Cardiology

Cannon, J. A., L. Shen, P. S. Jhund, S. L. Kristensen, L. Kober, F. Chen, J. Gong, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, K. Swedberg, M. R. Zile, S. D. Solomon, M. Packer and J. J. McMurray (2016). “Dementia-related adverse events in paradigm-hf and other trials in heart failure with reduced ejection fraction.” Eur J Heart Fail: 2016 Nov [Epub ahead of print].

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AIMS: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-beta peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. METHODS AND RESULTS: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. CONCLUSION: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

Mikhalkova, D., E. Novak and A. Cedars (2016). “Short-term costs and hospitalization rates in patients with adult congenital heart disease after pulmonic valve replacement.” Am J Cardiol 118(10): 1552-1557.

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In the adult congenital heart disease (ACHD) population, pulmonary valve replacement (PVR) is a common intervention, its benefit, however, has been incompletely investigated. This study investigates short- and intermediate-term outcomes after PVR in ACHD. Using State Inpatient Databases from the Healthcare Cost and Utilization Project, we investigated both hospitalization rate and financial burden accrued over the 12-month period after PVR compared with the 12 months before. Among 202 patients who underwent PVR, per patient-year hospitalization rates doubled in the year after PVR compared with the year before (0.16 vs 0.36, p = 0.006). With the exception of postprocedural complications, the most common reasons for hospitalization were unchanged after surgery: 22% of patients were admitted with equal or greater frequency after PVR. These patients experienced higher inpatient costs both at index admission and in the year after PVR (p = 0.004 and p <0.001, respectively). Univariate predictors of increased hospitalizations after PVR were age >/=50 years (p = 0.016), transposition of the great arteries, or conotruncal abnormalities (p <0.001), lipid disorders (p = 0.025), hypertension (p = 0.033), and number of chronic conditions >/=4 (p = 0.004). Multivariate analysis identified transposition of the great arteries or conotruncal abnormalities as an independent risk factor for increased hospitalization and cost post-PVR (p /=0.001). In conclusion, short-term costs and hospitalization rates increase after PVR in a small group of patients with ACHD.

Roberts, W. C., V. S. Won, A. Vasudevan and J. M. Guileyardo (2016). “Causes of death and heart weights in adults at necropsy in a tertiary texas hospital, 2013-2015.” Am J Cardiol 118(11): 1758-1768.

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The causes of death and heart weights at death appear to be quite different in the USA today than in the first few decades of the last century. We determined the causes of death and heart weights at necropsy in 231 adults and compared the heart weights to those reported in several studies in the first half of the 20th century. Of the 231 patients, 91 (39%) died of a cardiovascular (CV) condition, and 140 (61%), of a non-CV condition. Of the 91 fatal CV disease cases, 48 had fatal coronary artery disease (CAD); of the remaining 183 cases without fatal CAD, 25 had narrowing >75% of 1 or more major epicardial coronary arteries. Thus, 73 of the 231 (32%) patients at necropsy had severe CAD. Comparison between the fatal CV and fatal non-CV cases disclosed variable age (mean 64 years vs mean 57 years) and heart weight (529 g vs 449 g) to be significantly different. Heart weight was found to be the only significantly variable between men and women. Comparison of the heart weights in this study to those recorded as “normal” hearts 75 to 115 years earlier showed that today’s “average” heart is much larger than those reported earlier. In contrast to the earlier studies, heart weight presently appears to increase with age and with an increase in body mass index. In conclusion, early studies in heart weight did not take into account today’s longer survival and therefore a high prevalence of systemic hypertension, diabetes mellitus, obesity (and cardiac adiposity), and the presence of atherosclerotic CAD. Additionally, the cause of death (CV vs non-CV) was rarely considered in the early studies of heart weight.

Sannino, A., R. C. Stoler, B. Lima, M. Szerlip, A. C. Henry, R. Vallabhan, R. C. Kowal, D. L. Brown, M. J. Mack and P. A. Grayburn (2016). “Frequency of and prognostic significance of atrial fibrillation in patients undergoing transcatheter aortic valve implantation.” Am J Cardiol 118(10): 1527-1532.

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The prognostic implications of preexisting atrial fibrillation (AF) and new-onset AF (NOAF) in transcatheter aortic valve implantation (TAVI) remain uncertain. This study assesses the epidemiology of AF in patients treated with TAVI and evaluates their outcomes according to the presence of preexisting AF or NOAF. A retrospective analysis of 708 patients undergoing TAVI from 2 heart hospitals was performed. Patients were divided into 3 study groups: sinus rhythm (n = 423), preexisting AF (n = 219), and NOAF (n = 66). Primary outcomes of interest were all-cause death and stroke both at 30-day and at 1-year follow-up. Preexisting AF was present in 30.9% of our study population, whereas NOAF was observed in 9.3% of patients after TAVI. AF and NOAF patients showed a higher rate of 1-year all-cause mortality compared with patients in sinus rhythm (14.6% vs 6.5% for preexisting AF and 16.3% vs 6.5% for NOAF, p = 0.007). No differences in 30-day mortality were observed between groups. In patients with AF (either preexisting and new-onset), those discharged with single antiplatelet therapy displayed higher mortality rates at 1 year (42.9% vs 11.7%, p = 0.006). Preexisting AF remained an independent predictor of mortality at 1-year follow-up (hazard ratio [HR] 2.34, 95% CI 1.22 to 4.48, p = 0.010). Independent predictors of NOAF were transapical and transaortic approach as well as balloon postdilatation (HR 3.48, 95% CI 1.66 to 7.29, p = 0.001; HR 5.08, 95% CI 2.08 to 12.39, p <0.001; HR 2.76, 95% CI 1.25 to 6.08, p = 0.012, respectively). In conclusion, preexisting AF is common in patients undergoing TAVI and is associated with a twofold increased risk of 1-year mortality. This negative effect is most pronounced in patients discharged with single antiplatelet therapy compared with other antithrombotic regimens.

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics 47(6): 349-354.

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Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.