Relationship between nocturnal blood pressure patterns and end organ damage and diastolic dysfunction in heart transplant recipients.

BACKGROUND: We assessed the relationship between circadian blood pressure (BP) patterns and clinical outcomes in a contemporary cohort of adult heart transplant recipients. METHODS: This retrospective, cross-sectional study included adult heart transplant recipients at least 6 months post-transplant. Ambulatory BP measurements were recorded over 24 hours. Nondippers were defined as a decline in average nighttime BP ≤ 10% compared with daytime. Primary outcomes were the presence of end organ damage, that is, microalbuminuria, chronic kidney disease, and/or left ventricular hypertrophy. Secondary outcomes were measures of diastolic dysfunction (ie, mitral valve deceleration time, e/e', E/A, and isovolumetric relaxation time), microalbumin/creatinine ratio, eGFR, interventricular septal thickness, and left ventricular posterior wall thickness. RESULTS: Of 30 patients, 53.3% (n = 16) were systolic nondippers and 40% (n = 12) were diastolic nondippers. Diastolic nondippers had three times higher urine microalbumin/creatinine ratios than diastolic dippers (P = .03). Systolic nondippers had 16.3% lower mitral valve deceleration time (P = .05) than systolic dippers, while diastolic nondippers had 20.4% higher e/e' (P = .05) than diastolic dippers. There were no significant relationships between BP dipping status and any of the primary outcomes. CONCLUSIONS: These data suggest that systolic and diastolic nondipping BP patterns are associated with subclinical kidney damage and diastolic dysfunction in heart transplant recipients.

Will the Early Use of Biomarkers Prevent the Development of Heart Failure?

Alterations in biomarkers are associated with the development and progression of heart failure. As indicated by the study of Ergatoudes and colleagues in the current issue of this journal, biomarkers may also be the first sign of increased risk of developing heart failure. Prior studies also suggest that elevations in certain biomarkers can lead to more frequent clinical surveillance and initiation of therapeutic strategies that may prevent or delay the development of heart failure.

Comparison of office, home, and ambulatory blood pressure in heart transplant recipients.

BACKGROUND: The purpose of this study was to prospectively evaluate the relationship between office, home, and ambulatory blood pressure (BP) in heart transplant recipients. METHODS AND RESULTS: The study enrolled 30 adults ≥ 6 months after heart transplantation. Morning seated office BP was measured with the use of an automatic device at 3 outpatient visits. Seated home BP was measured in the morning and evening for 5 consecutive days. Ambulatory BP was measured over 24 hours with the use of a Spacelabs monitor. The strongest correlation was observed between home and 24-hour ambulatory BP (r = 0.79 systolic; r = 0.72 diastolic). Office and home systolic BPs were significantly lower than daytime ambulatory BP (office, -3.7 mm Hg, P = .009; home, -2.6 mm Hg, P = .05). Ambulatory monitoring identified more participants with BP above hypertensive limits than did office or home measurements (63%, 50%, and 13%, respectively; P = .003). Ambulatory monitoring also revealed high BP loads, abnormal nocturnal BP patterns (eg, 30% nondippers), and a high percentage of masked hypertension (37% home, 50% ambulatory). CONCLUSIONS: Office and home BP monitoring are acceptable but may underestimate BP burden in heart transplant recipients. Additional studies are needed to determine which BP method is superior for the management of hypertension and associated outcomes after heart transplantation.

Clinical Implications for Exercise at Altitude Among Individuals With Cardiovascular Disease: A Scientific Statement From the American Heart Association.

An increasing number of individuals travel to mountainous environments for work and pleasure. However, oxygen availability declines at altitude, and hypoxic environments place unique stressors on the cardiovascular system. These stressors may be exacerbated by exercise at altitude, because exercise increases oxygen demand in an environment that is already relatively oxygen deplete compared with sea-level conditions. Furthermore, the prevalence of cardiovascular disease, as well as diseases such as hypertension, heart failure, and lung disease, is high among individuals living in the United States. As such, patients who are at risk of or who have established cardiovascular disease may be at an increased risk of adverse events when sojourning to these mountainous locations. However, these risks may be minimized by appropriate pretravel assessments and planning through shared decision-making between patients and their managing clinicians. This American Heart Association scientific statement provides a concise, yet comprehensive overview of the physiologic responses to exercise in hypoxic locations, as well as important considerations for minimizing the risk of adverse cardiovascular events during mountainous excursions.

Right ventricular function and cardiopulmonary performance among patients with heart failure supported by durable mechanical circulatory support devices.

BACKGROUND: Patients with continuous-flow left ventricular assist devices (CF-LVADs) experience limitations in functional capacity and frequently, right ventricular (RV) dysfunction. We sought to characterize RV function in the context of global cardiopulmonary performance during exercise in this population. METHODS: A total of 26 patients with CF-LVAD (aged 58 ± 11 years, 23 males) completed a hemodynamic assessment with either conductance catheters (Group 1, n = 13) inserted into the right ventricle to generate RV pressure‒volume loops or traditional Swan‒Ganz catheters (Group 2, n = 13) during invasive cardiopulmonary exercise testing. Hemodynamics were collected at rest, 2 sub-maximal levels of exercise, and peak effort. Breath-by-breath gas exchange parameters were collected by indirect calorimetry. Group 1 participants also completed an invasive ramp test during supine rest to determine the impact of varying levels of CF-LVAD support on RV function. RESULTS: In Group 1, pump speed modulations minimally influenced RV function. During upright exercise, there were modest increases in RV contractility during sub-maximal exercise, but there were no appreciable increases at peak effort. Ventricular‒arterial coupling was preserved throughout the exercise. In Group 2, there were large increases in pulmonary arterial, left-sided filling, and right-sided filling pressures during sub-maximal and peak exercises. Among all participants, the cardiac output‒oxygen uptake relationship was preserved at 5.8:1. Ventilatory efficiency was severely abnormal at 42.3 ± 11.6. CONCLUSIONS: Patients with CF-LVAD suffer from limited RV contractile reserve; marked elevations in pulmonary, left-sided filling, and right-sided filling pressures during exercise; and severe ventilatory inefficiency. These findings explain mechanisms for persistent reductions in functional capacity in this patient population.

Myocardial glucose and lactate metabolism during rest and atrial pacing in humans.

There is minimal in vivo data in humans evaluating myocardial substrate utilization during increased heart work. This study was performed to determine the balance of myocardial glucose and lactate metabolism during rest and increased heart work induced by atrial pacing in seven healthy men and women (age, 49.7 +/- 3.9 years; body mass index, 23.4 +/- 1.1 kg m(-2), maximum oxygen consumption, 35.5 +/- 3.0 ml kg(-1) min(-1), ejection fraction, 68 +/- 3%). After 3 days of dietary control, catheters were placed in coronary sinus, femoral arterial and venous, and peripheral venous blood vessels. Subjects received a primed continuous infusion of [3,3,3-(2)H]lactate and [6,6-(2)H]glucose throughout the study. Arterial and coronary sinus blood sampling and measurements of coronary sinus blood flow were made during rest and atrial pacing at approximately 111 beats min(-1). Myocardial oxygen consumption increased (P = 0.04) from rest to atrial pacing. Net glucose uptake increased (P = 0.04) from rest to atrial pacing with unchanged fractional extraction (rest: 9.1 +/- 2.7%, atrial pacing 9.8 +/- 2.9%). The percentage of whole body glucose disposal from myocardial uptake also increased from rest to atrial pacing. Isotopically measured lactate uptake also increased significantly from rest to atrial pacing with no significant differences in fractional extraction. The myocardium released lactate throughout the experiment, which increased significantly from rest and atrial pacing (P < 0.05). The heart accounted for a significantly greater percentage of whole body lactate disposal during atrial pacing (15.0 +/- 4.4%) compared to rest (4.9 +/- 0.9%, P = 0.03). These data suggest: (1) in the absence of ischaemia the myocardium is constantly taking up and releasing lactate at rest which increases during atrial pacing, and (2) when arterial substrate delivery is unchanged, increased myocardial work is accomplished with similar proportions of glucose and lactate utilization in healthy humans in vivo.

Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.

BACKGROUND: Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy. METHODS: We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography. RESULTS: Twenty-six of 32 beta-blocker-treated patients (those with complete mRNA measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [+/-SE] increase, 18.8+/-1.8). As compared with the six beta-blocker-treated patients who did not have a response (mean change, a decrease of 2.5+/-1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mRNA and alpha-myosin heavy chain mRNA and a decrease in beta-myosin heavy chain mRNA. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mRNA or protein expression of beta-adrenergic receptors. CONCLUSIONS: In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.

Quality of life and prognosis in heart failure: results of the Beta-Blocker Evaluation of Survival Trial (BEST).

BACKGROUND: Quality of life (QOL) was a prespecified secondary end point in the Beta-Blocker Evaluation of Survival Trial. The Beta-Blocker Evaluation of Survival Trial used four QOL questionnaires to evaluate patient health status over time in response to treatment with placebo or bucindolol. The goal of the current study was to determine the relationship between the different questionnaires, assess the effect of treatment on health status, and evaluate the association between changes in health status and prognosis. METHODS: The San Diego Heart Failure (SDHF), Minnesota Living with Heart Failure (MLHF), Patient Global Assessment (PGA), and Physician Global Assessment (PhyGA) questionnaires were measured at baseline through 48 months of follow-up. For SDHF and MLHF, changes from baseline were calculated. Spearman correlation was used to assess relationships, and Cox Proportional Hazards regression was used to predict time to all-cause mortality, and mortality or heart failure hospitalization, bivariately and multivariately. To determine whether beta-blocker treatment affected QOL, the Wilcoxon rank-sum test was used to compare treatment groups. RESULTS: At 12 months, SDHF (r = +0.56, P = .0001), PGA (r = +0.36, P = .0001), and PhyGA (r = +0.37, P = .0001) correlated with MLHF. SDHF (P = .0001), MLHF (P = .0004), PGA (P = .0001), and PhyGA (P = .0001) were all strongly associated with all-cause mortality, with low values of each associated with a lower hazard. For the combined end point of all-cause mortality or heart failure hospitalization, change in QOL with each instrument had a P value of .0001. At 12 months, bucindolol-treated patients had improvement in both PhyGA and PGA compared with placebo; neither the SDHF nor the MLWF instrument distinguished between the two treatment groups unless a worst-rank assignment was used for patients who died. CONCLUSION: The four instruments correlate with each other and predict clinical end points, suggesting that each is a valid measure of health status. According to the PGA and the PhyGA, bucindolol improves QOL.

Should beta-blockers be used in the treatment of cocaine-associated acute coronary syndrome?

OBJECTIVE: To critically evaluate the 30 year debate of beta-blocker use in cocaine-induced acute coronary syndrome (CIACS). DATA SOURCES: An Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, and Ovid MEDLINE (1966-August 21, 2007) search of the medical literature was conducted using the key terms cocaine, myocardial infarction, acute coronary syndrome, and adrenergic beta-antagonists. STUDY SELECTION AND DATA EXTRACTION: All clinical trials, case reports, national cardiovascular guidelines, and reviews published in English were evaluated. Case reports were included based on whether (1) acute coronary syndrome was suspected, (2) a beta-blocker was used during the treatment course, and (3) objective and subjective patient-specific information was documented. DATA SYNTHESIS: Three case reports and 2 placebo-controlled trials were identified that used 4 beta-blockers (atenolol, labetalol, metoprolol, propranolol). Three national guidelines addressed beta-blocker use. Although published data are limited, propranolol and labetalol exert minimal to no effect on alleviating cocaine-induced coronary vasoconstriction. None of the evaluated national guidelines recommends beta-blockers as first-line agents in CIACS management. CONCLUSION: Beta-blockers should not be considered first-line agents for controlling chest pain in patients with documented CIACS. If long-term beta-blockade is warranted, its benefits should be weighed against recurrent use of cocaine and possible exacerbation of acute coronary syndrome. Given that carvedilol exhibits ancillary pharmacologic proprieties beneficial in CIACS, and post-myocardial infarction mortality data are available regarding its use, this agent could be considered to be appropriate therapy.

Sex differences in the effects of type 2 diabetes on exercise performance.

PURPOSE: People with uncomplicated type 2 diabetes (T2D) have impaired peak exercise performance compared with that of their nondiabetic counterparts. This impairment may represent the earliest indication of cardiovascular (CV) abnormalities in T2D. Women with T2D are known to have worse CV outcomes than those in men with T2D. We hypothesized that women with diabetes have a greater exercise impairment than that in men with diabetes compared with that in their nondiabetic counterparts. METHODS: We studied 15 women (premenopausal) and 14 men with T2D as well as their nondiabetic counterparts (22 women and 13 men). Exercise testing was performed. Additional outcomes included measurements of insulin sensitivity, endothelial function, blood flow, and resting cardiac function. RESULTS: Men and women with T2D but not controls had impaired insulin sensitivity. Women with T2D had a lower peak oxygen consumption (V˙O2peak) compared with that of nondiabetic women (24%, P < 0.05) than men with diabetes compared with that in nondiabetic men (16%, P < 0.05) (P value between groups < 0.05). The time constants (phase 2) of the V˙O2 kinetic response tended to be slower in men and women with T2D than those in nondiabetic controls (P = 0.08). There were no differences in resting ventricular function by Doppler echocardiography techniques between groups. Women with T2D had significantly lower flow-mediated dilation and blood flow responses to hyperemia than those in nondiabetic women (both P < 0.05), whereas men with T2D had lower flow-mediated dilation but not lower blood flow than those in nondiabetic men. CONCLUSIONS: Although both men and women with uncomplicated T2D had a lower V˙O2peak, the abnormality in women with T2D compared with that in nondiabetic women was greater than that seen in men. Because V˙O2peak has a strong inverse correlation with mortality, sex disparities observed in exercise capacity among people with T2D suggest a possible rationale for the increased CV morbidity and mortality observed in women compared with those observed in men with uncomplicated T2D.

Influence of alpha-adrenergic blockade on the catecholamine response to exercise at 4,300 meters.

This investigation examined the influence of alpha-adrenergic blockade on plasma and urinary catecholamine responses to both exercise and high-altitude exposure. Sixteen nonsmoking, eumenorrheic women (age 23.2 +/- 1.4 years, 68.7 +/- 1.0 kg) were studied at sea level and during 12 days of high-altitude exposure (4,300 m). Subjects received either alpha-blockade (prazosin 3 mg/d) or a placebo in a double-blinded, randomized fashion. Resting plasma and 24-hour urine samples were collected periodically throughout the duration of the study. Further, subjects participated in submaximal exercise tests (50 minutes at 50% sea level maximum oxygen consumption [Vo2max]) at Sea level and on days 1 and 12 at altitude. Urinary norepinephrine (NE) excretion rates increased significantly over time at altitude, with blocked subjects having greater values compared to controls. Plasma NE levels increased significantly with chronic altitude exposure compared to sea level and acute hypoxia both at rest and during exercise. NE levels at rest were greater for blocked compared to control subjects during all conditions. Urinary and plasma epinephrine (EPI) levels increased dramatically, with acute altitude exposure returning to sea level values by day 12 of altitude exposure. EPI levels were greater for blocked compared to placebo both at rest and during exercise for all conditions studied. Changes in alpha-adrenergic activity over time at altitude were associated with select metabolic and physiologic adjustments. The presence of alpha-blockade significantly affected these responses during chronic altitude exposure. It was concluded that: (1) alpha-adrenergic blockade elicited a potentiated sympathoadrenal response to the stress of both exercise as well as high-altitude exposure, and (2) the sympathetics, via alpha-adrenergic stimulation, contribute to a number of key adaptations associated with acclimatization to high altitude.

Pyruvate shuttling during rest and exercise before and after endurance training in men.

We describe the isotopic exchange of lactate and pyruvate after arm vein infusion of [3-(13)C]lactate in men during rest and exercise. We tested the hypothesis that working muscle (limb net lactate and pyruvate exchange) is the source of the elevated systemic lactate-to-pyruvate concentration ratio (L/P) during exercise. We also hypothesized that the isotopic equilibration between lactate and pyruvate would decrease in arterial blood as glycolytic flux, as determined by relative exercise intensity, increased. Nine men were studied at rest and during exercise before and after 9 wk of endurance training. Although during exercise arterial pyruvate concentration decreased to below rest values (P < 0.05), pyruvate net release from working muscle was as large as lactate net release under all exercise conditions. Exogenous (arterial) lactate was the predominant origin of pyruvate released from working muscle. With no significant effect of exercise intensity or training, arterial isotopic equilibration [(IE(pyruvate)/IE(lactate)).100%, where IE is isotopic enrichment] decreased significantly (P < 0.05) from 60 +/- 3.1% at rest to an average value of 12 +/- 2.7% during exercise, and there were no changes in femoral venous isotopic equilibration. These data show that 1). the isotopic equilibration between lactate and pyruvate in arterial blood decreases significantly during exercise; 2). working muscle is not solely responsible for the decreased arterial isotopic equilibration or elevated arterial L/P occurring during exercise; 3). working muscle releases similar amounts of lactate and pyruvate, the predominant source of the latter being arterial lactate; 4). pyruvate clearance from blood occurs extensively outside of working muscle; and 5). working muscle also releases alanine, but alanine release is an order of magnitude smaller than lactate or pyruvate release. These results portray the complexity of metabolic integration among diverse tissue beds in vivo.

Usefulness of Doppler echocardiographic left ventricular diastolic function and peak exercise oxygen consumption to predict cardiovascular outcomes in patients with systolic heart failure (from HF-ACTION).

Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) was a multicenter, randomized controlled trial designed to examine the safety and efficacy of aerobic exercise training versus usual care in 2,331 patients with systolic heart failure (HF). In HF-ACTION patients with rest transthoracic echocardiographic measurements, the predictive value of 8 Doppler echocardiographic measurements-left ventricular (LV) diastolic dimension, mass, systolic (ejection fraction) and diastolic (mitral valve peak early diastolic/peak late diastolic [E/A] ratio, peak mitral valve early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity [E/E'] ratio, and deceleration time) function, left atrial dimension, and mitral regurgitation severity-was examined for a primary end point of all-cause death or hospitalization and a secondary end point of cardiovascular disease death or HF hospitalization. Also compared was the prognostic value of echocardiographic variables versus peak oxygen consumption (Vo(2)). Mitral valve E/A and E/E' ratios were more powerful independent predictors of clinical end points than the LV ejection fraction but less powerful than peak Vo(2). In multivariate analyses for predicting the primary end point, adding E/A ratio to a basic demographic and clinical model increased the C-index from 0.61 to 0.62, compared with 0.64 after adding peak Vo(2). For the secondary end point, 6 echocardiographic variables, but not the LV ejection fraction or left atrial dimension, provided independent predictive power over the basic model. The addition of E/E' or E/A to the basic model increased the C-index from 0.70 to 0.72 and 0.73, respectively (all p values <0.0001). Simultaneously adding E/A ratio and peak Vo(2) to the basic model increased the C-index to 0.75 (p <0.0005). No echocardiographic variable was significantly related to the change from baseline to 3 months in exercise peak Vo(2). In conclusion, the addition of echocardiographic LV diastolic function variables improves the prognostic value of a basic demographic and clinical model for cardiovascular disease outcomes.

Myocardial FFA metabolism during rest and atrial pacing in humans.

There is limited in vivo data in humans evaluating myocardial fat utilization during increased heart work. This study was done to determine myocardial free fatty acid (FFA) metabolism during rest and atrial pacing, which increases cardiac work without changing arterial substrate concentration. We studied seven healthy men and women (age = 49.7 +/- 3.9 yr, BMI = 23.4 +/- 1.1 kg/m(2), Vo(2max) = 35.5 +/- 3.0 ml.kg(-1).min(-1), ejection fraction = 68 +/- 3%). After 3 days of dietary control, coronary sinus, femoral arterial and venous, and peripheral venous catheters were placed. Subjects received [(13)C]bicarbonate followed by a continuous infusion of [1-(13)C]palmitate through the end of the study. Arterial and coronary sinus blood sampling and measurements of resting coronary sinus blood flow were made during rest and atrial pacing to 120 beats/min. MVo(2) increased (P < 0.05) from rest to atrial pacing. Coronary sinus FFA concentration was significantly lower than arterial through rest and atrial pacing (P = 0.007). Isotopically measured myocardial palmitate uptake increased significantly from rest to atrial pacing (P = 0.03). Approximately one-third of palmitate delivery was extracted by the myocardium during rest and atrial pacing. Myocardial V(13)CO(2) production and palmitate oxidation increased significantly from rest (P < 0.01) to atrial pacing. Net glycerol balance was significantly greater than zero during rest (P = 0.04) but not different from zero during atrial pacing (P = 0.13). These data suggest that myocardial lipid uptake and oxidation increase with greater heart work during atrial pacing, with a similar relative proportion of fat oxidation to total myocardial energy expenditure.