Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Age-Related Normative Changes in Phasic Orthostatic Blood Pressure in a Large Population Study: Findings From The Irish Longitudinal Study on Ageing (TILDA)
- Dietary Fat Supply to Failing Hearts Determines Dynamic Lipid Signaling for Nuclear Receptor Activation and Oxidation of Stored Triglyceride
- β-Adrenergic Receptor–Mediated Cardiac Contractility Is Inhibited via Vasopressin Type 1A-Receptor–Dependent Signaling
- Clinical Trials in Peripheral Vascular Disease: Pipeline and Trial Designs: An Evaluation of the ClinicalTrials.gov Database
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Age-Related Normative Changes in Phasic Orthostatic Blood Pressure in a Large Population Study: Findings From The Irish Longitudinal Study on Ageing (TILDA)
Our increasing longevity is well recognized and evident in global demographics. The use of novel technologies to aid early identification and treatment of age-related disorders such as falls is a vital component of the global response to aging. One area of growing clinical interest is the role of hypotensive disorders as a risk factor for falls. Measures of phasic blood pressure (BP) have revolutionized our ability to assess orthostatic BP, and they afford new opportunities to better understand orthostatic (hemodynamic) disorders related to morbidity and mortality. This study is the first nationally representative study to describe the population distribution and age-related changes in phasic postural BP responses in older adults. It provides normative values that can be used in a clinical setting to guide management of orthostatic hemodynamic disorders. In addition, we describe definitions suitable for clinical use in identifying patients with impaired BP stabilization and orthostatic hypotension when using newer BP measurement technologies. Finally, the present study also establishes that impaired BP stabilization during standing is common and increases in prevalence significantly with age (40% of those ≥80 years of age). Given previous evidence, it is likely that impaired BP stabilization is a key component of understanding the role of hypotension in the risk management of falls as wells as other age-related disorders. These results may inform future diagnostic approaches in the management of hypotensive disorders and risk of falls at a global level, not only in specialist centers but also at a community level with the emergence of newer measurement technologies. See p 1780.
Dietary Fat Supply to Failing Hearts Determines Dynamic Lipid Signaling for Nuclear Receptor Activation and Oxidation of Stored Triglyceride
Pathogenic cardiac hypertrophy has long been associated with a low myocardial energy state, and, more recently, defects in metabolic pathways providing ATP. Recently, nondiabetic patients with heart failure were found to have reduced intramyocellular lipid in the form of triglyceride. That clinical finding recapitulated previous findings in animal models and established a link between reduced myocardial triglyceride and elevated lipotoxic intermediates. This current study, on a rat model of chronic pressure overload, enabled stable isotope measurements of the dynamics of triglyceride turnover and contribution to oxidative energy metabolism in the beating heart. Experiments elucidated differences in triglyceride content, turnover, and oxidation between hearts supplied with either of 2 major circulating and dietary long-chain fats, palmitate and oleate, in both normal and failing hearts. Oleate supported faster triglyceride turnover than did palmitate. Importantly, hypertrophied hearts supplied with palmitate had reduced triglyceride content, turnover, and contributions to oxidative metabolism that coincided with elevated levels of a lipotoxic fatty acid derivative, C16 ceramide. In contrast, hypertrophied hearts supplied with oleate had normal triglyceride content, turnover, oxidation, and C16 ceramide, with improved contractility. An intriguing benefit of oleate was the restoration of gene transcription for metabolic enzymes in failing hearts, which were greatly depressed with palmitate. The findings suggest that the increased triglyceride turnover induced by oleate restores lipolytic activation of nuclear receptors in the cardiomyocyte, with metabolic and functional benefits to the failing heart. The implication of this study is the potential for dietary mediation of cardiac performance in the decompensated, hypertrophied heart by shifting fat supplies. See p 1790.
β-Adrenergic Receptor–Mediated Cardiac Contractility Is Inhibited via Vasopressin Type 1A-Receptor–Dependent Signaling
Elevated levels of arginine vasopressin (AVP) are a characteristic feature of patients with heart failure (HF) and are directly related to worsening symptoms and increased mortality. Although AVP activates both cardiac V1A receptors (V1AR) and renal V2R, the development of pharmacological agents for HF therapy has focused on V2R antagonism to treat hyponatremia. However, V2R antagonism can increase circulating AVP levels, and cardiac V1AR expression has been shown to increase 2-fold in human patients with end-stage HF. We now demonstrate that acute stimulation of V1AR reduces β-adrenergic receptor (βAR) ligand affinity, downstream signaling, and cardiac contractility. Although V1AR is a Gq protein–coupled receptor, inhibition of Gq protein–dependent signaling did not prevent AVP-mediated attenuation of βAR responsiveness. However, mutation of the putative C-terminal GPCR kinase (GRK) phosphorylation sites of V1AR completely blocked the ability of AVP to inhibit βAR-mediated signaling. The ability of AVP to inhibit βAR responsiveness via a GRK-dependent mechanism is unique, because another GqPCR, the angiotensin II type 1A receptor, was unable to impact βAR signaling. Administration of the V1AR-selective antagonist SR 49059 normalized cardiac performance and both V1AR and βAR expression levels in mice with HF secondary to transaortic constriction. This newly discovered relationship between cardiac-expressed V1AR and βAR may explain the increased mortality observed in patients with acute HF and elevated AVP levels, alone or secondary to treatment with V2R-selective antagonists, and may provide support for the potential use of a V1AR antagonist in the treatment of these patients. See p 1800.
Clinical Trials in Peripheral Vascular Disease: Pipeline and Trial Designs: An Evaluation of the ClinicalTrials.gov Database
Despite advances in therapies for peripheral vascular disease (PVD) in both arterial and venous disease, little is known about the current state of the entire PVD trial portfolio and current trial designs. The ClinicalTrials.gov database allows analysis of clinical trials performed on various disease states. We found that PVD trials represented only a small fraction (1.7%) of the trials registered in the ClinicalTrials.gov database of 40 970 trials from October 2007 through September 2010. A placebo-controlled trial was used in only approximately one fourth of the trials. Compared with noncardiology disciplines, PVD trials were more likely to be double-blinded, to investigate the use of devices and procedures, and to have industry sponsorship and an assumed funding source; in addition, they were less likely to investigate drug and behavioral therapies. Enrollment in at least 1 US site decreased from 51% in 2007 to 41% of trials in 2010, and geographic access to PVD clinical trials within the United States is limited to primarily large metropolitan areas. Despite the high prevalence of vascular disease, the short supply, compounded by the decreasing number, of PVD trials in the United States is concerning and may limit the ability to inform current clinical practice of patients with PVD. See p 1812.
- © 2014 American Heart Association, Inc.
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