Causes and impact on survival of underuse of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in heart failure.

Guidelines recommend angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) for treatment of heart failure with reduced ejection fraction (HFrEF), but these medications are underprescribed in clinical practice. We reviewed the records of HF patients receiving a first visit in a tertiary outpatient clinic from January 1st 2004 to May 31st 2015, and selected those with a serum creatinine concentration (sCr) available at both the first and last visit and < 3.5 mg/dL at baseline, and a left ventricular ejection fraction (LVEF) < 50% at the first visit. Of 570 eligible patients, 92 (16.1%) never received ACEi/ARB. Compared to ACEi/ARB users, never-users were older, more often women, had higher sCr and lower systolic blood pressure, were less commonly on beta-blocker, and had more frequently anemia. Current or prior cancer also tended to be more common in ACEi/ARB never-users. ACEi/ARB users displayed an improvement in LVEF by ≥ 10% of the baseline value more often than ACEi/ARB never-users (33.7% vs. 20.7%, respectively, P = 0.01), whereas no difference in percent variation of sCr levels was found between the two groups (8.2% vs. 3.1%, respectively; P = 0.13). Over a median follow-up of 56 months (range 1-137 months), 215 (37.7%) patients died. After multiple adjustments, ACEi/ARB never-use was associated with an almost twofold increased risk of all-cause mortality (HR 1.97, 95%CI 1.39-2.80). ACEi/ARB underuse in HFrEF is a standing issue with dramatic prognostic consequences. Efforts are needed to eliminate perceived contraindications to these drugs and ensure their implementation in real-life cardiology.

Clinical characteristics and prognostic impact of atrial fibrillation in patients with chronic heart failure.

AIM: To assess the prevalence, clinical characteristics and independent prognostic impact of atrial fibrillation (AF) in chronic heart failure (CHF) patients, and the potential protective effect of disease-modifying medications, particularly beta-blockers (BB). METHODS: We retrospectively reviewed the charts of patients referred to our center since January 2004, and collected all clinical information available at their first visit. We assessed mortality to the end of June 2015. We compared patients with and without AF, and assessed the association between AF and all-cause mortality by multivariate Cox regression and Kaplan-Meyer analysis, particularly accounting for ongoing treatment with BB. RESULTS: A total of 903 patients were evaluated (mean age 68 ± 12 years, 73% male). Prevalence of AF was 19%, ranging from 10% to 28% in patients ≤ 60 and ≥ 77 years, respectively. Besides the older age, patients with AF had more symptoms (New York Heart Association II-III 60% vs 44%), lower prevalence of dyslipidemia (23% vs 37%), coronary artery disease (28% vs 52%) and left bundle branch block (9% vs 16%). On the contrary, they more frequently presented with an idiopathic etiology (50% vs 24%), a history of valve surgery (13% vs 4%) and received overall more devices implantation (31% vs 21%). The use of disease-modifying medications (i.e., BB and ACE inhibitors/angiotensin receptor blockers) was lower in patients with AF (72% vs 80% and 71% vs 79%, respectively), who on the contrary were more frequently treated with symptomatic and antiarrhythmic drugs including diuretics (87% vs 69%) and digoxin (51% vs 11%). At a mean follow-up of about 5 years, all-cause mortality was significantly higher in patients with AF as compared to those in sinus rhythm (SR) (45% vs 34%, P value < 0.05 for all previous comparisons). However, in a multivariate analysis including the main significant predictors of all-cause mortality, the univariate relationship between AF and death (HR = 1.49, 95%CI: 1.15-1.92) became not statistically significant (HR = 0.98, 95%CI: 0.73-1.32). Nonetheless, patients with AF not receiving BB treatment were found to have the worst prognosis, followed by patients with SR not receiving BB therapy and patients with AF receiving BB therapy, who both had similarly worse survival when compared to patients with SR receiving BB therapy. CONCLUSION: AF was highly prevalent and associated with older age, worse clinical presentation and underutilization of disease-modifying medications such as BB in a population of elderly patients with CHF. AF had no independent impact on mortality, but the underutilization of BB in this group of patients was associated to a worse long-term prognosis.

Pharmacokinetics and pharmacodynamics of ticagrelor in the treatment of cardiac ischemia.

INTRODUCTION: After acute coronary syndromes (ACS), the so-called dual antiplatelet therapy (DAPT), which usually consists of low-dose of aspirin in combination with a thienopyridine (clopidogrel, prasugrel) or with a cyclopentyltriazolopyrimidine (ticagrelor), reduces the risk of ischemic events. Ticagrelor, un particular, is an effective drug as it isn' a prodrug, doesn't require metabolic activation and demonstrates a rapid onset and faster offset of action. Areas covered: This article evaluates the pharmacokinetics, efficacy, safety and tolerability of ticagrelor during DAPT after ACS and its potential use beyond the canonical twelve months after PCI. The review discusses studies comparing: ticagrelor and clopidogrel (DISPERSE, DISPERSE-2, PLATO, RESPOND Trial, ONSET/OFFSET Trials), ticagrelor and placebo (PEGASUS TIMI 54 Trial). Expert opinion: For ACS patients, the PLATO trial showed that ticagrelor was superior to clopidogrel in the reduction of cardiovascular death, myocardial infarction and stroke. PEGASUS TIMI 54 showed that patients in whom ischemic events and cardiovascular death outweigh the risk of life-threatening bleeding, may benefit from prolonged ticagrelor-based dual antiplatelet therapy, over 12 months. This strategy has been recently approved by the ACC/AHA guidelines. Further studies are needed to evaluate and eventually validate the role of the prolonged DAPT in patients treated with new generation stents.

Mutation Analysis of PRKAR1A Gene in a Patient with Atrial Myxoma.

BACKGROUND: Intracardiac myxomas are frequent benign tumors of the heart and typically localize in the left atri- um and interatrial septum. When myxomas generate at other sites, they are designated as atypical. Mutations in the PRKAR1A gene (a tumor suppressor gene that encodes a protein kinase A [PKA] regulatory 1-alpha subunit) have been identified in both syndromic and non-syndromic cardiac atypical myxomas. METHODS: We report the case of a 33-year old woman suffering from night fever, weight loss, asthenia, and progressive dyspnea. RESULTS: The blood laboratory tests revealed microcytic anemia, leukocytosis, thrombocytosis, increased serum levels of C-reactive protein level, and negative blood cultures. Physical examination also demonstrated a 2/6 systolic murmur. Transthoracic and trans-esophageal echocardiography showed a voluminous, mobile mass in the left atrium with a secondary dynamic obstruction of the left cardiac chamber and a significant functional mitral stenosis. A myxoma was supposed and the patient underwent surgery. Histologically, the lesion was identified as myxomatous tumor with gelatinous pattern. No germline mutations of the PRKAR1A gene were detected. The postoperative course did not present any complications, and the patient was discharged on the sixth postoperative day in good clinical condition. Accordingly, there was an improvement in the laboratory tests' results and a resolution of symptoms. CONCLUSIONS: The patient presented an atrial giant gelatinous myxoma with peculiarity of fever of unknown origin, without PRKAR1A gene germline mutations.

[Distribution and appropriateness of hospital admissions, resource utilization in the Italian intensive cardiac care units. The BLITZ-3 study]. / Distribuzione e appropriatezza dei ricoveri ed utilizzo di risorse nelle unità di terapia intensiva cardiologica italiane. Lo studio BLITZ-3.

BACKGROUND: The BLITZ-3 study prospectively evaluated the epidemiology of hospital admissions, the patterns of care and the most important comorbidities in intensive cardiac care unit (ICCU) patients. METHODS: Distribution and level of appropriateness of hospital admissions in relation to type of ICCU were analyzed (type A, 32%, without cardiac cath lab or cardiac surgery; type B, 49%, with cath lab; type C, 19%, with both cath lab and cardiac surgery). The caseload was estimated on the basis of different levels of mortality risk during the ICCU stay: high (>5.1%), intermediate (0.7-5.1%), low (< or = 0.7%). RESULTS: A total of 6986 consecutive patients admitted to 332 ICCUs were enrolled. A median number of 19 patients (interquartile range 15-26) was admitted to each center during the 14 days of enrollment; 28% of the ICCUs admitted more than 25 patients, 48% between 15 and 25, and 24% less than 15. A higher number of type A ICCUs admitted less than 15 patients (p<0.0001), whereas a higher number of type C ICCUs admitted more than 25 patients (p<0.0001). Hospital admissions for ST-elevation myocardial infarction occurred more frequently in type B or C ICCUs (p<0.0001), whereas hospital admission for heart failure mostly occurred in type A ICCUs (p<0.0001). The number of patients not undergoing reperfusion (p<0.0001) or treated with thrombolytic therapy (p<0.0001) was higher in the type A ICCUs. Coronary revascularization with primary percutaneous coronary intervention was performed more frequently in type B and C ICCUs (p<0.0001). Similarly, patients hospitalized for acute coronary syndrome underwent coronary angiography (p<0.0001) and percutaneous coronary intervention more frequently in type B and C ICCUs (p<0.0001). Prevalence of low-risk rather than intermediate- or high-risk patients was higher in type A ICCUs (p<0.05), and prevalence of high- or intermediate-risk patients was higher in type C ICCUs (p<0.05). CONCLUSIONS: The results of the BLITZ-3 study should lead the Italian cardiological community to reflect upon the needed number of ICCUs, the role of Spoke centers for their integration in the interhospital network, and inappropriate hospital admissions for low-risk conditions.

Stress cardiomyopathy and arrhythmic storm in a 14-year-old boy.

Stress cardiomyopathy is a newly described reversible cardiomyopathy, characterized by transient cardiac dysfunction usually precipitated by intense emotional or physical stress. Apart from the classical apical ballooning syndrome (Takotsubo), it is now increasingly recognized that the spectrum of stress cardiomyopathies is quite wide, with significant individual variations in clinical and morphological pattern. Very recently, it has been suggested that, in young boys in stressful situations, atypical forms of stress cardiomyopathy could be associated with malignant arrhythmias. We describe the case of a 14-year-old boy, in whom stress cardiomyopathy with mid-ventricular ballooning started with an arrhythmic storm.

Percutaneous closure of a giant coronary arteriovenous fistula using free embolization coils in an adult patient.

Coronary artery fistulae may sometimes be asymptomatic and may spontaneously close, but they may also cause angina, myocardial infarction, endocarditis, atrial fibrillation and heart failure. Therefore, in patients with big or symptomatic fistulae, intervention is mandatory. In the literature, most of the patients who underwent transcatheter coil embolization of coronary artery fistulae were children; this is because of the early onset of symptoms in the most severe cases, but also because many adult patients are usually referred to surgery. We describe the case of an adult patient presenting with heart failure and a giant tortuous coronary fistula, with high shunt flow from right coronary artery to right atrium, which was successfully treated with transcatheter closure with free embolization coils. The most challenging technical aspect of transcatheter coil embolization is the precise release of the spirals.

[Italian clinical trials on cardiac cell therapy: where we are and where are we going?]. / Sperimentazioni cliniche di terapia cellulare cardiaca in Italia: come procedere?

BACKGROUND: In the last years translation from bench to bedside of findings regarding cardiac cell therapy is swinging between delays and accelerations. Based on experimental studies, clinical trials were started in 2001. To date in Europe more than 900 patients have been treated with cell transplantation or mobilization and new clinical trials are ongoing in many countries. Published data provide a limited idea of current Italian clinical research in this field. This investigation intends to report Italian clinical trials and projects using cell therapy in cardiology. METHODS: Italian Centers involved in cell therapy clinical studies have been detected exploring scientific bibliography and online search engine. Selected Centers have been classified by the origin of collected information: i) peer-reviewed journals; ii) abstract, poster or communications; iii) press or media. A questionnaire was used and face-to-face or telephonic interviews were performed to obtain further details where needed. RESULTS: Among the 16 selected Centers, 5 published their experiences on peer-reviewed journals, 5 produced abstracts or communications for scientific meetings and 6 bring out their protocols through press or media. Usually Italian clinical trials are monocenter (11 monocenter studies, 2 multicenter) and enrol few patients (an average of about 10 patients treated in each study); 2 Centers are waiting for protocol approval by the Italian Institute of Health; in one case approval was not obtained by the Ethics Committee. Few centers found projects on their own preclinical studies. CONCLUSIONS: The investigation on Italian clinical experiences with cardiac cell therapy demonstrates the limits of what has been produced so far. An Italian working group on cardiovascular regenerative therapies could represent a useful tool to improve national clinical research in this field.

[Cardiac cell therapy: the puzzle is waiting to be solved]. / Terapia cellulare cardiaca: un puzzle in attesa di composizione.

Cell therapy has been proposed as an innovative hypothesis to treat acute myocardial infarction and heart failure. However, the mechanism by which stem cells could improve cardiac function remains unclear and many controversies have been arisen in interpretation of experimental and clinical data. Answering the five "WH questions" we discuss the process that has led to consider cell therapy as a new treatment option for myocardial tissue regeneration after ischemic damage. 1) Why should we use stem cells? The rationale derives from the disclosure that apoptosis and regeneration occur at the myocardial level and stem cells migrate from bone marrow to repopulate the damaged cardiac tissue. 2) Which are the most appropriate cells, delivery methods and therapeutic purposes? Adult stem cells can be mobilized or directly transplanted in human hearts to accomplish myocardioneogenesis, neoangiogenesis and/or paracrine effects. 3) Where should we transplant these cells? The infarct border zone seems to be the best place to home and differentiate transplanted cells hampering post-ischemic cardiac remodeling. 4) When should we perform cell therapy? Cell therapy should be performed during or after an acute myocardial infarction: best setting and timing still need to be precisely addressed. 5) Who might be the suitable patient? Further multicenter randomized trials with adequate patient selection are needed to answer this crucial question.

Epidemiology of acute myocardial infarction in the Italian CCU network: the BLITZ study.

AIMS: A large number of descriptive data on patients with acute myocardial infarction are based on clinical trials and registries on non consecutive patients: these data may give only a partial picture on treatment delay, patient characteristics, treatment and outcome of acute myocardial infarction in the real world. METHODS AND RESULTS: The BLITZ survey prospectively enrolled all of the patients with acute myocardial infarction admitted in 296 (87%) Italian Coronary Care Units from 15-29 October 2001. Data on treatment delay, therapeutic strategies, duration of hospitalization and 30-day outcome were collected. One thousand nine hundred and fifty-nine consecutive patients (mean age 67+/-12 years, 70% males) were enrolled, 65% with ST-segment elevation (STEMI), 30% with no ST-segment elevation (NSTEMI) and 5% with undetermined ECG. The median delay between symptom onset and hospital arrival was 2h and 9 min with 76% of patients hospitalized within the sixth hour (26% within the first hour, 48% within the second). The median delay from hospital arrival to reperfusion therapy in STEMI was 45 min (IQR 26-85) for thrombolysis (50% of the patients) and 85 min (IQR 60-135) for primary angioplasty (15% of the patients). Coronary angiography was performed during hospital stay in 46% of the patients (STEMI 48%, NSTEMI 43%, undetermined AMI 35%), coronary angioplasty in 25% (STEMI 26%, NSTEMI 15%, undetermined AMI 13%) and coronary bypass in 1.4% (1%, 2.2% and 1% respectively). Twenty-two percent of the patients admitted to hospitals without cath-lab were transferred to a tertiary care hospital for invasive procedures. The overall median hospital stay was 10 days (IQR 7-12, STEMI 10, NSTEMI 9, undetermined AMI 11) and was not significantly different between hospitals with or without cath-lab (respectively, 9 and 10 days, P=0.38). After discharge and up to 30 days, coronary angiography was performed in 11% (STEMI 11%, NSTEMI 11%, undetermined MI 9%), angioplasty in 10% (STEMI 10%, NSTEMI 11%, undetermined MI 7%), bypass surgery in 7% (STEMI 5%, NSTEMI 11%, undetermined AMI 7%). The in-hospital and 30-day case fatality rates were 7.4% and 9.4%, respectively (7.5% and 9.5% for STEMI, 5.2% and 7.1% for NSTEMI, 18.2% and 21.2% for undetermined MI). CONCLUSIONS: Patients with acute myocardial infarction admitted to the Italian CCUs, are older than those represented in clinical trials. A high proportion of these cases has the chance to receive early reperfusion therapy. Short-term mortality is lower than expected for patients with STEMI, but higher than reported for NSTEMI.