Direct assessment of microcirculation in shock: a randomized-controlled multicenter study.

PURPOSE: Shock is a life-threatening condition characterized by substantial alterations in the microcirculation. This study tests the hypothesis that considering sublingual microcirculatory perfusion variables in the therapeutic management reduces 30-day mortality in patients admitted to the intensive care unit (ICU) with shock. METHODS: This randomized, prospective clinical multicenter trial-recruited patients with an arterial lactate value above two mmol/L, requiring vasopressors despite adequate fluid resuscitation, regardless of the cause of shock. All patients received sequential sublingual measurements using a sidestream-dark field (SDF) video microscope at admission to the intensive care unit (± 4 h) and 24 (± 4) hours later that was performed blindly to the treatment team. Patients were randomized to usual routine or to integrating sublingual microcirculatory perfusion variables in the therapy plan. The primary endpoint was 30-day mortality, secondary endpoints were length of stay on the ICU and the hospital, and 6-months mortality. RESULTS: Overall, we included 141 patients with cardiogenic (n = 77), post cardiac surgery (n = 27), or septic shock (n = 22). 69 patients were randomized to the intervention and 72 to routine care. No serious adverse events (SAEs) occurred. In the interventional group, significantly more patients received an adjustment (increase or decrease) in vasoactive drugs or fluids (66.7% vs. 41.8%, p = 0.009) within the next hour. Microcirculatory values 24 h after admission and 30-day mortality did not differ [crude: 32 (47.1%) patients versus 25 (34.7%), relative risk (RR) 1.39 (0.91-1.97); Cox-regression: hazard ratio (HR) 1.54 (95% confidence interval (CI) 0.90-2.66, p = 0.118)]. CONCLUSION: Integrating sublingual microcirculatory perfusion variables in the therapy plan resulted in treatment changes that do not improve survival at all.

Changes in left atrial function in patients undergoing cardioversion for atrial fibrillation: relevance of left atrial strain in heart failure.

BACKGROUND: Left atrial (LA) reservoir strain provides prognostic information in patients with and without heart failure (HF), but might be altered by atrial fibrillation (AF). The aim of the current study was to investigate changes of LA deformation in patients undergoing cardioversion (CV) for first-time diagnosis of AF. METHODS AND RESULTS: We performed 3D-echocardiography and strain analysis before CV (Baseline), after 25 ± 10 days (FU-1) and after 190 ± 20 days (FU-2). LA volumes, reservoir, conduit and active function were measured. In total, 51 patients were included of whom 35 were in SR at FU-1 (12 HF and preserved ejection fraction (HFpEF)), while 16 had ongoing recurrence of AF (9 HFpEF). LA maximum volume was unaffected by cardioversion (Baseline vs. FU-2: 41 ± 11 vs 40 ± 10 ml/m2; p = 0.85). Restored SR led to a significant increase in LA reservoir strain (Baseline vs FU-1: 12.9 ± 6.8 vs 24.6 ± 9.4, p < 0.0001), mediated by restored LA active strain (SR group Baseline vs. FU-1: 0 ± 0 vs. 12.3 ± 5.3%, p < 0.0001), while LA conduit strain remained unchanged (Baseline vs. FU-1: 12.9 ± 6.8 vs 13.1 ± 6.2, p = 0.78). Age-controlled LA active strain remained the only significant predictor of LA reservoir strain on multivariable analysis (ß 1.2, CI 1.04-1.4, p < 0.0001). HFpEF patients exhibited a significant increase in LA active (8.2 ± 4.3 vs 12.2 ± 6.6%, p = 0.004) and reservoir strain (18.3 ± 5.7 vs. 22.8 ± 8.8, p = 0.04) between FU-1 and FU-2, associated with improved LV filling (r = 0.77, p = 0.005). CONCLUSION: Reestablished SR improves LA reservoir strain by restoring LA active strain. Despite prolonged atrial stunning following CV, preserved SR might be of hemodynamic and prognostic benefit in HFpEF.

Right atrial-right ventricular coupling in heart failure with preserved ejection fraction.

BACKGROUND: Right ventricular (RV) function is prognostically relevant in heart failure with preserved ejection fraction (HFpEF) but data on profound assessment of RV and right atrial (RA) interaction in HFpEF are lacking. The current study characterizes RV and RA interaction using invasive pressure-volume-loop analysis and cardiac magnetic resonance imaging (CMR) data. METHODS AND RESULTS: We performed CMR and myocardial feature-tracking in 24 HFpEF patients and 12 patients without HFpEF. Invasive pressure-volume-loops were obtained to evaluate systolic and diastolic RV properties. RV early filling was determined from CMR RV volume-time curves. RV systolic function was slightly increased in HFpEF (RV EF 68 ± 8 vs. 60 ± 9%, p = 0.01), while no differences in RV stroke volume were found (45 ± 7 vs 42 ± 9 ml/m2, p = 0.32). RV early filling was decreased in HFpEF (21 ± 11 vs. 40 ± 11% of RV filling volume, p < 0.01) and RV early filling was the strongest predictor for VO2max even after inclusion of invasively derived RV stiffness and relaxation constant (Beta 0.63, p < 0.01). RA conduit-function was lower in HFpEF (RA conduit-strain - 11 ± 5 vs. - 16 ± 4%, p < 0.01) while RA booster-pump-function was increased (RA active-strain - 18 ± 6 vs. - 12 ± 6%, p = 0.01) as a compensation. RV filling was associated with RA conduit-function (r = - 0.55, p < 0.01) but not with invasively derived RV relaxation constant. CONCLUSION: In compensated HFpEF patients RV early filling was impaired and compensated by increased RA booster pump function, while RV systolic function was preserved. Impaired RV diastology and RA-RV interaction were linked to impaired exercise tolerance and RA-RV-coupling seems to be independent of RV relaxation, suggestive of an independent pathophysiological contribution of RA dysfunction in HFpEF. CLINICAL-TRIAL-REGISTRATION: NCT02459626 (www.clinicaltrials.gov).

Physiological and Clinical Consequences of Right Ventricular Volume Overload Reduction After Transcatheter Treatment for Tricuspid Regurgitation.

OBJECTIVES: This study sought to examine the impact of chronic right ventricular (RV) volume overload and implications of tricuspid regurgitation (TR) reduction on biventricular function. BACKGROUND: Severe TR is a major determinant of adverse outcomes in advanced heart failure patients. The understanding of TR pathophysiology and implications of correction is still limited. Transcatheter tricuspid edge-to-edge repair (TTVR) is a new treatment option in patients at high surgical risk and provides a unique pathophysiological model without confounding effects of cardiac surgery. METHODS: Twenty-nine patients (78 ± 4 years of age) with severe isolated TR and high surgical risk underwent TTVR using the MitraClip system, and of these 18 underwent repeated cardiac magnetic resonance. Clinical follow-up was realized at 1 and 6 months after the intervention. RESULTS: TR fraction was reduced from 41% to 21% (p < 0.01) without increase in RV afterload (p = 0.52) and RV end-diastolic volume (p < 0.01), and RV stroke volume decreased (p = 0.03), whereas RV effective forward flow increased (p = 0.03). Left ventricular (LV) filling improved with an increase in LV end-diastolic volume (p = 0.01) and LV stroke volume (p = 0.02), leading to an augmentation of cardiac indices (2.2 ± 0.6 l/min/m2 vs. 2.7 ± 0.6 l/min/m2; p < 0.01) with similar results at 6 months follow-up. After TTVR, New York Heart Association functional class significantly improved (p < 0.01), peripheral edema decreased (p = 0.01), and 6-min walk distance increased by 20% and 22% after 1 and 6 months, respectively (p < 0.01). CONCLUSIONS: TTVR reduces chronic RV volume overload without increase in RV afterload, improves RV performance and LV filling, and enhances cardiac output. These changes translate into symptomatic and functional improvement. These implications for biventricular physiology and clinical status are maintained at 6 months follow-up.

A Three-Arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients With Resistant Hypertension (RADIOSOUND-HTN).

BACKGROUND: Both radiofrequency and ultrasound endovascular renal sympathetic denervation (RDN) have proven clinical efficacy for the treatment of hypertension. We performed a head-to-head comparison of these technologies. METHODS: Patients with resistant hypertension were randomly assigned in a 1:1:1 manner to receive either treatment with (1) radiofrequency RDN of the main renal arteries; (2) radiofrequency RDN of the main renal arteries, side branches, and accessories; or (3) an endovascular ultrasound-based RDN of the main renal artery. The primary end point was change in systolic daytime ambulatory blood pressure at 3 months. RESULTS: Between June 2015 and June 2018, 120 patients were enrolled (mean age, 64±9 years±SD; mean daytime blood pressure, 153/86±12/13 mm Hg). Of these, 39 were randomly assigned to radiofrequency main renal artery ablation, 39 to combined radiofrequency ablation of the main artery and branches, and 42 to ultrasound-based treatment. Baseline daytime blood pressure, clinical characteristics, and treatment were well balanced between the groups. At 3 months, systolic daytime ambulatory blood pressure decreased by 9.5±12.3 mm Hg ( P<0.001) in the whole cohort. Although blood pressure was significantly more reduced in the ultrasound ablation group than in the radiofrequency ablation group of the main renal artery (-13.2±13.7 versus -6.5±10.3 mm Hg; mean difference, -6.7 mm Hg; global P=0.038 by ANOVA, adjusted P=0.043), no significant difference was found between the radiofrequency ablation groups (-8.3±11.7 mm Hg for additional side branch ablation; mean difference, -1.8 mm Hg; adjusted P>0.99). Similarly, the blood pressure reduction was not found to be significantly different between the ultrasound and the side branch ablation groups. Frequencies of blood pressure response ≥5 mm Hg were not significantly different (global P=0.77). CONCLUSIONS: In patients with resistant hypertension, endovascular ultrasound-based RDN was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories, and side branches was not. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02920034.

Predictors for profound blood pressure response in patients undergoing renal sympathetic denervation.

BACKGROUND: Renal sympathetic denervation (RDN) as treatment for hypertension shows highly variable results. Although some patients do not show any blood pressure (BP) change and in most patients a BP reduction of at least 5 mmHg can be found, some show a reduction at least 20 mmHg. We sought to identify predictors for such a profound BP response. METHODS: Profound BP response was defined as drop of at least 20 mmHg in daytime systolic ambulatory BP measurement (ABPM) 3 months after catheter-based RDN. Three different denervation devices were used for RDN, and pulse wave velocity was determined invasively in a subgroup of patients. RESULTS: One hundred and ninety consecutive patients were included in this analysis. Profound BP response was found in 33 patients. Patients with profound BP response were younger (P = 0.04), presented with higher baseline ABPM values (P < 0.001), were treated with ultrasound-based RDN and received more often a combined treatment with two different diuretics (P = 0.005 for both). After 3 months, a treatment target of daytime BP less than 135 mmHg could be achieved more frequently in patients with profound BP response (61 vs. 17%, P < 0.001). Age, use of ultrasound RDN, combined diuretic therapy and baseline BP independently predicted pronounced BP reduction. A second multivariate logistic regression model including pulse wave velocity if available identified baseline BP, pulse wave velocity and use of ultrasound denervation as independent predictors for profound BP response. CONCLUSION: Younger vascular age, higher baseline BP, treatment with ultrasound RDN and combined diuretic therapy were found as predictors for a pronounced BP reduction following RDN, improving BP control at follow-up.

Plasma and Cardiac Galectin-3 in Patients With Heart Failure Reflects Both Inflammation and Fibrosis: Implications for Its Use as a Biomarker.

BACKGROUND: Galectin (Gal)-3 is a ß-galactoside-binding lectin and currently intensely studied as a biomarker in heart failure. Gal-3 also exerts proinflammatory effects, at least in extracardiac tissues. Objective of this study was to characterize the relationship of plasma and myocardial Gal-3 levels with cardiac fibrosis and inflammation in patients with nonischemic dilated cardiomyopathy and inflammatory cardiomyopathy (iCMP). METHODS AND RESULTS: Endomyocardial biopsies and blood samples were obtained from patients with newly diagnosed cardiomyopathy and clinical suspicion of myocarditis. According to histopathologic findings, patients were classified as having dilated cardiomyopathy (n=40) or iCMP (n=75). Cardiac fibrosis was assessed histologically on endomyocardial biopsy sections. In patients with iCMP, myocardial Gal-3 expression significantly correlated with inflammatory cell count on endomyocardial biopsy (r=0.56; P<0.05). In contrast, an inverse association was observed between myocardial Gal-3 expression and cardiac fibrosis in patients with iCMP (r=-0.59; P<0.05). In patients with dilated cardiomyopathy, myocardial Gal-3 expression correlated with cardiac fibrosis on left ventricular biopsy (P=0.63; P<0.01). Of note, in both groups, plasma Gal-3 levels did not correlate with myocardial Gal-3 levels or left ventricular fibrosis, whereas a positive correlation between plasma Gal-3 levels and inflammatory cell count on endomyocardial biopsy was observed in patients with iCMP. CONCLUSIONS: The present study suggests that myocardial Gal-3 can be considered as a possible marker for both cardiac inflammation and fibrosis, depending on the pathogenesis of heart failure. However, circulating concentrations of Gal-3 do not seem to reflect endomyocardial Gal-3 levels or cardiac fibrosis.

Culprit lesion location and outcome in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.

BACKGROUND: In myocardial infarction without cardiogenic shock (CS), the affected coronary vessel has significant influence on the final infarct size and patient prognosis. CS data on this relation are scarce. The objective of this study was to determine the prognostic relevance of the culprit lesion location in patients with CS complicating acute myocardial infarction. METHODS: In the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial patients with CS were randomized to therapy with intraaortic balloon pump or control. Additional CS patients not eligible for the randomized trial were included in a registry. We compared the location of the culprit lesions in these patients with regard to the affected coronary vessel [left main (LM), left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA)] and location within the vessel (proximal, mid or distal) regarding short- and long-term outcome. RESULTS: Of 758 patients, the majority had the culprit lesion in the LAD (44 %) compared to RCA (27 %), LCX (19 %) or LM (10 %). Proximal lesions were more frequent than mid or distal culprit lesions (60 vs. 27 vs. 13 %, p < 0.001). No differences were observed for mortality with respect to either culprit vessel (log-rank p value = 0.54). In contrast, a higher mortality was observed for patients with distal culprit lesions after 1 year (log-rank p value = 0.04). This difference persisted after multivariable adjustment (hazard ratio for distal lesions 1.40; 95 % confidential interval 1.03-1.90; p = 0.03). CONCLUSION: For patients with CS complicating myocardial infarction, the culprit vessel seems to be unrelated with mortality whereas distal culprit lesions may have a worse outcome.

Gender differences in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.

BACKGROUND: Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is associated with high mortality. Previous studies regarding gender-specific differences in CS are conflicting and there are insufficient data for the presence of gender-associated differences in the contemporary percutaneous coronary intervention era. Aim of this study was therefore to investigate gender-specific differences in a large cohort of AMI patients with CS undergoing contemporary treatment. METHODS: In the randomized Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, 600 patients with CS complicating AMI undergoing early revascularization were assigned to therapy with or without intra-aortic balloon pump. We compared sex-specific differences in these patients with regard to baseline and procedural characteristics as well as short- and long-term clinical outcome. RESULTS: Of 600 patients 187 (31%) were female. Women were significantly older than men and had a significantly lower systolic and diastolic blood pressure at presentation (p < 0.05 for all). Diabetes mellitus and hypertension were more frequent in women, whereas smoking was more frequent in men (p < 0.05 for all). Women showed a higher mortality within the first day after randomization (p = 0.004). However, after multivariable adjustment this numerical difference was no longer statistically significant. No gender-related differences in clinical outcome were observed after 1, 6 and 12 months of follow-up. CONCLUSION: In this large-scale multicenter study in patients with CS complicating AMI, women had a worse-risk profile in comparison to men. No significant gender-related differences in treatment as well as short- and long-term outcome were observed.