathophysiology of right ventricular (RV) involvement in Tako-tsubo and its recovery time course. We prospectively recruited 31 patients with Tako-tsubo with predominantly ST-elevation electrocardiogram and 18 controls of similar gender, age, and co-morbidity distribution. Patients underwent echocardiography and cardiac magnetic resonance (CMR) imaging on a 3T Philips scanner in the acute phase (day 0 to 3 after presentation) and at 4-months follow-up. Visually, echocardiography was able to identify only 52% of patients who showed RV wall motion abnormalities on CMR. Only CMR-derived RV ejection fraction (p = 0.01) and echocardiography-estimated pulmonary artery pressure (p = 0.01) identify RV functional involvement in the acute phase. Although RV ejection fraction normalizes in most patients by 4 months, acutely there is RV myocardial edema in both functioning and malfunctioning segments, as measured by prolonged native T1 mapping (p = 0.02 for both vs controls), and this persists at 4 months in the acutely malfunctioning segments (p = 0.002 vs controls). The extracellular volume fraction was significantly increased acutely in all RV segments and remained increased at follow-up compared with controls (p = 0.004 for all). In conclusion, in a Tako-tsubo population presenting predominantly with ST-elevation electrocardiogram, we demonstrate that although RV functional involvement is seen in only half of the patients, RV myocardial edema is present acutely throughout the RV myocardium in all patients and results in microscopic fibrosis at 4-month follow-up.