Daniel Jacoby

Genetics of inherited cardiomyopathy

During the past two decades, numerous disease-causing genes for different cardiomyopathies have been identified. These discoveries have led to better understanding of disease pathogenesis and initial steps in the application of mutation analysis in the evaluation of affected individuals and their family members. As knowledge of the genetic abnormalities, and insight into cellular and organ biology has grown, so has appreciation of the level of complexity of interaction between genotype and phenotype across disease states. What were initially thought to be one-to-one gene-disease correlates have turned out to display important relational plasticity dependent in large part on the genetic and environmental backgrounds into which the genes of interest express. The current state of knowledge with regard to genetics of cardiomyopathy represents a starting point to address the biology of disease, but is not yet developed sufficiently to supplant clinically based classification systems or, in most cases, to guide therapy to any significant extent. Future work will of necessity be directed towards elucidation of the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype-phenotype relationship with the ultimate goal of furthering our ability to identify, diagnose, risk stratify, and treat this group of disorders which cause heart failure and sudden death in the young.

Reverse Takotsubo Cardiomyopathy Associated With the Consumption of an Energy Drink

A 24-year-old man presented to the emergency room with chest pain, acute respiratory failure, and palpitations shortly after the ingestion of small amounts of an energy drink in little cups one after another. He was afebrile, with frequent runs of supraventricular and ventricular tachycardia and underlying sinus tachycardia. The patient was treated with fluids and metoprolol but required intubation because of progressive hypoxia. Chest x-ray revealed bilateral fluffy pulmonary infiltrates. His ECG was free of ischemic changes, and an echocardiogram at that time showed hypokinesis of all basal left ventricular segments with apical sparing and an ejection fraction of 35% (Figure 1 and Movie I in the online-only Data Supplement). His troponin was mildly increased and serially measured brain natriuretic peptide was elevated at 8000 pg/mL. Figure 1. ECG recorded at admission showing sinus tachycardia and nonspecific T-wave inversion in leads I and aVL. After treatment with furosemide, nitroglycerine, heparin, and aspirin, the patient responded with clinical improvement of vital signs and chest x-ray. Episodes of agitation and delirium ensued, delaying extubation. Computerized tomography brain scan and electroencephalogram were negative, and toxicological testing demonstrated no cocaine, cannabis, or …

Outcomes of adults with restrictive cardiomyopathy after heart transplantation

BACKGROUND Restrictive cardiomyopathy (RCM) represents a spectrum of disorders with a common physiology but divergent etiologies. RCM commonly leads to progressive heart failure and the need for heart transplantation (HTx). Pediatric RCM is a more homogeneous disorder with post-HTx outcomes comparable to those for non-RCM patients. However, post-HTx outcomes in adult RCM patients have not been studied to date. METHODS Demographic, clinical and survival outcomes of 38,190 adult HTx-only recipients from 1987 to 2010 were acquired from the registry of the United Network of Organ Sharing. The study population included 544 RCM patients (1.4%) and 37,646 non-RCM patients (98.6%). RCM diagnoses included idiopathic (n = 227, 42%), amyloid (n = 142, 26%), sarcoid (n = 81, 15%), radiation/chemotherapy (XRT) (n = 35, 6%) and other (n = 59, 11%). RESULTS Follow-up began at the time of HTx (74±64 months). During the follow-up period, 224 (41%) patients in the RCM group died, whereas 18,791 (50%) in the non-RCM group died. Crude 1-, 5- and 10-year survival for RCM patients was 84%, 66% and 45%, and for non-RCM patients was 85%, 70% and 50%, respectively. The overall unadjusted hazard ratio of RCM vs non-RCM for all-cause mortality was 1.07 (confidence interval [CI] 0.93 to 1.22). Multivariate Cox proportional hazards regression analysis yielded a hazard ratio of 1.06 (CI 0.91 to 1.25). RCM subgroup analysis showed decreased survival at 1, 5 and 10 years in the XRT (71%, 47% and 32%) and amyloid (79%, 47% and 28%) patient groups. The unadjusted hazard ratio for the XRT and amyloid subgroups vs RCM for all-cause mortality was 1.81 (p = 0.002) and 1.85 (p = 0.0004), respectively. CONCLUSIONS Outcomes for RCM patients post-HTx are comparable to those of non-RCM patients. However, RCM subgroup analysis suggests increased mortality for XRT and amyloid subgroups. Further analysis is warranted to understand the contributing factors.

Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure.

Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium‐conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure.

Substantial Discrepancy Between Fluid and Weight Loss During Acute Decompensated Heart Failure Treatment.

BACKGROUND Net fluid and weight loss are used ubiquitously to monitor diuretic response in acute decompensated heart failure research and patient care. However, the performance of these metrics has never been evaluated critically. The weight and volume of aqueous fluids such as urine should be correlated nearly perfectly and with very good agreement. As a result, significant discrepancy between fluid and weight loss during the treatment of acute decompensated heart failure would indicate measurement error in 1 or both of the parameters. METHODS The correlation and agreement (Bland-Altman method) between diuretic-induced fluid and weight loss were examined in 3 acute decompensated heart failure trials and cohorts: (1) Diuretic Optimization Strategies Evaluation (DOSE) (n = 254); (2) Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) (n = 348); and (3) Penn (n = 486). RESULTS The correlation between fluid and weight loss was modest (DOSE r = 0.55; ESCAPE r = 0.48; Penn r = 0.51; P < .001 for all), and the 95% limits of agreement were wide (DOSE -7.9 to 6.4 kg-L; ESCAPE -11.6 to 7.5 kg-L; Penn -14.5 to 11.3 kg-L). The median relative disagreement ranged from ±47.0% to 63.5%. A bias toward greater fluid than weight loss was found across populations (-0.74 to -2.1 kg-L, P ≤ .002). A consistent pattern of baseline characteristics or in-hospital treatment parameters that could identify patients at risk of discordant fluid and weight loss was not found. CONCLUSIONS Considerable discrepancy between fluid balance and weight loss is common in patients treated for acute decompensated heart failure. Awareness of the limitations inherent to these commonly used metrics and efforts to develop more reliable measures of diuresis are critical for both patient care and research in acute decompensated heart failure.

Hypertrophic cardiomyopathy: diagnosis, risk stratification and treatment

Hypertrophic cardiomyopathy is a common inherited cardiomyopathy, occurring in about 1 in 500 individuals.[1][1] The first gene mutation for this condition was identified in a large French Canadian family cohort in 1989.[2][2] Clinical presentation typically includes left ventricular hypertrophy in

Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure

Background—Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed. Methods and Results—Based on well-established renal physiological principles, an equation was derived to predict net sodium output using a spot urine sample obtained 1 or 2 hours after loop diuretic administration. This equation was then prospectively validated in 50 acute decompensated heart failure patients using meticulously obtained timed 6-hour urine collections to quantify loop diuretic-induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91; P<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (area under the curve =0.95, 95% confidence interval 0.89–1.0; P<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66; P<0.001) and lesser ability to predict poor natriuretic response (area under the curve =0.76, 95% confidence interval 0.63–0.89; P=0.002). Conclusions—In patients being treated for acute decompensated heart failure, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.

Feasibility and Efficacy of a Self-Management Intervention for Insomnia in Stable Heart Failure.

BACKGROUND Chronic insomnia is common among patients with heart failure (HF) and may contribute to fatigue and poor function. However, to date there have been no randomized controlled trials focused on treatment of insomnia or daytime symptoms in this population. OBJECTIVES The purpose of this study was to examine the preliminary efficacy, feasibility, and acceptability of a self-management intervention (cognitive behavioral therapy [CBT-I]) for insomnia among patients with stable HF. METHODS We conducted a pilot randomized controlled trial (RCT) in which patients with stable Class I-III HF (n = 25/52.1% women; mean age = 59 ± 14.8 years) were randomized in groups to CBT-I (n = 29) or an attention control condition (HF self-management with sleep hygiene; n = 19). Participants completed 2 weeks of wrist actigraphy, the insomnia severity index, and measures of fatigue, depression, sleepiness, and functional performance at baseline and follow-up. We computed the size of the effects on the dependent variables and used MANOVA to evaluate the effects of CBT-I on insomnia and fatigue. RESULTS CBT-I was feasible and acceptable and had a statistically significant effect on insomnia and fatigue, while controlling for the effects of comorbidity and age. CONCLUSIONS CBT-I has short-term efficacy as a treatment for chronic insomnia among patients with stable HF. Future studies are needed to address its sustained effects.

Left ventricular assist device pump thrombosis: is there a role for glycoprotein IIb/IIIa inhibitors?

Left ventricular assist devices (LVADs) fill a critical need by providing circulatory support to patients with end-stage heart failure who are either ineligible for heart transplant or too ill to stably wait for an eventual donor organ. Furthermore, they are critical to the arsenal of the heart failure cardiologist, given the supply/demand mismatch for donor organs. Unfortunately, these devices present their own complications. Despite antiplatelet agents and systemic anticoagulation, a number of patients present with pump thrombosis, a life-threatening event requiring either pump exchange or treatment with systemic thrombolytics. In an effort to avoid these morbid therapies, glycogen IIb/IIIa inhibitors, which have both antiplatelet and thrombolytic properties, have been proposed to treat pump thrombosis. We report here the largest case series using these agents and document a previously unreported high failure rate with this therapy.

Left ventricular non-noncompaction: The mitral valve prolapse of the 21st century?

A spongiform epidemic is upon us - myocardial trabeculae are everywhere as left ventricular noncompaction (LVNC) ingratiates itself into modern day cardiology. Current understanding of the condition is evolving but remains incomplete, and brings to mind the chronicles of another great cardiac story: mitral valve prolapse. Anecdote suggests that many individuals with prominent trabeculae may be being falsely labelled with a disease - LVNC - using poor echocardiographic and cardiovascular magnetic resonance criteria. Until we have robust diagnostic criteria, aetiology, clinicopathological significance and prognosis, the risk of casualties from ascertainment bias will remain. We should look to history and learn from past mistakes - specifically from the mitral valve prolapse story to show the way forward for LVNC. Meanwhile, clinicians (and patients) should be wary, bearing in mind the possibility that they might be seeing LVNNC - left ventricular non-noncompaction.