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.

Venous Congestion and Systemic Hypoperfusion in Cardiorenal Syndrome: Two Sides of the Same Coin.

A wide range of comorbidities play a pivotal role in worsening outcomes and increasing mortality risk in patients with heart failure (HF). Among them, renal dysfunction has been recognized as a highly prevalent prognostic variable, with a strong impact on prognosis, length of hospital stay and need for intensive care. In this context, recent evidence has pointed out the relevance of both systemic hypoperfusion and venous congestion on the imbalance of renal function as well as on the conditioning the pathophysiological crosstalk between heart and kidneys through a wide range of haemodynamic and biochemical pathways. This narrative review aims to investigate the intricate interplay between impaired systemic perfusion and venous congestion in cardiorenal syndrome, as well as their haemodynamic and biochemical implications for renal damage in HF.

Structure Driven Prediction of Chromatographic Retention Times: Applications to Pharmaceutical Analysis.

Pharmaceutical drug development relies heavily on the use of Reversed-Phase Liquid Chromatography methods. These methods are used to characterize active pharmaceutical ingredients and drug products by separating the main component from related substances such as process related impurities or main component degradation products. The results presented here indicate that retention models based on Quantitative Structure Retention Relationships can be used for de-risking methods used in pharmaceutical analysis and for the identification of optimal conditions for separation of known sample constituents from postulated/hypothetical components. The prediction of retention times for hypothetical components in established methods is highly valuable as these compounds are not usually readily available for analysis. Here we discuss the development and optimization of retention models, selection of the most relevant structural molecular descriptors, regression model building and validation. We also present a practical example applied to chromatographic method development and discuss the accuracy of these models on selection of optimal separation parameters.

Predictors of cardiovascular outcome and rehospitalization in elderly patients with heart failure.

BACKGROUND: Heart failure (HF) is a major public health problem and represents the only cardiac disease continuing to increase in prevalence, in particular among elderly patients. The frequent rehospitalizations have a negative impact on quality of life of patients with HF, constituting a substantial cost for patients and the health system. The aim of this review was to look into biochemical, echocardiographic and socioeconomical parameters as predictors of clinical outcomes and rehospitalizations. METHODS: This narrative review is based on the material searched for and obtained via PubMed from January 2000 up to March 2018. The search terms we used were as follows: "elderly, heart failure, cardiovascular" in combination with "biomarker, echocardiography and hospitalization." RESULTS: This review analyses the potential predictive role of biochemical and echocardiographic and socioeconomical parameters on clinical outcomes (particularly cardiovascular) and hospital readmissions in patients with chronic HF. We focused on risk stratification of elderly patients with HF, who constitute a category of frail subjects at higher risk for readmission to hospital. CONCLUSIONS: In elderly subjects with chronic HF, the risk stratification could benefit of a multiparametric approach combining biochemical, echocardiographic, demographic and socioeconomical parameters, thus ensuring a better quality of life and at the same time a better allocation of financial resources.

Potential cardiac risk of immune-checkpoint blockade as anticancer treatment: What we know, what we do not know, and what we can do to prevent adverse effects.

Cancer immunotherapy has become a well-established treatment option for some cancers after the development of a family of drugs targeting the so-called immune checkpoints, such as CTLA4 and PD-1 with PD-L1. These co-receptors/ligands inhibit the activation of T-cell, thus preventing an excessive inflammatory response. Tumors exploit these pathways to induce immune tolerance to themselves. Thus, the main effect of checkpoint-blocking drugs is to awake an immune response primarily directed against cancer cells. Nonetheless, as the immune response elicited by these drugs is not completely tumor-specific, their use may actually cause several adverse effects, including adverse cardiovascular effects. In this review, we will discuss the principles and potentiality of immunotherapy for cancer treatment, the experimental and clinical data on the role of CTLA4 and PD-1 with PD-L1 as immune-checkpoints in the cancer environment and in the cardiovascular system, and strategies aimed at preventing possible cardiovascular adverse effects of immune-checkpoint blockers.

Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non-Small Cell Lung Cancer Patients.

BACKGROUND: Rare cases of severe myocarditis are reported during treatment with nivolumab. Troponin, a biomarker of cardiac damage, is a key component of the diagnostic workup of many cardiac disorders, including myocarditis. This study investigates the role of troponin to assess cardiac involvement during nivolumab therapy for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We evaluated 59 NSCLC patients, analyzing serum samples collected within a translational research study. Troponin above the upper normal limit (0.046 ng/mL) was defined as Tn+, whereas normal but detectable troponin (0.015-0.045) was defined as Tndet. Troponin alterations were interpreted on the grounds of the following elements: peak values and time curve, cardiac comorbidities, signs and symptoms coincident to troponin elevation, ECG, echocardiography, and disease progression. RESULTS: No patient had cardiovascular events. Among 362 available blood samples, Tn+ (max 0.317 ng/mL) was found in 13 determinations belonging to 6 patients. Seven other patients had isolated Tndet. In five patients, Tn+ was attributed to cardiac comorbidities, disease progression, or worsening clinical status. One patient without cardiac history and in good clinical condition had a sustained troponin increase-soon after the start of therapy-and after careful evaluation of all relevant elements, it was interpreted as a marker of nivolumab-related subclinical myocarditis. CONCLUSION: Tn+ may occur in NSCLC patients treated with nivolumab, but in most cases it does not indicate nivolumab cardiotoxicity. In some cases, however, a careful interpretation of troponin alteration, especially at the beginning of therapy, enables identification of subclinical myocarditis, thus allowing early cardiac treatment. IMPLICATIONS FOR PRACTICE: Myocarditis is a rare but serious adverse event of immune checkpoint blockade with nivolumab, which needs to be recognized as soon as possible. This article suggests that troponin, a user-friendly biomarker of myocardial cytotoxicity, might be useful for early detection of immune-mediated myocarditis. However, because troponin abnormalities might also be related to a number of conditions capable of causing myocardial oxygen demand-supply mismatch, a careful cardiac assessment should be performed in non-small cell lung cancer patients in order to properly interpret any troponin increase. According to the available evidence, monitoring troponin during the first weeks of treatment can be considered reasonable.

An increase in myocardial 18-fluorodeoxyglucose uptake is associated with left ventricular ejection fraction decline in Hodgkin lymphoma patients treated with anthracycline.

BACKGROUND: Doxorubicin (DOX)-based chemotherapy for Hodgkin lymphoma (HL) yields excellent disease-free survival, but poses a substantial risk of subsequent left ventricular (LV) dysfunction and heart failure, typically with delayed onset. At the cellular level, this cardiotoxicity includes deranged cardiac glucose metabolism. METHODS: By reviewing the hospital records from January 2008 through December 2016, we selected HL patients meeting the following criteria: ≥ 18 year-old; first-line DOX-containing chemotherapy; no diabetes and apparent cardiovascular disease; 18-fluoro-deoxyglucose positron emission tomography (18FDG-PET) scans before treatment (PETSTAGING), after 2 cycles (PETINTERIM) and at the end of treatment (PETEOT); at least one echocardiography ≥ 6 months after chemotherapy completion (ECHOPOST). We then evaluated the changes in LV 18FDG standardized uptake values (SUV) during the course of DOX therapy, and the relationship between LV-SUV and LV ejection fraction (LVEF), as calculated from the LV diameters in the echocardiography reports with the Teicholz formula. RESULTS: Forty-three patients (35 ± 13 year-old, 58% males) were included in the study, with 26 (60%) also having a baseline echocardiography available (ECHOPRE). LV-SUV gradually increased from PETSTAGING (log-transformed mean 0.20 ± 0.27) to PETINTERIM (0.27 ± 0.35) to PETEOT (0.30 ± 0.41; P for trend < 0.001). ECHOPOST was performed 22 ± 17 months after DOX chemotherapy. Mean LVEF was normal (68.8 ± 10.3%) and only three subjects (7%) faced a drop below the upper normal limit of 53%. However, when patients were categorized by median LV-SUV, LVEF at ECHOPOST resulted significantly lower in those with LV-SUV above than below the median value at both PETINTERIM (65.5 ± 11.8% vs. 71.9 ± 7.8%, P = 0.04) and PETEOT (65.6 ± 12.2% vs. 72.2 ± 7.0%, P = 0.04). This was also the case when only patients with ECHOPRE and ECHOPOST were considered (LVEF at ECHOPOST 64.7 ± 8.9% vs. 73.4 ± 7.6%, P = 0.01 and 64.6 ± 9.3% vs. 73.5 ± 7.0%, P = 0.01 for those with LV-SUV above vs. below the median at PETINTERIM and PETEOT, respectively). Furthermore, the difference between LVEF at ECHOPRE and ECHOPOST was inversely correlated with LV-SUV at PETEOT (P < 0.01, R2 = - 0.30). CONCLUSIONS: DOX-containing chemotherapy causes an increase in cardiac 18FDG uptake, which is associated with a decline in LVEF. Future studies are warranted to understand the molecular basis and the potential clinical implications of this observation.

Ivabradine in Cancer Treatment-Related Left Ventricular Dysfunction.

BACKGROUND: Patients developing cancer treatment-related left ventricular dysfunction (CTrLVD) require a prompt therapy. Hypotension, dizziness, and fatigue often limit the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and ß-blockers (BB) in cancer patients who may already be afflicted by these symptoms. Ivabradine is a heart rate-lowering drug that does not cause hypotension and may be used in heart failure with reduced left ventricular ejection fraction (LVEF). OBJECTIVE: The aim of this paper was to investigate the role of ivabradine to treat CTrLVD. METHODS: A retrospective analysis in a cohort of 30 patients with CTrLVD (LVEF < 50%) receiving ivabradine on top of the maximal tolerated dose of ACEi/ARB and BB was performed. We evaluated cardiovascular treatment, oncologic treatment, LVEF, functional class (New York Heart Association [NYHA]), and fatigue during the study period. RESULTS: Ivabradine was initially started at the dose of 2.5 mg/b.i.d. in most patients and then carefully titrated. Hypotension (70%) and fatigue (77%) were the main causes limiting the treatment with ACEi/ARB and BB. After a mean follow-up of 6.5 months, LVEF increased from 45.1% (SD = 6.4) to 53.2% (SD = 3.9; p < 0.001). When patients were analyzed according to the type of cancer therapy, no difference in LVEF changes across the groups was found. NYHA class ameliorated in 11 patients, while fatigue improved in 8 patients. No serious cardiovascular side effects were reported. CONCLUSIONS: The ability to improve symptoms and LVEF in unfit cancer patients makes ivabradine a reasonable pharmacological tool for treating CTrLVD.

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells.

BACKGROUND: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (KATP). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac KATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells. METHODS: The cardiomyoblast cell line H9c2 was treated for 24 h with glibenclamide or metformin, a known inhibitor of the mitochondrial respiratory chain. Cell viability was evaluated by sulforodhamine B assay. ATP and AMP were measured according to the enzyme coupling method and oxygen consumption by using an amperometric electrode, while Fo-F1 ATP synthase activity assay was evaluated by chemiluminescent method. Protein expression was measured by western blot. RESULTS: Glibenclamide deregulated energy balance of H9c2 cardiomyoblasts in a way similar to that of metformin. It inhibited mitochondrial complexes I, II and III with ensuing impairment of oxygen consumption and ATP synthase activity, ATP depletion and increased AMPK phosphorylation. Furthermore, glibenclamide disrupted mitochondrial subcellular organization. The perturbation of mitochondrial energy balance was associated with enhanced anaerobic glycolysis, with increased activity of phosphofructo kinase, pyruvate kinase and lactic dehydrogenase. Interestingly, some additive effects of glibenclamide and metformin were observed. CONCLUSIONS: Glibenclamide deeply alters cell metabolism in cardiac cells by impairing mitochondrial organization and function. This may further explain the risk of cardiovascular events associated with the use of this drug, alone or in combination with metformin.

Comparison of coronary flow reserve estimated by dynamic radionuclide SPECT and multi-detector x-ray CT.

BACKGROUND: Recent technical advances in multi-detector computed tomography (MDCT) allow for assessment of coronary flow reserve (CFR). We compared regional CFR by dynamic SPECT and by dynamic MDCT in patients with suspected or known coronary artery disease (CAD). METHODS: Thirty-five patients, (29 males, mean age 69 years) with greater than average Framingham risk of CAD, underwent dipyridamole vasodilator stress imaging. CFR was estimated using dynamic SPECT and dynamic MDCT imaging in the same patients. Myocardial perfusion findings were correlated with obstructive CAD (≥50% luminal narrowing) on CT coronary angiography (CA). RESULTS: Mean CFR estimated by SPECT and MDCT in 595 myocardial segments was not different (1.51 ± 0.46 vs. 1.50 ± 0.37, p = NS). Correlation of segmental CFR by SPECT and MDCT was fair (r 2 = 0.39, p < 0.001). Bland-Altman analysis revealed that MDCT in comparison to SPECT systematically underestimated CFR in higher CFR ranges. By CTCA, 12 patients had normal CA, 11 had non-obstructive, and 12 had obstructive CAD. CFR by both techniques was significantly higher in territories of normal CA than in territories subtended by non-obstructive or obstructive CAD. SPECT CFR was also significantly different in territories subtended by non-obstructive and obstructive CAD, whereas MDCT CFR was not. CONCLUSION: Despite relative underestimation of high CFR values, MDCT CFR shows promise for assessing the pathophysiological significance of anatomic CAD.

Neurohormonal activation and pharmacological inhibition in pulmonary arterial hypertension and related right ventricular failure.

During the last decade, hyperactivity of the sympathetic nervous and renin-angiotensin-aldosterone systems (SNS and RAAS, respectively) has repeatedly been related to the pathophysiology of pulmonary arterial hypertension (PAH) and PAH-related right ventricular failure (PAH-RVF), raising the question of whether neurohormonal inhibition may be indicated for these conditions. Experimental data indicate that the RAAS may be involved in pulmonary vascular remodeling, which is in fact halted by RAAS antagonism. Favorable actions of ß-blockers on the pulmonary vasculature have also been described, even if information about ß-adrenergic receptors in PAH is lacking. Furthermore, the available evidence suggests that stimulation of the pressure-overloaded RV by the SNS and RAAS is initially compensatory, but becomes maladaptive over time. Consistently, RV reverse remodeling has been shown in PAH animal models treated with either ß-blockers or RAAS inhibitors, although important differences with human PAH may limit the translational value of these findings. Only few observational studies of neurohormonal antagonism in PAH and PAH-RVF have been published. Nonetheless, ß-blockers on top of specific therapy appear to be safe and possibly also effective. The combination of mineralocorticoid receptor and endothelin-A receptor antagonists may result in an additive effect because of a positive pharmacodynamic interaction. While neurohormonal inhibitors cannot be recommended at present for treatment of PAH and PAH-RVF, they are worth being further investigated.

Update on cardiotoxicity of anti-cancer treatments.

BACKGROUND AND AIMS: Anti-cancer treatments markedly improved the prognosis of patients, but unfortunately might be hampered by cardiotoxicity. Both symptomatic and asymptomatic clinical forms of heart failure have been reported, which may be reversible or irreversible. The aim of this review is to provide an overview of the antineoplastic agents associated with cardiac toxicity and of the available diagnostic techniques. METHODS AND METHODS: This narrative review is based on material from MEDLINE and PUBMED up to November 2015. We looked at the terms antineoplastic drugs and cardiac toxicity in combination with echocardiography, troponins, cardiac magnetic resonance, and positron emission tomography. RESULTS: Anthracyclines, monoclonal antibodies, fluoropyrimidines, taxanes, alkylating agents, vinka alkaloids were reported to induce different clinical manifestations of cardioxicity. Chest radiotherapy is also associated with various forms of cardiac damage, which are indistinguishable from those found in patients with heart disease of other aetiologies and that may even appear several years after administration. Among diagnostic techniques, echocardiography is a noninvasive, cost-effective, and widely available imaging tool. Nuclear imaging and cardiac magnetic resonance may be used but are not so widely available and are more difficult to perform. Finally, some biomarkers, such as troponins, may be used to evaluate cardiac damage, but establishing the optimal timing of troponin assessment remains unclear and defining the cut-off point for positivity is still an important goal. CONCLUSIONS: Cardiotoxicity of anti-cancer treatments is associated with development of heart failure. Novel diagnostic tools might be relevant to early recognize irreversible forms cardiac diseases.

Recurrent and Residual Shunts After Patent Foramen Ovale Closure: Results From a Long-Term Transcranial Doppler Study.

OBJECTIVES: Assess the evolution of right-to-left shunt (RLS) after transcatheter patent foramen ovale (PFO) closure. BACKGROUND: Despite the high number of interventional procedures performed worldwide, limited systematic data on the long-term abolition of RLS after percutaneous closure are available. METHODS: All patients treated at our Institution between February 2001 and July 2009 were included in this single center, prospective study, and were asked to repeat late contrast transcranial Doppler (cTCD). Rate of complete closure, residual RLS (i.e., a shunt that persists after closure), and recurrent RLS (i.e., a shunt that reappears after a previous negative cTCD) was assessed. RESULTS: Long-term follow-up was completed in 120 patients (56% male). RLS was still detectable 4.9 ± 2.3 years (range 1.3-10.3) after the procedure in 55 patients; 20 (17%) had residual RLS and 35 (29%) had recurrent RLS. Multivariate analysis revealed that significant predictors of residual RLS included post-procedural shunt at transesophageal echocardiography (OR 3.07, 95%CI 0.97-9.7), use of a bigger device (35 vs 25 mm, OR 3.85, 95%CI 1.22-12.2) and length of follow-up (OR 0.75, 95%CI 0.57-0.98), while only length of follow-up (OR 0.77, 95%CI 0.62-0.95) was associated with recurrent RLS. Neurological recurrences (1 stroke, 6 transient ischemic attacks) were equally distributed between the groups. CONCLUSION: A significant number of recurrent and residual shunts may be observed by cTCD up to 5 years after PFO closure. Management of late RLSs includes periodic re-evaluation, exclusion of device-induced complications or secondary sources of RLS, and optimization of antithrombotic treatment with or without a second intervention.

Aberrant right subclavian artery (arteria lusoria) challenging 4-French homolateral transradial coronary catheterisation in adulthood.

We report a case of an accidental finding of an aberrant right subclavian artery diagnosed in an adult man during a 4-French coronary angiography performed by right transradial access, then confirmed by multi-slice computed tomography. Tips and tricks have been suggested to complete the 4-French procedure avoiding changing the vascular access.

Update on the efficacy of statin treatment in acute coronary syndromes.

BACKGROUND: The natural history of atherosclerosis might involve coronary plaque rupture/erosion, thrombus formation and vessel lumen occlusion, clinically recognized as acute coronary syndrome (ACS). International guidelines strongly recommend early statin administration in patients admitted for ACS. In addition to lowering circulating levels of low-density lipoprotein cholesterol (LDL-c), statin treatment was shown to promote plaque stabilization or regression in several ways, including reduction in necrotic lipid core, anti-inflammatory effects and improvement in endothelial function. The aim of this review is to summarize clinical evidence on the role of statins in secondary prevention of ACS. MATERIALS AND METHODS: This narrative review is based on the material found on medline and pubmed up to August 2013. We looked for the terms 'statin, acute coronary syndromes' in combination with 'atherosclerosis, acute myocardial infarction, pathophysiology'. RESULTS: This review article emphasizes the relevance of the timing of statin administration to improve the outcomes after ACS. Early and continuous statin administration has emerged as key features to prevent adverse events, especially in patients admitted for ACS undergoing percutaneous coronary intervention. Clinical trials matching the improved clinical outcome with the imaging of atherosclerotic plaque stabilization/regression, further supporting the effectiveness of statin therapy. However, the achievement of these goals requires high dose of statins, thus increasing the risk of adverse events. CONCLUSIONS: Although clinical trials and meta-analyses have provided conflicting results, it is likely that in clinical practice, the rate of adverse events is higher, so that many concerns still remain about a statin high-dose approach in ACS patients.

Transient left ventricular and stomach apical ballooning syndromes: when the trigger is also a clinical emergency.

A 59-year-old woman was referred to our emergency department because of epigastric pain and incoercible vomit. Electrocardiogram showed ST-segment elevation in anterior-lateral leads, but coronary angiogram revealed normal coronary tree and left ventricular angiography showed apical and midventricular akinesis with preserved basal systolic function: a diagnosis of apical ballooning syndrome was made. During the following days, the patient complained about persistent abdominal pain, and a nasogastric tube drained more than 1000 cc of dark fecaloid material. Urgent abdominal computed tomography scan showed a mural thrombus in the apex of the left ventricle and a huge diaphragmatic hernia through which more than one-half of the stomach was herniated and presented a sort of "apical stomach ballooning." Gastropexy was done; surgical diagnosis was a type IV giant diaphragmatic hernia complicated by recent gastric volvulus caused by rotation along the longitudinal cardiopyloric axis. Type IV giant diaphragmatic hernia is relatively rare, representing only about 5% to 7% of all hernias. Gastric volvulus is a severe complication, with acute mortality reported to be as high as 30% to 50%. In our case, a severe life-threatening condition as gastric volvulus triggered an apical ballooning syndrome, a transient cardiomyopathy, usually induced by emotional stressors with a long-term good prognosis. Apical ballooning syndrome must be considered an epiphenomenon of other organic diseases that may have an important role in the prognosis of the patient not only in acute but also in chronic setting. Only early determination of the true cause of apical ballooning syndrome ensures a proper treatment.