Christopher J. McLeod

Left atrial function: physiology, assessment, and clinical implications

The interest in the left atrium (LA) has resurged over the recent years. In the early 1980s, multiple studies were conducted to determine the normal values of LA size. Over the past decade, LA size as an imaging biomarker has been consistently shown to be a powerful predictor of outcomes, including major public health problems such as atrial fibrillation, heart failure, stroke, and death. More recently, functional assessment of the LA has been shown to be, at least as, if not more robust, a marker of cardiovascular outcomes. Current available data suggest that the combined evaluation of LA size and LA function will augment prognostication. The aim of this review is to provide a critical appraisal of current echocardiographic techniques for the assessment of LA function and the implications of such assessment for prediction and disease prevention.

Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram.

OBJECTIVES This study sought to clarify the frequency, clinical phenotype, and prognosis of those patients with hypertrophic cardiomyopathy (HCM) who present with a normal electrocardiogram (ECG). BACKGROUND Hypertrophic cardiomyopathy is the most common cause of sudden death in young people. Screening advocates have recommended a 12-lead ECG for the early detection of HCM in athletes, yet the clinical outcomes of those presenting with a normal ECG remains to be fully delineated. METHODS Baseline characteristic and echocardiographic data were collected on all patients with HCM who initially presented to our institution with a diagnostic echocardiogram but a normal ECG. Follow-up was obtained and compared with the prognosis of HCM patients who presented with abnormal ECGs. RESULTS We compared 135 HCM patients with a normal ECG with 2,350 HCM patients with an abnormal ECG. The latter group was more likely to have worse symptoms, have higher gradients, and a greater degree of septal wall thickness than the patients with a normal ECG. Severe obstructive symptoms requiring surgical myectomy and implantation of an implantable cardioverter-defibrillator were more common in patients with abnormal ECGs. Cardiac survival was significantly better in the group with a normal ECG at presentation-none of these patients had a cardiac death at follow-up. CONCLUSIONS Almost 6% of patients presenting with demonstrable echocardiographic evidence of HCM had a normal ECG at the time of diagnosis. This subset of patients with normal ECG-HCM appears to exhibit a less severe phenotype with better cardiovascular outcomes.

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Background—Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program. Methods and Results—Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P<0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (≥22% versus control, P<0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191±12% improvement in ADP-sensitive respiration (P=0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator–activated receptor gamma coactivator 1&agr;, were significantly induced in preconditioned myocardium. Conclusions—Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.

Differential outcome of cardiac resynchronization therapy in ischemic cardiomyopathy and idiopathic dilated cardiomyopathy.

BACKGROUND Cardiac resynchronization therapy (CRT) is a therapy of proven benefit in patients with advanced heart failure. Identifying potential responders remains challenging, and whether the etiology of the heart failure is related to the potential hemodynamic benefit and long-term outcome of CRT is unclear. OBJECTIVE The purpose of this study was to evaluate whether heart failure etiology (ischemic cardiomyopathy [ICM] vs nonischemic dilated cardiomyopathy [DCM]) was associated with CRT outcome and implantable cardioverter-defibrillator (ICD) shocks. METHODS The study included 503 CRT recipients (CRT-D 90%) in a longitudinal CRT database: ICM (n = 312) and DCM (n = 191). Clinical variables and echocardiographic measures preimplant and postimplant were collected. Actuarial survival and ICD therapy data were assessed with Kaplan-Meier curve and log rank tests. RESULTS Pre-CRT, ICM patients were older and had higher creatinine levels (P <.001). At median follow-up of 7.1 months, the DCM group experienced greater improvement in left ventricular ejection fraction (8.3% ± 10% vs 6.2% ± 10%, P = .05) and left ventricular end-diastolic volumes than did those with ICM (-28%.4 ± 53 mL vs -15.3 ± 46 mL, P = .024). Survival estimates at 4 years were 55% for ICM and 77% for DCM groups (P <.001), respectively, whereas no significant difference in the incidence of appropriate/inappropriate ICD shocks was observed. The ICM group remained at higher risk for death compared to the DCM group after controlling for preimplant variables (hazard ratio 1.6, 95% confidence interval 1.1-2.3, P = .008). CONCLUSION In response to CRT and in contrast to ICM, DCM patients experienced greater improvement in left ventricular systolic function and reverse remodeling while also sustaining a greater survival benefit.

Shared Decision Making in Atrial Fibrillation Where We Are and Where We Should Be Going

You are seeing Mr Roberts, a 69-year-old retired office manager referred from the emergency department for treatment of atrial fibrillation (AF). He presented the previous night to the emergency department with shortness of breath and palpitations and was found to be in AF with a rapid ventricular response and a heart rate of 140 bpm. He was treated with intravenous diltiazem and spontaneously converted to sinus rhythm. He was then discharged from the emergency department with an outpatient cardiology appointment. He has a background history of hypertension but no other cardiac disease. His only medication is a thiazide diuretic. On questioning, he reports experiencing several episodes of palpitations over the last 2 to 3 years; typically, these are brief and self-limited. His transthoracic echocardiogram, thyroid studies, and electrolytes are all within normal limits. His ECG shows sinus rhythm with no other significant abnormality. His CHADS2 score is 1 and CHA2DS2-Vasc score is 2. He has a family history of gastrointestinal hemorrhage–associated death and is uncomfortable about long-term anticoagulation. Additionally, he is reluctant about taking a daily medication plus his blood pressure pill. How might you present current best practice while ensuring that his treatment program is consistent with his goals, values, and preferences? AF is the most common arrhythmia requiring treatment, affecting ≈5 million Americans, with the prevalence expected to double by 2050.1–3 AF accounts for more than a third of all hospitalizations for cardiac rhythm disturbances. Hospitalization for AF has risen dramatically over the past 20 years and is projected to continue to rise as the population ages.4 Importantly, AF is associated with a doubling in patient-matched and adjusted mortality.5 Atrial fibrillation can range from completely asymptomatic to highly symptomatic and can negatively affect patients’ quality of life if …

Hypokalemia during the cooling phase of therapeutic hypothermia and its impact on arrhythmogenesis

BACKGROUND Mild to moderate therapeutic hypothermia (TH) has been shown to improve survival and neurological outcome in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) as the presenting rhythm. This approach entails the management of physiological variables which fall outside the realm of conventional critical cardiac care. Management of serum potassium fluxes remains pivotal in the avoidance of lethal ventricular arrhythmia. METHODS We retrospectively analyzed potassium variability with TH and performed correlative analysis of QT intervals and the incidence of ventricular arrhythmia. RESULTS We enrolled 94 sequential patients with OHCA, and serum potassium was followed intensively. The average initial potassium value was 3.9±0.7 mmol l(-1) and decreased to a nadir of 3.2±0.7 mmol l(-1) at 10 h after initiation of cooling (p<0.001). Eleven patients developed sustained polymorphic ventricular tachycardia (PVT) with eight of these occurring during the cooling phase. The corrected QT interval prolonged in relation to the development of hypothermia (p<0.001). Hypokalemia was significantly associated with the development of PVT (p=0.002), with this arrhythmia being most likely to develop in patients with serum potassium values of less than 2.5 mmol l(-1) (p=0.002). Rebound hyperkalemia did not reach concerning levels (maximum 4.26±0.8 mmol l(-1) at 40 h) and was not associated with the occurrence of ventricular arrhythmia. Furthermore, repletion of serum potassium did not correlate with the development of ventricular arrhythmia. CONCLUSIONS Therapeutic hypothermia is associated with a significant decline in serum potassium during cooling. Hypothermic core temperatures do not appear to protect against ventricular arrhythmia in the context of severe hypokalemia and cautious supplementation to maintain potassium at 3.0 mmol l(-1) appears to be both safe and effective.

Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport

Background: The function of the C. elegans mitochondrial uncoupling protein 4 (ceUCP4) has not been characterized. Results: Worms deficient in ceUCP4 displayed hypometabolic phenotypes and complex II dysfunction that corresponded with a significant loss of mitochondrial succinate import. Conclusion: ceUCP4 plays a novel role in the regulation of complex II by controlling succinate transport into mitochondria. Significance: Understanding how extramitochondrial succinate and ceUCP4 regulate complex II-mediated metabolism is critical for understanding the mechanisms of cellular respiration. The novel uncoupling proteins (UCP2–5) are implicated in the mitochondrial control of oxidant production, insulin signaling, and aging. Attempts to understand their functions have been complicated by overlapping expression patterns in most organisms. Caenorhabditis elegans nematodes are unique because they express only one UCP ortholog, ceUCP4 (ucp4). Here, we performed detailed metabolic analyzes in genetically modified nematodes to define the function of the ceUCP4. The knock-out mutant ucp4 (ok195) exhibited sharply decreased mitochondrial succinate-driven (complex II) respiration. However, respiratory coupling and electron transport chain function were normal in ucp4 mitochondria. Surprisingly, isolated ucp4 mitochondria showed markedly decreased succinate uptake. Similarly, ceUCP4 inhibition blocked succinate respiration and import in wild type mitochondria. Genetic and pharmacologic inhibition of complex I function was selectively lethal to ucp4 worms, arguing that ceUCP4-regulated succinate transport is required for optimal complex II function in vivo. Additionally, ceUCP4 deficiency prolonged lifespan in the short-lived mev1 mutant that exhibits complex II-generated oxidant production. These results identify a novel function for ceUCP4 in the regulation of complex II-based metabolism through an unexpected mechanism involving succinate transport.

Risk of stroke after catheter ablation versus cardioversion for atrial fibrillation: A propensity-matched study of 24,244 patients.

BACKGROUND Stroke is the major cause of morbidity and mortality related to atrial fibrillation (AF). Catheter ablation for AF is effective in reducing AF burden, but its impact on long-term stroke risk is unknown. OBJECTIVE We sought to evaluate the periprocedural and long-term stroke risk after catheter ablation or cardioversion for AF. METHODS This retrospective, propensity-matched study using a national administrative claims database identified patients with AF who underwent catheter ablation and a comparison group (matched on age, sex, year of treatment, CHA2DS2-Vasc score, and Charlson index) who underwent cardioversion between 2005 and 2012. The primary end points were (1) time to first ischemic or hemorrhagic stroke or transient ischemic attack (TIA) and (2) time to first ischemic or hemorrhagic stroke excluding TIA. We compared periprocedural incident stroke (within 30 days of ablation or cardioversion) as well as total strokes between the 2 groups. RESULTS A total of 24,244 patients (12,122 patients undergoing ablation and 12,122 patients undergoing cardioversion) were included in the analysis. Incident periprocedural stroke or TIA occurred in 0.5% of the ablation group and 0.3% of the cardioversion group (P = .04). There was a significant initial risk of stroke/TIA with ablation within the first 30 days (rate ratio 1.53; P = .05). After 30 days, this risk was significantly lower in the ablation group (rate ratio 0.78; P = .03). CONCLUSION In patients with AF, there is a small periprocedural stroke risk with ablation in comparison to cardioversion. However, over longer-term follow-up, ablation is associated with a slightly lower rate of stroke.

Ventricular Arrhythmia Risk Stratification in Patients With Tetralogy of Fallot at the Time of Pulmonary Valve Replacement

Background—Most patients with repaired tetralogy of Fallot require pulmonary valve replacement (PVR), but the evaluation for and management of ventricular arrhythmia remain unclear. This study is aimed at clarifying the optimal approach to this potentially life-threatening issue at the time of PVR. Methods and Results—A retrospective analysis was performed on 205 patients with repaired tetralogy of Fallot undergoing PVR at our institution between 1988 and 2010. Median age was 32.9 (range, 25.6) years. Previous ventricular tachycardia occurred in 16 patients (8%) and 37 (16%) had left ventricular dysfunction, defined as left ventricular ejection fraction <50%. Surgical right ventricular outflow tract cryoablation was performed in 22 patients (10.7%). The primary outcome was a combined event including ventricular tachycardia, out-of-hospital cardiac arrest, appropriate implantable cardioverter defibrillator therapy, and sudden cardiac death. Freedom from the combined event at 5, 10, and 15 years was 95%, 90%, and 79%, respectively. In the first year after PVR, 2 events occurred. Conversely, in the 22 patients who underwent surgical cryoablation, a single event occurred 7 years after PVR. A history of ventricular tachycardia and left ventricular dysfunction was associated with higher risk for the combined event (hazard ratio, 4.7; P=0.004 and hazard ratio, 0.8; P=0.02, respectively). Conclusions—Patients with repaired tetralogy of Fallot undergoing PVR with history of ventricular tachycardia or left ventricular dysfunction appear to be associated with a higher risk of arrhythmic events after operation. Events in the first year after PVR are rare, and in select high-risk patients, surgical cryoablation does not seem to increase arrhythmic events and may be protective.

Histologic characterization of hypertrophic cardiomyopathy with and without myofilament mutations.

BACKGROUND Between 30% and 60% of clinical cases of hypertrophic cardiomyopathy (HC) can be attributed to mutations in the genes encoding cardiac myofilament proteins. Interestingly, it appears that the likelihood of an underlying myofilament mutation can be predicted by echocardiographic assessment of left ventricular morphology. However, it is not known whether genotypically characterized HC exists as a separate entity with discrete phenotypic morphology and histology or to what extent recognized polymorphisms of the renin-angiotensin-aldosterone system (RAAS) influence this relationship. The presence of cardiac myofilament and mutations and RAAS polymorphisms will have a strong association with the severity of histologic features of HC and characteristic septal shape. METHODS We conducted a retrospective review of histology specimens, obtained at septal myectomy among 181 patients with medically refractory symptomatic HC. All patients underwent comprehensive genetic analysis for mutations in 8 myofilament-encoding genes; a subset was genotyped for 6 known RAAS-polymorphisms. Patients underwent comprehensive echocardiography by an expert blinded to genotype and microscopic status. RESULTS Microscopically, severity of myocyte hypertrophy appears to be associated with the presence of recognized HC cardiac myofilament mutations (P = .03). Other histologic features characteristic of HC were not consistently associated with myofilament mutation status. A higher burden of pro-LVH RAAS polymorphisms also appeared to predict only myocyte hypertrophy (P = .01). The presence of RAAS polymorphisms was not associated with the development of a specific septal morphology (P = .6). CONCLUSION Myofilament-positive HC does not appear to represent a distinct clinical phenotypic entity as evidenced by specific histologic characteristics and septal shape.