Cardiac amyloidosis: evolving approach to diagnosis and management.

OPINION STATEMENT: The systemic amyloidoses are a group of heterogeneous disorders characterized by extracellular deposition of misfolded fibrillar protein that results in organ dysfunction. Involvement of the heart (cardiac amyloidosis) is manifest by increased cardiac wall thickness and impairment of myocardial diastolic and systolic properties, changes that result in heart failure, dysrhythmia, and death. Amyloidosis is classified by precursor protein, with light-chain (AL) and transthyretin (TTR) disease being most common in the United States. TTR amyloid can result from misfolding of variant TTR, a genetically inherited disease, or wild-type TTR, an acquired form of disease (termed senile systemic amyloidosis). In recent years, advances in the diagnosis and treatment of cardiac amyloidosis include identification and validation of disease biomarkers, new imaging techniques, and consensus treatment guidelines. Elevations of B-type natriuretic peptide and cardiac troponins can identify cardiac amyloidosis with a high degree of precision and confer important prognostic information. Non-invasive cardiac imaging techniques, such as cardiac magnetic resonance imaging and echocardiography with strain quantification, afford the ability to diagnose cardiac amyloidosis most often without the need for a confirmatory heart biopsy. Treatment of heart failure resulting from cardiac amyloidosis differs in many respects from most other etiologies of cardiomyopathy. The mainstay of treatment involves volume control with diuretics, low dose ß-adrenergic antagonists or amiodarone for dysrhythmia, and warfarin to prevent thromboembolism. Although widely held to have a dismal prognosis, modern treatments such as high-dose melphalan with stem cell transplantation (HDM/SCT) for AL disease achieve a complete hematologic response in nearly half of eligible patients and yield long-term survival. For patients with advanced AL cardiac amyloidosis, cardiac transplantation followed by HDM/SCT is also an option that has proven highly effective. For familial amyloid derived from variant TTR, liver transplantation is the one validated treatment; however, small molecule therapeutic agents now in clinical trials appear capable of slowing or halting TTR amyloid deposition.

Macro- and microvascular reactivity during repetitive exposure to shortened sleep: sex differences.

Epidemiological studies have reported strong association between sleep loss and hypertension with unknown mechanisms. This study investigated macrovascular and microcirculation changes and inflammatory markers during repetitive sleep restriction. Sex differences were also explored. Forty-five participants completed a 22-day in-hospital protocol. Participants were assigned to, (1) eight-hour sleep per night (control), or (2) sleep restriction (SR) condition: participants slept from 0300 to 0700 h for three nights followed by a recovery night of 8-h sleep, repeated four times. Macrocirculation assessed by flow mediated dilation (FMD) and microcirculation reactivity tests were performed at baseline, last day of each experimental block and during recovery at the end. Cell adhesion molecules and inflammatory marker levels were measured in blood samples. No duration of deprivation (SR block) by condition interaction effects were found for FMD, microcirculation, norepinephrine, cell adhesion molecules, IL-6 or IL-8. However, when men and women were analyzed separately, there was a statistical trend (p = 0.08) for increased IL-6 across SR blocks in women, but not in men. Interestingly, men showed a significant progressive (dose dependent) increase in skin vasodilatation (p = 0.02). A novel and unexpected finding was that during the recovery period, men that had been exposed to repeated SR blocks had elevated IL-8 and decreased norepinephrine. Macrocirculation, microcirculation, cell adhesion molecules, and markers of inflammation appeared to be resistant to this model of short-term repetitive exposures to the blocks of shortened sleep in healthy sleepers. However, men and women responded differently, with women showing mild inflammatory response and men showing more vascular system sensitivity to the repetitive SR.

Repetitive exposure to shortened sleep leads to blunted sleep-associated blood pressure dipping.

BACKGROUND: Blood pressure (BP) dips at night during sleep in healthy individuals but in disturbed sleep, dipping is blunted. However, the impact of chronic insufficient sleep duration, with limited intermittent recovery sleep, on BP dipping is not known. The objective of this study was to examine, in a controlled experimental model, the influence of chronic sleep restriction on BP patterns at night and during the day. METHOD: In a highly controlled 22-day in-hospital protocol, 45 healthy participants (age 32 ±â€Š2 years; BMI 24 ±â€Š1 kg/m; 22 men and 23 women) were randomly assigned to one of two conditions: repeated sleep restriction (4 h of sleep/night from 0300 to 0700 h for three nights followed by recovery sleep of 8 h, repeated four times in succession) or a sleep control group (8 h/night from 2300 to 0700 h). RESULTS: Beat-to-beat BP and polysomnography were recorded and revealed that sleep-associated DBP dipping was significantly blunted during all four blocks of sleep restriction (P = 0.002). Further, DBP was significantly increased for the whole day during the first, second, and fourth block of sleep restriction (all P < 0.01), and SBP was significantly increased for the whole day during the first block of sleep restriction. CONCLUSION: Repeated exposure to significantly shortened sleep blunts sleep-associated BP dipping, despite intermittent catch-up sleep. Individuals frequently experiencing insufficient sleep may be at increased risk for hypertension due to repetitive blunting of sleep-associated BP dipping, and resultant elevations in average circadian BP.

Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis.

AIMS: To determine whether echocardiographic longitudinal systolic strain (LS) parameters identify short-term improvement following chemotherapy for light-chain (AL) cardiac amyloidosis (CA). Among patients with CA, standard echocardiographic measures are commonly unchanged at 1 year following successful chemotherapy, despite observed reductions in cardiac biomarkers. METHODS AND RESULTS: We retrospectively identified 61 patients with AL-CA treated with high-dose melphalan or bortezomib-based regimens. Patients were classified by hematologic response at 1 year into two groups: complete response (CR; n = 18, or 30%) or non-CR (non-CR; n = 43, or 70%), and followed for 20 months. Serum free light chains (FLC), B-type natriuretic peptide (BNP), troponin I (TnI), and echocardiography including LS, were acquired at baseline and 1 year. Seven patients died (11.5%), all in the non-CR group (P < 0.01). At 1 year, while reductions were observed in BNP (44% CR, 18% non-CR) and FLC (94% CR, 73% non-CR), both P < 0.05 from baseline, there were no differences in wall thickness, EF, or diastolic function in either group. LS improved only in the CR group with notable improvement in apical to basal strain ratio (P < 0.05). Strain improvement and BNP reduction were correlated (R = 0.6, P < 0.01). Baseline global LS < -10.2% was associated with survival and proved superior to BNP and TnI. The addition of global LS to biomarkers identified the patients at highest risk of mortality. CONCLUSION: These data suggest that LS is a sensitive measure of pre-treatment cardiac functional impairment in AL-CA, can predict survival over and above that of cardiac biomarkers, and detect early cardiac functional improvement following chemotherapy.

Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk.

OBJECTIVES: We sought to investigate the effects of sleep loss on high-sensitivity C-reactive protein (CRP) levels. BACKGROUND: Concentrations of high-sensitivity CRP are predictive of future cardiovascular morbidity. In epidemiologic studies, short sleep duration and sleep complaints have also been associated with increased cardiovascular morbidity. Two studies were undertaken to examine the effect of acute total and short-term partial sleep deprivation on concentrations of high-sensitivity CRP in healthy human subjects. METHODS: In Experiment 1, 10 healthy adult subjects stayed awake for 88 continuous hours. Samples of high-sensitivity CRP were collected every 90 min for 5 consecutive days, encompassing the vigil. In Experiment 2, 10 subjects were randomly assigned to either 8.2 h (control) or 4.2 h (partial sleep deprivation) of nighttime sleep for 10 consecutive days. Hourly samples of high-sensitivity CRP were taken during a baseline night and on day 10 of the study protocol. RESULTS: The CRP concentrations increased during both total and partial sleep deprivation conditions, but remained stable in the control condition. Systolic blood pressure increased across deprivation in Experiment 1, and heart rate increased in Experiment 2. CONCLUSIONS: Both acute total and short-term partial sleep deprivation resulted in elevated high-sensitivity CRP concentrations, a stable marker of inflammation that has been shown to be predictive of cardiovascular morbidity. We propose that sleep loss may be one of the ways that inflammatory processes are activated and contribute to the association of sleep complaints, short sleep duration, and cardiovascular morbidity observed in epidemiologic surveys.

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.

Paradoxical embolism in the left main coronary artery: diagnosis by transesophageal echocardiography.

We describe a patient with a paradoxical coronary embolism diagnosed by transesophageal echocardiography. The patient developed a stroke followed by a myocardial infarction. Coronary angiography showed an obstruction of the left main coronary artery. Transesophageal echocardiography showed the mechanism of the neurologic and cardiac events to be a paradoxical embolism. Emergency surgical retrieval of the thrombus lodged in the left main coronary ostium and of a separate thrombus traversing a patent foramen ovale was performed. To our knowledge, direct visualization of the paradoxical coronary embolism by echocardiography has not been reported previously. We discuss mechanisms responsible for paradoxical coronary embolism and review the literature pertaining to this condition.

Targeting the use of glycoprotein IIb/IIIa antagonists--the diabetic patient.

Diabetes mellitus is associated with an increased prevalence of and morbidity from coronary artery disease, which is present in at least 25% of diabetic patients. Diabetes mellitus is a risk factor for recurrent cardiovascular events after myocardial infarction and after percutaneous coronary intervention procedures or coronary artery bypass surgery. Less than half of the increase in cardiovascular events with diabetes mellitus is accounted for by the presence of traditional cardiac risk factors such as hypertension, hypercholesterolemia, and hypertriglyceridemia. Vascular inflammation reflected by increased levels of high-sensitivity C-reactive protein, endothelial dysfunction associated with hyperglycemia and hyperinsulinemia, impaired fibrinolysis mediated by hyperinsulinemia, and increased platelet aggregation are now recognized as promoting the development of arteriosclerosis in diabetic patients. These factors may be present long before a diagnosis of diabetes mellitus is established. Platelets in diabetic subjects appear to be in an activated state even in the absence of vascular injury, as evidenced by greater expression of the fibrinogen-binding glycoprotein IIb/IIIa receptor, which constitutes the final common pathway of platelet activation and allows for cross-linking of individual platelets by fibrinogen molecules and formation of thrombus. Platelet inhibition with intravenous glycoprotein IIb/IIIa inhibitors has been shown to reduce morbidity and mortality in patients undergoing percutaneous coronary intervention for acute coronary syndromes, and diabetic patients appear to derive an even greater relative benefit from this treatment. The ACC/AHA 2002 guidelines for the management of acute coronary syndromes recommend the use of abciximab in diabetic patients undergoing stent implantation.

Sleep, inflammation and cardiovascular disease.

In data from prospective cohort studies, self report of insufficient or disturbed sleep is related to increased overall and cardiovascular morbidity. Inflammation is established as a key mechanism in the development of arteriosclerotic heart and vascular disease. Inflammation has been considered a possible link between short sleep and cardiovascular disease and morbidity. Measures of inflammation are increased by experimental sleep deprivation, but in cohort studies a relationship of sleep duration to inflammatory markers is less clear. In these studies the association of self reported short sleep to cardiac morbidity is confounded by many psychological and socioeconomic variables. More studies are needed to explain the link between short sleep duration and cardiac morbidity. Experimental studies of sleep deprivation mimicking habitual shortened sleep over long time intervals, and studies employing sleep extension in habitual short sleepers will allow better characterization of the health benefits of adequate sleep duration. Prospective cohort studies should include objective measures of sleep duration and should to control for the known confounding variables.

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.

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.

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 amyloidosis (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.