Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In ‘salt-sensitive’ HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155 to 138 mmHg, p=.02) and diastolic BP (79 to 72 mmHg, p=.04), 24-hour ambulatory systolic (130 to 123 mmHg, p=.02) and diastolic BP (67 to 62 mmHg, p=.02), and carotid-femoral pulse wave velocity (12.4 to 11.0 m/s, p=.03). Urinary F2-isoprostanes decreased by 31% (209 to 144 pmol/mmol Cr, p=.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of ‘salt-sensitive’ hypertension, a phenotype present in many HFPEF animal models, and suggest shared pathophysiological mechanisms linking these two conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.
Background: In patients with heart failure (HF), malnutrition and dietary sodium excess are common and may worsen outcomes. No prior studies have provided low-sodium, nutritionally-complete meals following HF hospitalization. Methods and Results: The Geriatric OUt-of-hospital Randomized MEal Trial in Heart Failure (GOURMET-HF) study randomized patients discharged from HF hospitalization to four weeks of home-delivered sodium-restricted Dietary Approaches to Stop Hypertension meals (DASH/SRD; 1,500 mg sodium/day) vs. usual care. The primary outcome was the between-group change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Summary Score from discharge to four weeks post-discharge. Additional outcomes included changes in the KCCQ Clinical Summary Score and cardiac biomarkers. All patients were followed 12 weeks for death/all-cause readmission and potential diet-related adverse events (symptomatic hypotension, hyperkalemia, acute kidney injury). 66 patients were randomized 1:1 at discharge to DASH/SRD vs. usual care (age 71±8 years, 30% female, ejection fraction 39±18%). The KCCQ Summary Score increased similarly between groups (DASH/SRD 46±23 to 59±20 vs. usual care 43±19 to 53±24, p=0.38) but the KCCQ Clinical Summary Score increase tended to be greater in DASH/SRD participants (47±22 to 65±19 vs. 45±20 to 55±26, p=0.053). Potentially diet-related adverse events were uncommon; 30-day HF readmissions (11% vs. 27%, p=0.06) and days rehospitalized within that timeframe (17 vs. 55, p=0.055) trended lower in DASH/SRD participants. Conclusions: Home-delivered DASH/SRD following HF hospitalization appeared safe in selected patients, and had directionally favorable effects on HF clinical status and 30-day readmissions. Larger studies are warranted to clarify the effects of post-discharge nutritional support in patients with HF. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02148679
The Birnaviridae family, responsible for major economic losses to poultry and aquaculture, is composed of nonenveloped viruses with a segmented double-stranded RNA (dsRNA) genome that replicate in discrete cytoplasmic virus factories (VFs). Reassortment is common; however, the underlying mechanism remains unknown given that VFs may act as a barrier to genome mixing. In order to provide new information on VF trafficking during dsRNA virus coinfection, we rescued two recombinant infectious bursal disease viruses (IBDVs) of strain PBG98 containing either a split GFP11 or a tetracysteine (TC) tag fused to the VP1 polymerase (PBG98-VP1-GFP11 and PBG98-VP1-TC). DF-1 cells transfected with GFP1-10 prior to PBG98-VP1-GFP11 infection or stained with a biarsenical derivative of the red fluorophore resorufin (ReAsH) following PBG98-VP1-TC infection, had green or red foci in the cytoplasm, respectively, that colocalized with VP3 and dsRNA, consistent with VFs. The average number of VFs decreased from a mean of 60 to 5 per cell between 10 and 24 h postinfection (hpi) (P < 0.0001), while the average area increased from 1.24 to 45.01 μm2 (P < 0.0001), and live cell imaging revealed that the VFs were highly dynamic structures that coalesced in the cytoplasm. Small VFs moved faster than large (average 0.57 μm/s at 16 hpi compared to 0.22 μm/s at 22 hpi), and VF coalescence was dependent on an intact microtubule network and actin cytoskeleton. During coinfection with PBG98-VP1-GFP11 and PBG98-VP1-TC viruses, discrete VFs initially formed from each input virus that subsequently coalesced 10 to 16 hpi, and we speculate that Birnaviridae reassortment requires VF coalescence. IMPORTANCE Reassortment is common in viruses with segmented double-stranded RNA (dsRNA) genomes. However, these viruses typically replicate within discrete cytoplasmic virus factories (VFs) that may represent a barrier to genome mixing. We generated the first replication competent tagged reporter birnaviruses, infectious bursal disease viruses (IBDVs) containing a split GFP11 or tetracysteine (TC) tag and used the viruses to track the location and movement of IBDV VFs, in order to better understand the intracellular dynamics of VFs during a coinfection. Discrete VFs initially formed from each virus that subsequently coalesced from 10 h postinfection. We hypothesize that VF coalescence is required for the reassortment of the Birnaviridae. This study provides new information that adds to our understanding of dsRNA virus VF trafficking.
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