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Pulmonary arterial hypertension (PAH) is a rare and progressive cardiopulmonary disease, characterized by pulmonary vasculopathy. The disease can lead to increase pulmonary arterial pressures and eventual right ventricular (RV) failure due to elevated afterload. The prevalence of PAH in patients admitted to the intensive care unit (ICU) is unknown and pulmonary hypertension (PH) in the ICU is more commonly the result of left heart disease or hypoxic lung injury (PH due to left heart disease and PH due to lung diseases and/or hypoxia, respectively), as opposed to PAH. Management of PAH patients in the ICU is complex as it requires a careful balance to maintain perfusion while optimizing right sided heart function. A comprehensive understanding of the underlying physiology and underlying hemodynamics is crucial for the management of this population. In this review, we summarized the evidence for use of vasopressors and inotropes in the management of PH and extrapolated the data to patients with PAH. We strongly believe that the understanding of the hemodynamic consequences of inotropes and vasopressors, especially from data in the PH population, can lead to better management of this complex patient population.

BACKGROUND The relationship between office vs. ambulatory blood pressure (BP) indices are well-studied in patients with essential hypertension and based on these data, it is known that the average 24-h ambulatory BP is typically lower than office BP. However, emerging data show that office SBP underestimates arterial afterload in patients with coarctation of aorta (COA), and a minimal increase in stroke volume during low-intensity exercise results in an exaggerated rise in SBP as compared to those with essential hypertension. We hypothesized that COA patients will have higher ambulatory SBP and a higher prevalence of masked hypertension compared to patients with essential hypertension. METHODS Case-control study of 118 COA patients and 118 patients with essential hypertension matched by age, sex, BMI and office SBP. RESULTS Although both groups had similar office SBP (132 ± 17 mmHg) by design, the COA group had paradoxical increases in 24-h ambulatory SBP (135 ± 14 vs. 126 ± 13; P

Purpose Elite swimmers (Sw) have lower diastolic function compared to elite runners, possibly as an adaptation to the aquatic training environment. Water polo players (WP) and artistic swimmers (AS) are exposed to the same hydrostatic pressures as Sw, but are subject to different training intensities, postures, and hemodynamic stressors. Our purpose was to compare resting and exercising cardiac function in elite Sw, WP, and AS, to characterize the influence of training for aquatic-sport on left ventricular (LV) adaptation. Methods Ninety athletes (Sw:20 M/17F; WP:21 M/9F; AS:23F) at the 2019 FINA World Championships volunteered for resting and stress (3 min 30% maximal isometric handgrip) echocardiographic assessment of LV global function and mechanics. Results Male Sw displayed greater resting systolic and diastolic function compared to WP; however, both groups maintained stroke volume under high-pressure handgrip stress (Sw:[INCREMENT]-4 ± 12%; WP:[INCREMENT]-1 ± 13%, P = 0.11). There were no differences between female Sw and WP resting LV function, but Sw demonstrated greater function over AS. During isometric handgrip, all female sport athletes maintained stroke volume (Sw:[INCREMENT]3 ± 16%; WP:[INCREMENT]-10 ± 11%; AS:[INCREMENT]-2 ± 14%, P = 0.46), but WP had improved apical rotation ([INCREMENT]1.7 ± 4.5°), which was reduced in AS ([INCREMENT]-3.1 ± 4.5°) and maintained in Sw ([INCREMENT]-0.5 ± 3.8°, P = 0.04). Unlike Sw and WP, AS displayed a unique maintenance of early filling velocity during handgrip exercise (Sw:[INCREMENT]-3.5 ± 14.7 cm/s; WP:[INCREMENT]-15.1 ± 10.8 cm/s; AS:[INCREMENT]1.5 ± 15.3 cm/s, P = 0.02). Conclusion Among male athletes, Sw display primarily volume-based functional adaptations distinct from the mixed volume-pressure adaptations of WP; however, both groups can maintain stroke volume with increased afterload. Female Sw and WP do not demonstrate sport-specific differences like males, perhaps owing to sex-differences in adaptation, but have greater volume-based adaptations than AS. Lastly, AS display unique functional adaptations, that may be driven by elevated pressures under low-volume conditions.

Background Drug therapy for heart failure influences quality of life and work potential of affected persons and has contributed to decrease in hospitalizations and cardiovascular mortality. The current approach is the result of incremental progress in understanding the pathophysiology of the syndrome, introduction of new molecules, and repurposing existing drugs. Study question What are the milestones of the changes in the expert clinicians' approach to the pharmacological management in the past century? Study design To determine the changes in the experts' approach to the management of heart failure, as presented in a widely used textbook in the United States. Data sources The chapters on the management of heart failure in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. Results In 1927, heart failure was treated with powdered leaf or tincture of digitalis, mercury chloride, and theophylline. Patients with acute pulmonary edema received injections of atropine, adrenaline, and ouabain. The therapeutic milestones in heart failure were the introduction of loop diuretics and aldosterone antagonists (1971), vasodilator treatment with hydralazine and nitroglycerine (1979-1985), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and selective beta-adrenergic blockers (1992-2000), and sacubitril-valsartan (2016). For acute pulmonary edema, the durable milestone was the treatment with morphine and furosemide (1971). Conclusions The pharmacological management of heart failure in the past century has progressed in fits and starts, with latent periods between significant advances lasting 8-40 years. In chronological order, the major advances were efficient diuresis, afterload reduction, and blunting the neurohormonal response to hemodynamic stress and cardiac remodeling.

AIMS To assess if left atrial phasic function characteristics modulate functional capacity/survival by impacting on the pulsatile component of right ventricular (RV) afterload, as represented by pulmonary arterial compliance (PAC). MATERIALS AND METHODS Sixty heart failure patients (67 ± 11 years, ejection fraction 39 ± 11%, range 20--62%) underwent 6 min walk test (6MWT) and 3D transthoracic echocardiography. Left atrial conduit was computed off-line, gathering simultaneous real-time 3D multibeats (six cycles) left atrial and left ventricular (LV) volume curves, with conduit (time) = [LV (time) - LV minimum volume] - [left atrial maximum volume - left atrial (time)], expressed as % LV stroke volume. Atrial stiffness (Kla) was computed using noninvasively assessed wedge pressure divided by left atrial reservoir (maximum - minimum) volume. PAC was obtained as ratio between RV stroke volume, obtained as pulsed Doppler RV outflow tract envelope∗cross-sectional area, and pulmonary pulse pressure, obtained by transforming tricuspid regurgitant velocity in millimetres of mercury and considering diastolic pulmonary as a fixed fraction of systolic pressure. RESULTS Conduit averaged 34 ± 12%, PAC 3.1 ± 1.1 ml/mmHg, 6MWT 404 ± 154 m. Conduit was independent of LV volumes and ejection fraction, showing a direct dependence on noninvasive Kla (r = 0.56; P

Pulmonary hypertension (PH) is a progressive disease that leads to cardiopulmonary dysfunction and right heart failure from pressure and volume overloading of the right ventricle (RV). Mechanical cardiopulmonary support has theoretical promise as a bridge to organ transplant or destination therapy for these patients. Solving the challenges of mechanical cardiopulmonary support for PH and RV failure requires its testing in a physiologically relevant animal model. Previous PH models in large animals have used pulmonary bead embolization, which elicits unpredictable inflammatory responses and has a high mortality rate. We describe a step-by-step guide for inducing pulmonary hypertension and right ventricular hypertrophy (PH-RVH) in sheep by left pulmonary artery (LPA) ligation combined with progressive main pulmonary artery (MPA) banding. This approach provides a controlled method to regulate RV afterload as tolerated by the animal in order to achieve PH-RVH, while reducing acute mortality. This animal model can facilitate evaluation of mechanical support devices for PH and RV failure.

BACKGROUND Spinal anaesthesia-induced hypotension is frequently reported in patients undergoing caesarean section. Mechanistically, sympathetic blockade reduces the systemic vascular resistance and the left ventricular preload, causing hypotension, which is augmented by aortocaval compression. The corrected blood flow time (FTc) is affected by the preload and is inversely related to the afterload. OBJECTIVE We hypothesised that the preanaesthetic carotid artery FTc could predict hypotension after induction in patients undergoing a caesarean section with spinal anaesthesia. DESIGN A prospective observational study. SETTING A tertiary referral centre in South Korea from September 2018 to November 2019. PARTICIPANTS Thirty-eight parturients scheduled for elective caesarean section under spinal anaesthesia. INTERVENTIONS Using carotid ultrasonography, FTc was measured twice prior to inducing spinal anaesthesia. FTc was calculated using both Bazett's (B) and Wodey's (W) formulae. Hypotension was defined as an SBP decrease to less than 80 mmHg, or less than 75% of baseline, or if symptoms consistent with hypotension occurred from the time of injection of the spinal anaesthetic until delivery. MAIN OUTCOME MEASURES The primary endpoint was to determine the predictive value of preanaesthetic FTc for postspinal hypotension during caesarean delivery. RESULTS Among the 35 patients who completed this study, hypotension occurred in 21 (60%). The areas under the receiver-operating characteristic curves for FTc (B) and FTc (W) were 0.905 [95% confidence interval (CI), 0.757 to 0.978, P

Supplemental Digital Content is available in the text., Extracorporeal life support (ECLS) can result in complications due to increased left ventricular (LV) afterload. The percutaneous ventricular assist device (PVAD) and intra-aortic balloon pump (IABP) are both considered to be effective means of LV unloading. This study describes the efficacy of LV unloading and related outcomes with PVAD or IABP during ECLS. From January 2010 to April 2018, all cardiogenic shock patients who underwent ECLS plus simultaneous PVAD or IABP were analyzed. Forty-nine patients received ECLS + PVAD, while 91 received ECLS + IABP. At 48 hours, mean pulmonary artery pressure was significantly reduced in both groups [34 mm Hg to 22, p < 0.01; 32 mm Hg to 21, p < 0.01; ECLS + PVAD and ECLS + IABP group, respectively]. The two groups had similar 30 day survival rates [19 patients (39%) vs. 35 (39%), p = 0.56]. The ECLS + PVAD group had higher incidences of bleeding at the insertion site [11 (22%) vs. 0, p < 0.01] and major hemolysis [9 (18%) vs. 0, p < 0.01]. Both groups had improvement in LV end-diastolic dimension (61 ± 12 mm to 54 ± 12, p = 0.03; 60 ± 12 mm to 47 ± 10, p < 0.01), and LV ejection fraction (16 ± 7% to 22 ± 10, p < 0.01; 22 ± 12% to 29 ± 15, p = 0.01). Both ECLS + PVAD and ECLS + IABP effectively reduced pulmonary artery pressure and improved LV function. Bleeding at the PVAD or IABP insertion site occurred more frequently in the ECLS + PVAD group than the ECLS + IABP group (p < 0.01). Nine patients (18%) in the ECLS + PVAD group experienced major hemolysis, while there was no hemolysis in the ECLS + IABP group (p < 0.01). Careful considerations are required before selecting an additional support to ECLS.

PURPOSE OF REVIEW Over a thousand left ventricular-assist device (LVAD) implants were performed for heart failure destination therapy in 2017. With increasing survival, we are seeing increasing numbers of patients present for noncardiac surgery, including resections for cancer. This article will review the relevant literature and guidelines for patients with LVADs undergoing thoracic surgery, including lung resection. RECENT FINDINGS The International Society for Heart and Lung Transplant Mechanically Assisted Circulatory Support Registry has received data on more than 16 000 patients with LVADs. Four-year survival is more than 60% for centrifugal devices. There are increasing case reports, summaries and recommendations for patients with LVADs undergoing noncardiac surgery. However, data on thoracic surgery is restricted to case reports. SUMMARY Successful thoracic surgery requires understanding of the LVAD physiology. Modern devices are preload dependent and afterload sensitive. The effects of one-lung ventilation, including hypoxia and hypercapnia, may increase pulmonary vascular resistance and impair the right ventricle. Successful surgery necessitates a multidisciplinary approach, including thorough preoperative assessment; optimization and planning of intraoperative management strategies; and approaches to anticoagulation, right ventricular failure and LVAD flow optimization. This article discusses recent evidence on these topics.

Background Fluid responsiveness is an important factor to consider for fluid volume loading during major surgery. The effect of continuous vasopressor infusion on fluid responsiveness during prolonged major surgery is a concern. Objective We hypothesised that continuous vasopressor infusion during major surgery might not exert significant effects on changes in stroke volume variation (SVV) following fluid bolus infusion, and thereby on fluid responsiveness. Design Randomised controlled trial. Setting University hospital from April 2014 to August 2016. Patients Patients undergoing liver resection who were randomised to receive continuous intravenous infusion of phenylephrine (P group), norepinephrine (N group), or no vasopressor (C group) (n=17/group). Exclusion criteria were cardiac arrhythmia and severe cardiac, pulmonary or renal dysfunction. Intervention Patients received 4 ml kg fluid boluses of 6% hydroxyethyl starch solution when SVV was at least 12%. Vasopressors were administered continuously to maintain the systemic vascular resistance index at more than 1900 dyn s cm m. Main outcome measures Cardiac index and SVV were measured using the FloTrac/Vigileo system (Version 4.00). The number of fluid boluses with fluid responsiveness (i.e. >15% increase in cardiac index) was compared between groups using multilevel logistic regression analysis. Results Numbers of fluid responsive boluses in the C, P and N groups were 12 (14%), 22 (34%) and 19 (27%), respectively. Odds ratios on fluid responsiveness for phenylephrine and norepinephrine compared with the control were 3.65 (97.5% confidence interval, 1.15 to 11.6; P = 0.012) and 2.56 (97.5% confidence interval, 0.82 to 8.00; P = 0.064), respectively. Decreases in SVV after fluid bolus infusion for the P and N groups were comparable with the C group (P = 0.23 and 0.53, respectively). Conclusion Continuous administration of phenylephrine increased fluid responsiveness during liver resection, suggesting complex effects of continuous vasopressor infusion involving changes in cardiac preload and afterload. Trial registration UMIN000011024.

There is a need for a consistent, reproducible, and cost-effective method of determining cardiac recovery in patients who receive emerging novel therapeutics for advanced and end-stage heart failure (HF). With the increasing use of ventricular assist devices (VADs) in end-stage HF, objective device diagnostics are available for analysis. Pulsatility, one of the accessible diagnostic measures, is a variable gage of the differential between peak systolic and minimum diastolic flow during a single cardiac cycle. Following implantation of the VAD, HeartWare's HVAD records pulsatility regularly. Thus, we hypothesize that this measurement relates to the contractility of the heart and could be utilized as a metric for determining patient response to various therapeutics. In this study, therefore, we develop a translatable and effective predictive model characterizing pulsatility to determine HF status and potential HF recovery using the SynCardia Total Artificial Heart (TAH) in conjunction with a Donovan Mock Circulation System to create a simulation platform for the collection of pulsatility data. We set the simulation platform to patient conditions ranging from critical heart failure to a normal operating condition through the variation preload, afterload, and left ventricular (LV) pumping force or TAH "contractility." By manipulating these variables, pulsatility was found to accurately indicate significant (p < 0.05) improvements in LV contractility at every recorded afterload and preload, suggesting that it is a valuable parameter for the assessment of cardiac recovery in patients.

Left ventricular (LV) unloading with a LV assist device (LVAD) reverse remodels the heart and may lead to favorable changes in cellular architecture and LV geometry promoting myocardial recovery. Currently, there are no standardized methods for evaluating myocardial recovery. This study assesses the systolic slope of the LVAD outflow cannula as a marker for myocardial contractility. Doppler echocardiography (transthoracic echocardiogram [TTE]) of the LVAD outflow cannula and TTE of the LV cavity were prospectively collected in 57 patients with LVADs. Systolic acceleration of the LVAD outflow cannula was measured in each patient as the peak change of velocity over time (dv/dt) during systole from continuous-wave Doppler signal acquired from the LVAD outflow cannula. Ventricular volumes were concurrently measured by TTE. In a subset of 10 patients, the systolic slope was measured during each stage of a ramp study to study the properties of this parameter across a variety of loading conditions. The systolic slope of the LVAD outflow cannula was successfully measured in 53 of 57 patients (93%). Systolic slope strongly correlated with ejection fraction (EF) (R = 0.92). Analysis of systolic slope stratified by EF (EF >30%, EF 20–30%, EF 10–20%, and EF

Introduction: The objective of this study was to investigate the association of contractility, afterload, and diastolic dysfunction to exercise function between patients with heart failure and preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Hypothesis: Cardiac mechanical determinants of exercise would be different in HFrEF versus HFpEF Methods: Core-lab echocardiograms were obtained from the publically-available Pediatric Heart Network Fontan Cross-sectional Study database. Ejection fraction was considered abnormal if < 50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e’/end-diastolic volume) was > 10 th percentile. Patients were divided into three groups: 1 = normal EF and normal diastolic function, 2 = decreased EF with normal diastolic function (HFrEF), 3 = normal EF with abnormal diastolic function (HFpEF). End-systolic elastance (Ees), a measure of contractility, and arterial elastance (Ea), a measure of afterload, were calculated. Results: 238 patients were included. Differences between groups are reported in the Table. In group 1, there were no significant correlations between exercise and echocardiographic measures. In patients with HFrEF, Ea was correlated with percent predicted max O 2 pulse (ppO 2 P-max) (r = -0.40, p = 0.03). In patients with HFpEF, lateral E:e’/EDV was correlated with ppO 2 P-max (r = -0.57, p = 0.02). No measures correlated with percent predicted peak VO 2 in either group. Conclusions: As Fontan patients progress to heart failure, stroke volume during exercise is limited by afterload in patients with HFrEF. Alternatively, stroke volume is limited by diastolic dysfunction in HFpEF patients. These measures of cardiac mechanics may be useful in identifying the mechanisms that drive exercise dysfunction in Fontan patients of varying heart failure phenotypes.

Introduction: Afterload conferred by aortic stiffness contributes to heart failure (HF) pathogenesis. Hypothesis: Patients with HF have a greater rise in aortic stiffness with physical exertion compared to individuals without HF. Methods: Outpatients with HF (n=21) and without HF (n=26) underwent cardiovascular magnetic resonance (1.5T CMR) at rest and following submaximal supine bicycle ergometry. Short axis cine steady-state free precession (SSFP) images were obtained to quantify left ventricular volumes and ejection fraction. Cross-sectional aortic SSFP imaging at the level of the pulmonary artery bifurcation was obtained to measure descending aorta (DA) distensibility at rest and immediately after exercise. We compared least squares (LS) means of DA distensibility between HF and control groups, adjusting for age, sex, and metabolic equivalents (METs) achieved. Results: Characteristics of controls and HF patients are presented in the TABLE . There was no difference of DA distensibility between control and HF groups either at rest or after exercise (p=0.77 and p=0.13, respectively). However, compared to controls with no significant change in aortic stiffness with exercise, individuals with HF had a reduction in DA distensibility post-exercise in analyses adjusted for age, sex, and METs achieved ( TABLE ). In subgroup analyses, patients with HF with reduced ejection fraction (n=14) had lower post-exercise DA distensibility vs. rest (adjusted-LS means 3.06 x10 -3 mm Hg -1 , 95% CI 2.35x10 -3 —3.76x10 -3 mm Hg -1 , vs. 4.55 x10 -3 mm Hg -1 , 95% CI 3.84 x10 -3 —5.26 x10 -3 mm Hg - 1, respectively, p=0.020). DA distensibility at rest vs. exercise in patients with HF with preserved ejection fraction was similar (p=0.38). Conclusions: Patients with HF have exercise-induced aortic stiffness not seen in individuals without HF. This may result in less favorable ventricular-vascular coupling with exertion in HF patients. Character count: 1653 (limit=1700)

Introduction: Afterload at the myocardial level is a principal determinant of LV chamber and myocardial wall function, generated by interplay of LV pressure, volume, and mass. Quantitation has relied on wall stress indices which require additional measurements and calculations as well as incorrect assumptions. Unfamiliar to most clinicians, they have largely fallen out of use, but the role of myocardial afterload in contemporary heart failure pathophysiology and therapy merits reevaluation given the roles of EF and myocardial strains in prognostic indices and treatment guidelines. Hypothesis: A simple clinical afterload index using variables fundamental to wall stress indices (systolic pressure(mmHg) * LV volume(ml))/LV mass(g)) or PV/M correlates closely with stress indices and relates similarly to LV EF and myocardial strains. Methods: In 277 normals (54% female, mean age 50.9±12.9 yrs) and small cohorts with dilated non-ischemic cardiomyopathy(35), aortic stenosis(12) and cancer chemotherapy(43), each with matched controls, we used CMR LV volumes, mass and brachial systolic pressure during imaging to compare end-systolic PV/M to stress indices and systolic pressure alone using correlations and correlation standard errors(SEs). Results: There were extremely close correlations (r= 0.97-0.99, all p< 0.001) with minimal SEs between PV/M and Arts and Alters stress indices with similar slopes in all groups and in normal subgroups by age and gender. Negative correlations with EF, global strains and strain rates were also present and extremely similar in all groups. But Mirsky’s stress index and brachial pressure performed less well. Conclusions: A simple clinical afterload index correlates closely with wall stress indices and similarly with LV ejection fraction and strains. It can support efficient reassessment of the role of afterload at the myocardial level in research and potentially, in clinical practice.

Introduction: Cor Pulmonale or right ventricular (RV) dysfunction due to pulmonary disease is an expected complication of COPD resulting from increased afterload mediated by hypoxic pulmonary vasoconstriction as well as the destruction of the pulmonary vascular bed. Early detection of elevated RV afterload has been previously demonstrated by visualization of abnormal flow patterns in the proximal pulmonary arteries. Prior quantitative analysis of helicity in the pulmonary arteries of pulmonary hypertension patients has demonstrated a strong association between helicity and increased RV afterload. Hypothesis: Patients with COPD will have abnormal pulmonary flow as evaluated by 4D-Flow MRI and associated with RV function and pulmonary arterial stiffness. Methods: Patients with COPD (n=15) (65yrs ± 6) and controls (n=10) (58yrs ± 9) underwent 4D-Flow MRI to calculate helicity (Figure 1A). The helicity was calculated in 2 segments: 1) the main pulmonary artery (MPA) and 2) along the RV outflow tract (RVOT) - MPA axis. Main pulmonary arterial stiffness was measured using the relative area change (RAC). Results: COPD patients had decreased helicity relative to healthy controls in the MPA (19.4±7.8 vs 32.8±15.9 s -2 , P=0.007) (Figure 1B). Additionally, COPD patients had reduced helicity along the RVOT-MPA axis (33.2±9.0 vs 43.5±8.3 s -2 , P=0.010). The helicity measured in the MPA was associated with RV end-systolic volume (R=0.59, P = 0.002), RVEF (R=0.631, P Conclusion: Patients with COPD show quantitatively abnormal flow hemodynamics, when compared with healthy controls, as assessed by 4D-Flow MRI. A strong association between helicity along the MPA-RV outflow tract axis and RV function suggests that 4D-Flow MRI might be a sensitive tool in evaluating RV - pulmonary arterial coupling in COPD.

Background: Patients with Heart Failure with preserved Ejection Fraction (HFpEF) and Pulmonary Hypertension (PH) have increased right atrial (RA) pressures. Whether the higher RA pressures are related to increased afterload or overall stiffening of the heart is unknown. The aim of this study is to gain further insight into the right atrium in HFpEF-PH. Methods: This is a retrospective analysis of patients with HFpEF (no PH), HFpEF-PH and Pulmonary Arterial Hypertension (PAH) that underwent right heart catheterization and cardiac magnetic resonance (CMR) imaging. CMR was used to determine RA function by quantifying volume and strain on the 4-chamber view. Total, passive and active RA emptying fraction (RAEF) were calculated. RA stiffness was calculated by determining the slope of maximum and minimum pressure during v-wave and minimal and maximal RA volumes. Groups were compared with ANOVA and post-hoc comparison with Bonferroni correction. Results: 176 patients were included: 13 HFpEF, 33 HFpEF-PH and 130 PAH patients. Although afterload was lower in PAH and higher in HFpEF patients, as shown by mean pulmonary arterial pressure (mPAP) (41 ± 2 mmHg in HFpEF-PH vs 53 ± 21 mmHg in PAH vs 19 ± 1 mmHg in HFpEF, p ± 0.3 wu/m 2 in HFpEF-PH vs 5.7 ± 0.2 wu/m 2 in PAH vs 0.4 ± 0.06 wu/m 2 in HFpEF, p Conclusions: Despite lower afterload, HFpEF-PH patients have worse RA function and increased RA stiffness compared to PAH. Higher RA pressures in HFpEF-PH may reflect additional stiffening of the heart.

Introduction: Low-flow, low-gradient aortic stenosis (LFLG-AS) is associated with impaired left ventricular (LV) function and afterload mismatch. Indications and timing for transcatheter aortic valve replacement (TAVR) in LFLG-AS do not account for the presence of subclinical LV remodeling. We evaluated whether combining LV global longitudinal strain (GLS) and CT-derived extracellular volume (ECV), both markers of LV remodeling, provides incremental prediction of adverse outcomes in patients with LFLG-AS undergoing TAVR. Methods: We retrospectively evaluated patients with LFLG-AS undergoing TAVR in whom pre-TAVR CT-based ECV measurements were available. GLS was measured in pre-TAVR echocardiograms using speckle tracking. Cox regression analysis was performed with a primary outcome of heart failure hospitalization (HFH) or death. Four sub-groups were identified for analysis based on optimal cutoff points: Group 1 (n=64): ECV< 33 + GLS≥

Background: Often, pressure overload–induced myocardial remodeling does not undergo complete reverse remodeling after decreasing afterload. Recently, mitochondrial abnormalities and oxidative stress have been successively implicated in the pathogenesis of several chronic pressure overload cardiac diseases. Therefore, we aim to clarify the myocardial energetic dysregulation in (reverse) remodeling, mainly focusing on the mitochondria. Methods: Thirty-five Wistar Han male rats randomly underwent sham or ascending (supravalvular) aortic banding procedure. Echocardiography revealed that banding induced concentric hypertrophy and diastolic dysfunction (early diastolic transmitral flow velocity to peak early-diastolic annular velocity ratio, E/E′: sham, 13.6±2.1, banding, 18.5±4.1, P =0.014) accompanied by increased oxidative stress (dihydroethidium fluorescence: sham, 1.6×10 8 ±6.1×10 7 , banding, 2.6×10 8 ±4.5×10 7 , P Results: Two weeks later, hypertrophy decreased with the decline of oxidative stress (dihydroethidium fluorescence: banding, 2.6×10 8 ±4.5×10 7 , debanding, 1.96×10 8 ±6.8×10 7 , P P =0.029). The reduction of energetic demands imposed by overload relief allowed the mitochondria to reduce its activity and myocardial levels of phosphocreatine, phosphocreatine/ATP, and ATP/ADP to normalize in debanding towards sham values (phosphocreatine: sham, 38.4±7.4, debanding, 35.6±8.7, P =0.71; phosphocreatine/ATP: sham, 1.22±0.23 debanding, 1.11±0.24, P =0.59; ATP/ADP: sham, 6.2±0.9, debanding, 5.6±1.6, P =0.66). Despite the decreased mitochondrial area, complex III and V expression increased in debanding compared with sham or banding. Autophagy and mitophagy-related markers increased in banding and remained higher in debanding rats. Conclusions: During compensatory and maladaptive hypertrophy, mitochondria become more active. However, as the disease progresses, the myocardial energetic demands increase and the myocardium becomes energy deficient. During reverse remodeling, the concomitant attenuation of cardiac hypertrophy and oxidative stress allowed myocardial energetics, left ventricle hypertrophy, and diastolic dysfunction to recover. Autophagy and mitophagy are probably involved in the myocardial adaptation to overload and to unload. We conclude that these mitochondrial reversible changes underlie diastolic function adaptations during myocardial (reverse) remodeling.

Mechanical loading (e.g. blood pressure) is a critical component of heart disease. Here, we developed a simple, scalable iPSC-derived micro heart muscle (μHM) model by grafting μHM on elastomeric substrates with different stiffnesses to simulate afterload. For tissue traction force microscopy (TFM), substrates were fabricated by spin coating a PDMS base layer followed by spin coating an ultra-thin PDMS/fluorescent bead (1-micron) layer. Substrates were then covalently grafted with fibronectin via glutaraldehyde. Sylgard 184 ‘dog-bone’ shaped stencils were added onto substrates to control tissue geometry. Both isogenic control (WTC) and PKP2 -/- iPSC with GCaMP6f calcium indicator were differentiated using small molecule Wnt pathway modulators and were then purified (81±15% TNNT2 positive) for making tissue. Contractility was quantified using open source TFM software and calcium dynamics were measured using GCaMP6f intensity. At day 9, we observed a significant increase in contractility of isogenic control iPSC-μHM on stiffer substrates, the average traction from tissues formed on 5kPa, 15kPa and 30kPa substrates are 19.7μN, 28.7 μN and 36.7 μN. However, PKP2 -/- iPSC-μHM showed a non-significant traction force increase from 5kPa (23.6 μN) to 15kPa (26.9 μN) although prolonged calcium transients were found on stiffer substrates for both WTC and PKP2 -/- μHM, which may indicate calcium-contraction uncoupling of the PKP2 -/- μHM. Immunostaining shows a slightly increase in cell size towards stiffer substrates. These data suggest that mechanical load (e.g. afterload) may be necessary to reveal genotype-phenotype relationships within in vitro iPSC-based models.

The Pathophysiology of Aortic Cross-clamping and Unclamping. By Gelman S. ANesthesiology 1995; 82:1026–60. Reprinted with permission. Aortic cross-clamping (AoX) and unclamping are associated with severe hemodynamic disturbances in virtually all organs and systems. The main hemodynamic changes induced by AoX result from an increase in impedance to aortic flow, an increase in systemic vascular resistance and afterload, blood volume redistribution caused by collapse and constriction of venous vasculature distal to the aortic clamp, and a subsequent increase in preload. Preload may not increase if the aorta is clamped distal to the celiac artery; in that case, blood volume from distal venous vasculature may be redistributed to the splanchnic vasculature without associated increases in preload. Increases in afterload and preload demand an increase in contractility, which results in an autoregulatory increase in coronary blood flow. Without increases in coronary blood flow and myocardial contractility, decompensation may occur. Aortic cross-clamping is associated with the formation and release of many mediators which constitute a double-edged sword: they may mitigate or aggravate the harmful hemodynamic effects of AoX and unclamping. Injuries to the lungs, kidneys, spinal cord, or abdominal viscera are caused mainly by ischemia and reperfusion of organs distal to aortic cross-clamping. A clear understanding of the pathophysiologic mechanisms involved in these processes should help to promote rational, well-focused, and effective measures to prevent and treat homeostatic disturbances occurring during AoX and unclamping.

Tranilast is clinically indicated for the treatment of allergic disorders and is also a nonselective blocker of the transient receptor potential vanilloid 2 (TRPV2) channel. Previous studies have found that it has protective effects in various animal models of cardiac disease. Our laboratory has found that genetic deletion of TRPV2 results in a blunted hypertrophic response to increased afterload; thus, this study tested the hypothesis that tranilast through cardiomyocyte TRPV2 blockade can inhibit the hypertrophic response to pressure overload in vivo through transverse aortic constriction and ex vivo through isolated myocyte studies. The in vivo studies demonstrated that tranilast blunted the fibrotic response to increased afterload and, to a lesser extent, the hypertrophic response. After 4 weeks, this blunting was associated with improved cardiac function, although at 8 weeks, the cardiac function deteriorated similarly to the control group. Finally, the in vitro studies demonstrated that tranilast was not inhibiting these responses at the cardiomyocyte level. In conclusion, we demonstrated that tranilast blunting of the fibrotic and hypertrophic response occurs independently of cardiac TRPV2 channels and may be cardioprotective in the short term but not after prolonged administration.

PURPOSE OF REVIEW Pulmonary vascular disease (PVD) complicates the course of many cardiovascular, pulmonary and other systemic diseases in children. The physiological sequelae (pulmonary hypertension and elevated pulmonary vascular resistance) can overwhelm the right ventricle and lead to circulatory collapse. Despite the common end-point, the preceding pathophysiology is complex and variable and requires a tailored approach to diagnosis and management. In this article, we will review the most recent evidence and explore an approach to current controversies in the diagnosis and management of common or challenging patient subgroups. RECENT FINDINGS New methods of interpreting data derived from echocardiography and cardiac magnetic resonance imaging may assist in risk stratification and response to therapy. In specific patient subgroups, standard pharmacological therapies to reduce right ventricle afterload may be overutilized, ineffective and in some cases harmful. In the patient failing pharmacological therapy, new and novel techniques are being explored including temporary extracorporeal mechanical circulatory support, pumpless lung assist devices and novel surgical and catheterization procedures. SUMMARY PVD is a diverse entity, and attention to the underlying pathophysiology is essential for appropriate management. Despite significant advances in our understanding, the majority of data comes from small uncontrolled studies and must be interpreted with caution.

Mechanical circulatory support options remain limited for pediatric patients, especially neonates. The only U.S. Food and Drug Administration-approved pediatric device remains the Berlin Heart EXCOR, which unfortunately carries with it a 20-30% risk of neurologic complications, such as strokes. We demonstrate a new technique of direct echocardiographic color-Doppler imaging of the Berlin Heart valves to detect valve regurgitation. Increases in valve regurgitation could indicate issues with pump-valve thrombosis or increased afterload leading to valve insufficiency. Early recognition of valve thrombosis or insufficiency may reduce neurologic complications and lead to timely pump adjustments or replacement.

To investigate the usefulness of afterload-related cardiac performance (ACP) for assessing cardiac impairment and predicting prognosis in septic patients.Adult patients with sepsis in the intensive care unit were included. Cardiac output, cardiac index, cardiac power index, and ACP were calculated at the time of admission (D0) and 48-72 h after admission (D3). They were correlated with Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores, then the prognostic values were analyzed.A total of 41 patients with sepsis were selected. ACP showed a stronger negative correlation with Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores than cardiac output, cardiac index, and cardiac power index. ACP predicted 28-day mortality with an area under the curve of 0.775 and 0.976 on D0 and D3, respectively. In addition, most non-survivors had emergent cardiac impairment (ACP ≤ 80%) on D0, and cardiac function was deteriorated on D3. Survival analysis showed that the patients with a decreased ACP from D0 to D3 had the highest mortality. The decrease of ACP on D3 was an independent risk factor for mortality (hazard ratio, 11.89; P = .0028).ACP can be used to assess the severity of cardiac impairment in sepsis. Continued decline of ACP during the first 3 days strongly suggests a poor prognosis.

Introduction:The development and propagation of the aortic blood pressure wave remains poorly understood, despite its clear relevance to major organ blood flow and potential association with cardiovascular outcomes. The reservoir pressure model provides a unified description of the dual conduit and

Rationale: Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca 2+ occurs in pathological hypertrophy and is central to myocyte remodeling. STIM1 (stromal interaction molecule 1) regulates Ca 2+ signaling in many cell types by sensing low endoplasmic reticular Ca 2+ levels and then coupling to plasma membrane Orai channels to induce a Ca 2+ influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy, but its role in electrical and mechanical phenotypic alterations is not well understood. Objective: To define the contributions of STIM1-mediated Ca 2+ influx on electrical and mechanical properties of normal and diseased myocytes, and to determine whether Orai channels are obligatory partners for STIM1 in these processes using a clinically relevant large animal model of hypertrophy. Methods and Results: Cardiac hypertrophy was induced by slow progressive pressure overload in adult cats. Hypertrophied myocytes had increased STIM1 expression and activity, which correlated with altered Ca 2 + -handling and action potential (AP) prolongation. Exposure of hypertrophied myocytes to the Orai channel blocker BTP2 caused a reduction of AP duration and reduced diastolic Ca 2+ spark rate. BTP2 had no effect on normal myocytes. Forced expression of STIM1 in cultured adult feline ventricular myocytes increased diastolic spark rate and prolonged AP duration. STIM1 expression produced an increase in the amount of Ca 2+ stored within the sarcoplasmic reticulum and activated Ca 2+ /calmodulin-dependent protein kinase II. STIM1 expression also increased spark rates and induced spontaneous APs. STIM1 effects were eliminated by either BTP2 or by coexpression of a dominant negative Orai construct. Conclusions: STIM1 can associate with Orai in cardiac myocytes to produce a Ca 2+ influx pathway that can prolong the AP duration and load the sarcoplasmic reticulum and likely contributes to the altered electromechanical properties of the hypertrophied heart.

BACKGROUND: Pleural effusion is a common finding in critically ill patients and may contribute to circulatory instability and the need for inotropic support.OBJECTIVE: We hypothesised that dobutamine would affect the physiological determinants preload, afterload, contractility and changes of inferior vena cava characteristics during experimental pleural effusion.DESIGN: A randomised, controlled laboratory study.SETTING: Animal laboratory, conducted from March 2013 to May 2013.ANIMALS: Twenty-four Landrace and Yorkshire female piglets (21.3 ± 1.7 kg).INTERVENTION: Twenty piglets were included in the analyses. After inducing bilateral pleural effusion (30 ml kg), the piglets were block randomised to either incremental dobutamine infusion (n = 10) or control (n = 10).MAIN OUTCOME MEASURES: Ultrasonographic measures of left ventricular end-diastolic area, left ventricular afterload, left ventricular fractional area change and inferior vena cava diameter and distensibility were used to assess the basic physiological effect of incremental dobutamine administration during experimental pleural effusion.RESULTS: In the dobutamine group, preload, measured as left ventricular end-diastolic area, decreased from 11.3 ± 2.0 cm after creation of the pleural effusion to 8.1 ± 1.5 cm at a dobutamine infusion rate of 20 μg kg min (P CONCLUSION: In a porcine model of pleural effusion, dobutamine affected basic haemodynamic determinants substantially by decreasing left ventricular preload. Changes in central venous pressure and inferior vena cava characteristics were minimal, discouraging their use as indices of preload. This study underlines the significance of evaluating basic haemodynamic determinants to avoid inappropriate, potentially harmful treatment.

An accurate evaluation of cardiac function in patients with cirrhosis remains a challenge. We used robust echocardiographic indices to characterize left ventricular (LV) systolic function and its relationship to activation of the sympathetic nervous system and inflammation in 59 patients with cirrhosis and 59 age-matched controls. Additionally, in 11 patients we withdrew beta-blockers and diuretics and used phenylephrine and albumin infusion to evaluate the response to acute afterload and preload changes (interventional substudy). Measures of systolic LV function such as the ejection intraventricular pressure difference (EIVPD) and the systolic strain rate were higher in patients with cirrhosis than in controls (median [1st-3rd quartile], 4.0 [3.1-5.1] versus 2.9 [2.4-3.6] mm Hg and -1.3 [-1.6 to -1.1] versus -1.2 [-1.6 to -1.1)] s-1 , respectively; P Conclusion LV systolic function is enhanced in cirrhosis due to augmented adrenergic tone and modulated by treatment with beta-blockers; acute afterload stress induces a deeper impairment of systolic function in patients with more advanced degrees of vasodilatation and inflammation; these changes in LV function related to cirrhosis can be assessed using robust echocardiographic methods. (Hepatology 2017;65:2019-2030).

Hypertension (increased afterload) results in cardiomyocyte hypertrophy leading to left ventricular hypertrophy and subsequently, heart failure with preserved ejection fraction. This study was performed to test the hypothesis that transient receptor potential vanilloid 2 subtype (TRPV2) function regulates hypertrophy under increased afterload conditions.We used functional (pore specific) TRPV2 knockout mice to evaluate the effects of increased afterload-induced stretch on cardiac size and function via transverse aortic constriction (TAC) as well as hypertrophic stimuli including adrenergic and angiotensin stimulation via subcutaneous pumps. Wild-type animals served as control for all experiments. Expression and localization of TRPV2 was investigated in wild-type cardiac samples. Changes in cardiac function were measured in vivo via echocardiography and invasive catheterization. Molecular changes, including protein and real-time PCR markers of hypertrophy, were measured in addition to myocyte size.TRPV2 is significantly upregulated in wild-type mice after TAC, though not in response to beta-adrenergic or angiotensin stimulation. TAC-induced stretch stimulus caused an upregulation of TRPV2 in the sarcolemmal membrane. The absence of functional TRPV2 resulted in significantly reduced left ventricular hypertrophy after TAC, though not in response to beta-adrenergic or angiotensin stimulation. The decreased development of hypertrophy was not associated with significant deterioration of cardiac function.We conclude that TRPV2 function, as a stretch-activated channel, regulates the development of cardiomyocyte hypertrophy in response to increased afterload.

Acute right ventricular failure (RVF) is an increasing clinical problem and a life-threatening condition. Right ventricular assist devices represent a reasonable treatment option for patients with refractory RVF. We here present a novel percutaneously implantable device for right ventricular support. The PERKAT device is based on a nitinol stent cage, which is covered with valve-carrying foils. A flexible outlet trunk with a pigtail tip is connected to the distal part. The device is driven by an intra-aortic balloon pump (IABP) drive unit, which inflates/deflates a standard IABP-balloon placed within the stent cage. In-vitro evaluation was done in a liquid bath containing water or blood analog. The PERKAT device was tested in different afterload settings using two different IABP-balloons and varying inflation/deflation rates. We detected flow rates ranging from 1.97 to 3.93 L/min depending on the afterload setting, inflation/deflation rate, balloon size, and the medium used. Flow rates between water and blood analog were nearly comparable, and in the higher inflation/deflation rate settings slightly higher with water. Based on this promising in vitro data, the innovative percutaneously implantable PERKAT device has a potential to become a therapeutic option for patients with RVF refractory to medical treatment.

Lung disease in children often results in pulmonary hypertension and right heart failure. The availability of a pediatric artificial lung (PAL) would open new approaches to the management of these conditions by bridging to recovery in acute disease or transplantation in chronic disease. This study investigates the efficacy of a novel PAL in alleviating an animal model of pulmonary hypertension and increased right ventricle afterload. Five juvenile lambs (20-30 kg) underwent PAL implantation in a pulmonary artery to left atrium configuration. Induction of disease involved temporary, reversible occlusion of the right main pulmonary artery. Hemodynamics, pulmonary vascular input impedance, and right ventricle efficiency were measured under 1) baseline, 2) disease, and 3) disease + PAL conditions. The disease model altered hemodynamics variables in a manner consistent with pulmonary hypertension. Subsequent PAL attachment improved pulmonary artery pressure (p = 0.018), cardiac output (p = 0.050), pulmonary vascular input impedance (Z.0 p = 0.028; Z.1 p = 0.058), and right ventricle efficiency (p = 0.001). The PAL averaged resistance of 2.3 ± 0.8 mm Hg/L/min and blood flow of 1.3 ± 0.6 L/min. This novel low-resistance PAL can alleviate pulmonary hypertension in an acute animal model and demonstrates potential for use as a bridge to lung recovery or transplantation in pediatric patients with significant pulmonary hypertension refractory to medical therapies.

Article, see p 1463 Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, occurring in 1 in ≈2500 births and comprising ≈6% of all forms of critical congenital heart disease. Named for Etienne-Louis Arthur Fallot, who described the blue malady in 1888, the classic tetralogy consists of a ventricular septal defect, pulmonary outflow tract obstruction, aortic overriding, and right ventricular (RV) hypertrophy.1 After repair, RV dilation and dysfunction may be produced, in part, by ischemia-reperfusion injury, surgical scarring, RV volume overload from pulmonary regurgitation, and residual RV outflow obstruction. Pulmonary valve replacement has not been shown to improve RV function, arrhythmias, or other outcomes, despite improving pulmonary regurgitation and reducing RV volumes.2 In an attempt to halt or reverse the progression from compensated RV function to RV failure, treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors has crept into the practice of treatment of adults with TOF and other congenital heart defects associated with RV dysfunction. However, little is known about the RV molecular response to stress and its progression from a compensated state to failure.3 Standard left ventricular heart failure drugs (eg, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers [ARBs]) have shown mixed results in their ability to improve function or survival in patients with systemic RV failure in the setting of congenital heart disease,4–7 suggesting fundamental differences in the mechanisms of right versus left ventricular failure. Changes in shape, structure, and loading conditions between the right and left ventricles were once thought to be the primary reason for these differences.8 However, it is now appreciated that the right and left ventricle diverge early in development, before afterload differences become operative. The first and second heart fields lead …

Background: Veno-arterial extracorporeal life support (VA-ECLS) is widely used to treat refractory cardiogenic shock. However, increased left ventricular (LV) afterload in VA-ECLS can worsen pulmonary congestion and compromise myocardial recovery. Our objectives were to explore the efficacy, safety, and optimal timing of adjunctive LV venting strategies. Methods: A systematic search was performed on Medline, EMBASE, PubMed, CDSR, CCRCT, CINAHL, ClinicalTrials.Gov, and WHO ICTRP from inception until January 2019 for all relevant studies, including LV venting. Data were analyzed for mortality and weaning from VA-ECLS on the basis of timing of LV venting, along with adverse complications. Results: A total of 7995 patients were included from 62 observational studies, wherein 3458 patients had LV venting during VA-ECLS. LV venting significantly improved weaning from VA-ECLS (odds ratio, 0.62 [95% CI, 0.47–0.83]; P =0.001) and reduced short-term (30 day; risk ratio [RR], 0.86 [95% CI, 0.77–0.96]; P =0.008) but not in-hospital (RR, 0.92 [95% CI, 0.83–1.01] P =0.09) or long-term (6 months; RR, 0.96 [95% CI, 0.90–1.03]; P =0.27) mortality. Early (P =0.03) but not late (≥12 hours; RR, 0.99 [95% CI, 0.71–1.38]; P =0.93) LV venting significantly reduced short-term mortality. Patients with LV venting spent more time on VA-ECLS (3.6 versus 2.8 days, P P =0.013). With the exception of hemolysis (RR, 2.18 [95% CI, 1.58–3.01]; P Conclusions: LV venting, especially if done early (

Introduction: Anti-angiogenic tyrosine kinase inhibitors (TKIs) have efficacy against many solid neoplasms. Unfortunately, their on- and off-target effects frequently cause hypertension (HTN) and heart failure. Nearly all cases of cardiac dysfunction are associated with HTN, but the mechanism for this association is unclear. Aims: We have developed a novel in vitro 3D tissue engineering platform that uses a magnetically tunable elastomer to create dynamic alterations in afterload felt by cardiac microtissues. We are using this platform to examine the impact of increased in vitro afterload (a proxy for HTN) on cardiotoxicity of the TKI sunitinib. Hypotheses: 1) Increased afterload augments sunitinib-induced cardiotoxicity 2) Repeat exposures to sunitinib and increased afterload will further augment this toxicity. Methods: Human induced pluripotent stem cell cardiomyocytes (96%) and human cardiac fibroblasts (4%) from a commercial vendor (NCardia, Inc.) were allowed to self-assemble and form cardiac microtissues. Microtissues were exposed to sunitinib (0μM-10μM) at differing levels of afterload for a minimum of 8 hours. After a washout period, tissues were either harvested for analysis or exposures to sunitinib and afterload were repeated. Outcomes measured after each drug exposure included caspase activation, contractile ability, and force generation. Results: The applied magnetic field produced increases in afterload from 0.509±0.032 to 0.698±0.031 μN/μm. At 36 hours after exposure to supratherapeutic concentrations of sunitinib, recovery of contractile function as measured by force generation of microtissues was greater under soft afterload conditions compared with stiff afterload conditions (2.52μN soft vs 1.16μN stiff). Conclusion: Our platform creates dynamic alterations in afterload in engineered cardiac microtissues. Use of this versatile platform to examine the cardiotoxic effects of sunitinib has given promising initial results. Future studies examining removal/application of afterload, repeat exposures to sunitinib, and exposure to cardioprotective drugs will allow for insight into the mechanisms, treatment, and prevention of sunitinib-induced cardiotoxicity.

Background: Pulmonary arterial hypertension (PAH) is characterized by elevated mean PA pressures that increase right ventricular (RV) afterload, leading to RV failure. Whereas structural and mechanical decompensation in PAH are well established, the extent of electrophysiological (EP) remodeling and arrhythmia propensity are far less clear. This is, in large part, because PAH-related EP properties have been exclusively studied in the monocrotaline (MCT) model, which is confounded by major extra-pulmonary toxicities, including liver failure and direct myocardial damage. To address this knowledge gap, we performed a comprehensive evaluation of the EP substrate, including arrhythmia dynamics, in a new pure model of PAH. Methods: Sprague Dawley rats underwent surgical left pneumonectomy followed by injection of the VEGF inhibitor Sugen 5416 (S/P), or underwent no intervention (CTRL). 5 wks later, rats were euthanized for high-resolution optical action potential (AP) mapping studies in ex vivo perfused hearts. Results: 6/6 S/P vs 0/5 CTRL hearts were prone to pacing-induced VT (P Conclusion: In this pure model of PAH, we document highly selective RV-sided EP remodeling that facilitates the initiation of multi-wavelet micro-reentry underlying VT. The S/P model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extra-pulmonary toxicity.

Background: Early right heart failure (RHF) occurs commonly in left ventricular assist device (LVAD) recipients, and increased right ventricular (RV) afterload may contribute. Selective pulmonary vasodilators, like phosphodiesterase-5 inhibitors (PDE5i), are used off-label to reduce RV afterload before LVAD implantation, but the association between preoperative PDE5i use and early RHF after LVAD is unknown. Methods and Results: We analyzed adult patients from the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) who received a continuous flow LVAD after 2012. Patients on PDE5i were propensity-matched 1:1 to controls. The primary outcome was the incidence of severe early RHF, defined as the composite of death from RHF within 30 days, need for RV assist device support within 30 days, or use of inotropes beyond 14 days. Of 11 544 continuous flow LVAD recipients, 1199 (10.4%) received preoperative PDE5i. Compared to controls, patients on PDE5i had higher pulmonary artery systolic pressure (53.4 mm Hg versus 49.5 mm Hg) and pulmonary vascular resistance (2.6 WU versus 2.3 WU; P Conclusions: Patients treated with preoperative PDE5i had markers of increased RV afterload and HF severity compared to unmatched controls. Even after propensity matching, patients receiving preimplant PDE5i therapy had higher rates of post-LVAD RHF.

Background Patients with pulmonary hypertension caused by chronic lung disease (Group 3 PH ) have disproportionate right ventricle ( RV ) dysfunction, but the correlates and clinical implications of RV dysfunction in Group 3 PH are not well defined. Methods and Results We performed a cohort study of 147 Group 3 PH patients evaluated at the University of Minnesota. RV systolic function was quantified using right ventricular fractional area change ( RVFAC ) and + dP /dt max /instantaneous pressure. Tau and RV diastolic stiffness characterized RV diastolic function. Multivariate linear regression was used to define correlates of RVFAC . Kaplan‐Meier and Cox proportional hazards analyses were used to examine freedom from heart failure hospitalization and death. Positive correlates of RVFAC on univariate analysis were pulmonary arterial compliance, cardiac index, and left ventricular diastolic dimension. Conversely, male sex, N‐terminal pro‐brain natriuretic peptide, heart rate, right atrial enlargement, mean pulmonary arterial pressure, and pulmonary vascular resistance were negative correlates. Male sex was the strongest predictor of lower RVFAC , after adjusting for pulmonary vascular resistance and pulmonary arterial compliance. When comparing sexes, males had lower RVFAC (26% versus 31%, P =0.03) both overall and for any given mean pulmonary arterial pressure and pulmonary vascular resistance value. Males exhibited a reduction in + dP /dt max /instantaneous pressure as pulmonary vascular resistance increased, whereas females did not. There were no sex differences in RV diastolic function. RV dysfunction ( RVFAC CI : 1.04–3.10, P =0.035). Conclusions Male sex is associated with RV dysfunction in Group 3 PH , even after adjusting for RV afterload. RV dysfunction ( RVFAC PH patients at risk for poor outcomes.

Rationale Marfan syndrome (MFS) has been defined as a genetic disorder that affects various systems such as the musculoskeletal, orbital, and cardiovascular systems. Neonatal MFS is considered rare and the most severe form of MFS is characterized by rapidly progressive atrioventricular valve dysfunction, often leading to death during early childhood due to congestive heart failure. Patient concerns A newborn with neonatal MFS and severe cardiac involvement. He presented various severe clinical features such as arachnodactyly, camptodactyly, elbow and knee joint contracture, senile facial appearance, and deep settling with down-slanting palpebral fissure, hypoplastic ear cartilage, sagging mouth, brachycephaly, and ectopia lentis. Diagnosis Genetic analysis revealed a novel mutation at nucleotide 3964 (c.3964 + 1 G > T) in intron 32 of the fibrillin-1 gene. This mutation is identified to be in the so-called neonatal region of fibrillin-1 exon 24 to 32, as reported previously. Interventions The patient was managed medically for improving the low cardiac output according to severe mitral regurgitation and aortic regurgitation. Afterload reduction, full sedation, and use of diuretic were attempted to improve the oliguria and heart failure. Outcomes Despite the medical management, aortic regurgitation, mitral regurgitation, pulmonary hypertension, and cardiac contractility got worse. Surgical treatment is essential to prolong the patient's life, however, considerations for the grave progression of the disease make families decide to continue palliative care instead of surgical treatment. A few months after birth, he presented with rapidly progressive aortic regurgitation, mitral regurgitation, and congestive heart failure leading to death. Conclusions This review demonstrated the prominent characteristics of neonatal MFS mutations, it would be helpful for the recognition of novel neonatal MFS variants and valuable for the understanding of the genotype-phenotype correlations and using the plans for managements and counseling in neonatal MFS.

Symptomatic carotid artery disease stenosis warrants open surgical carotid endarterectomy (CEA). However, patients with continuous-flow left ventricular assist devices (CF-LVADs) present unique challenges when vasopressors and volume are used to maintain cerebral perfusion pressure after carotid cross-clamping. This report describes patients with CF-LVADs who underwent CEA. We identify how preload, contractility, afterload, pump speed, mean arterial pressure, and anticoagulation should be addressed to maintain CF-LVAD outflow and cerebral perfusion during the procedure. Anesthesiologists can combine an understanding of continuous-flow physiology with invasive monitors to optimize cardiac output and cerebral blood flow during CEA procedures.

Peripartum/postpartum cardiomyopathy (PPCM) is a rare condition associated with pregnancy in which there is left ventricular (LV) dysfunction resulting in symptoms of heart failure (). This occurs in previously healthy women and is seen in the last month of pregnancy or during the first 5 months postpartum (). Incidence ranges from 1 in 1,300 to 1 in 15,000 pregnancies in the United States (). A case study is presented of a patient with severe impairment of LV function seen in the emergency department (ED). The ED is a common location for initial presentation; therefore, the ED provider should be cognizant of key features of PPCM. The differential diagnosis and medical management of PPCM are discussed. Emergency department management should focus on 3 key elements: an increase in inotropy and a reduction in preload and afterload. Differences between postpartum and peripartum states are outlined.

Purpose of review The right ventricle (RV) plays a pivotal role during respiratory failure because of its high sensitivity to small loading changes during inspiration. Both RVs, preload and afterload, are altered during inspiration, either in spontaneous breathing or during mechanical ventilation. Some clinical situations especially affect RV load during inspiration, for example acute asthma and acute respiratory distress syndrome. The aim of this review is to explain and to summarize the different mechanisms leading to RV failure in these situations. Recent findings Research has recently reemphasized the importance to well known physiology of the venous return which is a contributor of RV preload. Authors recently focused on the mean systemic filling pressure which is one of the determinants of venous return. Venous return may change in opposite direction according to the type of ventilation (spontaneous or assisted). Recent works have also demonstrated the crucial impact of lung inflation and driving pressure on RV afterload, and have confirmed the deleterious effect of severe RV failure, described as acute cor pulmonale. In most situations of RV overload induced by inspiration, significant pulse pressure variations are observed, either called 'pulsus paradoxus' in spontaneously breathing patients or 'reverse pulsus paradoxus' in mechanically ventilated patients. Summary RV is very sensitive to abnormal inspiration, which is always responsible for an increase in its afterload. Pulse pressure variations, central venous pressure and especially echocardiography may monitor RV function in abnormal clinical situations. The pulmonary artery catheter was also proposed although now less used.

See related article, pp 633–640 Afterload is an important determinant of myocardial contraction and relaxation. Afterload dependency of relaxation has been demonstrated in the intact left ventricle (LV).1–4 Experimental animal2,3 and human4 studies demonstrate that the effects of afterload depend on its timing, with late systolic load inducing more profound impairments in LV relaxation, compared with early systolic load. In this issue of Hypertension , Gu et al5 report on a study that provides novel insights into diastolic–systolic coupling and helps us integrate and reconcile several previous findings. Although the terms myocardial afterload and ventricular afterload are often used interchangeably, it is important to recognize that the relationship between LV and myocardial afterload is markedly influenced by the time-varying LV geometry during systole, which in turn affects the myocardial wall stress (MWS) for any given LV chamber pressure. LV afterload is the hydraulic load imposed by the entire systemic circulation (aortic input impedance), which depends on the pressure required to generate flow (ejection) into the proximal aorta. In contrast, myocardial afterload is determined by the MWS required to generate fiber shortening. In line with Laplace's law of the heart, for any given LV pressure, lower MWS occurs as the ratio of LV chamber volume/LV wall volume decreases. When the MWS and LV geometry are such that LV pressure exceeds diastolic aortic pressure, LV ejection starts. Throughout ejection, the time-varying MWS (and fiber shortening) is determined by complex interactions between myocardial contractile elements, the instantaneous LV geometry and the time-varying hydraulic load imposed by the arterial tree.6 All key correlates of MWS (LV wall thickness, cavity size, and pressure, which for any given flow ejected, depends on the aortic input impedance) exhibit marked variations during ejection. Therefore, time-resolving MWS during ejection (rather …

The long-standing emphasis on ejection fraction (EF) is misguided. EF is erroneously assumed to be a measure of myocardial contractility. Of greater concern is the widespread classification of patients with heart failure (HF) based on whether EF is preserved (HFpEF) or reduced (HFrEF). In fact, EF does not provide any specific information on causation or underlying mechanisms. We believe that a revision or abandonment of this nomenclature is warranted, and categorization of patients with HF should more strongly emphasize underlying pathophysiology EF is a characterization of ventricular ejection: the stroke volume (SV) expressed as a fraction of end-diastolic volume (EDV). Knowledge of EDV is essential to translate SV expressed as a percentage (EF) into absolute SV, a quantity of more physiological and clinical significance, hence our admonition that no one should ever mention EF without, in the same breath, diastolic volume. In the 1950s, physiologists used the instantaneous change in SV/EDV (ie, the change in EF) as a measure of change in contractility under conditions of constant load. Over time we have largely forgotten that (1) EF is influenced by both preload (diastolic) and afterload (systolic) and cannot be interpreted as an index of contractility without knowledge of left ventricular (LV) loads; and (2) structural changes leading to increases or decreases in LVEDV will strongly influence the EF at a given level of contractility and SV. So EF is twice removed from an …

See Article by Lin et al Type 2 diabetes mellitus (T2DM) and obesity-induced cardiac remodeling occur independently of the presence of coronary disease, hypertension, or valvular disease.1 Importantly, both conditions are associated with an increased risk for developing heart failure and other adverse clinical outcomes,2,3 leading to substantial morbidity, mortality, and costs to the healthcare system.4 Furthermore, epidemiological studies have shown that individuals with an hemoglobin A1c in the range of 6.0% to 6.4% have a high risk for the future development of T2DM, supporting the use of this range to define pre–diabetes mellitus.5 Multiple pathophysiological processes contribute to the myocardial impairment seen in diabetes mellitus and pre–diabetes mellitus, including, but not limited to, hyperglycemia and hyperinsulinemia states, the increased uptake of free fatty acids into cardiomyocytes along with impaired glucose metabolism, myocardial triglyceride accumulation, and oxidative stress.1,2,4 These multifactorial metabolic, proinflammatory, and neurohormonal alterations collectively induce the process of pathological cardiac remodeling, which may manifest as different cardiac phenotypes.1 In patients with T2DM, cardiac remodeling such as the hypertrophic response may occur as a result of, but also independent of, the degree of left ventricular (LV) afterload. Potential pathogenesis include excess epicardial fat, along with the dysregulation of myocardial substrate oxidation leading to a reliance on free fatty acid oxidation.1 Mechanisms of remodeling in T2DM also occur in response to hyperinsulinemia and insulin resistance (eg, growth factor upregulation, such as Akt), along with altered calcium handling and myocardial apoptosis, which remain one of several mechanisms that may ultimately lead to diffuse and focal fibrosis.6 Importantly, even in …

Introduction: In animal models of afterload stress, eicosapentaenoic acid (EPA) prevents interstitial myocardial fibrosis and preserves diastolic dysfunction. Hypothesis: We hypothesized that EPA is similarly protective in humans. Methods: In the Multi-Ethnic Study of Atherosclerosis, we tested for an effect of plasma phospholipid EPA percent of total fatty acids on primary heart failure incidence across heart failure types including, heart failure with reduced ejection fraction (HFrEF; Results: A total of 6566 subjects had measured baseline EPA, including 1797 black, 794 Chinese, 1444 Hispanic, and 2531 white participants; 52% were female. Over a median follow-up of 13.0 years, 293 heart failure events occurred in subjects with measured EPA: 129 had HFrEF, 110 had HFpEF, and the remaining 54 had unknown ejection fraction status. Mean EPA in HF-free subjects was 0.77% (0.76 - 0.79), and was lower in heart failure subjects 0.70% (0.65 - 0.74), p=0.002. EPA was associated with lower incidence of HF, having a hazard ratio of 0.73 (0.60 - 0.89) per unit change in percentage of total fatty acids, p=0.001. Adjusting for age, sex, race, BMI, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, and albuminuria did not change this relationship. Sensitivity analysis showed no dependence on heart failure type. Adjusting for other fatty acids with clustering did not change hazards. In animals, >2.5% EPA is required for prevention of HF, between 2.5% and 1% is marginal, and Conclusion: High abundance of EPA is robustly associated with reduced risk for heart failure, independent of established risk factors and regardless of ejection fraction status.

BACKGROUND Stiffening of large arteries can result in changes of cardiac structure and function by increasing afterload to the left ventricle. Calcification has been proposed as a mechanism underlying progression of arterial stiffening. The aim of the current study was to investigate the relationship between aortic calcification, arterial stiffening, left ventricular hypertrophy, and diastolic dysfunction. METHODS One hundred and sixty-four hypertensive elderly (≥65 years old) male patients with normal left ventricular systolic function (left ventricular ejection fraction ≥55%) underwent transthoracic echocardiography, brachial-ankle pulse wave velocity (baPWV), and noncontrast computed tomography. Coronary artery calcium score and aorta calcium score (ACS) were measured on noncontrast computed tomography using the volume method. Left ventricular dimensions, mitral inflow velocities, and early mitral annular (E') velocity were measured using transthoracic echocardiography. The left ventricular mass index (LVMI) was calculated. RESULTS The logACS was associated with mean baPWV (r = 0.387, P = 0.001), LVMI (r = 0.241, P