Hyperlactataemia is a marker of reduced exercise capacity in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non-cardiac dyspnoea (NCD), and healthy volunteers. METHODS AND RESULTS: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom-limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31-73), 150 W (125-175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05-0.11), 0.06 mmol/L/W (0.05-0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03-0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m2 (3.7-5.5) in HFpEF, 5.2 L/min/m2 (4.3-6.2; P < 0.001) in NCD, and 9.1 L/min/m2 (8.0-9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175-1986) vs. 1758 mL/min (1361-2282; P = 0.024) in NCD and 3117 mL/min (2667-3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). CONCLUSIONS: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies.

The Impact of Diabetes on Haemodynamic and Cardiometabolic Responses in Heart Failure With Preserved Ejection Fraction.

AIMS: Heart failure with preserved ejection (HFpEF) and diabetes mellitus (DM) commonly co-exist. However, it is unclear if DM modifies the haemodynamic and cardiometabolic phenotype in patients with HFpEF. We aimed to interrogate the haemodynamic and cardiometabolic effects of DM in HFpEF. METHODS: We compared the haemodynamic and metabolic profiles of non-DM patients and patients with DM-HFpEF at rest and during exercise using right heart catheterisation and mixed venous blood gas analysis. RESULTS: Of 181 patients with HFpEF, 37 (20%) had DM. Patients with DM displayed a more adverse exercise haemodynamic response vs HFpEF alone (mean pulmonary arterial pressure: 47 mmHg [interquartile range {IQR} 42-55] vs 42 [38-47], p<0.001; workload indexed pulmonary capillary wedge pressure indexed: 0.80 mmHg/W [0.44-1.23] vs 0.57 [0.43-1.01], p=0.047). HFpEF-DM patients had a lower mixed venous oxygen saturation at rest (70% [IQR 66-73] vs 72 [69-75], p=0.003) and were unable to enhance O2 extraction to the same extent (Δ-28% [-33 to -15] vs -29 [-36 to -21], p=0.029), this occurred at a 22% lower median workload. Resting mixed venous lactate levels were higher in those with DM (1.5 mmol/L [IQR 1.1-1.9] vs 1 [0.9-1.3], p<0.001), and during exercise indexed to workload (0.09 mmol/L/W [0.06-0.13] vs 0.08 [0.05-0.11], p=0.018). CONCLUSION: Concurrent diabetes and HFpEF was associated with greater metabolic responses at rest, with enhanced wedge driven pulmonary hypertension and relative lactataemia during exercise without appropriate augmentation of oxygen consumption.

Atrial Fibrillation Ablation for Heart Failure With Preserved Ejection Fraction: A Randomized Controlled Trial.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) frequently develop atrial fibrillation (AF). There are no randomized trials examining the effects of AF ablation on HFpEF outcomes. OBJECTIVES: The aim of this study is to compare the effects of AF ablation vs usual medical therapy on markers of HFpEF severity, including exercise hemodynamics, natriuretic peptide levels, and patient symptoms. METHODS: Patients with concomitant AF and HFpEF underwent exercise right heart catheterization and cardiopulmonary exercise testing. HFpEF was confirmed with pulmonary capillary wedge pressure (PCWP) of 15 mm Hg at rest or ≥25 mm Hg on exercise. Patients were randomized to AF ablation vs medical therapy, with investigations repeated at 6 months. The primary outcome was change in peak exercise PCWP on follow-up. RESULTS: A total of 31 patients (mean age: 66.1 years; 51.6% females, 80.6% persistent AF) were randomized to AF ablation (n = 16) vs medical therapy (n = 15). Baseline characteristics were comparable across both groups. At 6 months, ablation reduced the primary outcome of peak PCWP from baseline (30.4 ± 4.2 to 25.4 ± 4.5 mm Hg; P < 0.01). Improvements were also seen in peak relative VO2 (20.2 ± 5.9 to 23.1 ± 7.2 mL/kg/min; P < 0.01), N-terminal pro-B-type natriuretic peptide levels (794 ± 698 to 141 ± 60 ng/L; P = 0.04), and MLHF (Minnesota Living with Heart Failure) score (51 ± -21.9 to 16.6 ± 17.5; P < 0.01). No differences were detected in the medical arm. Following ablation, 50% no longer met exercise right heart catheterization-based criteria for HFpEF vs 7% in the medical arm (P = 0.02). CONCLUSIONS: AF ablation improves invasive exercise hemodynamic parameters, exercise capacity, and quality of life in patients with concomitant AF and HFpEF.

Haemodynamic and metabolic adaptations in coronary microvascular disease.

OBJECTIVE: We aimed to evaluate the microcirculatory resistance (MR) and myocardial metabolic adaptations at rest and in response to increased cardiac workload in patients with suspected coronary microvascular dysfunction (CMD). METHODS: Patients with objective ischaemia and/or myocardial injury and non-obstructive coronary artery disease underwent thermodilution-derived microcirculatory assessment and transcardiac blood sampling during graded exercise with adenosine-mediated hyperaemia. We measured MR at rest and following supine cycle ergometry. Patients (n=24) were stratified by the resting index of MR (IMR) into normal-IMR (IMR<22U, n=12) and high-IMR groups (IMR≥22U, n=12). RESULTS: The mean age was 57 years; 67% were males and 38% had hypertension. The normal-IMR group had increased IMR response to exercise (16±5 vs 23±12U, p=0.03) compared with the high-IMR group, who had persistently elevated IMR at rest and following exercise (38±19 vs 33±15U, p=0.39) despite similar exercise duration and rate-pressure product between the groups, both p>0.05. The normal-IMR group had augmented oxygen extraction ratio following exercise (53±18 vs 64±11%, p=0.03) compared with the high-IMR group (65±14 vs 59±11%, p=0.26). The postexercise lactate uptake was greater in the high-IMR (0.04±0.05 vs 0.11±0.07 mmol/L, p=0.004) compared with normal-IMR group (0.08±0.06 vs 0.09±0.09 mmol/L, p=0.67). The high-IMR group demonstrated greater troponin release following exercise compared with the normal-IMR group (0.13±0.12 vs 0.001±0.05 ng/L, p=0.03). CONCLUSIONS: Patients with suspected CMD appear to have distinctive microcirculatory resistive and myocardial metabolic profiles at rest and in response to exercise. These differences in phenotypes may permit individualised therapies targeting microvascular responsiveness (normal-IMR group) and/or myocardial metabolic adaptations (normal-IMR and high-IMR groups).

The Gut Microbiome of Heart Failure With Preserved Ejection Fraction.

Background Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial-derived metabolites such as short-chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors. Methods and Results We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α-diversity (eg, number of microbes) and ß-diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF (P=0.001). We did not find an association between ß-diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so (P=0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short-chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day; P=0.016). Conclusions We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.

Prone and Supine 12-Lead ECG Comparisons: Implications for Cardiac Assessment During Prone Ventilation for COVID-19.

OBJECTIVES: This study sought to describe expected changes in a mirror-image prone electrocardiogram (ECG) compared with normal supine, including a range of cardiac conditions. BACKGROUND: Unwell COVID-19 patients are at risk of cardiac complications. Prone ventilation is recommended but poses practical challenges to acquisition of a 12-lead ECG. The effects of prone positioning on the ECG remain unknown. METHODS: 100 patients each underwent 3 ECGs: standard supine front (SF); prone position with precordial leads attached to front (PF); and prone with precordial leads attached to back in a mirror image to front (PB). RESULTS: Prone positioning was associated with QTc prolongation (PF 437 ± 32 ms vs. SF 432 ± 31 ms; p < 0.01; PB 436 ± 34 ms vs. SF 432 ± 31 ms; p = 0.02). In leads V1 to V3 on PB ECG, a qR morphology was present in 90% and changes in T-wave polarity in 84%. In patients with anterior ischemia, ST-segment changes in V1 to V3 on supine ECG were no longer visible on PB in 100% and replaced by an R-wave in V1. Bundle branch block (BBB) remained detectable in 100% on PB, with left BBB appearing as right BBB on PB in 71% and QRS narrowing with qR in V1 for right BBB. ST-segment/T-wave changes in limb leads and arrhythmia detection were largely unaffected in PB. CONCLUSIONS: As expected, the PB ECG is unreliable for the detection of anterior myocardial injury but remains useful for ST-segment/T-wave abnormalities in limb leads, BBB detection, and rhythm monitoring. The prone ECG is a useful screening tool with diagnostic utility in COVID-19 patients who require prone ventilation.

A prospective STudy using invAsive haemodynamic measurements foLLowing catheter ablation for AF and early HFpEF: STALL AF-HFpEF.

AIMS: The impact of atrial fibrillation (AF) ablation in early heart failure with preserved ejection fraction (HFpEF) is unknown. Our aim was to determine the impact of AF ablation on symptoms and exercise haemodynamic parameters of early HFpEF. METHODS AND RESULTS: Symptomatic AF patients referred for index AF ablation with ejection fraction ≥50% underwent baseline quality of life questionnaires, echocardiography, cardiac magnetic resonance imaging, exercise right heart catheterisation (exRHC), and brain natriuretic peptide (BNP) testing. HFpEF was defined by resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or peak exercise PCWP ≥25 mmHg. Patients with HFpEF were offered AF ablation and follow-up exRHC ≥6 months post-ablation. Of 54 patients undergoing baseline evaluation, 35 (65%) had HFpEF identified by exRHC. HFpEF patients were older (64 ± 10 vs. 54 ± 13 years, P < 0.01), and more frequently female (54% vs. 16%, P < 0.01), hypertensive (63% vs. 16%, P < 0.001), and suffering persistent AF (66% vs. 11%, P < 0.001), compared to those without HFpEF. Twenty HFpEF patients underwent AF ablation and follow-up exRHC 12 ± 6 months post-ablation. Nine (45%) patients no longer fulfilled exRHC criteria for HFpEF at follow-up. Patients remaining arrhythmia free (n = 9, 45%) showed significant improvements in peak exercise PCWP (29 ± 4 to 23 ± 2 mmHg, P < 0.01) and Minnesota Living with Heart Failure (MLHF) score (55 ± 30 to 22 ± 30, P < 0.01) while the remainder did not (PCWP 31 ± 5 to 30.0 ± 4 mmHg, P = NS; MLHF score 55 ± 23 to 25 ± 20, P = NS). CONCLUSION: Heart failure with preserved ejection fraction frequently coexists in patients with symptomatic AF and preserved ejection fraction. Restoration and maintenance of sinus rhythm in patients with comorbid AF and HFpEF improves haemodynamic parameters, BNP and symptoms associated with HFpEF.

The effect of parity on exercise physiology in women with heart failure with preserved ejection fraction.

AIMS: Women are overrepresented amongst patients with heart failure with preserved ejection fraction (HFpEF); however, the underpinning mechanism for this asymmetric distribution is unclear. Pregnancy represents a potential gender-specific risk factor for HFpEF. It leads to significant physiological adaption, and increasing parity has been associated with some cardiovascular risk. We sought to examine the relationship between prior parity with the rest and exercise haemodynamic and echocardiographic profile of women with HFpEF. METHODS AND RESULTS: Patients referred for assessment of exertional dyspnoea and confirmed to have a haemodynamic and clinical profile consistent with HFpEF were included. Detailed evaluation consisted of rest and exercise right heart catheterization and echocardiography. A socio-economic and obstetric history was also documented. Fifty-eight women were assessed and categorized as having either 0-2 births or ≥3 births, dividing the cohort equally. Women with ≥3 births achieved a lower symptom-limited workload than those with 0-2 births [38 (24-51) vs. 46 (31-68) W, P = 0.04]. Women with ≥3 births had a greater rise in pulmonary capillary wedge pressure indexed to workload with exercise [0.5 (0.3-0.8) vs. 0.3 (0.2-0.5) mmHg/W, P = 0.03], paralleled by a greater rise in right atrial pressure [10 (8-12) vs. 7 (3-11), P = 0.01]. Pulmonary vascular resistance was also higher in women with ≥3 births [1.9 (1.6-2.4) vs. 1.6 (1.4-1.9) mmHg/L/min rest, P = 0.046, and 1.9 (2.4-2.4) vs. 1.4 (1-1.8) mmHg/L/min exercise, P = 0.024]. Left ventricular ejection fraction was lower at rest [60 (57-61) vs. 63 (60-66), P = 0.008] and during exercise [65 (62-67) vs. 68 (66-70), P = 0.038] in women with higher parity. CONCLUSIONS: Higher parity is associated with greater impairments in multiple physiologic parameters of HFpEF severity in women, including diastolic reserve, pulmonary vascular resistance, and systolic dysfunction.

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

BACKGROUND: Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear. METHODS: We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week "blanking period") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up. RESULTS: Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01). CONCLUSIONS: Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.).

Sex Differences in Heart Failure With Preserved Ejection Fraction Pathophysiology: A Detailed Invasive Hemodynamic and Echocardiographic Analysis.

OBJECTIVES: This study sought to identify sex differences in central and peripheral factors that contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) by using complementary invasive hemodynamic and echocardiographic approaches. BACKGROUND: Women are overrepresented among patients with HFpEF, and there are established sex differences in myocardial structure and function. Exercise intolerance is a fundamental feature of HFpEF; however, sex differences in the physiological determinants of exercise capacity in HFpEF are yet to be established. METHODS: Patients with exertional intolerance with confirmed HFpEF were included in this study. Evaluation of the subjects included resting and exercise hemodynamics, echocardiography, and mixed venous blood gas sampling. RESULTS: A total of 161 subjects included 114 females (71%). Compared to males, females had a higher pulmonary capillary wedge pressure (PCWP) indexed to peak exercise workload (0.8 [0.5 to 1.2] mm Hg/W vs. 0.6 [0.4 to 1] mm Hg/W, respectively; p = 0.001) and lower systemic (1.1 [0.9 to 1.5] ml/mm Hg vs. 1 [0.7 to 1.2] ml/mm Hg, respectively; p = 0.019) and pulmonary (2.9 [2.2 to 4.2] ml/mm Hg vs. 2.4 [1.9 to 3] ml/mm Hg, respectively; p = 0.032) arterial compliance at exercise. Mixed venous blood gas analysis demonstrated a greater rise in lactate indexed to peak workload (0.05 [0.04 to 0.09] mmol/l/W vs. 0.04 [0.03 to 0.06] mmol/l/W, respectively; p = 0.007) in women compared to men. Women had higher mitral inflow velocity to diastolic mitral annular velocity at early filling (E/e') ratios at rest and peak exercise, along with a higher ejection fraction and smaller ventricular dimensions. CONCLUSIONS: Women with HFpEF demonstrate poorer diastolic reserve with higher echocardiographic and invasive measurements of left ventricular filling pressures at exercise, accompanied by lower systemic and pulmonary arterial compliance and poorer peripheral oxygen kinetics.

Impaired left atrial strain predicts abnormal exercise haemodynamics in heart failure with preserved ejection fraction.

BACKGROUND: Elevated left atrial (LA) pressure, particularly during exercise, is associated with symptomatic status and survival in patients with heart failure with preserved ejection fraction (HFpEF). We aimed to characterize the contribution of abnormal LA mechanical properties to exercise haemodynamics in HFpEF. METHODS AND RESULTS: Simultaneous echocardiography and right heart catheterization were performed in 71 subjects with left ventricular ejection fraction ≥ 50% referred for assessment of exertional dyspnoea. According to haemodynamic evaluation, 49 patients were diagnosed with HFpEF [pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg at rest and/or ≥ 25 mmHg at maximal exertion] and 22 as non-cardiac dyspnoea. Apical two- and four-chamber views were used for blinded two-dimensional LA speckle tracking analysis. HFpEF was characterized by impaired LA reservoir (24.3 ± 9.6 vs. 36.7 ± 8.4%, P < 0.001) and pump strain (-11.5 ± 3.2 vs. -17.0 ± 3.4%, P < 0.001); and increased stiffness (0.8 ± 0.7 vs. 0.2 ± 0.1 mmHg/%, P < 0.001). Reservoir and pump strain correlated with exercise PCWP (r = -0.64 and r = 0.72, P < 0.001), and remained independent predictors after adjusting for left ventricular mass index, LA volume index, mean E/e' and systolic blood pressure (B = -0.66 and B = 1.41, respectively, P < 0.001). LA stiffness was strongly related to B-type natriuretic peptide levels (r = 0.73, P < 0.001; B = 173.0, P < 0.001). Reservoir strain at cut-off of ≤ 33% predicted invasively verified HFpEF diagnosis with 88% sensitivity and 77% specificity, providing a net reclassification improvement of 12% in comparison to the 2016 European Society of Cardiology criteria for non-invasive diagnosis of HFpEF. CONCLUSIONS: Impaired LA reservoir and pump function and increased stiffness are associated with abnormal exercise haemodynamics in HFpEF. These markers provide significant HFpEF diagnostic utility in elderly ambulatory patients with dyspnoea.

Mechanisms responsible for increased circulating levels of galectin-3 in cardiomyopathy and heart failure.

Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM; fibrotic cardiomyopathy, ischemia-reperfusion, I/R; treatment with ß-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and diverse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced ß-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism.

Hemodynamic Profile of Patients With Heart Failure and Preserved Ejection Fraction Vary by Age.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit a range of cardiovascular phenotypic profiles modified by several common comorbidities. In particular, patients with HFpEF tend to be older; however, it is unclear whether the effects of cardiovascular aging per se modify the expression of HFpEF. We therefore sought to investigate the interaction between age and physiologic profile in patients with HFpEF. METHODS AND RESULTS: We assessed the hemodynamic and metabolic profile of 40 patients with HFpEF. Patients underwent right heart catheterization at rest and during supine cycle ergometry, and were segregated into 2 groups by the median age of the cohort. Older patients with HFpEF demonstrated reduced resting cardiac output (4.8±1.2 L/min versus 5.7±1.1 L/min). With exercise, older patients demonstrated a marked rise in arteriovenous oxygen content difference (10.8±1.8 versus 7.9±2.4 mL, P≤0.001), driven by enhanced oxygen extraction. There was no significant difference in peak pulmonary capillary wedge pressure (30±7 mm Hg versus 27±6, P=0.135), including when indexed to workload (pulmonary capillary wedge pressure/W, 0.88 mm Hg/W versus 0.92; P=0.83). CONCLUSIONS: Older patients with HFpEF display a different physiological phenotype compared with younger patients, with enhanced oxygen extraction and lower increment in cardiac output to increase oxygen consumption from rest to peak supine exercise. This finding highlights the importance in considering age when considering therapeutic options in patients with HFpEF.

Exercise Hemodynamics as a Predictor of Myocardial Recovery in LVAD Patients.

Mechanical circulatory support using left ventricular assist devices (LVADs) has been demonstrated to improve survival in patients with advanced heart failure. Left ventricular assist device therapy also promotes reverse ventricular remodeling, which in some cases has led to sufficient myocardial recovery to allow LVAD removal. Identification of suitable patients for LVAD removal however remains challenging. We investigated the hypothesis that invasive assessment of exercise hemodynamics may provide additional information in relation to the assessment of contractile reserve in potential candidates for LVAD explant.

The transcardiac gradient of cardio-microRNAs in the failing heart.

AIMS: Differential microRNA expression in peripheral blood has been observed in patients with heart failure, suggesting their value as potential biomarkers and likely contributors to disease mechanisms. In the present study, we aimed to evaluate the transcardiac gradient of 84 cardio-microRNAs in healthy and failing hearts to determine which microRNAs are released or absorbed by the myocardium in heart failure. METHODS AND RESULTS: Eight healthy volunteers and nine patients with congestive heart failure were included. Arterial and coronary sinus blood samples were collected, and microRNAs were extracted. The expression of microRNAs was analysed using real-time PCR by the miScript miRNA PCR Array Human Cardiovascular Disease. In coronary sinus samples, the microRNAs miR-16-5p, miR-27a-3p, miR-27b-3p, miR-29b-3p, miR-29c-3p, miR-30e-5p, miR-92a-3p, miR-125b-5p, miR-140-5p, miR-195-5p, miR-424-5p, and miR-451a were significantly down-regulated, and let-7a-5p, let-7c-5p, let-7e-5p, miR-23b-3p, miR-107, miR-155-5p, miR-181a-5p, miR-181b-5p and miR-320a were up-regulated in heart failure. Left ventricular filling pressure was negatively correlated with miR-195, miR-16, miR-29b-3p, miR-29c-3p, miR-451a, and miR-92a-3p. The failing heart released let-7b-5p, let-7c-5p, let-7e-5p, miR-122-5p, and miR-21-5p, and absorbed miR-16-5p, miR-17-5p, miR-27a-3p, miR-30a-5p, miR-30d-5p, miR-30e-5p, miR-130a-3p, miR-140-5p, miR-199a-5p, and miR-451a. In silico analyses suggest that the transcardiac gradient of microRNAs in heart failure may target pathways related to heart disease. CONCLUSION: We determined the transcardiac gradient of cardio-microRNAs in failing hearts, which supports the use of these microRNAs as potential biomarkers. The microRNAs described here may have a role in the pathophysiology of heart failure as they might be involved in pathways related to disease progression, including fibrosis.

Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus.

We recently demonstrated that reconstituted high-density lipoprotein (rHDL) modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin. Given the key roles of both AMPK and insulin in fatty acid metabolism, the current study investigated the effect of rHDL infusion on fatty acid oxidation and lipolysis. Thirteen patients with type 2 diabetes received separate infusions of rHDL and placebo in a randomized, cross-over study. Fatty acid metabolism was assessed using steady-state tracer methodology, and plasma lipids were measured by mass spectrometry (lipidomics). In vitro studies were undertaken in 3T3-L1 adipocytes. rHDL infusion inhibited fasting-induced lipolysis (P = 0.03), fatty acid oxidation (P < 0.01), and circulating glycerol (P = 0.04). In vitro, HDL inhibited adipocyte lipolysis in part via activation of AMPK, providing a possible mechanistic link for the apparent reductions in lipolysis observed in vivo. In contrast, circulating NEFA increased after rHDL infusion (P < 0.01). Lipidomic analyses implicated phospholipase hydrolysis of rHDL-associated phosphatidylcholine as the cause, rather than lipolysis of endogenous fat stores. rHDL infusion inhibits fasting-induced lipolysis and oxidation in patients with type 2 diabetes, potentially through both AMPK activation in adipose tissue and elevation of plasma insulin. The phospholipid component of rHDL also has the potentially undesirable effect of increasing circulating NEFA.