Clinical outcomes and predictors of success with Impella weaning in cardiogenic shock: a single-center experience.

Introduction: Cardiogenic shock (CS) is a severe syndrome with poor prognosis. Short-term mechanical circulatory support with Impella devices has emerged as an increasingly therapeutic option, unloading the failing left ventricle (LV) and improving hemodynamic status of affected patients. Impella devices should be used for the shortest time necessary to allow LV recovery because of time-dependent device-related adverse events. The weaning from Impella, however, is mostly performed in the absence of established guidelines, mainly based on the experience of the individual centres. Methods: The aim of this single center study was to retrospectively evaluate whether a multiparametrical assessment before and during Impella weaning could predict successful weaning. The primary study outcome was death occurring during Impella weaning and secondary endpoints included assessment of in-hospital outcomes. Results: Of a total of 45 patients (median age, 60 [51-66] years, 73% male) treated with an Impella device, 37 patients underwent impella weaning/removal and 9 patients (20%) died after the weaning. Non-survivors patients after impella weaning more commonly had a previous history of known heart failure (p = 0.054) and an implanted ICD-CRT (p = 0.01), and were more frequently treated with continuous renal replacement therapy (p = 0.02). In univariable logistic regression analysis, lactates variation (%) during the first 12-24 h of weaning, lactate value after 24 h of weaning, left ventricular ejection fraction (LVEF) at the beginning of weaning, and inotropic score after 24 h from weaning beginning were associated with death. Stepwise multivariable logistic regression identified LVEF at the beginning of weaning and lactates variation (%) in the first 12-24 h from weaning beginning as the most accurate predictors of death after weaning. The ROC analysis indicated 80% accuracy (95% confidence interval = 64%-96%) using the two variables in combination to predict death after weaning from Impella. Conclusions: This single-center experience on Impella weaning in CS showed that two easily accessible parameters as LVEF at the beginning of weaning and lactates variation (%) in the first 12-24 h from weaning begin were the most accurate predictors of death after weaning.

Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy.

AIM: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosomal genes, characterized by progressive fibro-adipose replacement of the myocardium, arrhythmias, and sudden death. It is still unclear which cell type is responsible for fibro-adipose substitution and which molecular mechanisms lead to this structural change. Cardiac mesenchymal stromal cells (C-MSC) are the most abundant cells in the heart, with propensity to differentiate into several cell types, including adipocytes, and their role in ACM is unknown. The aim of the present study was to investigate whether C-MSC contributed to excess adipocytes in patients with ACM. METHODS AND RESULTS: We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mesenchymal origin. Therefore, we isolated C-MSC from endomyocardial biopsies of ACM and from not affected by arrhythmogenic cardiomyopathy (NON-ACM) (control) patients. We found that both ACM and control C-MSC express desmosomal genes, with ACM C-MSC showing lower expression of plakophilin (PKP2) protein vs. CONTROLS: Arrhythmogenic cardiomyopathy C-MSC cultured in adipogenic medium accumulated more lipid droplets than controls. Accordingly, the expression of adipogenic genes was higher in ACM vs. NON-ACM C-MSC, while expression of cell cycle and anti-adipogenic genes was lower. Both lipid accumulation and transcription reprogramming were dependent on PKP2 deficiency. CONCLUSIONS: Cardiac mesenchymal stromal cells contribute to the adipogenic substitution observed in ACM patients' hearts. Moreover, C-MSC from ACM patients recapitulate the features of ACM adipogenesis, representing a novel, scalable, patient-specific in vitro tool for future mechanistic studies.

Rhythm-symptom correlation in patients on continuous monitoring after catheter ablation of atrial fibrillation.

INTRODUCTION: Correlation between symptoms and atrial fibrillation (AF) episodes after catheter ablation may have clinical relevance, especially for anticoagulation usage. The aim of our project was to analyze the relationship between symptoms and AF recurrences in unselected patients following AF catheter ablation during long-term follow-up. METHODS AND RESULTS: One hundred and forty-three consecutive patients (mean age 59 ± 9 years, 85% male) were implanted with a continuous cardiac monitor (RevealXT, Medtronic Inc., Minneapolis, MN, USA) following first pulmonary vein ablation procedure. Device data were downloaded every 3 months and correlated to patients' symptom diary. AF was paroxysmal in 55% and persistent in 45%. At a mean follow-up of 14 ± 6 months, 98/143 (69%) patients had at least one AF recurrence. Among these, 53 (54%) reported AF-related symptoms while 45 (46%) were totally asymptomatic. Conversely, 13 (29%) out of 45 patients without AF recurrences reported symptoms. Globally, a significant reduction of symptoms (from 82% at baseline to 44% at last follow-up; P < 0.0001) was observed. SF-12 questionnaire showed a significant improvement of physical and mental functioning (respectively 44.5 ± 8.5 vs 51.0 ± 6.7, and 45.7 ± 9.3 vs 49.2 ± 6.1, P < 0.05 baseline vs last follow-up). At the 12-month follow-up, 80% and 77% of patients were on AAD and anticoagulant drugs, respectively. There were not differences in AAD usage in symptomatic and asymptomatic patients. CONCLUSIONS: Continuous ECG monitoring is a valuable tool for long-term follow-up after AF catheter ablation facilitating reliable assessment of symptomatic and asymptomatic AF episodes. This may have clinical implications with regards to anticoagulation therapy in high-risk patients.

Left ventricular ejection fraction for the risk stratification of sudden cardiac death: friend or foe?

More than 450000 Americans die suddenly each year from sustained ventricular tachycardia or fibrillation. A correct identification of these patients is crucial for a rational clinical management, because the demonstrated effectiveness of implantable cardioverter-defibrillators (ICD) on the reduction of sudden cardiac death. Basing on the results of multiple clinical trials, left ventricular systolic function, measured as ejection fraction, is currently the only recommended tool to identify patients at higher risk of sudden death that would benefit from a prophylactic ICD. However, the systematic implementation of prophylactic ICD recommendations results in a substantial number of inappropriate ICD implantations, while failing to prevent the majority of sudden deaths occurring in the general population. That has been the case implementing arrhythmic risk stratification with a rough arrhythmic risk marker, such as ejection fraction, that lacks sensitivity and specificity in the prediction of sudden cardiac death. The aim of this viewpoint is to critically revise the value of ejection fraction in the identification of patients at risk of sudden cardiac death.

Intracardiac echocardiography in electrophysiology.

Intracardiac echocardiography (ICE) is a recent, invaluable tool which can provide real-time anatomical guidance in electrophysiological procedures. By inserting intravenously an ultrasound probe and advancing it into the heart, various different views can be obtained which allow to better visualize patient anatomy, to guide the placement of electrophysiological catheters, and to detect immediately procedural complications as they occur. In atrial fibrillation ablation, ICE proves particularly useful to achieve a safer trans-septal puncture (especially in the presence of anatomical anomalies of the interatrial septum) and to help to monitor the visualization of the mapping catheters (circular, high density), or the monitoring of the balloons catheter (Cryo, Laser) position. In ventricular tachycardia ablation, on the other hand, ICE allows for continuous correlation between electrophysiological and structural findings (such as wall motion anomalies or changes in echodensity), and helps to ensure correct catheter contact and to position it, particularly around delicate structures such as the aortic cusps. In any procedure, ICE is also useful to immediately detect procedural complications, such as thrombus formation along catheters, or pericardial effusion. Thanks to its real-time morphological information, ICE provides an ideal complement to simple fluoroscopy or to more complex electroanatomic mapping techniques and is set to gain a wider role in a broad range of electrophysiological procedures.

Risk of arrhythmia in type I myotonic dystrophy: the role of clinical and genetic variables.

OBJECTIVE: To examine the association between the presence of arrhythmia in type 1 myotonic dystrophy (DM1) and clinical-genetic variables, evaluating their role as predictors of the risk of arrhythmia. METHODS: 245 patients with genetically proven DM1 underwent clinical and non-invasive cardiological evaluation. Severity of muscular involvement was assessed according to the 5 point Muscular Disability Rating Score (MDRS). Data were analysed by univariate and multivariate models. RESULTS: 245 patients were examined and cardiac arrhythmias were found in 63 subjects, 40 of whom required a device implant. Statistical analyses revealed that men had more than double the risk of developing arrhythmias compared with women (p = 0.018). Addition of each year of age caused an increased risk of arrhythmia equal to 3% (p = 0.030). Subjects with MDRS 5 had a risk of arrhythmia 12 times higher than patients with MDRS 1-2 (p<0.001). Although all of these variables were significantly associated with cardiac rhythm dysfunction, they had a low sensitivity for the prediction of arrhythmic risk CONCLUSION: Male sex, age and muscular disability were strongly associated with the development of arrhythmia in DM1. However, all of these variables were weak predictors of arrhythmic risk. These results suggest that other factors may be involved in the development of cardiac conduction abnormalities in DM1.

Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition.

BACKGROUND AND OBJECTIVES: Total parenteral nutrition (TPN) is a lifesaving therapy in children with intestinal failure, frequently complicated by liver dysfunction. Plant sterols (phytosterols) of lipid emulsions have been supposed to contribute to cholestasis in TPN-treated children. The present study aimed to evaluate the plasma and red blood cell membrane (RBCM) phytosterol levels in newborns after a short period of TPN. PATIENTS AND METHODS: Phytosterols, cholesterol, and other sterol levels were quantified by gas chromatography-mass spectrometry in 15 healthy control infants, 22 patients after TPN, and 11 patients before TPN. Sterols of lipid emulsions were quantified. RESULTS: Plasma and RBCM phytosterol levels were, respectively, on average 56 micromol/L and 83 micromol/g per protein in patients after TPN, 13 micromol/L and 15 micromol/g per protein in patients before TPN, and 9 micromol/L and 13 micromoL/g per protein in control infants (P < 0.05 for differences). The days of TPN and the total amount of infused lipids correlated significantly with RBCM phytosterol (P < 0.05); correlations for plasma were positive but not significant. No correlation was observed with plasma bilirubin, gamma-glutamyltransferase, or alanine transaminase. CONCLUSIONS: Plasma and RBCM phytosterols increase significantly in newborns after a short period of TPN. Higher phytosterol levels were observed in some patients that could have been due to their individual variability in phytosterol metabolism and/or clearance. A greater accumulation of phytosterols in membranes may induce TPN-related cholestasis.

Vitamin D status in patients affected by Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by developmental delay and multiple malformations. Some of the patients have skin photosensitivity and therefore tend to avoid direct exposure to sunlight.SLOS patients typically have low concentrations of cholesterol and abnormally high concentrations of its precursor 7-dehydrocholesterol (7-DHC) in biological fluids and tissues. 7-DHC is also a precursor in the cutaneous synthesis of vitamin D. Sunlight exposure plays a major role in this pathway and reactions transforming 7-DHC into vitamin D and then into 25-hydroxyvitamin D are known not to be specifically regulated. The aim of this study was to evaluate vitamin D status in SLOS patients. We measured 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations and markers of calcium metabolism in five SLOS patients. Despite abnormally high concentrations of 7-DHC, circulating concentrations of vitamin D metabolites were not significantly different from appropriate controls matched for sex, age and season of blood collection. The analysis of historical serum samples stored in our laboratory from the same cases plus 10 other SLOS patients further supported these findings. Our data suggest that SLOS patients have a peculiar vitamin D metabolism that protects them from vitamin D intoxication. This appears to be due in most cases to decreased transformation of 7-DHC into 25-hydroxyvitamin D, perhaps depending on reduced sunlight exposure as a consequence of photosensitivity. Possible alternative mechanisms are discussed.

Rate-control or rhythm-control: where do we stand?

Atrial fibrillation is the most common sustained rhythm disturbance and its prevalence is increasing worldwide due to the progressive aging of the population. Current guidelines clearly depict the gold standard management of acute symptomatic atrial fibrillation but the best-long term approach for first or recurrent atrial fibrillation is still debated with regard to quality of life, risk of new hospitalizations, and possible disabling complications, such as thromboembolic stroke, major bleeds and death. Some authors propose that regaining sinus rhythm in all cases, thus re-establishing a physiologic cardiac function not requiring a prolonged antithrombotic therapy, avoids the threat of intracranial or extracranial haemorrhages due to Vitamin K antagonists or aspirin. On the contrary, advocates of a rate control approach with an accurate antithrombotic prophylaxis propose that such a strategy may avoid the risk of cardiovascular and non cardiovascular side effects related to antiarrhythmic drugs. This review aims to explore the state of our knowledge in order to summarize evidences and issues that need to be furthermore clarified.

Prolonged asystolia in a young athlete: a case of sinus arrest during REM sleep.

A young asymptomatic male athlete came to our laboratory to be enrolled in a research protocol on physical fatigue. Routine clinical and cardiological evaluations including echocardiogram were in the normal range. Several consecutive cardiopulmonary tests showed a fairly good tolerance to exercise, with no symptoms even when the effort was abruptly arrested. On the other hand, Holter ECG recordings showed long nocturnal sinus pauses. As he was absolutely asymptomatic and free from any structural heart disease, he underwent a follow-up with repeated Holter monitorings for one year. During this period he decided on his own to stop practising sports; in spite of this sharp reduction in his overall physical activity, consecutive Holter monitorings showed that the sinus pauses were progressively increasing in duration (up to 9.2 seconds). With the hypothesis of a malignant vagotonia, he underwent a tilt test; however, we could not elicit any pauses or symptoms. The pauses grew longer over time; a endocavitary electrophysiologic test was performed, which showed no evidence of disease. To rule out the hypothesis of a sleep apnoea syndrome, he also underwent a polysomnography, including EEG, eye movement electromyography, arterial blood oxygen saturation and thoracic impedance: no alterations were detected with the exception of the sinus pauses, which appeared to be strictly linked to REM sleep, as suggested by the concurrent increase in rapid eye movements and desynchronized EEG. We hence made a diagnosis of sinus arrest during REM sleep (SAdRS), a very uncommon disease belonging to the parasomnias. Pauses were then quantified for one month by implanting a ECG loop recorder. As the patient became more and more upset and worried, and the pauses increased to nearly 12 seconds, we decided to implant a pacemaker, which is the only therapeutic option established in the literature for patients with SAdRS.

Impairment of cardiac autonomic function in patients with Duchenne muscular dystrophy: relationship to myocardial and respiratory function.

BACKGROUND: Previous studies reported an impairment of nervous autonomic activity in patients with Duchenne muscular dystrophy (DMD). However, the relationship of the autonomic dysfunction to the impairment of cardiac mechanical function and of respiratory failure is not completely understood. METHODS: We evaluated cardiac autonomic function by time- and frequency-domain heart rate variability (HRV) analysis on 24-hour Holter recordings in 60 patients with DMD (16.8 +/- 4.8 years) and 28 healthy control patients (15.2 +/- 4.6 years, P = not significant). The circadian rhythm of R-R interval, low frequency, high frequency, and low-frequency/high-frequency ratio was also assessed. In all patients, left ventricular ejection fraction was measured by 2D echocardiography; respiratory function was assessed by spirometry. RESULTS: All HRV parameters were lower in patients with DMD than in control subjects, with the percentage of differences between adjacent R-R intervals >50 ms (11.6% +/- 8.5% vs 27.3% +/- 14.1%, P =.00001) and high frequency (23.9 +/- 10.3 ms vs 36.1 +/- 12.2 ms, P =.0001) showing the strongest differences. A significant circadian rhythm of HRV variables was present in both groups, but it was considerably flattened in patients with DMD. There was no correlation between left ventricular ejection fraction and HRV indexes except for a weak correlation with high frequency (r = 0.30, P =.02) and with low-frequency to high-frequency ratio (r = -0.29, P <.03). Similarly modest correlations were found between forced vital capacity and high frequency (r = 0.4, P =.007) and low-frequency/high-frequency ratio (r = -0.32, P =.026). Multiple regression analysis did not show any independent predictive variable for the autonomic impairment. CONCLUSIONS: Our data show a marked impairment of cardiac autonomic function in patients with DMD, which appears to mainly involve the parasympathetic branch and appears to have a multifactorial origin.

Clinical, electrocardiographic and electrophysiological predictors of atrial fibrillation development in different cardiac substrates.

We performed a review of the current literature in order to evaluate clinical, electrocardiographic and electrophysiologic parameters predictive of atrial fibrillation development. Clinical parameters were obtained from two large observational studies (the Framingham heart study and the Cardiovascular health study). Different laboratoristic predictors were also reviewed: ECG-derived predictors, among which we separately evaluated those derived from the 12-lead surface ECG and those derived from the signal averaged P-wave, and other electrophysiologic predictors as atrial monophasic action potential analysis. We also evaluated the clinical value of these different parameters in atrial fibrillation in patients with no overt structural heart disease and in the most common clinical conditions known to be related to atrial fibrillation development such as hypertension, heart failure, cardiovascular surgery.

Olive oil and reduced need for antihypertensive medications.

BACKGROUND: The blood pressure (BP) effects of changing the total fat intake and saturated-unsaturated fat ratio are still controversial, despite evidence that saturated fat-enriched diets are associated with higher BP levels. This double-blind, randomized crossover study evaluated a possible difference between antihypertensive effects of monounsaturated (MUFA) (extra-virgin olive oil) and polyunsaturated fatty acids (PUFA) (sunflower oil). METHODS: Twenty-three hypertensive patients were assigned randomly to MUFA or PUFA diet for 6 months and then crossed over to the other diet; effects were evaluated on the basis of daily antihypertensives needed. RESULTS: Diets high in MUFA and PUFA differed from the habitual diet for reduced total and saturated fats, whereas they differed from each other for MUFA (17.2% vs 10.5%) and PUFA content (3.8% vs 10.5%). Resting BP was significantly lower (P = .05 for systolic BP; P = .01 for diastolic BP) at the end of the MUFA diet compared with the PUFA diet. Blood pressure responses during sympathetic stimulation with the cold pressor test and isometric exercise were similar. Daily drug dosage was significantly reduced during the MUFA but not the PUFA diet (-48% vs - 4%, P<.005). All patients receiving the PUFA diet required antihypertensive treatment, whereas 8 of those receiving the MUFA diet needed no drug therapy. CONCLUSIONS: A slight reduction in saturated fat intake, along with the use of extra-virgin olive oil, markedly lowers daily antihypertensive dosage requirement, possibly through enhanced nitric oxide levels stimulated by polyphenols.

Complete remission in acute myeloid leukaemia with t(8;21) following treatment with G-CSF: flow cytometric analysis of in vivo and in vitro effects on cell maturation.

A 75-year-old patient diagnosed as having acute myeloid leukaemia with t(8;21) received G-CSF alone as induction therapy. Complete remission was achieved following 2 weeks of treatment. Flow cytometric analysis, performed by CD45 technique modified by the introduction of preliminary gating with LDS-751, confirmed the disappearance of blast cells along with myeloid maturation. Finally, in vitro studies demonstrated that G-CSF, as compared to other differentiation inducers, was able to induce a striking effect toward neutrophilic differentiation.

In vitro exposure of acute promyelocytic leukemia cells to arsenic trioxide (As2O3) induces the solitary expression of CD66c (NCA-50/90), a member of the CEA family.

Arsenic trioxide (As2O3) is a useful drug for the treatment of acute promyelocytic leukemia (APL), acting through a complex mechanism involving the induction of apoptosis. We investigated by flow cytometry whether in vitro treatment of APL leukemic cells with As2O3 determined specific surface membrane changes. Twelve APL bone marrow aspirates were analyzed following 7 days of in vitro treatment with As2O3 (0.25, 0.5 and 2.5 microM) with regard to the expression of a series of differentiation antigens. Twelve acute myeloid leukemia (AML) samples of non-APL morphotype were analyzed as controls. Exposure of APL as well as non-APL samples to any concentration of As2O3 did not affect the expression of beta2 integrins (CD11a and CD11b), CD45 isoforms (RA, RB and R0), CD44/H-CAM, CD33 and the CEA-related antigen family members CD66ade and CD66b, thus failing to disclose any maturating effect. Of interest, in all APL samples (but not in AML) every tested dose of As2O3 determined a dramatic upregulation of CD66c display; intermediate concentration (0.5 microM) of As2O3 increased the median percentage of CD66c+ cells from 5% in control cultures (25th-75th percentile 2-12%) to 80% in drug-exposed cultures (25th-75th percentile 58-90%) (P<0.001). The induction of solitary expression of CD66c is a new finding which demonstrates As2O3 capability of generating phenotypic changes absolutely restricted to APL cells Moreover, these results provide experimental basis for considering the involvement of the newly described CD66 signalling pathway in As2O3-driven programmed cell death.