Hans K. Meier-Ewert

Cardiovascular, Inflammatory, and Metabolic Consequences of Sleep Deprivation

That insufficient sleep is associated with poor attention and performance deficits is becoming widely recognized. Fewer people are aware that chronic sleep complaints in epidemiologic studies have also been associated with an increase in overall mortality and morbidity. This article summarizes findings of known effects of insufficient sleep on cardiovascular risk factors including blood pressure, glucose metabolism, hormonal regulation, and inflammation with particular emphasis on experimental sleep loss, using models of total and partial sleep deprivation, in healthy individuals who normally sleep in the range of 7 to 8 hours and have no sleep disorders. These studies show that insufficient sleep alters established cardiovascular risk factors in a direction that is known to increase the risk of cardiac morbidity.

Sleep Loss Reduces Diurnal Rhythm Amplitude of Leptin in Healthy Men

The aim of the current study was to investigate the effects of sleep loss on the diurnal rhythm of circulating leptin levels. An indwelling forearm catheter was used to sample blood at 90‐min intervals for a total of 120 h, which included 88 h of sustained sleeplessness, in 10 healthy men. The diurnal amplitude of leptin was reduced during total sleep deprivation and returned toward normal during the period of recovery sleep. This finding provides evidence that sleep influences the nocturnal leptin profile, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome.

Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.

Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

Sleep Loss and Inflammation

Controlled, experimental studies on the effects of acute sleep loss in humans have shown that mediators of inflammation are altered by sleep loss. Elevations in these mediators have been found to occur in healthy, rigorously screened individuals undergoing experimental vigils of more than 24h, and have also been seen in response to various durations of sleep restricted to between 25 and 50% of a normal 8h sleep amount. While these altered profiles represent small changes, such sub-clinical shifts in basal inflammatory cytokines are known to be associated with the future development of metabolic syndrome disease in healthy, asymptomatic individuals. Although the mechanism of this altered inflammatory status in humans undergoing experimental sleep loss is unknown, it is likely that autonomic activation and metabolic changes play key roles.

Endocardial pacemaker or defibrillator leads with infected vegetations: a single-center experience and consequences of transvenous extraction.

BACKGROUND Removal of infected endovascular leads if often required for cure of systemic infection, but the perceived risk of embolic events in the presence of large (>10 mm) vegetations has been considered a relative contraindication to transvenous removal. Surgical removal of pacemaker leads has been suggested in this situation to avoid occurrence of pulmonary embolization. METHODS Of 38 patients with infection of implanted pacemaker or cardioverter-defibrillator devices, those with evidence for systemic infection underwent transesophageal echocardiography to assess for the presence of vegetations. RESULTS Vegetations on endocardial leads or right-sided cardiac structures ranging in size from 10 mm to 38 mm in their largest dimension were detected in 9 patients. All patients underwent successful transvenous removal of endocardial leads. Five of 9 patients (55%) had evidence of pulmonary embolism. However, all 5 patients made a full recovery with antibiotic treatment and anticoagulation. Among patients with endocardial vegetations, there was no difference in hospitalization periods between those with or without pulmonary embolism (14.6 +/- 0.8 days vs 18.0 +/- 4.5 days, P =.7). CONCLUSIONS Transvenous removal of infected pacemaker leads is an alternative to open-thoracotomy removal of infected leads. Fifty-five percent of patients with vegetations on endocardial leads in our series experienced pulmonary embolism, but neither survival nor length of hospital stay were affected by this complication.

Increasing sleep duration to lower beat‐to‐beat blood pressure: a pilot study

Strong evidence has accumulated over the last several years, showing that low sleep quantity and/or quality plays an important role in the elevation of blood pressure. We hypothesized that increasing sleep duration serves as an effective behavioral strategy to reduce blood pressure in prehypertension or type 1 hypertension. Twenty‐two participants with prehypertension or stage 1 hypertension, and habitual sleep durations of 7 h or less, participated in a 6‐week intervention study. Subjects were randomized to a sleep extension group (48 ± 12 years, N = 13) aiming to increase bedtime by 1 h daily over a 6‐week intervention period, or to a sleep maintenance group (47 ± 12 years, N = 9) aiming to maintain habitual bedtimes. Both groups received sleep hygiene instructions. Beat‐to‐beat blood pressure was monitored over 24 h, and 24‐h urine and a fasting blood sample were collected pre‐ and post‐intervention. Subjects in the sleep extension group increased their actigraphy‐assessed daily sleep duration by 35 ± 9 min, while subjects in the sleep maintenance condition increased slightly by 4 ± 9 min (P = 0.03 for group effect). Systolic and diastolic beat‐to‐beat blood pressure averaged across the 24‐h recording period significantly decreased from pre‐ to post‐intervention visit in the sleep extension group by 14 ± 3 and 8 ± 3 mmHg, respectively (P < 0.05). Though the reduction of 7 ± 5 and 3 ± 4 mmHg in the sleep maintenance group was not significant, it did not differ from the blood pressure reduction in the sleep extension group (P = 0.15 for interaction effect). These changes were not paralleled by pre‐ to post‐intervention changes in inflammatory or sympatho‐adrenal markers, nor by changes in caloric intake. While these preliminary findings have to be interpreted with caution due to the small sample size, they encourage future investigations to test whether behavioral interventions designed to increase sleep duration serve as an effective strategy in the treatment of hypertension.

Matrix Metalloproteinases and Their Tissue Inhibitors in Cardiac Amyloidosis Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition

Background—Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition has an accelerated clinical course and a worse prognosis compared with non-light chain cardiac amyloidoses (ie, forms associated with wild-type or mutated transthyretin [TTR]). We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) would have distinct patterns and contribute to the pathogenesis of AL-CMP versus TTR-related amyloidosis. Methods and Results—We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, ie, senile systemic amyloidois (involving wild-type TTR) or mutant TTR, and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and -9, TIMP-1, -2, and -4, brain natriuretic peptide values, and echocardiography were determined. AL-CMP and TTR-related amyloidosis groups had similar degrees of increased left ventricular wall thickness. However, brain natriuretic peptide, MMP-9, and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group versus no or minimal increases in the TTR-related amyloidosis group. Brain natriuretic peptide, MMPs, and TIMPs were not correlated with the degree of left ventricular wall thickness but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in TTR-related amyloidosis hearts. Conclusions—Despite comparable left ventricular wall thickness with TTR-related cardiac amyloidosis, AL-CMP patients have higher brain natriuretic peptide, MMPs, and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non-light chain cardiac amyloidoses.Background— Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition has an accelerated clinical course and a worse prognosis compared with non–light chain cardiac amyloidoses (ie, forms associated with wild-type or mutated transthyretin [TTR]). We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) would have distinct patterns and contribute to the pathogenesis of AL-CMP versus TTR-related amyloidosis. Methods and Results— We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, ie, senile systemic amyloidois (involving wild-type TTR) or mutant TTR, and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and -9, TIMP-1, -2, and -4, brain natriuretic peptide values, and echocardiography were determined. AL-CMP and TTR-related amyloidosis groups had similar degrees of increased left ventricular wall thickness. However, brain natriuretic peptide, MMP-9, and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group versus no or minimal increases in the TTR-related amyloidosis group. Brain natriuretic peptide, MMPs, and TIMPs were not correlated with the degree of left ventricular wall thickness but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in TTR-related amyloidosis hearts. Conclusions— Despite comparable left ventricular wall thickness with TTR-related cardiac amyloidosis, AL-CMP patients have higher brain natriuretic peptide, MMPs, and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non–light chain cardiac amyloidoses. Received April 25, 2008; accepted September 23, 2008.

Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement.

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

Effect of age on differences in upper esophageal sphincter and pharynx pressures between patients with dysphagia and control subjects.

OBJECTIVES:The aim of this study was to explore the effect of age and food consistency on manometric data of the swallow sequence in patients with dysphagia.METHODS:Manometric data from 41 patients (age range, 32–88 yr) and 41 age-matched control subjects was examined for differences between subgroups <60 yr and ≥60 yr of age, as well as for changes with food consistency.RESULTS:Only pharynx peak pressure showed an age-dependent decrease (144.1 ± 21.4 mm Hg vs 95.8 ± 15.1 mm Hg, p < 0.05) in patients. Significant higher upper esophageal sphincter residual pressure and delayed onset of upper esophageal sphincter relaxation were noted in patients aged <60 yr compared to age-matched controls, whereas only pharynx peak pressure was significantly lower in patients compared to controls aged ≥60 yr. Food consistency did not have a consistent effect on manometric results in patients with dysphagia.CONCLUSIONS:This is the first study to systematically explore the influence of age and food consistency on manometric parameters in dysphagia patients. These results may provide useful insights when identifying actual manometric abnormalities in patients with dysphagia. They also suggest possible different underlying mechanisms of dysphagia in younger versus older patients.

High-dose melphalan and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center.

To the editor: We recently reported the outcomes of 421 consecutive patients with immunoglobulin light chain (AL) amyloidosis treated with high-dose melphalan and autologous stem cell transplantation (HDM/SCT)[1][1] from July 1994 through December 2008. Median survival was 6.3 years and the