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Background After renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in renal transplant recipients. Methods and Results Renal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty-four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group ( P =0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P =0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group ( P =0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P =0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P =0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity. Conclusions MSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

Background: Assessment of left ventricular (LV) function in patients with secondary mitral regurgitation (SMR) remains challenging but is an important parameter for risk stratification. The association of LV myocardial work components (work index [GWI], constructive [GCW] and wasted [GWW] work, and work efficiency) derived from pressure-strain loops obtained with speckle tracking echocardiography, and all-cause mortality in patients with SMR was investigated., Methods: LV myocardial GWI, GCW, GWW, and global work efficiency were measured with speckle tracking strain echocardiography in 373 patients (72% men, median age 68 years) with various grades of SMR. All-cause mortality was the primary end point., Results: Mild SMR was observed in 143 patients, 128 had moderate SMR, and 102 had severe SMR. Patients with severe SMR had the largest LV volumes and the worst LV ejection fraction and LV global longitudinal strain. In patients with severe SMR, LV GWI and GCW were more impaired (500 mm Hg% versus 680 mm Hg% P =0.024 and 678 mm Hg% versus 851 mm Hg% P =0.006, respectively), while GWW was lower (130 mm Hg% versus 260 mm Hg% P <0.001, respectively) and global work efficiency was significantly higher (82% versus 76%, P =0.001) compared with patients with mild SMR. After a median follow-up of 56 months, 161 patients died. LV GWI≤500 mm Hg%, LV GCW≤750 mm Hg%, and LV GWW<300 mm Hg% were independently associated with excess mortality., Conclusions: Patients with severe SMR had the worst LV GWI and LV GCW but better LV GWW and global work efficiency reflecting the unloading of the LV in the low-pressure left atrial chamber. These parameters were independently associated with worse long-term survival in patients with SMR.

Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) represents a heterogeneous clinical conundrum accounting for about 6%-8% of all acute MI who are referred for coronary angiography. Current guidelines and consensus documents recommend that these patients are appropriately diagnosed, uncovering the causes of MINOCA, so that specific therapies can be prescribed. Indeed, there are a variety of causes that can result in this clinical condition, and for this reason diagnostic cardiac imaging has an emerging critical role in the assessment of patients with suspected or confirmed MINOCA. In last years, different cardiac imaging techniques have been evaluated in this context, and the comprehension of their strengths and limitations is of the utmost importance for their effective use in clinical practice. Moreover, recent evidence is clearly suggesting that a multimodality cardiac imaging approach, combining different techniques, seems to be crucial for a proper management of MINOCA. However, great variability still exists in clinical practice in the management of patients with suspected MINOCA, also depending on the availability of diagnostic tools and local expertise. Herein, we review the current knowledge supporting the use of different cardiac imaging techniques in patients with MINOCA, underscoring the importance of a comprehensive multimodality cardiac imaging approach and proposing a practical diagnostic algorithm to properly identify and treat the specific causes of MINOCA, in order to improve prognosis and the quality of life in these patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Takotsubo syndrome (TTS) is associated to serious adverse in-hospital complications. We evaluated the role of invasively assessed left ventricular end-diastolic pressure (LVEDP) for predicting in-hospital complications in TTS patients compared to the most widely used echocardiographic parameters of ventricular function., Methods and Results: We prospectively enrolled 130 patients (mean age 71.2 ± 11.3 years, 114 [87.7%] female) with TTS. Invasive measurement of LVEDP was performed at the time of cardiac catheterization. The rate of in-hospital complications (composite of acute heart failure, life-threatening arrhythmias and all-cause death) was examined. In-hospital complications occurred in 37 (28.5%) patients. Patients who experienced in-hospital complications had a higher prevalence of neurological trigger and lower prevalence of emotional trigger, higher LVEDP and mean E/e' ratio and lower LV ejection fraction (LVEF) values compared to those who did not experience in-hospital complications. At multivariate logistic regression, higher LVEDP [odds ratio (OR) 1.12, 95% confidence interval (CI) [1.05-1.20], P < 0.001] and lower LVEF (OR 0.95, 95% CI [0.91-0.99], P = 0.011) remained independently predictors of in-hospital complications, while emotional trigger was associated to a lower risk (OR 0.24, 95% CI [0.06-0.96], P = 0.044). The area under the curve (AUC) for LEVDP in the prediction of in-hospital events was 0.776 (95% CI [0.69-0.86], P <0.001, with a sensitivity and specificity of 95% and 58% using a LVEDP cut-off value of 22.5 mmHg). The AUC was significantly higher for LVEDP than for E/e' ratio (P = 0.037)., Conclusions: LVEDP measured at the time of catheterization may help in identifying TTS patients at higher risk of cardiovascular deterioration with relevant therapeutic implications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The recurrence of angina after percutaneous coronary intervention affects 20-35% of patients with stable coronary artery disease; however, few data are available in the setting of ST-segment elevation myocardial infarction. We evaluated the relation between coronary microvascular obstruction and the recurrence of angina at follow-up., Methods: We prospectively enrolled patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Microvascular obstruction was defined as thrombolysis in myocardial infarction flow less than 3 or 3 with myocardial blush grade less than 2. The primary endpoint was the recurrence of angina at follow-up. Moreover, angina status was evaluated by the Seattle angina questionnaire summary score (SAQSS). Therapy at follow-up and the occurrence of major adverse cardiovascular events were also collected., Results: We enrolled 200 patients. Microvascular obstruction occurred in 52 (26%) of them. Follow-up (mean time 25.17±9.28 months) was performed in all patients. Recurrent angina occurred in 31 (15.5%) patients, with a higher prevalence in patients with microvascular obstruction compared with patients without microvascular obstruction (13 (25.0%) vs. 18 (12.2%), P =0.008). Accordingly, SAQSS was lower and the need for two or more anti-anginal drugs was higher in patients with microvascular obstruction compared with patients without microvascular obstruction. At multiple linear regression analysis a history of previous acute coronary syndrome and the occurrence of microvascular obstruction were the only independent predictors of a worse SAQSS. Finally, the occurrence of major adverse cardiovascular events was higher in patients with microvascular obstruction compared with patients without microvascular obstruction., Conclusions: The recurrence of angina in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention is an important clinical issue. The occurrence of microvascular obstruction portends a worse angina status and is associated with the use of more anti-anginal drugs., (© The European Society of Cardiology 2019.)

Background Myocardial bridging (MB) may represent a cause of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). Herein, we assessed the interplay between MB and coronary vasomotor disorders, also evaluating their prognostic relevance in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) or stable NOCAD. Methods and Results We prospectively enrolled patients with NOCAD undergoing intracoronary acetylcholine provocative test. The incidence of major adverse cardiac events, defined as the composite of cardiac death, non-fatal myocardial infarction, and rehospitalization for unstable angina, was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires summary score. We enrolled 310 patients (mean age, 60.6±11.9; 136 [43.9%] men; 169 [54.5%] stable NOCAD and 141 [45.5%] MINOCA). MB was found in 53 (17.1%) patients. MB and a positive acetylcholine test coexisted more frequently in patients with MINOCA versus stable NOCAD. MB was an independent predictor of positive acetylcholine test and MINOCA. At follow-up (median, 22 months; interquartile range, 13-32), patients with MB had a higher rate of major adverse cardiac events, mainly driven by a higher rate of hospitalization attributable to angina, and a lower Seattle Angina Questionnaires summary score (all P <0.001) compared with patients without MB. In particular, the group of patients with MB and a positive acetylcholine test had the worst prognosis. Conclusions Among patients with NOCAD, coronary spasm associated with MB may predict a worse clinical presentation with MINOCA and a higher rate of hospitalization attributable to angina at long-term follow-up with a low rate of hard events.

Aims: Killip classification is a simple and fast clinical tool for risk stratification of patients presenting with acute coronary syndrome (ACS). However, the clinical features and predictors of high Killip class at admission, and its prognostic impact in patients presenting with anterior ST elevation MI (STEMI) as first clinical cardiovascular event are still poorly known. The aim of this study was to identify the predictors of high Killip class and its impact on in-hospital and follow-up outcomes., Methods: We prospectively enrolled patients with unheralded anterior STEMI because of proximal or mid left anterior descending (LAD) artery categorized according to Killip classification. Patients' characteristics, in-hospital complications and major adverse cardiovascular events (MACEs; composite of all-cause death, heart failure hospitalization and new-onset ACS) at follow-up were collected., Results: We enrolled 147 patients [age 66.16±13.33, 113 male patients (76.9%)]. Killip class III--IV occurred in 22 (15%) patients. The median duration of follow-up was 12 [6--15.1] months. At multivariate analysis age [hazard ratio 1.137, 95% CI (1.068--1.209), P < 0.001], prehospital cardiac arrest [hazard ratio 12.145, 95% CI (1.710--86.254), P = 0.013] and proximal LAD lesion [hazard ratio 5.066, 95% CI (1.400--18.334), P = 0.013] were predictive of Killip class III--IV at admission. At multivariate analysis, Killip class III--IV was an independent predictor of in-hospital mortality [hazard ratio 7.790, 95% CI (1.024--59.276], P = 0.047 and of MACEs [hazard ratio 4.155 (1.558--11.082), P = 0.004) at follow-up., Conclusion: Killip classification performed at the time of admission is a simple and useful clinical marker of a high risk of early and late adverse cardiovascular events., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Takotsubo syndrome (TS) is an acute and reversible form of myocardial stunning preceded by emotional or physical stress, not explained by an obstruction of an epicardial coronary artery as in acute coronary syndrome. Over the last decades, TS is receiving growing attention, leading to an increase in awareness and diagnostic rate. Chest pain and dyspnea are the most common presenting symptoms; however, nonspecific presentations make the diagnosis challenging for clinicians. Here, we present the case of a 76-year-old female who experienced two completely asymptomatic episodes of TS 20 years apart.

The paradigm for the management of patients presenting with angina and/or myocardial ischemia has been historically centered on the detection and treatment of obstructive coronary artery disease (CAD). However, in a considerable proportion (30-50%) of patients undergoing coronary angiography, obstructive CAD is excluded. Thus, functional mechanisms may be involved in determining myocardial ischemia and should be investigated. In particular, coronary vasomotor disorders both at epicardial and at microvascular level may play a crucial role, but a definitive diagnosis of these disorders can at times be difficult, given the transience of symptoms, and often requires the use of coronary provocative tests. Of importance, these tests may provide relevant information on the pathogenic mechanism of myocardial ischemia, allowing physicians to tailor the therapies of their patients. Furthermore, several studies underscored the important prognostic information deriving from the use of coronary provocative tests. Nevertheless, their use in clinical practice is currently limited and mainly restricted to specialized centers, with only a minority of patients receiving a benefit from this diagnostic approach. In this review, we explain the pathophysiological bases for the use of provocative tests, along with their clinical, prognostic and therapeutic implications., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Myocardial infarction with non-obstructive coronary artery (MINOCA) disease represents a heterogeneous clinical conundrum accounting for about 6% of all acute myocardial infarction (MI) cases. Initially believed to be a benign condition, is now becoming clear that MINOCA is associated with a non-negligible risk of mortality, rehospitalization, disability and angina burden at follow-up, with high socioeconomic costs. To date, there are no prospective clinical trials in this population and cannot be assumed that benefits observed in patients suffering from MI with obstructive coronary artery disease may successfully translate to this syndrome. Herein, we comment on the importance of the multimodality assessment to properly identify and treat the specific causes of MINOCA, in order to improve prognosis and the quality of life in these patients.

About 50% of patients diagnosed with ST-segment elevation myocardial infarction have multivessel disease on coronary angiography. Recent evidence has shown that a staged percutaneous coronary intervention (PCI) strategy of non-culprit lesions, achieving complete revascularization, significantly reduces the rate of recurrent cardiovascular events compared with a PCI strategy limited to culprit lesion. Although functional evaluation of intermediate coronary stenoses by functional flow reserve (FFR) or instantaneous wave-free ratio (iFR) is widely used to detect residual myocardial ischaemia, the reliability of the study of non-culprit lesions in the acute phase of heart attack is controversial. On the other hand, the excess of new events in patients with acute coronary syndrome in whom PCI was deferred on the basis of FFR/iFR compared to patients with stable CAD could be due to both an inadequate functional evaluation and an intrinsic higher risk, related to the presence of untreated vulnerable plaques. In this context, intra-coronary imaging has shown that the presence of vulnerability features in non-culprit plaques is associated with an increased rate of ischaemic recurrence., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Over the past few months, health systems worldwide have been put to the test with the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though the leading clinical manifestations of the SARS-CoV-2 infection involve the respiratory tract, there is a non-negligible risk of systemic involvement leading to the onset of multi-organ failure with fatal consequences. Since the onset of COVID-19, patients with underlying cardiovascular disease have been at increased risk of poor clinical outcomes with higher death rates. Moreover, the occurrence of new-onset cardiac complications is not uncommon among patients hospitalised for COVID-19. Of importance, a significant portion of COVID-19 patients present with myocardial injury. Herein, the authors discuss the mechanisms leading to myocardial and microvascular injury in SARS-CoV-2 infection and their clinical implications., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2020, Radcliffe Cardiology.)

Primary percutaneous coronary intervention (PCI) represents the reperfusion strategy of choice for patients presenting with ST-segment elevation myocardial infarction. However, despite the restoration of epicardial flow, primary PCI may not determine an effective reperfusion of myocardial tissue due to the occurrence of microvascular obstruction. This phenomenon also known as "no-reflow" may occur in 30-60% of patients treated with primary PCI. Of importance, no-reflow attenuates the benefit of reperfusion therapy and is associated with a poor clinical outcome in terms of adverse ventricular remodeling, heart failure and mortality. The pathophysiology of no-reflow is complex and multiple players may be involved. Indeed, distal embolization, ischemia-reperfusion injury and an individual predisposition to microvascular dysfunction synergically interact to determine the occurrence of no-reflow. In this review, we will analyze the pathophysiological mechanisms, the diagnostic tools and the main therapeutic targets of no-reflow, with particular attention to the most recent acquisitions in this field.

Objective: Patients with Takotsubo syndrome (TTS) present an acute microvascular dysfunction that leads to an impaired myocardial perfusion and, in more severe forms, an impaired epicardial flow. However, clinical relevance of a delayed coronary flow, the coronary slow flow (CSF), has never been investigated. We studied the prognostic value of CSF occurring in the acute phase of TTS., Methods: This cohort study prospectively evaluated patients with a diagnosis of TTS. CSF was defined as angiographically non-obstructive coronary arteries with thrombolysis in myocardial infarction-2 flow. The incidence of overall mortality and major adverse cardiovascular events (MACEs), defined as the composite of TTS recurrence, cardiac rehospitalisation, cerebrovascular events and mortality, was assessed at follow-up., Results: We enrolled 101 patients (mean age 71.0±11.1 years, 86 (85.1%) female); CSF occurred in 18 (17.8%) patients. At admission, patients with CSF presented more frequently with Killip class III/IV, moderate-to-severe left ventricle systolic dysfunction and right ventricle dysfunction. During the index admission, patients with CSF had a higher rate of intrahospital complications (12 (66.7%) vs 28 (33.7%), p=0.01). At long-term follow-up, patients with CSF had a significantly higher occurrence of overall mortality (9 (50%) vs 19 (22.9%), p=0.011), mainly due to non-cardiac causes (89.3%), and a higher rate of MACE (10 (55.5%) vs 27 (32.5%), p=0.06). At multivariable Cox regression, CSF was independently associated with death from any causes., Conclusions: Patients with TTS presenting with CSF have a worse clinical presentation with a higher rate of intrahospital complications and a poor long-term clinical outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

s: The natural history of non-optic central nervous system (CNS) tumors in neurofibromatosis type 1 (NF1) is largely unknown. Here, we describe prevalence, clinical presentation, treatment, and outcome of 49 non-optic CNS tumors observed in 35 pediatric patients (0-18 years). Patient- and tumor-related data were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated. Eighteen patients (51%) harbored an optic pathway glioma (OPG) and eight (23%) had multiple non-optic CNS lesions. The majority of lesions (37/49) were managed with a wait-and-see strategy, with one regression and five reductions observed. Twenty-one lesions (42.9%) required surgical treatment. Five-year OS was 85.3%. Twenty-four patients progressed with a 5-year PFS of 41.4%. Patients with multiple low-grade gliomas progressed earlier and had a lower 5-year PFS than those with one lesion only (14.3% vs. 57.9%), irrespective of OPG co-presence. Non-optic CNS tumors are common in young patients with NF1. Neither age and symptoms at diagnosis nor tumor location influenced time to progression in our series. Patients with multiple lesions tended to have a lower age at onset and to progress earlier, but with a good OS., Competing Interests: The authors declare no conflict of interest.

Background: Coronary vasomotor dysfunction represents an important mechanism responsible for myocardial ischaemia in patients with non-obstructive coronary artery disease (CAD). The use of invasive provocative tests allows identifying patients with epicardial or microvascular spasm. Of note, clinical characteristics associated with the occurrence of epicardial or microvascular spasm have still not completely clarified., Methods and Results: We prospectively enrolled consecutive patients undergoing coronary angiography for suspected myocardial ischaemia/necrosis with evidence of non-obstructive CAD and undergoing intracoronary provocative test for suspected vasomotor dysfunction. Patients with a positive provocative test were enrolled. Clinical, echocardiographic and angiographic characteristics of patients were evaluated according to the pattern of vasomotor dysfunction (epicardial vs. microvascular spasm). We included 120 patients [68 patients with stable angina and 52 patients with myocardial infarction and non-obstructive coronary arteries (MINOCA)]. In particular, 77 (64.2%) patients had a provocative test positive for epicardial spasm and 43 (35.8%) patients for microvascular spasm. Patients with epicardial spasm were more frequently males, smokers, had higher rates of diffuse coronary atherosclerosis at angiography and more frequently presented with MINOCA. On the other hand, patients with microvascular spasm presented more frequently diastolic dysfunction. At multivariate logistic regression analysis male sex, smoking, and diffuse coronary atherosclerosis were independent predictors for the occurrence of epicardial spasm., Conclusions: Our study showed that specific clinical features are associated with different responses to intracoronary provocative test. Epicardial spasm is more frequent in males and in MINOCA patients, whereas microvascular spasm is more frequent in patients with stable angina and is associated with diastolic dysfunction.

Takotsubo syndrome (TS) is a condition of transient regional ventricular systolic dysfunction, usually presenting with acute chest pain and/or dyspnea, that is increasingly recognized especially in post-menopausal women following a psychological or physical stress. Initially considered as a benign condition with an isolated and self-limiting episode, it is now recognized that it is associated with a significant risk of in-hospital mortality and of recurrence. We herein describe a case of a 61-year-old female with left ventricular non-compaction cardiomyopathy (LVNC) who experienced a recurrence of TS, highlighting the potential pathophysiological role for LVNC in predisposing this syndrome and its recurrence. Moreover, we underscored possible therapeutic implications deriving from this case., (Copyright © 2019 Elsevier B.V. All rights reserved.)