Cardiac mechanics in response to proteasome inhibition: a prospective study.

AIM: Ubiquitin-Proteasome System (UPS) is of paramount importance regarding the function of the myocardial cell. Consistently, inhibition of this system has been found to affect myocardium in experimental models; yet, the clinical impact of UPS inhibition on cardiac function has not been comprehensively examined. Our aim was to gain insight into the effect of proteasome inhibition on myocardial mechanics in humans. METHODS AND RESULTS: We prospectively evaluated 48 patients with multiple myeloma and an indication to receive carfilzomib, an irreversible proteasome inhibitor. All patients were initially evaluated and underwent echocardiography with speckle tracking analysis. Carfilzomib was administered according to Kd treatment protocol. Follow-up echocardiography was performed at the 3rd and 6th month. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells.At 3 months after treatment, we observed early left ventricular (LV) segmental dysfunction and deterioration of left atrial (LA) remodelling, which was sustained and more pronounced than that observed in a cardiotoxicity control group. At 6 months, LV and right ventricular functions were additionally attenuated (P < 0.05 for all). These changes were independent of blood pressure, endothelial function, inflammation, and cardiac injury levels. Changes in PrA were associated with changes in global longitudinal strain (GLS), segmental LV strain, and LA markers (P < 0.05 for all). Finally, baseline GLS < -18% or LA strain rate > 1.71 were associated with null hypertension events. CONCLUSION: Inhibition of the UPS induced global deterioration of cardiac function.

The behavior of three types of large sinus node arteries with regard to the blood supply of the atrial myocardium.

PURPOSE: We describe angiographic findings of sinus node arteries (SNAs), focusing in the large sinus node artery (LSNA) variants, regarding the blood supply of the SN and atrial myocardium. METHODS: We examined the SN arteries via postmortem angiographic visualization in six hundred hearts derived from victims of various accidents. RESULTS: The main stem or a branch of the SNA supplied the right atrium (RA) and part of the interatrial septum (IS) in 32% of cases (Group A), one atrium, the IS and a small part of the other atrium (Group B) in 39% and the entire atrial myocardium (LSNAs) (Group C) in 29%. Forty-two percent (42%) of LSNAs were arising from the anterior part of the right coronary artery (RCA) (type 1), 9% from its intermediate part (type 2) and 49% from the posterolateral portion of the left circumflex artery (LCx) (type 3). Type 2 can be injured by surgical procedures, type 3 by interventional ones, while type 1 is not affected by any. The SN area was supplied in Groups A and B by the main stem of SN arteries in 370 cases (62%) and by branches (Br) in 55 (9%). The 175 cases of group C (29%) were supplied only by branches. The clockwise (40% of cases) and counterclockwise rotations (60%) of the SNA around the superior vena cava, concern surgical procedures. CONCLUSION: The above findings are essential for every day surgical and interventional procedures.

Activated Clotting Time as a Marker of Inflammation in Hospitalized Patients.

Inflammation and coagulation pathways are implicated in circulatory disease, but their interaction has not been completely deciphered yet. In this study, we investigated the association of coagulation and inflammation indices (activated clotting time [ACT], C-reactive protein, neutrophils) in hospitalized patients. Blood samples were drawn from consecutive patients at admission and at 48 hours for the assessment of the aforementioned parameters (n = 63). Healthy controls matched for sex and age were also examined (n = 39). Activated clotting time positively correlated with CRP on admission (r = 0.354, P = .005), while the correlation was more robust on the second day (r = 0.775, P < .001). Activated clotting time was significantly more prolonged in patients with abnormal CRP or abnormal absolute neutrophil count compared to patients with normal inflammatory markers (U = 55.0, P < .001 and U = 310.5, P = .035, respectively). At 48 hours, a positive relationship was observed between ACT and relative percentage of neutrophils (r = 0.358, P = .004). These findings suggest a link between ACT and inflammation indices for the first time in humans. Further research is needed to determine whether these interrelations can be used to improve patient management.

Electrical Storm: Current Evidence, Clinical Implications, and Future Perspectives.

PURPOSE OF REVIEW: Electrical storm (ES) is a life-threatening medical emergency of repetitive episodes of sustained ventricular arrhythmias within a short period. Its occurrence is associated with poor short- and long-term survival, even in patients with implantable cardioverter defibrillators (ICD). Management of ES is challenging and mainly based on retrospective studies. This article reviews the existing literature on ES, presents the available data regarding its management, and proposes a new algorithm based on current evidence. RECENT FINDINGS: Recent research could modify the management of ES supporting the role of non-selective ß1 and ß2 blockade and the early intervention with catheter ablation as well as strengthening the role of cardiac sympathetic denervation. A multipronged approach should be considered for the management of ES including identification and correction of reversible causes, ICD reprogramming, drug therapy (beta-blockers-especially non-selective ones-and other anti-arrhythmic drugs) and non-pharmacologic therapies such as catheter ablation and techniques of neuroaxial modulation. Although current data suggest early aggressive management, further research is required to clarify the optimal order and combination of therapies for the prevention of future events.

Late T-wave inversion following resolution of non-ischemic acute pulmonary edema.

Electrocardiographic (ECG) changes occurring several hours after the onset of acute cardiogenic pulmonary edema have been seldom described. The proposed explanatory mechanisms are various and not fairly established. In the absence of significant coronary artery disease, these ECG abnormalities could be attributed to mechanisms implicated in coronary microcirculatory dysfunction.

A Recalcitrant Electrical Storm and Implantable Defibrillator Exhaustion: Treatment Implications According to and Beyond Guidelines.

A 60-year-old patient presented with recalcitrant electrical storm (ES). Mild sedation and initial antiarrhythmic combination of esmolol and amiodarone did not affect the intensity of ES, which resulted in battery exhaustion. Oral propranolol in addition to intravenous amiodarone might be preferred in hemodynamically stable patients before interventional therapies. (Level of Difficulty: Intermediate.).

"Low-" versus "high"-frequency oscillation and right ventricular function in ARDS. A randomized crossover study.

BACKGROUND: Recent, large trials of high-frequency oscillation (HFO) versus conventional ventilation (CV) in acute respiratory distress syndrome (ARDS) reported negative results. This could be explained by an HFO-induced right ventricular (RV) dysfunction/failure due to high intrathoracic pressures and hypercapnia. We hypothesized that HFO strategies aimed at averting/attenuating hypercapnia, such as "low-frequency" (i.e., 4 Hz) HFO and 4-Hz HFO with tracheal-gas insufflation (HFO-TGI), may result in an improved RV function relative to "high-frequency" (i.e., 7 Hz) HFO (which may promote hypercapnia) and similar RV function relative to lung protective CV. METHODS: We studied 17 patients with moderate-to-severe ARDS [PaO2-to-inspiratory O2 fraction ratio (PaO2/FiO2) < 150]. RV function was assessed by transesophageal echocardiography (TEE). Patients received 60 min of CV for TEE-guided, positive end-expiratory pressure (PEEP) "optimization" and subsequent stabilization; 60 min of 4-Hz HFO for "study mean airway pressure (mPaw)" titration to peripheral oxygen saturation ≥ 95%, without worsening RV function as assessed by TEE; 60 min of each tested HFO strategy in random order; and another 60 min of CV using the pre-HFO, TEE-guided PEEP setting. Study measurements (i.e., gas exchange, hemodynamics, and TEE data) were obtained over the last 10 min of pre-HFO CV, of each one of the three tested HFO strategies, and of post-HFO CV. RESULTS: The mean "study HFO mPaw" was 8-10 cmH2O higher relative to pre-HFO CV. Seven-Hz HFO versus 4-Hz HFO and 4-Hz HFO-TGI resulted in higher mean ± SD right-to-left ventricular end-diastolic area ratio (RVEDA/LVEDA) (0.64 ± 0.15 versus 0.56 ± 0.14 and 0.52 ± 0.10, respectively, both p < 0.05). Higher diastolic/systolic eccentricity indexes (1.33 ± 0.19/1.42 ± 0.17 versus 1.21 ± 0.10/1.26 ± 0.10 and 1.17 ± 0.11/1.17 ± 0.13, respectively, all p < 0.05). Seven-Hz HFO resulted in 18-28% higher PaCO2 relative to all other ventilatory strategies (all p < 0.05). Four-Hz HFO-TGI versus pre-HFO CV resulted in 15% lower RVEDA/LVEDA, and 7%/10% lower diastolic/systolic eccentricity indexes (all p < 0.05). Mean PaO2/FiO2 improved by 77-80% during HFO strategies versus CV (all p < 0.05). Mean cardiac index varied by ≤ 10% among strategies. Percent changes in PaCO2 among strategies were predictive of concurrent percent changes in measures of RV function (R2 = 0.21-0.43). CONCLUSIONS: In moderate-to-severe ARDS, "short-term" 4-Hz HFO strategies resulted in better RV function versus 7-Hz HFO, partly attributable to improved PaCO2 control, and similar or improved RV function versus CV. TRIAL REGISTRATION: This study was registered 40 days prior to the enrollment of the first patient at ClinicalTrials.gov, ID no. NCT02027129, Principal Investigator Spyros D. Mentzelopoulos, date of registration January 3, 2014.

Simultaneous "traumatic Gerbode" and aortic rupture due to blunt chest trauma.

The Gerbode defect is characterized by a perimembranous ventricular septal defect between the left ventricle and the right atrium. This intracardiac shunt is a congenital defect but may be iatrogenic after valve surgery or atrioventricular node ablation, may be the result of endocarditis or may be traumatic. It is really rarely encountered as sequelae of non-penetrating heart trauma, and their clinical manifestations may often be unrecognized in the multi-injured patient. However, they are serious complications, and their diagnostic approach is not always feasible. We hereby present a case of a young man with the left ventricle to the right atrium communication after blunt thoracic trauma due to a car accident and concomitant rupture of the thoracic aorta. We present also the case and the ways of treatment according to the international bibliography.

Variation in the blood supply of the sinus node.

PURPOSE: The purpose of the study was to examine the anatomical variations in the blood supply to the sinus node. METHODS: Gross anatomical examination and angiographic evaluation were performed in 400 human hearts derived from victims of various accidents. RESULTS: The sinus node artery was a branch of the right coronary artery in 245 cases, the left circumflex in 147 cases, and both coronary arteries in 8 cases. In one subject, two sinus node arteries were found to arise from the left circumflex artery, a finding never reported before. CONCLUSIONS: Anatomic and postmortem angiographic findings of a previously unreported case where the sinus node is perfused by two sinus node arteries originating from the left circumflex coronary artery are demonstrated. Knowledge of this anatomical variation is useful for anatomists and of clinical significance for the interventional cardiologists and mainly for the cardiac surgeons in planning the surgical procedures.

Transplacental infection of Coxsackievirus B3 pathological findings in the fetus.

Coxsackievirus intrauterine infection has been documented mostly on the basis of indirect evidence of transplacental transmission, with neonatal manifestations ranging from asymptomatic infection to meningoencephalitis, myocarditis, and generalized sepsis. This is the first report of prenatal findings and fetoplacental pathology in a third trimester fetus with coxsackie B3 transplacental infection confirmed by molecular techniques. Prenatal ultrasound detected severe reduction of fetal movements at the 27th week. Late onset fetal akinesia deformation sequence with mild arthrogryposis, necrotic meningoencephalitis with vascular calcifications, interstitial pneumonitis, mild myocardial hypertrophy, and chronic monocytic placental villitis were the cardinal findings at fetal autopsy following interruption of the pregnancy.

Prenatal diagnosis of glycogen storage disease type IV.

BACKGROUND: Glycogen storage disease type IV (GSD-IV) is a rare autosomal recessive disorder due to mutations in the GBE1 gene causing deficiency of the glycogen branching enzyme (GBE). Prenatal diagnosis has occasionally been performed by the measurement of the GBE activity in cultured chorionic villi (CV) cells. METHODS: Two unrelated probands with severe hypotonia at birth and death during the neonatal period were diagnosed with GSD-IV on the basis of postmortem histological findings. DNA analysis revealed truncating GBE1 mutations in both families. RESULTS: Prenatal diagnosis was performed in subsequent pregnancies by determination of branching enzyme activity and DNA analysis of CV or cultured amniocytes. Detailed autopsies of the affected fetuses at 14 and 24 weeks of gestation demonstrated intracellular inclusions of abnormal glycogen characteristic of GSD-IV. CONCLUSION: Prenatal diagnosis of GSD-IV by DNA analysis is highly accurate in genetically confirmed cases.