Objective The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured mRNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed mRNA expression in non-failing and failing human hearts. Design Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease (IHD), or dilated cardiomyopathy (DCM), in comparison to non-failing hearts. Setting Intensive care units (ICUs) at Barnes-Jewish Hospital, St. Louis, Missouri. Patients 20 sepsis patients, 11 IHD, 9 DCM, 11 non-failing donors. Interventions None other than those performed as part of patient care. Measurements and Main Results mRNA expression levels for 198 mitochondrially-localized energy production components, including Krebs cycle and electron transport genes, decreased by 43±5% (mean±s.d.). mRNAs for 9 genes responsible for sarcomere contraction and excitation-contraction coupling decreased by 43±4% in septic hearts. Surprisingly, the alterations in mRNA levels in septic cardiomyopathy were both distinct from and more profound than changes in mRNA levels in the hearts of patients with end stage heart failure. Conclusions The expression profile of mRNAs in the heart of septic patients reveals striking decreases in expression levels of mRNAs that encode proteins involved in cardiac energy production and cardiac contractility, and is distinct from that observed in patients with heart failure. Although speculative, the global nature of the decreases in mRNA expression for genes involved in cardiac energy production and contractility suggests that these changes may represent a short-term adaptive response of the heart in response to acute change in cardiovascular homeostasis.
Activation of the renin-angiotensin (Ang)-aldosterone system (RAAS) plays an important role in the development of hypertension and end-organ damage. RAAS suppression is, therefore, an important goal of antihypertensive therapy, and RAAS inhibitors, such as Ang-converting enzyme (ACE) inhibitors and Ang receptor blockers (ARBs), have proven to be highly successful treatments for hypertension, heart failure and related cardiovascular disorders. [1] Although renin was discovered more than a century ago, [2,3] the significance of this system in the pathogenesis of cardiovascular and renal disorders has gained wide acceptance only during the past 3 decades, in large part because of the availability of specific pharmacologic agents that can block the system. [2] The concept of blocking the RAAS at its origin by inhibiting renin has existed for at least 50 years. The first synthetic renin inhibitor was pepstatin, which was followed by first-generation agents that were active but required parenteral administration. Oral agents that were subsequently developed, such as enalkiren, remikiren, and zankiren, had limited clinical use because they demonstrated poor bioavailability (,2%), short half-lives and weak antihypertensive activity. [4] Aliskiren Intensive efforts have been made to discover therapeutic, nonpeptide and orally effective hypertensive drugs. Drugs that
In a model of triolein‐induced fat embolism (FE) in the rat, we have reported that the acute pulmonary histopathological changes were ameliorated by losartan (Los). The chronic pulmonary changes of FE persisted at 6 weeks and symptoms were exacerbated by a “second hit” at that time using LPS. The present experiment extended FE study to 10 weeks and examined whether the FE effects plus LPS would continue to be blocked by Los. Groups of rats were given FE (triolein i.v. or i.v. saline controls) followed 6 weeks later by LPS (3 mg/kg i.p). One‐hour after LPS rats were treated with saline or Los (2 mg/kg i.p. and then 0.1 mg/ml Los in the drinking water for 4 more weeks). In confirmation of our previous results, the FE group showed normal weight gain both at 6 and 10 weeks and appeared to be in no distress. However the lungs showed reduced lumen patency at 10 weeks, accompanied by inflammatory and fibrotic changes that were greater than what had been found previously at 6 weeks whether or not LPS was added. These changes were reduced or blocked by Los. In addition pulmonary arteries of all Los‐treated animals had increased lumen patency compared to their respective controls. The data suggest that the effect of FE continues to progress at 10 weeks. The involvement of the renin‐angiotensin system in the pathology of FE is supported by the action of the type 1 receptor blocker, Los. In addition, the enhanced effect of LPS on FE (second hit) was also blocked by Los. These results support the possibility of using angiotensin blockade in clinical situations where fat embolism is suspected . Grant Funding Source: Supported by Geldmacher Foundation
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