Healthcare professional’s guide to cardiopulmonary exercise testing

Cardiopulmonary exercise testing (CPEX) is a valuable clinical tool that has proven indications within the fields of cardiovascular, respiratory and pre-operative medical care. Validated uses include investigation of the underlying mechanism in patients with breathlessness, monitoring functional status in patients with known cardiovascular disease and pre-operative functional state assessment. An understanding of the underlying physiology of exercise, and the perturbations associated with pathological states, is essential for healthcare professionals to provide optimal patient care. Healthcare professionals may find performing CPEX to be daunting, yet this is often due to a lack of local expertise and guidance with testing. We outline the indications for CPEX within the clinical setting, present a typical protocol that is easy to implement, explain the key underlying physiological changes assessed by CPEX, and review the evidence behind its use in routine clinical practice. There is mounting evidence for the use of CPEX clinically, and an ever-growing utilisation of the test within research fields; a sound knowledge of CPEX is essential for healthcare professionals involved in routine patient care

Cardiac metabolism — A promising therapeutic target for heart failure

Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants. Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed

Biventricular pacemaker therapy improves exercise capacity in patients with non‐obstructive hypertrophic cardiomyopathy via augmented diastolic filling on exercise

Aims Treatment options for patients with non‐obstructive hypertrophic cardiomyopathy (HCM) are limited. We sought to determine whether biventricular (BiV) pacing improves exercise capacity in HCM patients, and whether this is via augmented diastolic filling. Methods and results Thirty‐one patients with symptomatic non‐obstructive HCM were enrolled. Following device implantation, patients underwent detailed assessment of exercise diastolic filling using radionuclide ventriculography in BiV and sham pacing modes. Patients then entered an 8‐month crossover study of BiV and sham pacing in random order, to assess the effect on exercise capacity [peak oxygen consumption (VO2)]. Patients were grouped on pre‐specified analysis according to whether left ventricular end‐diastolic volume increased (+LVEDV) or was unchanged/decreased (–LVEDV) with exercise at baseline. Twenty‐nine patients (20 male, mean age 55 years) completed the study. There were 14 +LVEDV patients and 15 –LVEDV patients. Baseline peak VO2 was lower in –LVEDV patients vs. +LVEDV patients (16.2 ± 0.9 vs. 19.9 ± 1.1 mL/kg/min, P = 0.04). BiV pacing significantly increased exercise ΔLVEDV (P = 0.004) and Δstroke volume (P = 0.008) in –LVEDV patients, but not in +LVEDV patients. Left ventricular ejection fraction and end‐systolic elastance did not increase with BiV pacing in either group. This translated into significantly greater improvements in exercise capacity (peak VO2 + 1.4 mL/kg/min, P = 0.03) and quality of life scores (P = 0.02) in –LVEDV patients during the crossover study. There was no effect on left ventricular mechanical dyssynchrony in either group. Conclusion Symptomatic patients with non‐obstructive HCM may benefit from BiV pacing via augmentation of diastolic filling on exercise rather than contractile improvement. This may be due to relief of diastolic ventricular interaction. Clinical Trial Registration: ClinicalTrials.gov NCT00504647

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans

Supported by Medical Research Council program grant MRC G1001340 (to M Madhani, M Feelisch, and MP Frenneaux). We thank Lesley Cheyne for their contributions to the present study. The authors’ responsibilities were as follows—VSV, M Madhani, JDH, MF, DD, MPF: designed the research; MN, NEKP, KS, BLL, M Minnion, BOF, DV, DC-T, PGC: conducted the research; DV: provided essential materials; MN, NEKP, M Minnion, BOF, DC-T, MF, PGC: analyzed the data; MN, NEKP, PGC, MPF: wrote the paper; MPF: had primary responsibility for the final manuscript; and all authors: read and approved the final manuscript. None of the authors reported a conflict of interest related to the study.Peer reviewedPublisher PD

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005)

Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation

Aims: Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared to healthy volunteers (HV) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF-AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood. Methods and Results: Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF-AF patients (n = 29) and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using Western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared to healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP. Conclusion: We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the “platelet NO resistance” phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO

Impact of CV Risk Factors/Disease on Length of Stay and Mortality in Patients Presenting with MI

Background: Classical risk factors for cardiovascular disease such as hypertension and diabetes, and their association with myocardial infarction (MI), have been thoroughly investigated. However, more research is needed to investigate the correlation between these risk factors and the impact on length of stay (LOS) and mortality in patients presenting with MI, which was the aim of this study. Methods: We reviewed anonymous patient data including demographics, LOS, prevalence of cardiovascular comorbidities, and mortality during 25,287 consecutive admissions for MI from seven hospitals in the North West of England between 1 January 2000 and 31 March 2013. The ACALM (Algorithm for Comorbidities, Associations, Length of stay and Mortality) protocol, using ICD-10 and OPCS-4 coding systems, was used to track patient data. LOS and mortality of MI patients with and without cardiovascular comorbidities was compared by multinomial logistic regression. P values <0.05 were taken as statistically significant. Results: Of 25,287 patients admitted with MI over the study period, mean (± SD) age was 66.6 ± 14.3 and 64.2% were male. The mean (± SD) LOS was 7.0 ± 16.2 days and there were a total of 9,653 (38.2%) deaths. The classical cardiovascular risk factors hypertension and hyperlipidaemia were associated with a decreased LOS and mortality (7.0 and 4.8 days respectively, P < 0.001; 36.8% OR 0.72 [95% CI 0.67–0.77] and 19.4% OR 0.42 [95% CI 0.39–0.46] respectively, P < 0.001), whereas diabetes was associated with a longer LOS and higher mortality (7.8 days, P < 0.05; 44.4% OR 1.3 [95% CI 1.20–1.41], P < 0.001). Angina pectoris was associated with shorter LOS and reduced mortality (5.4 days; 33.5% OR 0.75 [95% CI 0.68–0.82], P < 0.001). Other concomitant cardiovascular diseases were associated with an increased LOS and mortality: PVD (8.6 days, P < 0.05; 53% OR 1.93 [95% CI 1.68–2.21], P < 0.001), AF (10.9 days; 63.5% OR 1.51 [95% CI 1.38–1.66], P < 0.001), Cerebrovascular disease (15.9 days; 76% OR 2.29 [95% CI 1.67–3.15], P < 0.001), HF (11 days; 69.9% OR 3.28 [95% CI 3.03–3.56], P < 0.001), and IHD (6.7 days, P < 0.001; 38.7% OR 1.16 [95% CI 1.06–1.26], P < 0.05). Conclusion: Cardiovascular risk factors and concomitant disease have a significant impact on LOS and mortality in patients presenting with MI. The presence of these diseases should be used to identify patients at an increased risk of prolonged admissions and death post MI, and services should be directed accordingly

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans

BACKGROUND: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may reduce nitrate to nitrite, which may subsequently be reduced to nitric oxide during conditions of hypoxia and in the presence of "nitrite reductases" such as heme- and molybdenum-containing enzymes.OBJECTIVE: We aimed to explore the putative effects of inorganic nitrate and nitrite on mitochondrial function in skeletal muscle.METHODS: Mice were subjected to a nitrate/nitrite-depleted diet for 2 wk, then supplemented with sodium nitrate, sodium nitrite, or sodium chloride (1 g/L) in drinking water ad libitum for 7 d before killing. Skeletal muscle mitochondrial function and expression of uncoupling protein (UCP) 3, ADP/ATP carrier protein (AAC) 1 and AAC2, and pyruvate dehydrogenase (PDH) were assessed by respirometry and Western blotting. Studies were also undertaken in human skeletal muscle biopsies from a cohort of coronary artery bypass graft patients treated with either sodium nitrite (30-min infusion of 10 μmol/min) or vehicle [0.9% (wt:vol) saline] 24 h before surgery.RESULTS: Neither sodium nitrate nor sodium nitrite supplementation altered mitochondrial coupling efficiency in murine skeletal muscle, and expression of UCP3, AAC1, or AAC2, and PDH phosphorylation status did not differ between the nitrite and saline groups. Similar results were observed in human samples.CONCLUSIONS: Sodium nitrite failed to improve mitochondrial metabolic efficiency, rendering this mechanism implausible for the purported exercise benefits of dietary nitrate supplementation. This trial was registered at clinicaltrials.gov as NCT04001283.</p