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.

Impella in Acute Myocardial Infarction Complicated by Cardiogenic Shock: History and Current Controversies.

In this review, the authors discuss a brief history of the Impella mechanical circulatory support device, a mechanistic role for the device in the context of the underlying pathophysiology of acute myocardial infarction cardiogenic shock (AMI-CS), the current body of literature evaluating its role in AMI-CS, and upcoming efforts to identify a role more clearly for the device in AMI-CS.

Toward Brief Dual Antiplatelet Therapy and P2Y12 Inhibitors for Monotherapy After PCI.

The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention remains a controversial topic. The European Society of Cardiology and the American College of Cardiology/American Heart Association recommend at least 6 and 12 months of DAPT after PCI in patients with stable coronary artery disease or acute coronary syndrome, respectively. Although prolonging DAPT duration reduces ischemic events, it is associated with higher rates of bleeding and possible fatal outcomes. The DAPT score can be an important tool to identify patients who may still benefit from prolonged therapy. Nevertheless, several recent randomized controlled trials showed that shortening DAPT duration from 12 to 1-3 months reduces bleeding rates without significantly increasing ischemic event rates. These trials also suggested replacing acetylsalicylic acid (aspirin) with P2Y12 inhibitors after short-term DAPT. We review and compare past and present studies regarding DAPT and analyze the evidence favoring a short DAPT duration and the long-term single antiplatelet agent of choice.

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.

Pooled diagnostic accuracy of resting distal to aortic coronary pressure referenced to fractional flow reserve: The importance of resting coronary physiology.

INTRODUCTION: Both resting and hyperemic physiologic methods to guide coronary revascularization improve cardiovascular outcomes compared with angiographic guidance alone. Fractional flow reserve (FFR) remains underutilized due to concerns regarding hyperemia, prompting study of resting distal to aortic coronary pressure (Pd/Pa). Pd/Pa is a vasodilator-free resting index unlike FFR. While Pd/Pa is similar to another resting index, instantaneous wave-free ratio (iFR), it is a whole-cycle measurement not limited to the wave-free diastolic period. Pd/Pa is not validated clinically although multiple accuracy studies have been performed. Our meta-analysis examines the overall diagnostic accuracy of Pd/Pa referenced to FFR, the accepted invasive standard of ischemia. METHODS: We searched PubMed, EMBASE, Central, ProQuest, and Web of Science databases for full text articles published through August 9, 2017 addressing the diagnostic accuracy of Pd/Pa referenced to FFR < 0.80. The following keywords were used: "distal coronary artery pressure" OR "Pd/Pa" AND "fractional flow reserve" OR "FFR." RESULTS: In total, 14 studies comprising 7004 lesions were identified. Pooled diagnostic accuracy estimates of Pd/Pa versus FFR < 0.80 were: sensitivity, 0.77 (95% CI, 0.75-0.78); specificity, 0.82 (0.81-0.83); positive likelihood ratio, 4.7 (3.3-6.6); negative likelihood ratio, 0.29 (0.24-0.34); diagnostic odds ratio, 18.1 (14.4-22.6); area under the summary receiver-operating characteristic curve of 0.88; and diagnostic accuracy of 0.80 (0.76-0.83). CONCLUSIONS: Pd/Pa shows adequate agreement with FFR as a resting index of coronary stenosis severity without the undesired effects and cost of hyperemic agents. Pd/Pa has the potential to guide coronary revascularization with easier application and availability compared with iFR and FFR.

Instantaneous wave-free ratio as an alternative to fractional flow reserve in assessment of moderate coronary stenoses: A meta-analysis of diagnostic accuracy studies.

BACKGROUND/PURPOSE: Fractional flow reserve (FFR) remains underutilized due to practical concerns related to the need for hyperemic agents. These concerns have prompted the study of instantaneous wave-free ratio (iFR), a vasodilator-free index of coronary stenosis. Non-inferior cardiovascular outcomes have been demonstrated in two recent randomized clinic trials. We performed this meta-analysis to provide a necessary update of the diagnostic accuracy of iFR referenced to FFR based on the addition of eight more recent studies and 3727 more lesions. METHODS: We searched the PubMed, EMBASE, Central, ProQuest, and Web of Science databases for full text articles published through May 31, 2017 to identify studies addressing the diagnostic accuracy of iFR referenced to FFR≤0.80. The following keywords were used: "instantaneous wave-free ratio" OR "iFR" AND "fractional flow reserve" OR "FFR." RESULTS: In total, 16 studies comprising 5756 lesions were identified. Pooled diagnostic accuracy estimates of iFR versus FFR≤0.80 were: sensitivity, 0.78 (95% CI, 0.76-0.79); specificity, 0.83 (0.81-0.84); positive likelihood ratio, 4.54 (3.85-5.35); negative likelihood ratio, 0.28 (0.24-0.32); diagnostic odds ratio, 17.38 (14.16-21.34); area under the summary receiver-operating characteristic curve, 0.87; and an overall diagnostic accuracy of 0.81 (0.78-0.84). CONCLUSIONS: In conclusion, iFR showed excellent agreement with FFR as a resting index of coronary stenosis severity without the undesired effects and cost of hyperemic agents. When considering along with its clinical outcome data and ease of application, the diagnostic accuracy of iFR supports its use as a suitable alternative to FFR for physiology-guided revascularization of moderate coronary stenoses. SUMMARY: We performed a meta-analysis of the diagnostic accuracy of iFR referenced to FFR. iFR showed excellent agreement with FFR as a resting index of coronary stenosis severity without the undesired effects and cost of hyperemic agents. This supports its use as a suitable alternative to FFR for physiology-guided revascularization of moderate coronary stenoses.

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.

Role of ventricular interdependence as an early echocardiographic sign of cardiac surgical postoperative pericardial tamponade.

Pericardial effusions are common in postoperative cardiac surgical patients. Cardiac tamponade occurs relatively infrequently postoperatively and may mimick other conditions, such as heart failure, renal failure, and pulmonary emboli. Echocardiographic examination is frequently hampered in the immediate postoperative period due to suboptimal imaging. The current case series focuses on the echocardiographic findings in tamponade in the postoperative patient with emphasis on ventricular interdependence as an early sign of impending tamponade.

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.