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.

Sex Differences in Pharmacotherapy and Long-Term Outcomes in Patients With Ischaemic Heart Disease and Comorbid Left Ventricular Dysfunction.

BACKGROUND: Left ventricular (LV) dysfunction and ischaemic heart disease (IHD) are common among women. However, women tend to present later and are less likely to receive guideline-directed medical therapy (GDMT) compared with men. METHODS: We analysed prospectively collected data (2005-2018) from a multicentre registry on GDMT 30 days after percutaneous coronary intervention in 13,015 patients with LV ejection fraction <50%. Guideline-directed medical therapy was defined as beta blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker±mineralocorticoid receptor antagonist. Long-term mortality was determined by linkage with the Australian National Death Index. RESULTS: Women represented 20% (2,634) of the total cohort. Mean age was 65±12 years. Women were on average >5 years, with higher body mass index and higher rates of hypertension, diabetes, renal dysfunction, prior stroke, and rheumatoid arthritis. Guideline-directed medical therapy was similar between sexes (73% vs 72%; p=0.58), although women were less likely to be on an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (80% vs 82%; p=0.02). Women were less likely to be on statin therapy (p<0.001) or a second antiplatelet agent (p=0.007). Women had higher unadjusted long-term mortality (25% vs 19%; p<0.001); however, there were no differences in long-term mortality between sexes on adjusted analysis (hazard ratio 0.99; 95% confidence interval 0.87-1.14; p=0.94). CONCLUSIONS: Rates of GDMT for LV dysfunction were high and similar between sexes; however, women were less likely to be on appropriate IHD secondary prevention. The increased unadjusted long-term mortality in women was attenuated in adjusted analysis, which highlights the need for optimisation of baseline risk to improve long-term outcomes of women with IHD and comorbid LV dysfunction.

Trends in Intra-Aortic Balloon Pump Use in Cardiogenic Shock After the SHOCK-II Trial.

Myocardial infarction complicated by cardiogenic shock (MI-CS) has a poor prognosis, even with early revascularization. Previously, intra-aortic balloon pump (IABP) use was thought to improve outcomes, but the IABP-SHOCK-II (Intra-aortic Balloon Pump in Cardiogenic Shock-II study) trial found no survival benefit. We aimed to determine the trends in IABP use in patients who underwent percutaneous intervention over time. Data were taken from patients in the Melbourne Interventional Group registry (2005 to 2018) with MI-CS who underwent percutaneous intervention. The primary outcome was the trend in IABP use over time. The secondary outcomes included 30-day mortality and major adverse cardiovascular and cerebrovascular events (MACCEs). Of the 1,110 patients with MI-CS, IABP was used in 478 patients (43%). IABP was used more in patients with left main/left anterior descending culprit lesions (62% vs 46%), lower ejection fraction (<35%; 18% vs 11%), and preprocedural inotrope use (81% vs 73%, all p <0.05). IABP use was associated with higher bleeding (18% vs 13%) and 30-day MACCE (58% vs 51%, both p <0.05). The rate of MI-CS per year increased over time; however, after 2012, there was a decrease in IABP use (p <0.001). IABP use was a predictor of 30-day MACCE (odds ratio 1.6, 95% confidence interval 1.18 to 2.29, p = 0.003). However, IABP was not associated with in-hospital, 30-day, or long-term mortality (45% vs 47%, p = 0.44; 46% vs 50%, p = 0.25; 60% vs 62%, p = 0.39). In conclusion, IABP was not associated with reduced short- or long-term mortality and was associated with increased short-term adverse events. IABP use is decreasing but is predominately used in sicker patients with greater myocardium at risk.

Meta-Analysis on Drug and Device Therapy of New York Heart Association Functional Class IV Heart Failure With Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is associated with significant morbidity and mortality, particularly in patients with New York Heart Association (NYHA) functional class IV symptoms. Decades of discovery have heralded significant advancements in the pharmacologic management of HFrEF. However, patients with NYHA IV symptoms remain an under-represented population in almost every clinical trial to date, leaving clinicians with limited evidence with which to guide drug treatment decisions in this patient group with severe heart failure. Randomized controlled trials of adult patients with NYHA IV symptoms of HFrEF randomized to current guideline-recommended medical therapy were included in this systematic review and meta-analysis. The outcomes of interest included the rate of all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A total of 39 randomized controlled trials were included. A total of 6 studies examined angiotensin converting enzyme inhibitors, with meta-analyses of 2 demonstrating a reduced risk of all-cause mortality (relative risk (RR) 0.76, 95% confidence interval 0.59 to 0.97, p = 0.03). A total of 11 studies examined ß blockers, with meta-analysis of 6 demonstrating a reduced risk of all-cause mortality (risk ratio 0.74, 95% confidence interval 0.60 to 0.92, p = 0.008). A study examined the mineralocorticoid antagonist spironolactone, reporting a reduced risk of all-cause mortality in the NYHA IV subgroup. A total of 6 studies examined device therapy, demonstrating the benefit of cardiac resynchronization therapy with or without an implantable cardiac defibrillator in reducing hospitalization in the NYHA IV subgroup. Although trial evidence exists for angiotensin converting enzyme inhibitors, ß-blockers, and mineralocorticoid antagonist therapy in the NYHA IV population, the role of angiotensin receptor blockers is unclear. Ivabradine, angiotensin receptor neprilysin inhibitors, and sodium-glucose transport protein 2 inhibitors remain underinvestigated and have not been proved to provide any benefit above standard heart failure therapy in patients with HFrEF and NYHA IV symptoms.

Sex differences in prehospital analgesia in patients presenting with acute coronary syndromes and their association with clinical outcomes.

OBJECTIVES: This study examined if sex differences in prehospital pain scores, opioid administration, and clinical outcomes exist in acute coronary syndrome (ACS) patients. BACKGROUND: Sex differences persist in ACS presentation, management, and outcomes. The impact of sex differences on prehospital pain management of ACS with opioids is unknown. METHODS: Patients presenting with ACS via ambulance (2014-2018) that underwent percutaneous coronary intervention (PCI) were prospectively collected via the Victorian Cardiac Outcomes Registry and Melbourne Interventional Group, linked to the Ambulance Victoria database. The primary outcome was 30-day major adverse cardiac events (MACE). Secondary outcomes were descriptive analyses of prehospital pain score, intravenous morphine equivalent analgesic dosing, plus predictors of MACE and thrombolysis in myocardial infarction (TIMI) 0-1 flow pre-PCI. RESULTS: A total of 10,547 patients were included (female: 2775 [26%]). Opioids were administered to 1585 (57%) females, 5068 (65%) males (p < 0.001). Adjusted 30-day MACE was similar between opioid groups in both sexes (female: odds ratio [OR]: 1.21, confidence interval [CI] 0.82-1.79, p = 0.34; male: OR: 0.89, CI: 0.68-1.16, p = 0.40). Median pain score at presentation was 6 (interquartile range [IQR]: 4, 8) for both sexes. Median opioid dose was 2.5 mg (IQR: 0, 10) in females and 5 mg (IQR: 0, 10) in males (p < 0.001), with similar pain relief achieved. Adjusted rates of TIMI 0-1 pre-PCI were higher in patients administered opioids (female: OR 2.9, CI: 2.07-4.07, p < 0.001; male: OR: 2.67, CI: 2.19-3.25, p < 0.001). CONCLUSIONS: Female patients undergoing PCI received less opioid analgesia, but no sex differences in prehospital pain scores were seen. Opioid administration was associated with impaired antegrade flow in the culprit artery in both sexes, but not short-term MACE. Trials evaluating nonopioid analgesics in ACS are needed.

Efficacy of immune checkpoint inhibitors for in-transit melanoma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM. METHODS: A retrospective review of patients with ITM commenced on an ICI between March 2013 and February 2018 at three tertiary centers in Australia. Patients were excluded if they had previous or synchronous distant metastases. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were based on a composite of radiological and clinical assessments. RESULTS: Fifty-four patients were included: 27 (50%) female; median age 75 (range 26-94); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10 (19%) BRAF mutant. Forty (74%) received single-agent anti-PD-1 (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PD-L1 (atezolizumab) and MEK inhibitor (cobimetinib). The median follow-up was 15 months (2-46).ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single-agent anti-PD-1, 38% for single-agent anti-CTLA4 and 40% for anti-PD-1/anti-CTLA-4. The median PFS was 11.7 months (6.6-not reached). 1-year and 2-year PFS were 48% and 39%, respectively,. Fourteen progressed locoregionally and 11 progressed distantly. The median OS was not reached. 1-year and 2-year OS were 85% and 63%, respectively. No clinicopathological features were associated with ORR. CONCLUSIONS AND RELEVANCE: ICI produce objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence.

Systemic therapies for unresectable locoregional melanoma: a significant area of need.

Immune checkpoint inhibitors and BRAF-MEK inhibitors have revolutionized the management and prognosis of patients with metastatic melanoma. However, there is minimal evidence to guide their incorporation into current treatment paradigms for unresectable stage III disease. The era of effective systemic therapies has prompted a discussion about what constitutes unresectable disease. Patients with unresectable stage III disease can experience significant morbidity from their disease and locoregional therapies, and may progress with distant metastases. Despite increasing use of systemic therapies in unresectable stage III disease, further evidence is needed to establish their degree of benefit in this population.

The Prognosis and Natural History of In-Transit Melanoma Metastases at a High-Volume Centre.

BACKGROUND: Patients with in-transit melanoma metastases (ITM) experience a diverse spectrum of clinical presentations and a highly variable disease course. There is no standardized treatment protocol for these patients due to the limited data comparing treatment modalities for ITM. This is the first study to describe the disease trajectory and natural history of a large cohort of patients with ITM. METHODS: A retrospective study of patients treated for ITM between 2004 and 2018 at the Peter MacCallum Cancer Centre was performed. Clinical and pathological characteristics for primary and in-transit episodes were analyzed for predictors of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival. RESULTS: A total of 109 patients with 303 episodes of ITM were identified: 52 (48%) females, median age 70.1 years (range 35-92). The median RFS for all episodes was 5 months (95% confidence interval [CI] 4.2-5.7). Eighty-seven percent of episodes involving isolated in-transit lesions underwent surgical excision, compared with 17% involving more than five in-transit lesions. A trend was seen between a greater number of lesions and shorter RFS (p = 0.055). The median DMFS was 34.8 months (95% CI 22.8-51.6). Factors associated with shorter DMFS included primary tumor thickness (hazard ratio [HR] 1.08, 95% CI 1.01-1.15; p = 0.026), site of primary tumor (p = 0.008), and BRAF mutation (HR 2.12, 95% CI 1.14-3.94; p = 0.018). CONCLUSIONS: Locoregional relapse is common in patients with ITM regardless of treatment modality. Characteristics of the ITM may predict for RFS, while primary tumor characteristics remain important predictors of DMFS.

Management of in-transit melanoma metastases: a review.

In-transit metastases (ITM) of cutaneous melanoma are locoregional recurrences confined to the superficial lymphatics that occur in 3.4-6.2% of patients diagnosed with melanoma. ITM are a heterogeneous disease that poses a therapeutic dilemma. Patients may have a prolonged disease trajectory involving multiple or repeat treatment modalities for frequent recurrences. The management of ITM has evolved without the development of a standardized protocol. Owing to the variability of the disease course there are few dedicated clinical trials, with a number of key trials in stage III melanoma excluding ITM patients. Thus, there is a paucity of quality data on the efficacy of the treatment modalities available for ITM and even fewer studies directly comparing modalities. At present the mainstay of ITM treatment is surgical resection, with intralesional therapies, isolated limb infusion and radiotherapy utilized as second-line measures. The developing role of targeted therapies and immunotherapy has yet to be explored completely in these patients. This review addresses the evidence base of the efficacy of the various treatment modalities available and those factors that have impacted their clinical uptake.