Research Spotlight

Piccini, J. P., K. Stromberg, K. P. Jackson, V. Laager, G. Z. Duray, M. El-Chami, C. R. Ellis, J. Hummel, D. R. Jones, R. C. Kowal, C. Narasimhan, R. Omar, P. Ritter, P. R. Roberts, K. Soejima, S. Zhang and D. Reynolds (2017). “Long-term outcomes in leadless micra transcatheter pacemakers with elevated thresholds at implantation: Results from the micra transcatheter pacing system global clinical trial.” Heart Rhythm 14(5): 685-691.

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BACKGROUND: Device repositioning during Micra leadless pacemaker implantation may be required to achieve optimal pacing thresholds. OBJECTIVE: The purpose of this study was to describe the natural history of acute elevated Micra vs traditional transvenous lead thresholds. METHODS: Micra study VVI patients with threshold data (at 0.24 ms) at implant (n = 711) were compared with Capture study patients with de novo transvenous leads at 0.4 ms (n = 538). In both cohorts, high thresholds were defined as >1.0 V and very high as >1.5 V. Change in pacing threshold (0-6 months) with high (1.0 to 1.5 V) thresholds were compared using the Wilcoxon signed-rank test. RESULTS: Of the 711 Micra patients, 83 (11.7%) had an implant threshold of >1.0 V at 0.24 ms. Of the 538 Capture patients, 50 (9.3%) had an implant threshold of >1.0 V at 0.40 ms. There were no significant differences in patient characteristics between those with and without an implant threshold of >1.0 V, with the exception of left ventricular ejection fraction in the Capture cohort (high vs low thresholds, 53% vs 58%; P = .011). Patients with an implant threshold of >1.0 V decreased significantly (P < .001) in both cohorts. Micra patients with high and very high thresholds decreased significantly (P < .01) by 1 month, with 87% and 85% having 6-month thresholds lower than the implant value. However, when the capture threshold at implant was >2 V, only 18.2% had a threshold of 2 V. CONCLUSIONS: Pacing thresholds in most Micra patients with elevated thresholds decrease after implant. Micra device repositioning may not be necessary if the pacing threshold is

Pierobon, M., C. Ramos, S. Wong, K. A. Hodge, J. Aldrich, S. A. Byron, S. P. Anthony, N. J. Robert, D. W. Northfelt, M. Jahanzeb, L. Vocila, J. D. Wulfkuhle, G. Gambara, R. I. Gallagher, B. Dunetz, N. Hoke, T. Dong, D. W. Craig, M. Cristofanilli, B. Leyland Jones, L. Liotta, J. A. O’Shaughnessy, J. D. Carpten and E. F. Petricoin (2017). “Enrichment of pik3-akt-mtor pathway activation in hepatic metastases from breast cancer.” Clin Cancer Res: Apr [Epub ahead of print].

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Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.

Experimental Design: NGS-based whole exome sequencing was coupled with Reverse Phase Protein Microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 un-matched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and non-hepatic lesions.

Results:PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than non-hepatic lesions (p<0.01, p=0.056, and p=0.053 respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (p=0.32 and p=0.19 for activated AKT and p70S6K respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis (AKT (S473), mTOR (S2448), and 4EBP1 (S65); p<0.01, p=0.02, and p=0.01 respectively). Similar results were also seen between liver metastases and primary breast tumors (AKT (S473) p<0.01, mTOR (S2448) p<0.01, 4EBP1 (S65) p=0.01). This signature was lost when primary tumors were compared to all metastatic sites combined.

Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network.

Roberts, W. C., P. A. Grayburn, J. M. Guileyardo and R. C. Stoler (2017). “Full development of consequences of congenital pulmonic stenosis in eighty-four years.” Am J Cardiol 119(8): 1284-1287.

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Described herein is an 84-year-old woman, the oldest reported, with severe pulmonic stenosis who underwent a highly successful pulmonic valvotomy at age 77 and highly unsuccessfully attempted percutaneous pulmonic valve implantation at age 84. During the 84 years she developed nearly all clinical and morphologic consequences of pulmonic stenosis, including heavy calcification of the pulmonic valve, heavy calcification of the tricuspid valve annulus, severe right ventricular wall thickening without ventricular cavity dilation, aneurysm of the pulmonary truck, multiple focal ventricular wall scars without narrowing of the epicardial coronary arteries, wall thickening and luminal narrowing of the intramural coronary arteries, and extremely low 12-lead QRS electrocardiographic voltage.

Holland-Carter, L., P. W. Tuerk, T. A. Wadden, K. N. Fujioka, L. E. Becker, K. Miller-Kovach, P. L. Hollander, W. T. Garvey, D. Weiss, D. M. Rubino, R. F. Kushner, R. J. Malcolm, W. J. Raum, K. L. Hermayer, J. L. Veliko, S. L. Rost, N. D. Sora, J. L. Salyer and P. M. O’Neil (2017). “Impact on psychosocial outcomes of a nationally available weight management program tailored for individuals with type 2 diabetes: Results of a randomized controlled trial.” J Diabetes Complications 31(5): 891-897.

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AIMS: Type 2 diabetes mellitus (T2DM) can substantially decrease quality of life (QOL). This study examined the effects on QOL-relevant psychosocial measures of a widely available commercial weight loss program enhanced for individuals with T2DM. METHODS: A year-long multi-site randomized clinical trial compared the Weight Watchers (WW) approach, supplemented with phone and email counseling with a certified diabetes educator (CDE), to brief standard diabetes nutrition counseling and education (Standard Care; SC). Participants were 400 women and 163 men (N=279 WW; 284 SC) with T2DM [mean (+/-SD) HbA1c 8.32+/-1%; BMI=37.1+/-5.7kg/m2; age=55.1 +/- 9.1years]. Psychosocial outcomes were assessed at baseline, month 6, and month 12 using a diabetes specific psychosocial measure (Diabetes Distress Scale [DDS]), Impact of Weight on Quality of Life-Lite scale (IWQOL), a generic QOL measure (SF-36), and a depression screen (PHQ-9). RESULTS: WW participants showed significantly greater improvements than did SC participants on all DDS subscales and total score and on IWQOL total score and physical function, sex life and work domains (all ps<.05). There was no significant treatment effect on SF-36 scores or PHQ-9. CONCLUSIONS: WW enhanced for individuals with T2DM was superior to SC in improving psychosocial outcomes most specific to T2DM and obesity. Available commercial WL programs, combined with scalable complementary program-specific diabetes counseling, may have benefits that extend to diabetes-related distress and weight-relevant QOL.

Dayal, S., G. L. Baumbach, E. Arning, T. Bottiglieri, F. M. Faraci and S. R. Lentz (2017). “Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia.” PLoS One 12(4): e0175732.

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There is an emerging consensus that hyperhomocysteinemia is an independent risk factor for cerebral vascular disease and that homocysteine-lowering therapy protects from ischemic stroke. However, the mechanisms by which hyperhomocysteinemia produces abnormalities of cerebral vascular structure and function remain largely undefined. Our objective in this study was to define the mechanistic role of superoxide in hyperhomocysteinemia-induced cerebral vascular dysfunction and hypertrophy. Unlike previous studies, our experimental design included a genetic approach to alter superoxide levels by using superoxide dismutase 1 (SOD1)-deficient mice fed a high methionine/low folate diet to produce hyperhomocysteinemia. In wild-type mice, the hyperhomocysteinemic diet caused elevated superoxide levels and impaired responses to endothelium-dependent vasodilators in cerebral arterioles, and SOD1 deficiency compounded the severity of these effects. The cross-sectional area of the pial arteriolar wall was markedly increased in mice with SOD1 deficiency, and the hyperhomocysteinemic diet sensitized SOD1-deficient mice to this hypertrophic effect. Analysis of individual components of the vascular wall demonstrated a significant increase in the content of smooth muscle and elastin. We conclude that superoxide is a key driver of both cerebral vascular hypertrophy and vasomotor dysfunction in this model of dietary hyperhomocysteinemia. These findings provide insight into the mechanisms by which hyperhomocysteinemia promotes cerebral vascular disease and ischemic stroke.