Heart failure with preserved ejection fraction management: a systematic review of clinical practice guidelines and recommendations.

Multiple guidelines exist for the diagnosis and management of heart failure with preserved ejection fraction (HFpEF). We systematically reviewed current guidelines and recommendations, developed by national and international medical organizations, on the management of HFpEF in adults to aid clinical decision-making. We searched MEDLINE and EMBASE on 28 February 2024 for publications over the last 10 years as well as websites of organizations relevant to guideline development. Of the ten guidelines and recommendations retrieved, seven showed considerable rigour of development and were subsequently retained for analysis. There was consensus on the definition of HFpEF and the diagnostic role of serum natriuretic peptides and resting transthoracic echocardiography. Discrepancies were identified in the thresholds of serum natriuretic peptides and transthoracic echocardiography parameters used to diagnose HFpEF. There was agreement on the general pharmacological and supportive management of acute and chronic HFpEF. However, differences exist in strategies to identify and address specific phenotypes. Contemporary guidelines for HFpEF management agree on measures to avoid its development and the consideration of cardiac transplantation in advanced disease. There were discrepancies in recommended frequency of surveillance for patients with HFpEF and sparse recommendations on screening for HFpEF in the general population, use of diagnostic scoring systems, and the role of newly emerging therapies.

Infective endocarditis: Do we have an effective risk score model? A systematic review.

Background: Infective endocarditis (IE) is a rare, highly morbid condition with 17% in-hospital mortality. A total of 25-30% require surgery and there is ongoing debate with regard to markers predicting patient outcomes and guiding intervention. This systematic review aims to evaluate all IE risk scores currently available. Methods: Standard methodology (PRISMA guideline) was used. Papers with risk score analysis for IE patients were included, with attention to studies reporting area under the receiver-operating characteristic curve (AUC/ROC). Qualitative analysis was carried out, including assessment of validation processes and comparison of these results to original derivation cohorts where available. Risk-of-bias analysis illustrated according to PROBAST guidelines. Results: Of 75 articles initially identified, 32 papers were analyzed for a total of 20 proposed scores (range 66-13,000 patients), 14 of which were specific for IE. The number of variables per score ranged from 3 to 14 with only 50% including microbiological variables and 15% including biomarkers. The following scores had good performance (AUC > 0.8) in studies proposing the score (often the derivation cohort); however fared poorly when applied to a new cohort: PALSUSE, DeFeo, ANCLA, RISK-E, EndoSCORE, MELD-XI, COSTA, and SHARPEN. DeFeo score demonstrated the largest discrepancy with initial AUC of 0.88, compared to 0.58 when applied to different cohorts. The inflammatory response in IE has been well documented and CRP has been found to be an independent predictor for worse outcomes. There is ongoing investigation on alternate inflammatory biomarkers which may assist in IE management. Of the scores identified in this review, only three have included a biomarker as a predictor. Conclusion: Despite the variety of available scores, their development has been limited by small sample size, retrospective collection of data and short-term outcomes, with lack of external validation, limiting their transportability. Future population studies and large comprehensive registries are required to address this unmet clinical need.

18F-FDG PET/CT improves diagnostic certainty in native and prosthetic valve Infective Endocarditis over the modified Duke Criteria.

BACKGROUND: International guidance recognizes the shortcomings of the modified Duke Criteria (mDC) in diagnosing infective endocarditis (IE) when transoesophageal echocardiography (TOE) is equivocal. 18F-FDG PET/CT (PET) has proven benefit in prosthetic valve endocarditis (PVE), but is restricted to extracardiac manifestations in native disease (NVE). We investigated the incremental benefit of PET over the mDC in NVE. METHODS: Dual-center retrospective study (2010-2018) of patients undergoing myocardial suppression PET for NVE and PVE. Cases were classified by mDC pre- and post-PET, and evaluated against discharge diagnosis. Receiver Operating Characteristic (ROC) analysis and net reclassification index (NRI) assessed diagnostic performance. Valve standardized uptake value (SUV) was recorded. RESULTS: 69/88 PET studies were evaluated across 668 patients. At discharge, 20/32 had confirmed NVE, 22/37 PVE, and 19/69 patients required surgery. PET accurately re-classified patients from possible, to definite or rejected (NRI: NVE 0.89; PVE 0.90), with significant incremental benefit in both NVE (AUC 0.883 vs 0.750) and PVE (0.877 vs 0.633). Sensitivity and specificity were 75% and 92% in NVE; 87% and 86% in PVE. Duration of antibiotics and C-reactive Protein level did not impact performance. No diagnostic SUV cut-off was identified. CONCLUSION: PET improves diagnostic certainty when combined with mDC in NVE and PVE.

Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide.

BACKGROUND AND PURPOSE: NO is a vasodilator and independent modulator of cardiac remodelling. Commonly, in cardiac disease (e.g., heart failure), endothelial dysfunction (synonymous with NO deficiency) has been implicated in increased BP, cardiac hypertrophy and fibrosis. Currently, no effective therapies replacing NO have succeeded in the clinic. Inorganic nitrate (NO3 - ), through chemical reduction to nitrite and then to NO, exerts potent BP lowering, but whether it might be useful in treating undesirable cardiac remodelling is not known. EXPERIMENTAL APPROACH: We analysed demographics in a nested age- and sex-matched case-control study of hypertensive patients with or without left ventricular hypertrophy (NCT03088514) and assessed the effects of dietary nitrate in mouse models of cardiac dysfunction. KEY RESULTS: Lower plasma nitrite concentrations and vascular dysfunction accompanied cardiac hypertrophy and fibrosis in patients. In mouse models of cardiac remodelling, restoration of circulating nitrite levels using dietary nitrate improved endothelial dysfunction through targeting the xanthine oxidoreductase-driven increase in levels of H2 O2 and superoxide, and decreased cardiac fibrosis through NO-mediated block of SMAD phosphorylation leading to improvements in cardiac structure and function. CONCLUSIONS AND IMPLICATIONS: Dietary nitrate offers easily translatable therapeutic options for delivery of NO and thereby treatment of cardiac dysfunction.

20-hydroxyeicosatetraenoic acid (20-HETE) is a pivotal endogenous ligand for TRPV1-mediated neurogenic inflammation in the skin.

BACKGROUND AND PURPOSE: Transient receptor potential cation channel subfamily V member 1 (TRPV1) is localized to sensory C-fibres and its opening leads to membrane depolarization, resulting in neuropeptide release and neurogenic inflammation. However, the identity of the endogenous activator of TRPV1 in this setting is unknown. The arachidonic acid metabolites 12-hydroperoxyeicosatetraenoyl acid (12-HpETE) and 20-hydroxyeicosatetraenoic acid (20-HETE) have emerged as potential endogenous activators of TRPV1. However, whether these lipids underlie TRPV1-mediated neurogenic inflammation remains unknown. EXPERIMENTAL APPROACH: We analysed human cantharidin-induced blister samples and inflammatory responses in TRPV1 transgenic mice. KEY RESULTS: In a human cantharidin-blister model, the potent TRPV1 activators 20-HETE but not 12-HETE (stable metabolite of 12-HpETE) correlated with arachidonic acid levels. Similarly, in mice, levels of 20-HETE (but not 12-HETE) and arachidonic acid were strongly positively correlated within the inflammatory milieu. Furthermore, LPS-induced oedema formation and neutrophil recruitment were substantially and significantly attenuated by pharmacological block or genetic deletion of TRPV1 channels, inhibition of 20-HETE formation or SP receptor neurokinin 1 (NK1 ) blockade. LPS treatment also increased cytochrome P450 ω-hydroxylase gene expression, the enzyme responsible for 20-HETE production. CONCLUSION AND IMPLICATIONS: Taken together, our findings suggest that endogenously generated 20-HETE activates TRPV1 causing C-fibre activation and consequent oedema formation. These findings identify a novel pathway that may be useful in the therapeutics of diseases/conditions characterized by a prominent neurogenic inflammation, as in several skin diseases.

Recurrent strokes in an occult case of recurrent Cutibacterium acnes prosthetic valve infective endocarditis: a case report.

BACKGROUND: Infective endocarditis (IE) is a known but uncommon cause of cardioembolic stroke and there are rare but recognized cases of IE without an inflammatory response. Cutibacterium acnes is an increasingly recognized source of invasive infections, including IE, but diagnosis is challenging due to its low virulence and fastidious nature. CASE SUMMARY: A 47-year-old man presented with a multi-focal stroke suggestive of a cardioembolic source. Outpatient transoesophageal echocardiography (TOE) was concerning for vegetation or thrombus associated with his previous mitral valve repair. He remained clinically well, with no evidence of an inflammatory response and sterile blood cultures. Computed tomography-positron emission tomography (CT-PET) corroborated the TOE findings, however, given the atypical presentation, he was treated for valvular thrombus. Following discharge, he quickly re-presented with further embolic phenomena and underwent emergency mitral valve replacement. Intraoperative findings were consistent with prosthetic valve IE (PVE) and a 6-week course of antibiotics commenced. C. acnes was identified on molecular testing. Eighteen months later, he re-presented with further neurological symptoms. Early TOE and CT-PET were consistent with IE. Blood cultures grew C. acnes after prolonged incubation. Given the absence of surgical indications, he was managed medically, and the vegetation resolved without valvular dysfunction. He continues to be followed up in an outpatient setting. DISCUSSION: In patients presenting with multi-territory stroke, IE should be considered despite sterile blood cultures and absent inflammatory response. C. acnes is an increasingly recognized cause of PVE in this context, often requiring surgical intervention. A high index of suspicion and collaboration with an Endocarditis Team is therefore essential to diagnose and treat.

Clinical and echocardiographic predictors of decompensation in acute severe aortic regurgitation due to infective endocarditis.

BACKGROUND: Patients with acute severe aortic regurgitation (AR) due to infective endocarditis can progress rapidly from the hemodynamically stable patient to pulmonary edema and cardiogenic shock. We sought to identify patients at risk of decompensation where emergent surgery should be undertaken. METHODS: We identified 90 patients with acute severe AR from the echocardiography laboratory database. Baseline clinical, hemodynamic (heart rate (HR) and blood pressure (BP)), and echocardiographic data including mitral filling, premature mitral valve closure (PMVC), and diastolic mitral regurgitation (DMR) were identified. The primary endpoint was subsequent development of pulmonary edema or severe hemodynamic instability. RESULTS: Patients who met the primary endpoint had a higher HR (98.5 bpm vs 80.5 bpm), lower diastolic BP (54 mm Hg vs 61.5 mm Hg), higher mitral E-wave velocity (113 cm/s vs 83 cm/s), higher E/e' ratio (12.4 vs 8), higher proportion of DMR (27.8% vs 7.4%), and PMVC (25% vs 9.3%) than patients who did not meet the endpoint. The proportion of patients with the primary endpoint increased as HR increased ((≤81 bpm) 3/30 (10%), (81-94 bpm) 11/31 (35.5%), (≥94 bpm) 22/29 (75.9%), P < .0001) and as the diastolic BP reduced ((≤54 mm Hg) 19/31 (61.3%), (54-63 mm Hg) 12/31 (38.7%), (≥63 mm Hg) 5/28 (17.9%), P = .003). Independent predictors were a higher HR (OR 1.08 (95% CI 1.04-1.13) P = .0003) and DMR (OR 4.71 (95% CI 1.23-18.09), P = .02). CONCLUSION: Decompensation in acute severe AR is common. Independent predictors of decompensation are increasing HR(≥94 bpm) and the presence of DMR. Those with these adverse markers should be considered for emergent surgery.

Association of Vegetation Size With Valve Destruction, Embolism and Mortality.

AIM: The mortality of patients with infective endocarditis (IE) is high. The management of patients with large vegetations is controversial. This study sought to investigate the association of vegetation size on outcomes including valve destruction, embolism and mortality. METHODS AND RESULTS: One hundred and forty-two (142) patients with definite IE and transoesophageal echocardiography (TEE) imaging available for analysis were identified and data retrospectively reviewed. Vegetation length, width and area were measured. Severe valve destruction was defined as the composite of one or more of severe valve regurgitation, abscess, pseudoaneurysm, perforation or fistula. Associations with 6-month mortality were identified by Cox regression analysis. Eighty (80) (56.3%) patients had evidence of valve destruction on TEE. Vegetation length ≥10 mm and vegetation area ≥50 mm2 were significantly associated with increased risk of valve destruction, (both odds ratio OR 1.21, p=0.03 and p=0.02 respectively). Thirty-nine (39) (72.2%) patients who had an embolic event, did so prior initiation of antibiotics. Six (6)-month mortality was 18.3%. In the surgically managed group, vegetation size was not associated with mortality. In the medically managed group, vegetation area (mm2) was associated with increased mortality (HR 1.01, p<0.01) along with age (HR 1.06, p=0.03). CONCLUSION: Vegetation length ≥10 mm or area ≥50 mm2 are associated with increased risk of valve destruction. Vegetation size may also predict mortality in medically managed but not surgically managed patients with IE. Further studies to evaluate whether surgery in patients with large vegetation size improves outcomes is warranted.

Randomised, double-blind, placebo-controlled clinical trial investigating the effects of inorganic nitrate in hypertension-induced target organ damage: protocol of the NITRATE-TOD study in the UK.

INTRODUCTION: Arterial stiffness and left ventricular (LV) hypertrophy are the key markers of hypertensive target organ damage (TOD) associated with increased cardiovascular morbidity and mortality. We have previously shown that dietary inorganic nitrate supplementation lowers blood pressure (BP) in hypertension, however, whether this approach might also improve markers of hypertensive TOD is unknown. In this study, we will investigate whether daily dietary inorganic nitrate administration reduces LV mass and improves measures of arterial stiffness. METHODS AND DESIGN: NITRATE-TOD is a double-blind, randomised, single-centre, placebo-controlled phase II trial aiming to enrol 160 patients with suboptimal BP control on one or more antihypertensives. Patients will be randomised to receive 4 months once daily dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo). The primary outcomes are reduction in LV mass and reduction in pulse wave velocity (PWV) and central BP.The study has a power of 95% for detecting a 9 g LV mass change by cardiovascular MRI (~6% change for a mildly hypertrophied heart of 150 g). For PWV, we have a power of >95% for detecting a 0.6 m/s absolute change. For central systolic BP, we have a>90% power to detect a 5.8 mm Hg difference in central systolic BP.Secondary end points include change in ultrasound flow-mediated dilation, change in plasma nitrate and nitrite concentration and change in BP. ETHICS AND DISSEMINATION: The study was approved by the London-City and East Research Ethics Committee (10/H0703/98). Trial results will be published according to the Consolidated Standards of Reporting Trials statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03088514.