Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Mitochondrial Pathobiology and Metabolic Remodeling in Progression to Overt Systolic Heart Failure.

The mitochondria are mostly abundant in the heart, a beating organ of high- energy demands. Their function extends beyond being a power plant of the cell including redox balance, ion homeostasis and metabolism. They are dynamic organelles that are tethered to neighboring structures, especially the endoplasmic reticulum. Together, they constitute a functional unit implicated in complex physiological and pathophysiological processes. Their topology in the cell, the cardiac myocyte in particular, places them at the hub of signaling and calcium homeostasis, making them master regulators of cell survival or cell death. Perturbations in mitochondrial function play a central role in the pathophysiology of myocardial remodeling and progression of heart failure. In this minireview, we summarize important pathophysiological mechanisms, pertaining to mitochondrial morphology, dynamics and function, which take place in compensated hypertrophy and in progression to overt systolic heart failure. Published work in the last few years has expanded our understanding of these important mechanisms; a key prerequisite to identifying therapeutic strategies targeting mitochondrial dysfunction in heart failure.

Peripheral venous congestion causes time- and dose-dependent release of endothelin-1 in humans.

Endothelin-1 (ET-1) is a pivotal mediator of vasoconstriction and inflammation in congestive states such as heart failure (HF) and chronic kidney disease (CKD). Whether peripheral venous congestion (VC) increases plasma ET-1 at pressures commonly seen in HF and CKD patients is unknown. We seek to characterize whether peripheral VC promotes time- and dose-dependent increases in plasma ET-1 and whether these changes are sustained after decongestion. We used a randomized, cross-over design in 20 healthy subjects (age 30 ± 7 years). To experimentally model VC, venous pressure was increased to either 15 or 30 mmHg (randomized at first visit) above baseline by inflating a cuff around the subject's dominant arm; the nondominant arm served as a noncongested control. We measured plasma ET-1 at baseline, after 20, 60 and 120 min of VC, and finally at 180 min (60 min after cuff release and decongestion). Plasma ET-1 progressively and significantly increased over 120 min in the congested arm relative to the control arm and to baseline values. This effect was dose-dependent: ET-1 increased by 45% and 100% at VC doses of 15 and 30 mmHg, respectively (P < 0.05), and declined after 60 min of decongestion though remaining significantly elevated compared to baseline. In summary, peripheral VC causes time- and dose-dependent increases in plasma ET-1. Of note, the lower dose of 15 mmHg (more clinically relevant to HF and CKD patients) was sufficient to raise ET-1. These findings support the potentially contributory, not merely consequential, role of VC in the pathophysiology of HF and CKD.

Peripheral venous congestion causes inflammation, neurohormonal, and endothelial cell activation.

AIMS: Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF. METHODS: To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray. RESULTS: Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2. CONCLUSION: Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.

Imagine how many lives you save: angiotensin-converting enzyme inhibition for atherosclerotic vascular disease in the present era of risk reduction.

INTRODUCTION: Angiotensin-converting enzyme (ACE) inhibition is clearly beneficial in patients with hypertension, heart failure, and post-myocardial infarction left ventricular (LV) dysfunction. However, whereas initial trials had reported a benefit of ACE inhibition in high-risk vascular patients, current trials of ACE inhibition have failed to demonstrate a clear benefit in vascular patients who are receiving risk-reduction interventions. The purpose of this review is to analyze the reasons behind the failure of the most recent trials of ACE inhibitors in vascular patients without overt LV dysfunction. The reader will gain an understanding of the time-dependent trend towards a reduction in the absolute benefit conferred by ACE inhibition in patients with vascular atherosclerosis as risk reduction interventions are increasingly implemented. AREAS COVERED: Major trials with a follow-up period of at least 1 year assessing the use of ACE inhibitors in patients with a history of cardiac or vascular events were identified via a PubMed literature search. All-cause and cardiovascular mortality outcomes were reported for each trial, as well as the use of aspirin, lipid-lowering drugs and ß-blockers, and the mean LV ejection fraction. EXPERT OPINION: The findings of recent trials do not support the use of ACE inhibitors in vascular patients who, adherent with risk reduction therapy, do not have hypertension, diabetes, or LV dysfunction.

Early revascularization is beneficial across all ages and a wide spectrum of cardiogenic shock severity: A pooled analysis of trials.

BACKGROUND: A pooled analysis in cardiogenic shock due to acute coronary syndromes is desirable to assess the effect of early revascularization (ERV) across all ages and a wide spectrum of disease severity. METHODS: Only two randomized controlled trials (RCT), i.e. SMASH and SHOCK, met the inclusion criteria and were combined for a pooled analysis using individual patient data (n = 348). RESULTS: SMASH patients (n = 54, 16%) had more severe disease than SHOCK patients (n = 294, 84%). After adjustment for age, anoxic brain damage, non-inferior myocardial infarction, prior coronary artery bypass graft surgery, renal failure, systolic blood pressure, and selection for coronary angiography, one-year mortality was similar (relative risk SHOCK versus SMASH 0.87, 95% CI: 0.61-1.25). Relative risk of one-year death for ERV versus initial medical stabilization was 0.82 (95% CI: 0.70-0.96). There was no significant difference in the treatment effect by age (≤75 years relative risk at one year 0.79, 95% CI: 0.63-0.99; > 75 years relative risk at one year 0.93, 95% CI: 0.56-1.53; interaction P = 0.10). CONCLUSIONS: Only two RCT have been published emphasizing the difficulty of enrolling critically ill patients. Despite large differences in shock severity, ERV benefit is similar across all ages and not significantly different for the elderly.

Prognostic importance of comorbidities in heart failure with preserved left ventricular ejection fraction.

The relative impact of comorbidities and parameters of left ventricular diastolic function on clinical outcome has not been thoroughly investigated in patients who are hospitalized for heart failure decompensation and found to have preserved ejection fraction. We identified 98 HFpEF patients among 1452 patients admitted with acute heart failure. Clinical characteristics, hemoglobin levels, estimated glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP) and Doppler-echocardiographic parameters were analyzed. The primary end point of the study combined death and rehospitalization for decompensated heart failure after the index hospitalization. Mean age was 76 ± 9 years. LV ejection fraction, E/E (a) ratio, and estimated systolic pulmonary artery pressure were 61 (55-67)%, 12.9 (9.4-15.1), 40 (32-46) mmHg, respectively. BNP values, hemoglobin and eGFR were 287 (164-562) pg/mL, 11.3 (10.4-12.4) g/dL and 45 (37-74) mL/min/m(2), respectively. During a mean follow-up of 17 ± 11 months, 56% reached the primary endpoint of the study: 31 died and 24 were re-hospitalised for heart failure. Diabetes [HR = 1.76 (1.03-3.00), P = 0.039], lower systolic blood pressure [HR = 0.99 (0.97-0.99), P = 0.016], hemoglobin [HR = 0.62 (0.49-0.76), P < 0.0001], and eGFR [HR = 0.98 (0.97-0.99), P = 0.004] were associated with a poor outcome. Neither BNP nor echocardiographic parameters were correlated with outcome. Comorbidities primarily correlate with outcome in patients with HFpEF.

Impact of valvuloarterial impedance on left ventricular longitudinal deformation in patients with aortic valve stenosis and preserved ejection fraction.

BACKGROUND: Left ventricular (LV) longitudinal deformation is a good marker of intrinsic myocardial dysfunction in pressure overload cardiomyopathies. AIM: To assess the effect of valvuloarterial haemodynamic load on LV longitudinal deformation in patients with aortic valve stenosis (AVS) and preserved LV ejection fraction (LVEF). METHODS: Global LV longitudinal strain (GLS) was measured using speckle tracking imaging in a series of 82 consecutive patients with AVS (mean age 75+/-10 years; 50% men). The global (valvular+arterial) haemodynamic load imposed on the LV was estimated by the valvuloarterial impedance (Z(va)), and was calculated using either arm-cuff systolic peripheral blood pressure or systolic central aortic blood pressure estimated by SphygmoCor. RESULTS: Among this series of 82 patients with preserved LVEF, 79% had reduced LV GLS (<-18%). LV GLS correlated weakly with AVS severity, systemic vascular resistance and systemic arterial compliance. However, there was a good inverse correlation between increase in Z(va) and impairment of LV GLS (r=0.41 p<0.0001). On multivariable analysis, impaired GLS was associated with increased Z(va) (p<0.0001), increased E/Ea ratio (p=0.001) and increased LV end-diastolic volume index (p=0.021), while indices of valvular load were not. Utilization of estimated central aortic blood pressure in place of brachial pressure did not improve the performance of Z(va) to predict GLS. CONCLUSION: The magnitude of the global haemodynamic load as reflected by Z(va) is a powerful determinant of altered LV longitudinal deformation in AVS patients with preserved LVEF. The calculation of Z(va) may be useful to identify the patients who are potentially at higher risk for the development of myocardial dysfunction. Use of estimated central aortic pressure in the calculation of Z(va) does not appear to provide any incremental predictive value over that calculated with the simple measurement of brachial pressure.

Acute heart failure due to transient left ventricular dyssynchrony: case study.

This case study describes an unusual cause of acute heart failure that resolved with early beta-blockade therapy. A 52-year-old woman who had acute heart failure with severe left ventricular systolic dysfunction and left bundle branch block was admitted to a university medical center. Contrast-enhanced magnetic resonance images of the heart did not show any evidence of myocardial infarction or myocarditis. Rate-related left bundle branch block and subsequent left ventricular dyssynchrony resulted in acute systolic dysfunction that resolved with beta-blockade therapy that allowed heart rate control and narrowing of the QRS complex. Of note, the use of inotropic agents would have dramatically worsened the cardiac condition.

Ghrelin resistance occurs in severe heart failure and resolves after heart transplantation.

AIMS: Severe heart failure (HF) is often associated with cachexia that reverses post-heart transplantation (HTx) with frequent development of obesity. Ghrelin is a novel appetite-stimulating hormone. The aim was to determine the role of ghrelin in regulating appetite, food intake, and body composition in HF and post-HTx. METHODS AND RESULTS: We measured serial ghrelin, hunger sensation, caloric intake, and body composition in 12 HF patients awaiting HTx, 12 patients 12.7 +/- 8.6 months post-HTx, and 7 controls. Seven of 12 HF patients were followed for longitudinal analysis post-HTx. Body mass index was 23.1 +/- 3.1 in HF and 31.5 +/- 5.5 post-HTx (P < 0.001). Heart transplantation patients had gained 18.0 +/- 7.7 kg since HTx. Ghrelin area under the curve between controlled meals (control: 186 +/- 39; HF: 264 +/- 71; HTx: 194 +/- 47 ng min/mL, P < 0.007) was higher in HF, but test meal caloric intake (control: 1185 +/- 650; HF: 391 +/- 103; HTx: 831 +/- 309 kcal, P < 0.008) was lower in HF. The longitudinal analysis confirmed these findings. CONCLUSION: Heart failure may be associated with resistance to the appetite-stimulating effects of ghrelin, which may contribute to cachexia. Heart transplantation may be associated with resolution of ghrelin resistance, which may contribute to weight gain. These findings are preliminary and should be confirmed in larger trials.

Growth hormone resistance in severe heart failure resolves after cardiac transplantation.

AIMS: Severe heart failure (HF) is associated with cachexia; this is often reversed post cardiac transplantation (HTx) with frequent development of obesity. Growth hormone (GH) resistance is common in HF and may contribute to cachexia. Whether GH resistance resolves post HTx is unknown. We aimed to confirm that HF is associated with GH resistance and to test the hypothesis that GH resistance resolves post HTx. METHODS AND RESULTS: We measured GH, insulin-like growth factor-1 (IGF-1), and body composition in 10 HF patients awaiting HTx, in 18 patients 11 +/- 8 months post HTx, and seven controls. Body mass index was 23.5 +/- 3.2 in HF patients and 29.3 +/- 5.7 post HTx. HTx patients had gained 14 +/- 8 kg since HTx. GH was elevated in HF (control: 0.21 +/- 0.25; HF: 1.13 +/- 1.19; HTx: 0.11 +/- 0.13 ng/mL; P < 0.007), while IGF-1 was higher in HTx (control: 114 +/- 57; HF: 94 +/- 52; HTx: 190 +/- 106 ng/mL; P < 0.02). HTx had higher total body and abdominal fat %. CONCLUSION: GH resistance is present in severe HF and resolves post HTx. These findings should be confirmed through larger trials.

Left ventricular abnormal response during dynamic exercise in patients with heart failure and preserved left ventricular ejection fraction at rest.

BACKGROUND: The mechanisms that contribute to limit functional capacity are incompletely understood in patients with preserved resting ejection fraction (HFpREF). We assessed left ventricular (LV) systolic response to dynamic exercise in patients with HFpREF and in patients with similar comorbidities to HFpREF patients but without history or evidence of heart failure. METHODS AND RESULTS: Twenty-five HFpREF patients in steady-state clinical condition without significant coronary artery disease and 25 hypertensive controls underwent exercise echocardiography. At rest, systolic pulmonary artery pressure, left atrial area, E/A and E/e' ratios were greater in patients with HFpREF than in control patients, whereas peak systolic mitral annular velocity was lower in HFpREF patients. The exercise-induced changes in LVEF, forward stroke volume, and cardiac output were significantly lower in HFpREF compared with control patients (-4 +/- 8 vs. +6 +/- 6 %, P = .001; -4 +/- 9 vs. +10 +/- 10 mL, P < .0001, and 1.6 +/- 1.2 vs. 3.5 +/- 1.8 L/min, P < .0001, respectively). Exercise-induced changes in effective arterial elastance significantly differed in HFpREF and control patients (0.5 +/- 0.6 vs. -0.2 +/- 0.5 mm Hg/mL, P < .0001). In addition, 7 of the 25 HFpREF patients developed functional mitral regurgitation during exercise and none in controls. CONCLUSIONS: When compared with patients with similar comorbidities but without history or evidence of heart failure, patients with HFpREF experience greater arterial stiffening and thereby a deterioration of global LV systolic performance during dynamic exercise.

Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea.

BACKGROUND: Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. METHODS AND RESULTS: Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP > or = 4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP > or = 4 hours daily. CONCLUSIONS: OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Exercise does not enhance the prognostic value of Doppler echocardiography in patients with left ventricular systolic dysfunction and functional mitral regurgitation at rest.

BACKGROUND: Functional mitral regurgitation (MR) is a powerful predictor of poor prognosis in patients with chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD). However, severity of MR varies with dynamic exercise. Accordingly, we sought to assess the prognostic value of exercise-induced changes in functional MR in patients with LVSD and functional MR at rest. METHODS: One hundred four patients with chronic heart failure due to LVSD (ejection fraction [EF] < 45%) and functional MR at rest underwent conventional continuous 2-dimensional Doppler echocardiography at rest and during maximal symptom-limited exercise. The primary end point of the study was all-cause mortality. The median follow-up period was 20 months. RESULTS: Fifty-six patients (54%) had ischemic cardiomyopathy. When feasible, all 56 patients with ischemic cardiomyopathy had undergone revascularization procedures before enrollment into the study. In the whole patient cohort, resting LV end-diastolic volume was 205 +/- 76 mL and EF was 26% +/- 9%. Univariate predictors of death were functional class (New York Heart Association), LV EF, LV end-diastolic volume, resting mitral effective regurgitant orifice, mitral E deceleration time, tricuspid annular plane systolic excursion < or = 14 mm, systolic blood pressure, LV EF, and trans-tricuspid pressure gradient response to exercise. Exercise-induced change in mitral effective regurgitant orifice did not predict survival (HR 0.99, 95% CI 0.94-1.04, P = .63). By Cox multivariate analysis, resting LV end-diastolic volume and tricuspid annular plane systolic excursion < or = 14 mm were the independent predictors of death. CONCLUSIONS: Exercise Doppler echocardiography does not refine the predictive value of resting Doppler echocardiography in patients with LVSD and functional MR at rest.

Prognostic importance of tissue Doppler-derived diastolic function in patients presenting with acute coronary syndrome: a bedside echocardiographic study.

AIMS: We sought to evaluate the prognostic value of bedside tissue Doppler derived diastolic function in patients presenting with acute coronary syndrome (ACS) on top of major clinical predictors of mortality and routine laboratory testings. METHODS AND RESULTS: Bedside Doppler echocardiography and laboratory tests were prospectively performed in 239 consecutive patients (mean age 62 +/- 14, 69% men) admitted for ACS. Ratio of early transmitral flow (E) to early mitral annulus velocities (e') was calculated. The study endpoint was cardiac death. The median follow-up period was 2 years. E/e' was >15 in 39 patients. Multivariate predictors of E/e' > 15 were older age, diabetes, non-ST-segment elevation ACS, and decreased LV ejection fraction (LVEF). Survival free from cardiac death was lower in patients with E/e' ratio >15 (P = 0.01). History of coronary artery disease, lower creatinine clearance, higher glycemia on admission, decreased LVEF, and E/e' >15 were independent predictors of cardiac death. CONCLUSION: Bedside Doppler echocardiography provides prognostic information on top of major clinical predictors of mortality and routine laboratory testings in patients presenting with ACS.

Cardiac correlates of exercise induced pulmonary hypertension in patients with chronic heart failure due to left ventricular systolic dysfunction.

BACKGROUND: Patients with chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD) may develop pulmonary hypertension at rest and during exercise. The cardiac correlates of pulmonary hypertension have been ascertained in the resting state, but seldom during exercise in these patients. AIMS: We sought to determine the cardiac correlates of exercise induced pulmonary hypertension in patients with LVSD by monitoring the estimated pulmonary artery systolic pressure (PASP) by continuous Doppler echocardiography during semirecumbent bicycle exercise. METHODS: Eighty-five patients (mean age 57 +/- 13 years, 75% male) with CHF due to LVSD (LV ejection fraction [EF] <45%, mean LVEF 26 +/- 8%) were studied. RESULTS: Mitral effective regurgitant orifice area and E-wave were independent predictors of resting PASP. Resting PASP and exercise induced changes in PASP were unrelated (r =-0.08, P = 0.45). Decrease in LV end-systolic volume, increase in left atrial (LA) area, resting LV asynchrony, and decreased tricuspid annular plane systolic excursion (TAPSE) were independent predictors of exercise PASP. CONCLUSIONS: Resting LV asynchrony, impaired LV contractile reserve, and increase in LA dilatation correlate with the severity of exercise induced pulmonary hypertension in patients with CHF due to LVSD, while right ventricular systolic dysfunction is inversely related to the severity of exercise induced pulmonary hypertension.

Coexistent chronic obstructive pulmonary disease and heart failure in the elderly.

The prevalence of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) increases substantially with age. The coexistence of COPD and CHF is common but often unrecognized in elderly patients. To avoid overlooking COPD in elderly patients with known CHF pulmonary function tests should be routinely obtained. Likewise, to avoid overlooking CHF in elderly patients with known COPD left ventricular (LV) function should be routinely assessed. Plasma brain natriuretic peptide levels are useful to differentiate COPD exacerbation from CHF decompensation in patients presenting with acute dyspnea. Aging exacerbates skeletal muscle alterations that occur in patients with CHF and COPD. Skeletal muscle metabolic alterations and atrophy and the resulting deterioration of functional capacity progress rapidly in elderly patients with COPD and CHF. Physical conditioning reverses rapidly progressing skeletal muscle metabolic alterations and atrophy and promotes independence and life quality in the elderly. Physical conditioning is clearly an essential component of the management of elderly patients with COPD and CHF. The pharmacological management of patients with coexistent COPD and CHF should focus on not depriving these patients from long-term beta adrenergic blockade. Long-term beta adrenergic blockade has been repeatedly shown to improve survival in elderly patients with CHF due to LV systolic dysfunction and, contrary to conventional belief, is well tolerated by patients with COPD.