Is Takotsubo cardiomyopathy still looking for its own nosological identity?

Despite several efforts to provide a proper nosological framework for Takotsubo cardiomyopathy (TCM), this remains an unresolved matter in clinical practice. Several clinical, pathophysiologic and histologic findings support the conceivable hypothesis that TCM could be defined as a unique pathologic entity, rather than a distinct subset of myocardial infarction with non-obstructive coronary arteries. Further investigations are needed in order to define TCM with the most appropriate disease taxonomy.

Nabiximols effect on blood pressure and heart rate in post-stroke patients of a randomized controlled study.

Background: Cannabinoids may be useful to treat pain, epilepsy and spasticity, although they may bear an increased risk of cardiovascular events. This study aims to evaluate the cardiovascular safety of nabiximols, a cannabis-based drug, in patients with spasticity following stroke, thus presenting an increased cardiovascular risk. Methods: This is an ancillary study stemming from the SativexStroke trial: a randomized double-blind, placebo-controlled, crossover study aimed at assessing the effect of nabiximols on post-stroke spasticity. Patients were treated with nabiximols oromucosal spray or placebo and assessed before and after two phases of 1-month duration each. Only the phase with the active treatment was considered for each patient who completed the study. The average values of blood pressure (diastolic, systolic, differential) and heart rate from the first 5 days of the phase (lowest nabiximols dosage) were compared to the average values recorded during the last 5 days at the end of the phase (highest nabiximols dosage). Baseline comparisons between gender, stroke type and affected side and correlation between age and blood pressure and heart rate were performed. The study was registered with the EudraCT number 2016-001034-10. Results: Thirty-four patients completed the study and were included in the analysis. Thirty-one were taking antihypertensive drugs and, among these, 12 were taking beta-blockers. During the study, no arrhythmic events were recorded, blood pressure and heart rate did not show pathological fluctuations, and no cardiovascular or cerebrovascular events occurred. At baseline blood pressure and heart rate were comparable concerning gender, stroke type and affected side. A significant direct correlation emerged between differential blood pressure and age and an inverse correlation between diastolic blood pressure and age. No correlation emerged between systolic blood pressure or heart rate and age. Blood pressure and heart rate did not change during nabiximols treatment compared to the baseline condition. Conclusion: This ancillary study adds evidence that, in patients who already underwent a cerebrovascular accident, nabiximols does not determine significant blood pressure and heart rate variation or cardiovascular complications. These data support the cardiovascular safety of nabiximols, encouraging more extensive studies involving cannabinoids characterized by slow absorption rates.

Cannabinoid Effect and Safety in Spasticity Following Stroke: A Double-Blind Randomized Placebo-Controlled Study.

Background: Nabiximols is a cannabis-based drug to treat spasticity-associated symptoms currently approved for patients with multiple sclerosis only. Cannabinoids are useful in an increasing number of medical conditions but may bear an increased risk for cardiovascular events. SativexStroke is a double-blind randomized placebo-controlled crossover monocentric clinical trial investigating the efficacy and safety of nabiximols in patients with spasticity following stroke. Methods: Patients were treated with nabiximols oromucosal spray or placebo and assessed before and after two phases of 1-month duration each. Cardiovascular safety was assessed before and during the trial. Primary endpoints were changes in spasticity numeric rating scale scores and electromyographic recording of the stretch reflex in affected wrist flexors. Secondary outcome measures were numeric rating scale scores for pain, sleep and bladder function, the number of daily spasms and clinical assessment of spasticity with the modified Ashworth scale. The study was registered with the EudraCT number 2016-001034-10. Results: Between May 2, 2018, and February 20, 2020, 41 patients entered the study. Seven patients did not complete the study, so 34 were included in the analysis. Two serious adverse events occurred, but none related to cardiovascular function. Primary and secondary efficacy outcome measures did not change from baseline during nabiximols treatment relative to placebo. Conclusion: This study suggests that nabiximols use is probably safe in stroke patients, therefore cannabinoid usefulness may be further investigated. The lack of nabiximols effect could be related to low pain levels in recruited patients or different spasticity mechanisms between post-stroke and multiple sclerosis patients. Similarly, a beneficial effect of nabiximols could have emerged if more patients with a higher level of spasticity at baseline were recruited. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001034-10/IT.

Cardiac herniation: A practical review in the emergency setting.

INTRODUCTION: Albeit described since 1948, cardiac herniations still represent an under-recognized clinical entity in the general population, due to their difficult diagnostic detection and to a limited knowledge in clinical practice. This paper aims to provide an updated overview focusing on definition, clinical presentation and diagnostic work-up of cardiac herniations, as well as on further findings concerning prognoses and available therapeutic options. METHODS: This narrative review was performed by following the standard methods of the Cochrane Collaboration and the PRISMA statement. A Pubmed search was conducted using the following keywords (in Title and/or Abstract): ("cardiac" OR "heart") AND ("herniation" OR "hernia"). All available high quality resources containing information on epidemiology, etiopathogenesis, clinical findings, diagnostic tools and therapeutic strategies, were included in our search. RESULTS: Causative agents, location and the degree of haemodynamic impairment were found to play a pivotal role in defining the patient's natural history and prognostic outcomes, and in detecting potential associated clinical conditions which may significantly impact on first line decision-making strategy. CONCLUSIONS: Cardiac herniations remain a rare and life-threatening pathological injury, whose knowledge is still very limited in clinical practice. Clinicians should be aware of such a clinical entity and of its wide spectrum of clinical manifestations, particularly in high-risk subsets of patients, in order to provide the most appropriate decision-making strategy and timely therapeutic approach.

Pregnancy-related acute myocardial infarction: a review of the recent literature.

Pregnancy-related acute myocardial infarction is a rare and potentially life-threatening cardiovascular event, the incidence of which is growing due to the heightened prevalence of several risk factors, including increased maternal age. Its main aetiology is spontaneous coronary artery dissection, which particularly occurs in pregnancy and may engender severe clinical scenarios. Therefore, despite frequently atypical and deceptive presentations, early recognition of such a dangerous complication of gestation is paramount. Notwithstanding diagnostic and therapeutic improvements, pregnancy-related acute myocardial infarction often carries unfavourable outcomes, as emergent management is difficult owing to significant limitations in the use of ionising radiation-e.g. during coronary angiography, potentially harmful to the foetus even at low doses. Notably, however, maternal mortality has steadily decreased in recent decades, indicating enhanced awareness and major medical advances in this field. In our paper, we review the recent literature on pregnancy-related acute myocardial infarction and highlight the key points in its management.

Cardiac Outpouchings: Definitions, Differential Diagnosis, and Therapeutic Approach.

BACKGROUND AND AIMS: Cardiac outpouchings encounter a series of distinct congenital or acquired entities (i.e. aneurysms, pseudoaneurysms, diverticula, and herniations), whose knowledge is still poorly widespread in clinical practice. This review aims to provide a comprehensive overview focusing on definition, differential diagnosis, and prognostic outcomes of cardiac outpouchings, as well as further insights on therapeutic options, in order to assist physicians in the most appropriate decision-making. METHODS: The material reviewed was obtained by the following search engines: MEDLINE (PubMed), EMBASE, Google Scholar, and Clinical Trials databases, from January 1966 until March 2021. We searched for the following keywords (in title and/or abstract): ("cardiac" OR "heart") AND ("outpouching" OR "outpouch" OR "aneurysm" OR "pseudoaneurysm" OR "false aneurysm" OR "diverticulum" OR "herniation"). Review articles, original articles, case series, and case reports with literature review were included in our search. Data from patients with congenital or acquired cardiac outpouchings, from prenatal to geriatric age range, were investigated. RESULTS: Out of the 378 papers initially retrieved, 165 duplicates and 84 records in languages other than English were removed. Among the 129 remaining articles, 76 were included in our research material, on the basis of the following inclusion criteria: (a) papers pertaining to the research topic; (b) peer-reviewed articles; (c) using standardized diagnostic criteria; and (d) reporting raw prevalence data. Location, morphologic features, wall motion abnormalities, and tissue characterization were found to have a significant impact in recognition and differential diagnosis of cardiac outpouchings as well as to play a significant role in defining their natural history and prognostic outcomes. CONCLUSIONS: Careful recognition of cardiac outpouchings remains a diagnostic challenge in clinical practice. Due to a broad cluster of distinctive and heterogeneous entities, their knowledge and timely recognition play a pivotal role in order to provide the most appropriate clinical management and therapeutic approach.

Atrial fibrillation and Alzheimer's disease: A conundrum.

During ageing, the prevalence of Alzheimer's disease (AD) and of cardiovascular disease CVD) increases. Our aim is to investigate the relationship between AD and CVD and its risk factors, with a view to explaining the underlying mechanisms of this association. This review is based on the material obtained via MEDLINE (PubMed), Embase and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease", combined with "cardiovascular disease", "hypertension", "dyslipidaemia", "diabetes mellitus", "atrial fibrillation", "coronary artery disease", "heart valve disease", "heart failure". Out of the 1328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed; thus, only 98 papers were included in our research material. We have found that AD and CVD are frequently associated, while both of them, alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of CVD and its risk factors on AD, in order to better comprehend the effects of subclinical and clinical cardiovascular diseases on the brain. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being: hypoperfusion and emboli, atherosclerosis, furthermore in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs. We need to clarify the real impact of these underlying hypothesized mechanisms and to investigate gender issues.

Echocardiography of right ventricular-arterial coupling predicts survival of elderly patients with heart failure and reduced to mid-range ejection fraction.

Echocardiography of right ventricular (RV)-arterial coupling obtained by the estimation of the ratio of the longitudinal annular systolic excursion of the tricuspid annular plane and pulmonary artery systolic pressure (TAPSE/PASP) has been found to be a remarkable prognostic indicator in patients with HF. Our aim was to evaluate the impact of TAPSE, PASP and their ratio in the prognostic stratification of outpatients with HF aged ≥70 years and reduced to mid-range ejection fraction (EF). A complete echocardiographic examination was performed in 400 outpatients with chronic HF and left ventricular (LV) EF ≤50% who averaged 77 years in age. During a median follow-up period of 25 months (interquartile range: 8-46), there were 135 cardiovascular deaths. Two different Cox regression models were evaluated, one including TAPSE and PASP, separately, and the other with TAPSE/PASP. In the first model, LV end-systolic volume index, age, no angiotensin converting enzyme (ACE) inhibitor use, TAPSE, PASP and gender were found to be independently associated with the outcome after adjustment for demographics, clinical, biochemical, echocardiographic data. In the second model, TAPSE/PASP resulted the most important independent predictor of outcome (hazard ratio [HR]:0.07, p<0.0001) followed by LV end-systolic volume index, no ACE inhibitor use, age and gender. The use of the variable TASPE/PASP improved the predictive value of the new multivariable model (area under the curve [AUC] of 0.74 vs AUC of 0.71; p<0.05). TASPE/PASP improved the net reclassification (NRI = 14.7%; p<0.01) and the integrated discrimination (IDI = 0.04; p<0.01). In conclusion, the study findings showed that assessment of RV-arterial coupling by TAPSE/PASP was of major importance to assess the prognosis of patients with chronic HF and LV EF ≤50% aged ≥70 years.

Alzheimer's Disease and Cardiovascular Disease: A Particular Association.

METHODS: This review is based on the material obtained via MEDLINE (PubMed), EMBASE, and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease," combined with "cardiovascular disease," "hypertension," "dyslipidaemia," "diabetes mellitus," "atrial fibrillation," "coronary artery disease," "heart valve disease," and "heart failure." Out of the 1,328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed. Among the 681 remaining studies, 98 were included in our research material on the basis of the following inclusion criteria: (a) the community-based studies; (b) using standardized diagnostic criteria; (c) reporting raw prevalence data; (d) with separate reported data for sex and age classes. RESULTS: While AD and CVD alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of vascular factors on these diseases. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being hypoperfusion and emboli, atherosclerosis, and the fact that, in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs. CONCLUSIONS: AD and CVD are frequently associated. Further studies are needed in order to understand the effect of CVD and its risk factors on AD in order to better comprehend the effects of subclinical and clinical CVD on the brain. Finally, we need to clarify the impact of the underlying hypothesized mechanisms of this association and to investigate gender issues.

PCSK9 inhibitors for treating hypercholesterolemia.

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.

An Emerging Cardiovascular Disease: Takotsubo Syndrome.

Takotsubo syndrome (TTS) is a recently identified cardiac disease, which is far from being completely known. The aims of this narrative review are to provide a better understanding of the pathophysiological features of TTS and to update clinical findings in order to improve the management of subjects affected by this syndrome (according to the most recent consensus papers issued by the international scientific societies). We based our search on the material obtained via PubMed up to April 2019. The terms used were "Takotsubo Syndrome and Takotsubo cardiomyopathy" in combination with "heart failure, pathophysiology, complications, diagnosis, and treatment." TTS is a reversible form of ventricular dysfunction usually characterized by akinesia of the apex in the absence of obstructive coronary artery disease. In its initial phase, TTS may be indistinguishable from AMI and is usually triggered by a sudden emotional/physical stressor which abruptly increases catecholamine levels. However, the mechanisms by which catecholamines or other unidentified molecules can cause myocardial dysfunction is unknown. In-hospital stay may be hampered by various life-threatening complications, while data on long-term survival remain scarce and unclear. Furthermore, TTS may sometimes recur. We believe that TTS is clearly a much more complex condition than previously thought. Much remains to be discovered about its pathophysiologic mechanisms, the role of the link between the heart and brain and that of triggering factors and gender, and the reasons why this syndrome displays different phenotypes and sometimes recurs. Undoubtedly, preliminary evidence from pathophysiological studies (mainly genetic studies) has shown promising advances. However, prospective randomized clinical trials are still needed in order to identify and to tailor the best medical treatments for TTS patients.

Clinical Characteristics and Long-Term Mortality Rate in Female Patients with Takotsubo Syndrome Compared with Female Patients with ST-Elevation Acute Myocardial Infarction: A Retrospective Study from a Single Center.

BACKGROUND: Takotsubo syndrome (TTS) is characterized by acute transient, stress-induced, left ventricular systolic dysfunction, generally presenting with apical ballooning. It can mimic an acute coronary syndrome, but with a milder increase in cardiac enzymes and without culprit coronary artery disease on angiography. Data on long-term follow-up and survival in patients with TTS, compared with patients with ST-elevation myocardial infarction (STEMI), are scarce. PURPOSE: To assess all-cause mortality rate and survival in a consecutive series of female patients with TTS compared with age- and sex-matched STEMI patients on long-term follow-up. METHODS AND RESULTS: We collected data of 65 TTS female patients (TTS group) with a mean age of 73.42 ± 11.35 years from 2001 to 2013. Collection of follow-up information was concluded for all patients in 2016. To compare the mortality and survival of TTS patients with those of the STEMI population, we used data from our STEMI Registry, a prospective registry of 7446 STEMI patients admitted from 2001 to 2013 to our cath-lab for primary percutaneous coronary intervention (p-PCI). From the registry, we selected 104 STEMI patients (STEMI group) comparable to our TTS group in terms of age (mean age of 72.33 ± 11.92 years) and sex. On follow-up examination after a median of 1000 days, the TTS group had a lower all-cause mortality rate than the STEMI group (7.69% versus 23.08%). This difference was statistically different between the two groups (log-rank test, p value = 0.03). CONCLUSIONS: In our study, TTS and STEMI patients displayed a statistically significant difference in long-term survival. Specifically, the TTS group had a lower mortality rate than the STEMI group. This seems to suggest that TTS and STEMI are two different clinical entities with two different clinical outcomes.

The Organ Handling of Soluble Klotho in Humans.

BACKGROUND: Chronic kidney disease (CKD) reduces both Klotho expression and its shedding into circulation, an effect that accelerates progression and cardiovascular complications. However, the mechanisms that regulate Klotho release by the human kidney are still unknown. METHODS: We measured plasma Klotho across the kidney, splanchnic organs and lung in 22 patients (71 ± 2 years, estimated glomerular filtration rate [eGFR] 60 ± 5.4 mL/min 1.73 m2) during elective diagnostic cardiac catheterizations. RESULTS: Although the Klotho average renal vein concentrations were remarkably higher (by ∼9%) than arterial values, the kidney removed Klotho (or was at zero balance) in 7 subjects, indicating that the kidney contribution to systemic Klotho is not constant. Klotho fractional enrichment across the kidney was inversely related to plasma sodium (r = 0.43, p = 0.045) and acid uric acid levels (r = 0.38, p = 0.084) and directly, to renal oxygen extraction (r = 0.56, p = 0.006). In multivariate analysis, renal oxygen extraction was the only predictor of the enrichment of Klotho across the kidney, suggesting the dependence of renal Klotho release on tubular hypoxia or oxidative metabolism. Klotho balance was neutral across the lung. In patients with eGFR <60 mL/min, Klotho was also removed by splanchnic organs (single pass fractional extraction ∼11%). CONCLUSIONS: The present study identifies kidney oxygen uptake as a predictor of Klotho release, and splanchnic organs as a site for Klotho removal. This study provides new understanding of kidney Klotho release and suggests that modulating kidney oxygen metabolism could increase Klotho delivery, as an option to slow disease progression and blunt organ damage.

Impaired Left Ventricular Global Longitudinal Strain among Patients with Chronic Kidney Disease and End-Stage Renal Disease and Renal Transplant Recipients.

BACKGROUND: Although heart failure is the most prevalent cardiovascular disease associated with adverse outcome in chronic kidney disease (CKD) and after kidney transplantation, left ventricular (LV) systolic function is often preserved in renal patients. The aim of this study was to evaluate global longitudinal strain (GLS), which is reportedly a more accurate tool for detecting subclinical LV systolic dysfunction, in patients with various degrees of renal function impairment, including kidney transplant recipients (KTRs). METHODS: This prospective study evaluated demographic, clinical, and ultrasound data, including the assessment of LV GLS and mitral E peak velocity and averaged ratio of mitral to myocardial early velocities (E/e'), of 70 consecutive renal patients (20 with stage 2-4 CKD, 25 with end-stage renal disease on hemodialysis [HD], and 25 KTRs). All patients had an LV ejection fraction ≥50% and no history of heart failure or coronary artery disease. We used multivariable logistic analysis to assess the risk of compromised GLS. One hundred and twenty control subjects with or without hypertension served as controls. RESULTS: A compromised GLS <-18% was shown in 55% of patients with stage 2-4 CKD, 60% of HD patients, and 28% of KTRs, while it was 32% in hypertensive controls and 12% in non-hypertensive controls (p < 0.0001). Patients with HD had higher systolic pressure and a significantly greater prevalence of increased LV mass and diastolic dysfunction. In renal patients, E/e' (p = 0.025), and LV mass index (p = 0.063) were independent predictors of compromised GLS at logistic regression analysis. E/e', systolic artery pressure, and LV mass also exhibited the greatest areas under the curve on receiver operating characteristic analysis to identify a compromised GLS. CONCLUSIONS: Renal disease proved to be associated with early and subclinical impairment of LV systolic function, which persists after starting dialysis and even in spite of successful kidney transplantation. An increased E/e' resulted to be the most powerful independent predictor of abnormal GLS.

Echo- and B-Type Natriuretic Peptide-Guided Follow-Up versus Symptom-Guided Follow-Up: Comparison of the Outcome in Ambulatory Heart Failure Patients.

Recent European Society of Cardiology and American Heart Association/American College of Cardiology Guidelines did not recommend biomarker-guided therapy in the management of heart failure (HF) patients. Combination of echo- and B-type natriuretic peptide (BNP) may be an alternative approach in guiding ambulatory HF management. Our aim was to determine whether a therapy guided by echo markers of left ventricular filling pressure (LVFP), lung ultrasound (LUS) assessment of B-lines, and BNP improves outcomes of HF patients. Consecutive outpatients with LV ejection fraction (EF) ≤ 50% have been prospectively enrolled. In Group I (n=224), follow-up was guided by echo and BNP with the goal of achieving E-wave deceleration time (EDT) ≥ 150 ms, tissue Doppler index E/e' < 13, B-line numbers < 15, and BNP ≤ 125 pg/ml or decrease >30%; in Group II (n=293), follow-up was clinically guided, while the remaining 277 patients (Group III) did not receive any dedicated follow-up. At 60 months, survival was 88% in Group I compared to 75% in Group II and 54% in Group III (χ 2 53.5; p < 0.0001). Survival curves exhibited statistically significant differences using Mantel-Cox analysis. The number needed to treat to spare one death was 7.9 (Group I versus Group II) and 3.8 (Group I versus Group III). At multivariate Cox regression analyses, major predictors of all-cause mortality were follow-up E/e' (HR: 1.05; p=0.0038) and BNP >125 pg/ml or decrease ≤30% (HR: 4.90; p=0.0054), while BNP > 125 pg/ml or decrease ≤30% and B-line numbers ≥15 were associated with the combined end point of death and HF hospitalization. Evidence-based HF treatment guided by serum biomarkers and ultrasound with the goal of reducing elevated BNP and LVFP, and resolving pulmonary congestion was associated with better clinical outcomes and can be valuable in guiding ambulatory HF management.