Blood pressure reactivity to psychological stress is associated with clinical outcomes in patients with heart failure

© 2017 Elsevier Inc. Introduction: Cardiovascular (CV) reactivity to psychological stress has been implicated in the development and exacerbation of cardiovascular disease (CVD). Although high CV reactivity traditionally is thought to convey greater risk of CVD, the relationship between reactivity and clinical outcomes is inconsistent and may depend on the patient population under investigation. The present study examined CV reactivity in patients with heart failure (HF) and its potential association with long-term clinical outcomes. Methods: One hundred ninety-nine outpatients diagnosed with HF, with ejection fraction ≤40%, underwent an evaluation of blood pressure (BP) and heart rate reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and heart rate reactivity on a combined end point of death or CV hospitalization over a 5-year median follow-up period. Results: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity, quantified as continuous variables, were inversely related to risk of death or CV hospitalization (Ps < .01) after controlling for established risk factors, including HF disease severity and etiology. In similar models, heart rate reactivity was unrelated to outcome (P = .12). In models with tertiles of reactivity, high SBP reactivity, compared with intermediate SBP reactivity, was associated with lower risk (hazard ratio [HR] = .498, 95% CI .335-.742, P =.001), whereas low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared with intermediate DBP reactivity (HR = .767, 95% CI .515-1.14, P =.193), whereas low DBP reactivity was associated with greater risk (HR = 1.49, 95% CI 1.027-2.155, P =.0359). No relationship of heart rate reactivity to outcome was identified. Conclusions: For HF patients with reduced ejection fraction, a robust increase in BP evoked by a laboratory-based psychological challenge was associated with lower risk for adverse CVD events and may be a novel and unique marker of left ventricular systolic reserve that is accompanied by a more favorable long-term prognosis

Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde

Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA cross-linker. Contrary to current dogma, we show that both efficient DNA cross-linking and potent synergy in combination with formaldehyde correlate with the anthracycline’s ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better cross-linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracycline prodrug design and development

Fasting oxLDL Levels (units/L).

<p>*Wilcoxon signed rank statistic for change from baseline within group.</p><p>^†Wilcoxon rank sum statistic for differences between groups.</p><p>Fasting oxLDL Levels (units/L).</p

Coronary Artery Atherosclerosis in Insulin Resistant Pigs.

<p>Panels A1 to A5: Representative serial sections from the proximal to distal left anterior descending coronary artery are shown from an IR pig with severe and diffuse distal coronary atherosclerosis. The mean intimal area as a percent of medial area for all three coronary arteries for this pig was 203.6% proximally and 338.5% distally. Panels B1 to B5: In contrast, a pig with moderate coronary atherosclerosis had a mean intimal area as a percent of medial area for all three coronary arteries of 11.3% proximally and 5.8% distally. Features of coronary atherosclerosis in rows A and B are shown at higher magnification in rows C and D, respectively: intimal thickening (IT) and calcification in a pig with moderate atherosclerosis (Ca²⁺ (moderate), Panels B1 and D1), calcification in a pig with severe atherosclerosis (Ca²⁺ (severe), Panels A4 and C2), fibrous cap (FC, Panel A2 and C1), hemorrhage into the plaque (H, Panels A4 and C3), medial thinning (MT, Panels A4 and D2), necrosis (N, Panels A4 and D3). (Hematoxylin and Eosin, mag bar = 500 μm is shown in B5 for rows A and B; mag bar = 10 μm in all panels in rows C and D).</p

Fasting Insulin Levels and Bergman Si Values.

<p>*Wilcoxon signed rank statistic for change from baseline within group.</p><p>^†Wilcoxon rank sum statistic for differences between groups.</p><p>Fasting Insulin Levels and Bergman Si Values.</p

Mean Coronary Artery Total IEL Area (mm²), Percent of Coronary Artery Cross Sections Containing Fibrous Caps (FC), and Fibrous Cap Thickness (mm) in All 3 Coronary Arteries.

<p>*percent of coronary artery sections containing fibrous caps (FC),</p><p>^† Wilcoxon rank sum statistic for differences between groups,</p><p>N/A is not applicable,</p><p>Mean Coronary Artery Total IEL Area (mm²), Percent of Coronary Artery Cross Sections Containing Fibrous Caps (FC), and Fibrous Cap Thickness (mm) in All 3 Coronary Arteries.</p

Study Design.

<p>The 42 pigs entered into this study are listed according to the diet they were fed, genotype (NL = normal, FH het = FH heterozygous) and gender.</p

Fasting Total and LDL Cholesterol.

<p>*Wilcoxon signed rank statistic for change from baseline within group.</p><p>^†Wilcoxon rank sum statistic for differences between groups.</p><p>Fasting Total and LDL Cholesterol.</p

Proximal and Distal Coronary Artery Atherosclerosis Morphometry.

<p>* Wilcoxon rank sum statistic for differences between groups.</p><p>Proximal and Distal Coronary Artery Atherosclerosis Morphometry.</p

Fasting HDL Cholesterol and Triglycerides.

<p>*Wilcoxon signed rank statistic for change from baseline within group.</p><p>^†Wilcoxon rank sum statistic for differences between groups.</p><p>Fasting HDL Cholesterol and Triglycerides.</p