Heart rate variability (HRV) falls in humans with sepsis, but the mechanism is not well understood. We utilized a mouse model of endotoxemia to test the hypothesis that cytokines play a role in abnormal HRV during sepsis. Adult male C57BL/6 mice underwent surgical implantation of probes to continuously monitor electrocardiogram and temperature or blood pressure via radiotelemetry. Administration of high-dose LPS (Escherichia coli LPS, 10 mg/kg, n = 10) caused a biphasic response characterized by an early decrease in temperature and heart rate at 1 h in some mice, followed by a prolonged period of depressed HRV in all mice. Further studies showed that LPS doses as low as 0.01 mg/kg evoked a significant decrease in HRV. With high-dose LPS, the initial drops in temperature and HR were temporally correlated with peak expression of TNFalpha 1 h post-LPS, whereas maximal depression in HRV coincided with peak levels of multiple other cytokines 3-9 h post-LPS. Neither hypotension nor hypothermia explained the HRV response. Pretreatment with dexamethasone prior to LPS significantly blunted expression of 7 of the 10 cytokines studied and shortened the duration of depressed HRV by about half. Interestingly, dexamethasone treatment alone caused a dramatic increase in both low- and high-frequency HRV. Administration of recombinant TNFalpha caused a biphasic response in HR and HRV similar to that caused by LPS. Understanding the role of cytokines in abnormal HRV during sepsis could lead to improved strategies for detecting life-threatening nosocomial infections in intensive care unit patients.

BackgroundChronic kidney disease (CKD) is an adverse prognostic marker for valve intervention patients; however, the prevalence and related outcomes of valvular heart disease in CKD patients is unknown.Methods and ResultsIncluded patients underwent echocardiography (1999–2013), had serum creatinine values within 6 months before index echocardiogram, and had no history of valve surgery. CKD was defined as diagnosis based on the International Classification of Diseases, Ninth Revision or an estimated glomerular filtration rate <60 mL/min per 1.73 m2. Qualitative assessment determined left heart stenotic and regurgitant valve lesions. Cox models assessed CKD and aortic stenosis (AS) interaction for subsequent mortality; analyses were repeated for mitral regurgitation (MR). Among 78 059 patients, 23 727 (30%) had CKD; of these, 1326 were on hemodialysis. CKD patients were older; female; had a higher prevalence of hypertension, hyperlipidemia, diabetes, history of coronary artery bypass grafting/percutaneous coronary intervention, atrial fibrillation, and heart failure ≥mild AS; and ≥mild MR (all P<0.001). Five‐year survival estimates of mild, moderate, and severe AS for CKD patients were 40%, 34%, and 42%, respectively, and 69%, 54%, and 67% for non‐CKD patients. Five‐year survival estimates of mild, moderate, and severe MR for CKD patients were 51%, 38%, and 37%, respectively, and 75%, 66%, and 65% for non‐CKD patients. Significant interaction occurred among CKD, AS/MR severity, and mortality in adjusted analyses; the CKD hazard ratio increased from 1.8 (non‐AS patients) to 2.0 (severe AS) and from 1.7 (non‐MR patients) to 2.6 (severe MR).ConclusionsPrevalence of at least mild AS and MR is substantially higher and is associated with significantly lower survival among patients with versus without CKD. There is significant interaction among CKD, AS/MR severity, and mortality, with increasingly worse outcomes for CKD patients with increasing AS/MR severity.

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Total right heart function requires normal function of both the right ventricle and the right atrium. However, the degree to which right atrial (RA) function and right ventricular (RV) function each contribute to total right heart function has not been quantified. In this study, we aimed to quantify the contribution of RA function to total right heart function in a group of pulmonary arterial hypertension (PAH) patients compared to a cohort of normal controls without cardiovascular disease. The normal cohort comprised 35 subjects with normal clinical echocardiograms, while the PAH cohort included 37 patients, of whom 31 had echocardiograms before and after initiation of PAH-specific therapy. Total right heart function was measured via tricuspid annular plane excursion (TAPSE). TAPSE was broken down into two components, the excursion occurring during RA contraction (TAPSE RA ) and that occurring before RA contraction (TAPSE RV ). RA fractional area change (RA-FAC) was also compared between the two groups. In the PAH cohort, more than half of the total TAPSE occurred during atrial systole, compared to less than one-third in the normal cohort (51.0% vs. 32.1%; P < 0.0001). There was a significant correlation between RA-FAC and TAPSE in the PAH cohort but not in the normal cohort. TAPSE improved significantly in the posttreatment cohort (1.7 vs. 2.1 cm), but TAPSE RA continued to account for about half of the total TAPSE after treatment. RA function accounts for a significantly greater proportion of total right heart function in patients with PAH than in normal subjects. Pulmonary arterial hypertension (PAH) is characterized by marked increases in right ventricular (RV) afterload, which if left untreated leads to progressive RV dysfunction, exercise intolerance, and potentially death.1-3 As recently emphasized by the International Right Heart Foundation Working Group, the right ventricle (also RV) is only one part of the total right heart system, and the other components, including the right atrium (RA), contribute importantly to total right heart function. 4It has been recognized that in the setting of RV failure, preserved right atrial (also RA) function is essential to maintain adequate total right heart function. After RV infarction, for example, preserved RA function has been shown to improve RV filling and performance, whereas diminished RA function compromises cardiac output. 5,6 Loss of atrial function, in the form of supraventricular arrhythmias with resulting atrioventricular dyssynchrony, is also known to be poorly tolerated among patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH). 7,8 Moreover, animal models have shown that RA systolic function is, in fact, augmented in the setting of RV ischemia and that if there is a subsequent ischemic insult to the RA, RV function is significantly reduced. 7 Taken together, these studies suggest that RA function must not only be maintained but at times augmented, in order to optimize total right heart function in the setting of RV c...

Background: Pulmonary hypertension (PH) is frequently reported in patients with advanced chronic kidney disease (CKD) and is associated with early allograft failure and death. However, the causes of PH are heterogeneous, and patient prognosis may vary by etiologic subtype.Methods: Data from the UNC Cardiorenal Registry were examined to determine associations between pulmonary hypertension (PH), with or without elevated left atrial pressure (eLAP), and mortality in candidates for kidney transplantation. PH and eLAP were determined by Doppler echocardiography and by tissue Doppler imaging, respectively.Results: From 2006-2013, 778 registry patients were screened preoperatively by echocardiography. Most patients were black (64%) and male (56%); the mean age was 56 years. PH was identified in 97 (12%) patients; of these, eLAP was prevalent in half. During a median follow up of 4.4 years, 179 (23%) received a kidney transplant, and 195 (25%) died. After adjustments for demographics, comorbidities, dialysis vintage and kidney transplantation, PH was associated with twice the 5-year mortality (HR = 2.11; 95% CI: 1.48 -3.03), with stronger associations in the absence of eLAP (HR = 2.87; 95% CI: 1.83 -4.49) than with eLAP (HR = 1.11; 95% CI: 0.57 -2.17); P for interaction = 0.01. Conclusion:The mortality risk associated with PH among patients with advanced CKD appears to differ by etiology. Patients with PH in the absence of eLAP are at high risk of death and in need of focused attention. Future research efforts should investigate potential strategies to improve outcomes for these patients.