Ayesha Hasan

Wireless Pulmonary Artery Pressure Monitoring Guides Management to Reduce Decompensation in Heart Failure with Preserved Ejection Fraction

Background—No treatment strategies have been demonstrated to be beneficial for the population for patients with heart failure (HF) and preserved ejection fraction (EF). Methods and Results—The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial was a prospective, single-blinded, randomized controlled clinical trial testing the hypothesis that hemodynamically guided HF management decreases decompensation leading to hospitalization. Of the 550 patients enrolled in the study, 119 had left ventricular EF ≥40% (average, 50.6%), 430 patients had low left ventricular EF (<40%; average, 23.3%), and 1 patient had no documented left ventricular EF. A microelectromechanical system pressure sensor was permanently implanted in all participants during right heart catheterization. After implant, subjects were randomly assigned in single-blind fashion to a treatment group in whom daily uploaded pressures were used in a treatment strategy for HF management or to a control group in whom standard HF management included weight-monitoring, and pressures were uploaded but not available for investigator use. The primary efficacy end point of HF hospitalization rate >6 months for preserved EF patients was 46% lower in the treatment group compared with control (incidence rate ratio, 0.54; 95% confidence interval, 0.38–0.70; P<0.0001). After an average of 17.6 months of blinded follow-up, the hospitalization rate was 50% lower (incidence rate ratio, 0.50; 95% confidence interval, 0.35–0.70; P<0.0001). In response to pulmonary artery pressure information, more changes in diuretic and vasodilator therapies were made in the treatment group. Conclusions—Hemodynamically guided management of patients with HF with preserved EF reduced decompensation leading to hospitalization compared with standard HF management strategies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00531661.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure

AIMS Periodic breathing with central sleep apnoea (CSA) is common in heart failure patients and is associated with poor quality of life and increased risk of morbidity and mortality. We conducted a prospective, non-randomized, acute study to determine the feasibility of using unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure patients. METHODS AND RESULTS Thirty-one patients from six centres underwent attempted transvenous lead placement. Of these, 16 qualified to undergo two successive nights of polysomnography-one night with and one night without phrenic nerve stimulation. Comparisons were made between the two nights using the following indices: apnoea-hypopnoea index (AHI), central apnoea index (CAI), obstructive apnoea index (OAI), hypopnoea index, arousal index, and 4% oxygen desaturation index (ODI4%). Patients underwent phrenic nerve stimulation from either the right brachiocephalic vein (n = 8) or the left brachiocephalic or pericardiophrenic vein (n = 8). Therapy period was (mean ± SD) 251 ± 71 min. Stimulation resulted in significant improvement in the AHI [median (inter-quartile range); 45 (39-59) vs. 23 (12-27) events/h, P = 0.002], CAI [27 (11-38) vs. 1 (0-5) events/h, P≤ 0.001], arousal index [32 (20-42) vs. 12 (9-27) events/h, P = 0.001], and ODI4% [31 (22-36) vs. 14 (7-20) events/h, P = 0.002]. No significant changes occurred in the OAI or hypopnoea index. Two adverse events occurred (lead thrombus and episode of ventricular tachycardia), though neither was directly related to phrenic nerve stimulation therapy. CONCLUSION Unilateral transvenous phrenic nerve stimulation significantly reduces episodes of CSA and restores a more natural breathing pattern in patients with heart failure. This approach may represent a novel therapy for CSA and warrants further study.

S3 Detection as a Diagnostic and Prognostic Aid in Emergency Department Patients With Acute Dyspnea

STUDY OBJECTIVE Dyspneic emergency department (ED) patients present a diagnostic dilemma. Recent technologic advances have made it possible to capture information about pathologic heart sounds at ECG recording. This study evaluates the effect of an S3 captured by acoustic cardiography on emergency physician diagnostic accuracy and confidence in their diagnosis of acute decompensated heart failure, as well as the patients prognosis. METHODS Dyspneic ED patients older than 40 years who were not dialysis dependent were prospectively enrolled in this multinational study. Treating emergency physicians, initially blinded to all laboratory and acoustic cardiography results, estimated acute decompensated heart failure probability from 0% to 100% on a visual analog scale. The emergency physician repeated the visual analog scale after acoustic cardiography results were provided. Physician diagnostic accuracy for and confidence in acute decompensated heart failure were evaluated against a reference standard diagnosis, as determined by 2 independent cardiologists blinded to acoustic cardiography. Patients were followed through 90 days to determine the relationship of the S3 to adverse events. RESULTS Nine hundred ninety-five patients with acoustic cardiography results were enrolled from March to October 2006 at 7 US and 2 international sites. Median age was 63 years, 55% were men, and 44% were white. The reference diagnosis was acute decompensated heart failure in 41.5%. After initial history and physical examination, the treating physicians initial sensitivity, specificity, and accuracy for acute decompensated heart failure as a possible diagnosis were 89.0% (95% confidence interval [CI] 85.5% to 91.8%), 58.2% (95% CI 54.0% to 62.2%), and 71.0% (95% CI 68.4% to 73.8%), respectively. Acoustic cardiography had an accuracy of 68% (95% CI 65.4% to 71.3%), sensitivity of 40.2% (95% CI 35.5% to 45.1%), and specificity of 88.5% (95% CI 85.5% to 90.9%). Emergency physician confidence and diagnostic accuracy were influenced by adding information about the presence or absence of S3. In a multivariable model, the S3 added no independent prognostic information for 30-day (odds ratio 1.20; 95% CI 0.67 to 2.14) or 90-day events (odds ratio 1.22; 95% CI 0.78 to 1.90). CONCLUSION In patients presenting with acute dyspnea, the acoustic cardiography S3 was specific for acute decompensated heart failure and affected physician confidence but did not improve diagnostic accuracy for acute decompensated heart failure, largely because of its low sensitivity. Further, the acoustic cardiography S3 provided no significant independent prognostic information.

Percutaneous left ventricular partitioning in patients with chronic heart failure and a prior anterior myocardial infarction: Results of the PercutAneous Ventricular RestorAtion in Chronic Heart failUre PaTiEnts Trial

OBJECTIVES The aim of this study was to assess the feasibility, safety, and preliminary efficacy of a novel percutaneous left ventricular partitioning device (VPD) in patients with chronic heart failure (HF) and a prior anterior myocardial infarction. BACKGROUND Anterior myocardial infarction is frequently followed by left ventricular remodeling, HF, and increased long-term morbidity and mortality. METHODS Thirty-nine patients were enrolled in a multinational, nonrandomized, longitudinal investigation. The primary end point was an assessment of safety, defined as the successful delivery and deployment of the VPD and absence of device-related major adverse cardiac events over 6 months. Secondary (exploratory) efficacy end points included changes in hemodynamics and functional status and were assessed serially throughout the study. RESULTS Ventricular partitioning device placement was not attempted in 5 (13%) of 39 subjects. The device was safely and successfully implanted in 31 (91%) of the remaining 34 patients or 79% of all enrolled patients. The 6-month rate of device-related major adverse cardiac event occurred in 5 (13%) of 39 enrolled subjects and 5 (15%) of 34 treated subjects, with 1 additional event occurring between 6 and 12 months. For patients discharged with the device to 12 months (n = 28), New York Heart Association class (2.5 ± 0.6 to 1.3 ± 0.6, P < .001) and quality-of-life scores (38.6 ± 6.1 to 28.4 ± 4.4, P < .002) improved significantly; however, the 6-minute hall walk distance (358.5 ± 20.4 m to 374.7 ± 25.6 m, P nonsignificant) only trended toward improvement. CONCLUSIONS The left VPD appears to be relatively safe and potentially effective in the treatment for patients with HF and a prior anterior myocardial infarction. However, these limited results suggest the need for further evaluation in a larger randomized controlled trial.

Strong Transthyretin Immunostaining: Potential Pitfall in Cardiac Amyloid Typing

Although systemic amyloidosis commonly presents with renal disease, cardiac involvement usually determines the patients prognosis. Cardiac involvement is seen in light chain amyloid and transthyretin amyloidosis. Distinguishing between these two is critical because prognosis and treatment differ. Our study demonstrates the unreliability of transthyretin immunostaining in subtyping cardiac amyloid. Between January 2003 and August 2010, we retrieved 229 native endomyocardial biopsies, of which 24 had amyloid. Immunohistochemistry for &kgr;, &lgr;, transthyretin, and serum amyloid A protein was performed on formalin-fixed, paraffin-embedded sections. Staining was graded as weak (trace to 1+) or strong (2 to 3+). Mass spectrometry (MS)-based proteomic typing of microdissected amyloid material was performed on selected cases. Fifteen patients had monoclonal gammopathy/plasma cell dyscrasia with cardiac amyloid. Eight of them (53%) showed strong transthyretin staining in the cardiac amyloid deposits. MS was performed in 5 of these 8 biopsies, and all 5 biopsies revealed light chain amyloid-type amyloid. Two of these 5 light chain amyloid biopsies did not even have concomitant strong staining for the appropriate light chain. Among the 15 cases with plasma cell dyscrasia, only 7 biopsies showed strong staining for the corresponding monoclonal light chain. Strong, false-positive immunostaining for transthyretin in cardiac amyloid is a potential pitfall, augmented by the frequent lack of staining for immunoglobulin light chains. Therefore, the presence of amyloid in the cardiac biopsy should prompt a search for plasma cell dyscrasia irrespective of transthyretin staining. Confirmation with MS should be sought, particularly if there is any discrepancy between &kgr;/&lgr; staining and serum immunofixation results.

Telemonitoring in chronic heart failure

Clinical management of refractory heart failure remains challenging, with a high rate of rehospitalizations despite advances in medical and device therapy. Care can be provided in person, via telehomecare (by telephone), or telemonitoring, which involves wireless technology for remote follow-up. Telemonitoring wirelessly transmits parameters such as weight, heart rate, or blood pressure for review by health-care professionals. Cardiac implantable devices (defibrillators and cardiac resynchronization therapy) also transmit continually interrogated physiological data, such as heart rate variability or intrathoracic impedance, which may be of value to predict patients at greater risk of hospitalization for heart failure. The use of remote monitoring techniques facilitates a rapid and regular review of such data by health-care workers as part of a heart failure management programme. Current evidence supports the feasibility of such an approach but routinely assessed parameters have been shown not to impact patient outcomes. Devices that directly assess cardiac haemodynamic status through invasive measurement of pressures are currently under investigation and could potentially increase the sensitivity and specificity of predicting heart failure events. The current evidence for telemonitoring and remote monitoring, including implantable haemodynamic devices, will be reviewed.

Safety and accuracy of a wireless pulmonary artery pressure monitoring system in patients with heart failure.

BACKGROUND Implantable hemodynamic monitoring to guide heart failure (HF) therapy is a promising area of active research. The goal of this investigation was to evaluate the safety and technical performance of a novel wireless pulmonary artery pressure monitoring system in 17 patients with symptomatic HF. METHODS The monitoring system consists of a sensor, delivery catheter, interrogator, and home monitoring device. The HF sensor was implanted into a distal branch of the pulmonary artery. Pulmonary artery pressures were monitored using the external device, which powers the HF sensor and transmits the hemodynamic data from the patients home to a secure Internet database. The accuracy of the system was assessed by comparison with standard right heart catheterization (RHC). RESULTS The HF sensor was safely and successfully implanted in all patients. Agreement between the HF sensor and RHC for systolic, diastolic, and mean pulmonary artery pressures was excellent, with correlation coefficients of 0.94, 0.85, and 0.95, respectively (all P < .0001). Using Bland-Altman plots, the average differences for systolic, diastolic, and mean pulmonary artery pressures for the HF sensor vs RHC were -4.4 ± 0.3, 2.5 ± 1.0, and -0.8 ± 1.3 mm Hg, respectively. There were no serious device-related adverse events. A postmortem analysis of the HF sensor in a patient who died 12 months after implant demonstrated complete endothelialization and no evidence of thrombosis. CONCLUSIONS This trial supports the safety and accuracy of this pulmonary artery pressure monitoring system in patients with HF and the conduct of randomized trials of implantable hemodynamic monitoring in HF, using this system.

TGF-β3 modulates the inflammatory environment and reduces scar formation following vocal fold mucosal injury in rats.

Transforming growth factor (TGF)-β1 and TGF-β3 have been reported to exert differential effects on wound healing, and possibly even account for tissue-specific differences in scar formation. Scarring is particularly detrimental in the vocal fold mucosa (VFM), where destruction of the native extracellular matrix causes irreparable biomechanical changes and voice impairment. Here, in a series of in vitro and in vivo experiments, we identified differences in TGF-β1 and TGF-β3 transcription and immunolocalization to various cell subpopulations in naïve and injured rat VFM, compared with oral mucosa (which undergoes rapid healing with minimal scar) and skin (which typically heals with scar). Treatment of cultured human vocal fold fibroblasts with TGF-β3 resulted in less potent induction of profibrotic gene transcription, extracellular matrix synthesis and fibroblast-myofibroblast differentiation, compared with treatment with TGF-β1 and TGF-β2. Finally, delivery of exogenous TGF-β3 to rat VFM during the acute injury phase modulated the early inflammatory environment and reduced eventual scar formation. These experiments show that the TGF-β isoforms have distinct roles in VFM maintenance and repair, and that TGF-β3 redirects wound healing to improve VFM scar outcomes in vivo.

Device Interactions in Patients With Advanced Cardiomyopathy

To the Editor: Device therapy for advanced cardiac failure has created the potential for device interactions and raised a significant clinical consideration before implementation of therapy. Here we present 2 case vignettes where implantation of an approved left ventricular assist device (LVAD)

Role of Ccr4-Not complex in heterochromatin formation at meiotic genes and subtelomeres in fission yeast.

BackgroundHeterochromatin is essential for chromosome segregation, gene silencing and genome integrity. The fission yeast Schizosaccharomyces pombe contains heterochromatin at centromeres, subtelomeres, and mating type genes, as well as at small islands of meiotic genes dispersed across the genome. This heterochromatin is generated by partially redundant mechanisms, including the production of small interfering RNAs (siRNAs) that are incorporated into the RITS protein complex (RNAi-Induced Transcriptional Silencing). The assembly of heterochromatin islands requires the function of the RNA-binding protein Mmi1, which recruits RITS to its mRNA targets and to heterochromatin islands. In addition, Mmi1 directs its targets to an exosome-dependent RNA elimination pathway.ResultsCcr4-Not is a conserved multiprotein complex that regulates gene expression at multiple levels, including RNA degradation and translation. We show here that Ccr4-Not is recruited by Mmi1 to its RNA targets. Surprisingly, Ccr4 and Caf1 (the mRNA deadenylase catalytic subunits of the Ccr4-Not complex) are not necessary for the degradation or translation of Mmi1 RNA targets, but are essential for heterochromatin integrity at Mmi1-dependent islands and, independently of Mmi1, at subtelomeric regions. Both roles require the deadenylase activity of Ccr4 and the Mot2/Not4 protein, a ubiquitin ligase that is also part of the complex. Genetic evidence shows that Ccr4-mediated silencing is essential for normal cell growth, indicating that this novel regulation is physiologically relevant. Moreover, Ccr4 interacts with components of the RITS complex in a Mmi1-independent manner.ConclusionsTaken together, our results demonstrate that the Ccr4-Not complex is required for heterochromatin integrity in both Mmi1-dependent and Mmi1-independent pathways.