Liviu Klein

Acute Heart Failure Syndromes Current State and Framework for Future Research

Acute heart failure syndromes (AHFS) poses unique diagnostic and management challenges. This syndrome has recently received attention from researchers, clinicians, regulatory agencies, and the pharmaceutical industry. However, there is no consensus on its definition, epidemiology, pathophysiology, appropriate therapeutic options, and directions for future research. This document is the result of the First and Second International Workshop on Acute Heart Failure Syndrome that took place in May 2004 and April 2005. At these workshops, a selected group of physician scientists, epidemiologists, clinicians, regulatory and governmental funding agencies, and industry representatives from North and South America and Europe convened to develop a platform for future investigative approaches and management of AHFS. Subsequently, emergency physicians, who play a pivotal role in the early management of AHFS, contributed to this document. AHFS is defined as gradual or rapid change in heart failure (HF) signs and symptoms resulting in a need for urgent therapy. These symptoms are primarily the result of severe pulmonary congestion due to elevated left ventricular (LV) filling pressures (with or without low cardiac output). AHFS can occur in patients with preserved or reduced ejection fraction (EF). Concurrent cardiovascular conditions such as coronary heart disease (CHD), hypertension, valvular heart disease, atrial arrhythmias, and/or noncardiac conditions (including renal dysfunction, diabetes, anemia) are often present and may precipitate or contribute to the pathophysiology of this syndrome.1–3 HF hospitalizations have risen steadily, with >1 million in 2004 in the United States4; a similar number has been reported in Europe. In the United States, it is estimated that these hospitalizations account for >75% of the 46 billion dollars spent each year on the care of HF patients.4 Although much has been accomplished in the management of chronic HF, the absence of evidence-based clinical practice guidelines for AHFS is striking in comparison to …

Lower Serum Sodium Is Associated With Increased Short-Term Mortality in Hospitalized Patients With Worsening Heart Failure Results From the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Study

Background—The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well defined. Methods and Results—The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction hospitalized for worsening heart failure to receive 48 to 72 hours of intravenous milrinone or placebo in addition to standard therapy. In a retrospective analysis, we investigated the relationship between admission serum sodium and the primary end point of days hospitalized for cardiovascular causes within 60 days of randomization, as well as the secondary end points of in-hospital mortality, 60-day mortality, and 60-day mortality/rehospitalization. The number of days hospitalized for cardiovascular causes was higher in the lowest sodium quartile: 8.0 (4.5, 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus 6 (4, 12) days (P<0.015 for comparison with the lowest quartile). Lower serum sodium was associated with higher in-hospital and 60-day mortality: 5.9% versus 1% versus 2.3% versus 2.3% (P<0.015) and 15.9% versus 6.4% versus 7.8% versus 7% (P=0.002), respectively. There was a trend toward higher mortality/rehospitalization for patients who were in the lowest sodium quartile. Multivariable-adjusted Cox proportional hazards analysis showed that serum sodium on admission, when modeled linearly, predicted increased 60-day mortality: sodium (per 3-mEq/L decrease) had a hazard ratio of 1.18 with a 95% CI of 1.03 to 1.36 (P=0.018). Conclusions—In patients hospitalized for worsening heart failure, admission serum sodium is an independent predictor of increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge.

Admission or Changes in Renal Function During Hospitalization for Worsening Heart Failure Predict Postdischarge Survival Results From the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF)

Background—Admission measures of renal function (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR]) in patients hospitalized for worsening heart failure are predictors of in-hospital outcomes. Less is known about the changes and relationships among these variables and the postdischarge survival rate. Methods and Results—In a retrospective analysis of 949 patients from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure, we investigated the relation between admission values and changes in BUN and eGFR and rate of death by 60 days after discharge. On admission, median eGFR was 51 mL · min−1 · 1.73 m−2 (interquartile range, 37 to 70 mL · min−1 · 1.73 m−2), and BUN was 25 mg/dL (interquartile range, 17 to 41 mg/dL). On average, there was a 1.1–mL · min−1 · 1.73 m−2 decrease in eGFR and a 4.7-mg/dL increase in BUN from admission to discharge. By discharge, 12% of patients had a >25% decrease in eGFR, and 39% had a >25% increase in BUN. Although both lower admission eGFR and higher admission BUN were associated with higher risk of death by 60 days after discharge, multivariable-adjusted Cox proportional-hazards analysis showed that BUN was a stronger predictor of death by 60 days than was eGFR (&khgr;2, 11.6 and 0.6 for BUN and eGFR, respectively). Independently of admission values, an increase of ≥10 mg/dL in BUN during hospitalization was associated with worse 60-day survival rate: BUN (per 5-mg/dL increase) had a hazard ratio of 1.08 (95% CI, 1.01 to 1.16). Although milrinone treatment led to a minor improvement in renal function by discharge, the 60-day death and readmission rates were similar between the milrinone and placebo groups. Conclusions—A substantial number of patients admitted with heart failure have worsening renal function during hospitalization. Higher admission BUN and increasing BUN during hospitalization, independently of admission values, are associated with a worse survival rate. Use of milrinone in these high-risk patients does not improve outcomes despite minor improvements in the renal function.

Consistently Stable or Decreased Body Mass Index in Young Adulthood and Longitudinal Changes in Metabolic Syndrome Components The Coronary Artery Risk Development in Young Adults Study

Background— Data are sparse regarding the association of stable body mass index (BMI) over the long term with metabolic syndrome components in young adults. Methods and Results— Participants in the Coronary Artery Risk Development in Young Adults Study, including white and black adults 18 to 30 years of age at the initial examination in 1985 to 1986, were stratified into groups by baseline BMI and change in BMI (stable/decreased, increased >2 kg/m2, or fluctuating) across all 6 examinations between years 0 and 15 of the study. Changes in metabolic syndrome components were compared between groups. Among 1358 men and 1321 women, 16.3% maintained a stable BMI, 73.9% had an increased BMI, and 9.8% had a fluctuating BMI. Over 15 years, participants with stable BMI had essentially unchanged levels of metabolic syndrome components, regardless of baseline BMI, whereas those with increased BMI had progressively worsening levels. For example, men with a baseline BMI of 20.0 to 24.9 kg/m2 and stable BMI during follow-up had a mean increase of only 15 mg/dL in fasting triglycerides over 15 years compared with 65 mg/dL (P<0.001) in those whose BMI increased. Incidence of metabolic syndrome at year 15 was lower in the stable BMI group (2.2%) compared with the increased BMI group (18.8%; P<0.001). Conclusions— Adverse progression of metabolic syndrome components with advancing age may not be inevitable. Young adults who maintained stable BMI over time had minimal progression of risk factors and lower incidence of metabolic syndrome regardless of baseline BMI. Greater public health efforts should be aimed at long-term weight stabilization.

Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac disorder impairing the ability of the ventricles to fill with or eject blood. The approach to pharmacologic treatment has become a combined preventive and symptomatic management strategy. Ideally, treatment should be initiated in patients at risk, preventing disease progression. In patients who have progressed to symptomatic left ventricular dysfunction, certain therapies have been demonstrated to improve survival, decrease hospitalizations, and reduce symptoms. The mainstay therapies are angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (bisoprolol, carvedilol, and metoprolol XL/CR), with diuretics to control fluid balance. In patients who cannot tolerate ACE inhibitors because of angioedema or severe cough, valsartan can be substituted. Valsartan should not be added in patients already taking an ACE inhibitor and a beta-blocker. Spironolactone is recommended in patients who have New York Heart Association (NYHA) class III to IV symptoms despite maximal therapies with ACE inhibitors, beta-blockers, diuretics, and digoxin. Low-dose digoxin, yielding a serum concentration <1 ng/mL can be added to improve symptoms and, possibly, mortality. The combination of hydralazine and isosorbide dinitrate might be useful in patients (especially in African Americans) who cannot tolerate ACE inhibitors or valsartan because of hypotension or renal dysfunction. Calcium antagonists, with the exception of amlodipine, oral or intravenous inotropes, and vasodilators, should be avoided in HF with reduced systolic function. Amiodarone should be used only if patients have a history of sudden death, or a history of ventricular fibrillation or sustained ventricular tachycardia, and should be used in conjunction with an implantable defibrillator [corrected]. Finally, anticoagulation is recommended only in patients who have concomitant atrial fibrillation or a previous history of cerebral or systemic emboli.

Risk factors for atrial fibrillation and their population burden in postmenopausal women: The Women's Health Initiative Observational Study

Objective Atrial fibrillation (AF) is the most common arrhythmia in women. Large studies evaluating key AF risk factors in older women are lacking. We aimed to identify risk factors for AF in postmenopausal women and measure population burden of modifiable risk factors. Design Prospective observational study. Setting The Womens Health Initiative (WHI) Observational Study. Patients 93 676 postmenopausal women were followed for an average of 9.8 years for cardiovascular outcomes. After exclusion of women with prevalent AF or incomplete data, 8252 of the remaining 81 892 women developed incident AF. Main outcome measures Incident AF was identified by WHI-ascertained hospitalisation records and diagnosis codes from Medicare claims. Multivariate Cox hazard regression analysis identified independent risk factors for incident AF. Results Age, hypertension, obesity, diabetes, myocardial infarction and heart failure were independently associated with incident AF. Hypertension and overweight status accounted for 28.3% and 12.1%, respectively, of the population attributable risk. Hispanic and African–American participants had lower rates of incident AF (HR 0.58, 95% CI 0.47 to 0.70 and HR 0.59, 95% CI 0.53 to 0.65, respectively) than Caucasians. Conclusions Caucasian ethnicity, traditional cardiovascular risk factors and peripheral arterial disease were independently associated with higher rates of incident AF in postmenopausal women. Hypertension and overweight status accounted for a large proportion of population attributable risk. Measuring burden of modifiable AF risk factors in older women may help target interventions.

Risk of Heart Failure Among Postmenopausal Women: A Secondary Analysis of the Randomized Trial of Vitamin D Plus Calcium of the Women's Health Initiative

Background—Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results—Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P=0.46. However, CaD supplementation had differential effects (P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P=0.51, in the high-risk subgroups. Conclusions—CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.Background— Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results— Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P =0.46. However, CaD supplementation had differential effects ( P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P =0.51, in the high-risk subgroups. Conclusions— CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration— URL: . Unique identifier: [NCT00000611][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00000611&atom=%2Fcirchf%2F8%2F1%2F49.atom

Quality of Care and Outcomes in Women Hospitalized for Heart Failure

Background— Although women account for a significant proportion of heart failure (HF) hospitalizations, data on the quality of care and in-hospital outcomes in women are limited. Methods and Results— We examined The Joint Commission performance measures, other quality metrics, length of stay, and in-hospital mortality in women using 99 841 HF admissions (January 2005 to June 2009) at 248 hospitals participating in the American Heart Association Get With The Guidelines-Heart Failure registry. Women accounted for 50% of the HF admissions and were older (mean age, 74±14 versus 69±14 years), more likely to have hypertension (77% versus 72%), and less likely to have coronary disease (44% versus 53%) or renal insufficiency (18% versus 23%) than men (all P<0.001). The presenting symptoms were similar to men, but women had higher admission systolic blood pressure (mean, 144±31 versus 137±30 mm Hg; P<0.001) and ejection fraction (mean, 0.44±0.17% versus 0.34±0.16%; P<0.001). After adjustment for baseline differences, eligible women were less likely than men to have measurement of left ventricular function (adjusted odds ratio [OR], 0.81; 95% CI, 0.76 to 0.86) and to receive anticoagulation for atrial fibrillation (adjusted OR, 0.91; 95% CI, 0.86 to 0.96) or implantable cardioverter-defibrillators (adjusted OR, 0.70; 95% CI, 0.65 to 0.75) but were as likely to receive discharge instructions, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, &bgr;-blockers, and smoking cessation counseling at discharge. Although the median length of stay was 4 days, women were more likely than men to be hospitalized >4 days (adjusted OR, 1.13; 95% CI, 1.10 to 1.16) and >7 days (adjusted OR, 1.07; 95% CI, 1.04 to 1.11). Women had comparable in-hospital mortality to men (adjusted OR, 1.05; 95% CI, 0.96 to 1.14). Conclusions— Compared to men, women hospitalized for HF differ in many clinical characteristics and length of stay but have similar clinical presentations, receive similar quality of care for most but not all measures, and experience similar in-hospital mortality.

Toward Continuous, Noninvasive Assessment of Ventricular Function and Hemodynamics: Wearable Ballistocardiography

Ballistocardiography, the measurement of the reaction forces of the body to cardiac ejection of blood, is one of the few techniques available for unobtrusively assessing the mechanical aspects of cardiovascular health outside clinical settings. Recently, multiple experimental studies involving healthy subjects and subjects with various cardiovascular diseases have demonstrated that the ballistocardiogram (BCG) signal can be used to trend cardiac output, contractility, and beat-by-beat ventricular function for arrhythmias. The majority of these studies has been performed with “fixed” BCG instrumentation-such as weighing scales or chairs-rather than wearable measurements. Enabling wearable, and thus continuous, recording of BCG signals would greatly expand the capabilities of the technique; however, BCG signals measured using wearable devices are morphologically dissimilar to measurements from “fixed” instruments, precluding the analysis and interpretation techniques from one domain to be applied to the other. In particular, the time intervals between the electrocardiogram (ECG) and BCG-namely, the R-J interval, a surrogate for measuring contractility changes-are significantly different for the accelerometer compared to a “fixed” BCG measurement. This paper addresses this need for quantitatively normalizing wearable BCG measurement to “fixed” measurements with a systematic experimental approach. With these methods, the same analysis and interpretation techniques developed over the past decade for “fixed” BCG measurement can be successfully translated to wearable measurements.

A Wearable Patch to Enable Long-Term Monitoring of Environmental, Activity and Hemodynamics Variables

We present a low power multi-modal patch designed for measuring activity, altitude (based on high-resolution barometric pressure), a single-lead electrocardiogram, and a tri-axial seismocardiogram (SCG). Enabled by a novel embedded systems design methodology, this patch offers a powerful means of monitoring the physiology for both patients with chronic cardiovascular diseases, and the general population interested in personal health and fitness measures. Specifically, to the best of our knowledge, this patch represents the first demonstration of combined activity, environmental context, and hemodynamics monitoring, all on the same hardware, capable of operating for longer than 48 hours at a time with continuous recording. The three-channels of SCG and one-lead ECG are all sampled at 500 Hz with high signal-to-noise ratio, the pressure sensor is sampled at 10 Hz, and all signals are stored to a microSD card with an average current consumption of less than 2 mA from a 3.7 V coin cell (LIR2450) battery. In addition to electronic characterization, proof-of-concept exercise recovery studies were performed with this patch, suggesting the ability to discriminate between hemodynamic and electrophysiology response to light, moderate, and heavy exercise.