Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Effective prognostic and clinical risk stratification in COVID-19 using multimodality biomarkers.

In acute coronavirus disease 19 (COVID-19) patients, effective clinical risk stratification has important implications on treatment and therapeutic resource distribution. This article reviews the evidence behind a wide range of biomarkers with prognostic value in COVID-19. Patient characteristics and co-morbidities, such as cardiovascular and respiratory diseases, are associated with increased mortality risk. Peripheral oxygen saturation and arterial oxygenation are predictive of severe respiratory compromise, whereas risk scores such as the 4C-score enable multi-factorial prognostic risk estimation. Blood tests such as markers of inflammation, cardiac injury and d-dimer and abnormalities on electrocardiogram are linked to inpatient prognosis. Of the imaging modalities, lung ultrasound and echocardiography enable the bedside assessment of prognostic abnormalities in COVID-19. Chest radiograph (CXR) and computed tomography (CT) can inform about prognostic pulmonary pathologies, whereas cardiovascular CT detects high-risk features such as coronary artery and aortic calcification. Dynamic changes in biomarkers, such as blood tests, CXR, CT and electrocardiogram findings, can further inform about disease severity and prognosis. Despite the vast volumes of existing evidence, several gaps exist in our understanding of COVID-19 biomarkers. First, the pathophysiological basis on which these markers can foretell prognosis in COVID-19 remains poorly understood. Second, certain under-explored tests such as thoracic impedance assessment and cardiovascular magnetic resonance imaging deserve further investigation. Lastly, the prognostic values of most biomarkers in COVID-19 are derived from retrospective analyses. Prospective studies are required to validate these markers for guiding clinical decision-making and to facilitate their translation into clinical management pathways.

Glycosylated apolipoprotein J in cardiac ischaemia: molecular processing and circulating levels in patients with acute ischaemic events.

AIM: Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI. METHODS AND RESULTS: Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008). CONCLUSIONS: These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI.

Phenotype-based management of coronary microvascular dysfunction.

40-70% of patients undergoing invasive coronary angiography with signs and symptoms of ischemia are found to have no obstructive coronary artery disease (INOCA). When this heterogeneous group undergo coronary function testing, approximately two-thirds have demonstrable coronary microvascular dysfunction (CMD), which is independently associated with adverse prognosis. There are four distinct phenotypes, or subgroups, each with unique pathophysiological mechanisms and responses to therapies. The clinical phenotypes are microvascular angina, vasospastic angina, mixed (microvascular and vasospastic), and non-cardiac symptoms (reclassification as non-INOCA). The Coronary Vasomotor Disorders International Study Group (COVADIS) have proposed standardized criteria for diagnosis. There is growing awareness of these conditions among clinicians and within guidelines. Testing for CMD can be done using invasive or non-invasive modalities. The CorMicA study advocates the concept of 'functional angiography' to guide stratified medical therapy. Therapies broadly fall into two categories: those that modulate cardiovascular risk and those to alleviate angina. Management should be tailored to the individual, with periodic reassessment for efficacy. Phenotype-based management is a worthy endeavor for both patients and clinicians, aligning with the concept of 'precision medicine' to improve prognosis, symptom burden, and quality of life. Here, we present a contemporary approach to the phenotype-based management of patients with INOCA.

Evolving Roles of Optimal Medical Therapy and PCI in Chronic Coronary Syndrome Patients with Stable Angina: Introduction.

This Introduction sets the stage for 5 subsequent papers that will follow, and which describe several key features of the ISCHEMIA Trial in depth, including clinical outcomes, beginning with a detailed discussion by Dr. David L. Brown from Washington University, St. Louis, MO on the "importance of OMT in the management of CCS patients" and how the results of ISCHEMIA reinforce the findings of earlier strategy trials in CCS patients. Drs. Rasha Al-Lamee and Darrel Francis from Royal College of London, UK, will discuss the important topic of "how to assess quality of life improvement with revascularization in CCS patients with chronic angina and lessons learned the ORBITA trial, including the importance of unblinded vs. blinded trials". Drs. Kreton Mavromatis from Emory University, Atlanta, GA and Eric Bates from the University of Michigan, Ann Arbor, MI, will next discuss whether (and how) the "role of revascularization and, in particular, PCI in CCS patients has changed following the publication of the ISCHEMIA Trial", followed by a paper highlighting the important role of assessing myocardial ischemia and no obstructive coronary arteries (INOCA) in patients with CCS and why this represents both an under-diagnosed and under-treated cause of chronic angina, especially in women with suspected CAD. Finally, the concluding paper by Drs. Boden, Kaski, and Bernard Gersh from the Mayo Clinic, Rochester, MN, will summarize "the future of managing chronic stable angina and how best to synthesize recent clinical trials evidence with evolving CCS management guidelines".

Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group.

AIMS: To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA). METHODS AND RESULTS: The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365-744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05). CONCLUSIONS: This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis.

The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure.

BACKGROUND: CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy. METHODS: We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants' RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George's Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline. DISCUSSION: This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded. TRIAL REGISTRATION: EudraCT number 2020-002946-18. Registered on 08 June 2020. Online record pending.

Inflammatory Mechanisms in COVID-19 and Atherosclerosis: Current Pharmaceutical Perspectives.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with excess mortality worldwide. The cardiovascular system is the second most common target of SARS-CoV-2, which leads to severe complications, including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism, as well as other major thrombotic events because of direct endothelial injury and an excessive systemic inflammatory response. This review focuses on the similarities and the differences of inflammatory pathways involved in COVID-19 and atherosclerosis. Anti-inflammatory agents and immunomodulators have recently been assessed, which may constitute rational treatments for the reduction of cardiovascular events in both COVID-19 and atherosclerotic heart disease.

Inferior ST-Elevation Myocardial Infarction Presenting When Urgent Primary Percutaneous Coronary Intervention Is Unavailable: Should We Adhere to Current Guidelines?

The pivotal studies that led to the recommendations for emergent reperfusion therapy for ST-elevation myocardial infarction (STEMI) were conducted for the most part over 25 years ago. At that time, contemporary standard treatments including aspirin, statin, and even anticoagulation were not commonly used. The 2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines and the 2017 European Society of Cardiology guidelines give a class I recommendation (with the level of evidence A) for primary percutaneous coronary intervention (pPCI) in patients with STEMI and ischemic symptoms of less than 12 h. However, if the patient presents to a hospital without pPCI capacity, and it is anticipated that pPCI cannot be performed within 120 min of first medical contact, fibrinolytic therapy is indicated (if there are no contraindications) (class I indication, level of evidence A). Our review of the pertinent literature shows that the current recommendation for inferior STEMI is based on the level of evidence lower than A. We can consider level B even C, supporting the recommendation for fibrinolytic therapy if pPCI is not available for inferior STEMI.

Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization.

Persistence or recurrence of angina after a percutaneous coronary intervention (PCI) may affect about 20-40% of patients during short-medium-term follow-up. This appears to be true even when PCI is 'optimized' using physiology-guided approaches and drug-eluting stents. Importantly, persistent or recurrent angina post-PCI is associated with a significant economic burden. Healthcare costs may be almost two-fold higher among patients with persistent or recurrent angina post-PCI vs. those who become symptom-free. However, practice guideline recommendations regarding the management of patients with angina post-PCI are unclear. Gaps in evidence into the mechanisms of post-PCI angina are relevant, and more research seems warranted. The purpose of this document is to review potential mechanisms for the persistence or recurrence of angina post-PCI, propose a practical diagnostic algorithm, and summarize current knowledge gaps.

Reappraisal of Ischemic Heart Disease.

In recent years, it has become apparent that coronary microvascular dysfunction plays a pivotal pathogenic role in angina pectoris. Functional and structural mechanisms can affect the physiological function of the coronary microvasculature and lead to myocardial ischemia in people without coronary atheromatous disease and also in individuals with obstructive coronary artery disease. Abnormal dilatory responses of the coronary microvessels, coronary microvascular spasm, and extravascular compressive forces have been identified as pathogenic mechanisms in both chronic and acute forms of ischemic heart disease. The condition characterized by anginal symptoms and evidence of myocardial ischemia triggered by coronary microvascular dysfunction, in the absence of obstructive coronary disease, is known as microvascular angina. The concept of microvascular angina, however, may extend further to include patients with obstructive coronary artery disease and individuals with angina after coronary revascularization or heart transplantation because coronary microvascular dysfunction contributes to myocardial ischemia in many such patients. Patients with microvascular angina constitute a sizeable proportion of all cases of stable angina undergoing diagnostic coronary angiography and of those with persisting angina after successful coronary revascularization. Coronary microvascular dysfunction is also often responsible for angina in individuals with cardiomyopathy and heart valve disease as well as acute coronary syndrome cases such as Takotsubo syndrome and myocardial infarction with no obstructive coronary artery disease. Patients with stable microvascular angina present typically with effort or rest chest pain and a reduced coronary flow reserve or microvascular spasm. This condition, which affects women and men, can markedly impair quality of life and prognosis and represents a substantial cost burden to healthcare systems and individuals alike. In recent years, progress in the diagnosis of myocardial ischemia and the use of tests to investigate functional and structural causes for a reduced coronary flow reserve and microvascular spasm have allowed the identification of an increased number of cases of microvascular angina in everyday clinical practice. Although some of the available anti-anginal drugs may be helpful, treatment of coronary microvascular dysfunction remains a major challenge. The present article discusses the fundamental role that coronary microvascular dysfunction plays in the pathogenesis of ischemic heart disease, the clinical characteristics of patients presenting with microvascular angina, and possible diagnostic and therapeutic strategies.

MINOCA presenting with STEMI: incidence, aetiology and outcome in a contemporaneous cohort.

Historical data indicate that approximately 10% of acute coronary syndrome patients have no obstructive coronary artery disease (CAD) but contemporary incidence of non-obstructed coronary arteries in ST-segment elevation myocardial infarction (STEMI) is not clear. We aimed both to identify the contemporary incidence of MI without obstructive CAD (MINOCA)-using the ESC definition-and assess clinical outcomes. We assessed consecutive unselected STEMI patients presenting to the cardiac catheterisation laboratory with a view to undergoing primary percutaneous coronary intervention (PPCI). MINOCA was defined according to ESC criteria. Electronic patient records, blood results, angiographic and echocardiographic data were interrogated to determine final diagnosis, as well as 30-day and 1-year mortality rate. Of 2521 patients with full electronic dataset, 2158 (85.6%) underwent PPCI for obstructive CAD (angiographic stenosis > 70%). A further 167 (6.6%) with obstructive CAD were treated medically or surgically. The remaining 196 (7.8%) patients had absence of obstructive CAD at angiography, of whom 167 had no stenosis (< 30%) and 29 had mild coronary atheroma (stenosis > 30% but < 50%). A total of 110 (4.4%) patients met diagnostic criteria for MINOCA. All-cause mortality at 30-days and 1-year were 3.6% and 4.5%, respectively. In our cohort, 1 in 20 patients presenting with STEMI had MINOCA. This is the first description of the relatively high incidence of MINOCA in a STEMI cohort using current ESC definition and diagnostic criteria and could help power future trials in this area. Mortality rate was relatively high in our study and similar to that in large meta-analyses.

Pathophysiology of Takotsubo Syndrome.

Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment-elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.

No additional value of conventional and high-sensitivity cardiac troponin over clinical scoring systems in the differential diagnosis of type 1 vs. type 2 myocardial infarction.

BACKGROUND: The distinction of type 1 and type 2 myocardial infarction (MI) is of major clinical importance. Our aim was to evaluate the diagnostic ability of absolute and relative conventional cardiac troponin I (cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in the distinction between type 1 and type 2 MI in patients presenting at the emergency department with non-ST-segment elevation acute chest pain within the first 12 h. METHODS: We measured cTnI (Dimension Vista) and hs-cTnT (Cobas e601) concentrations at presentation and after 4 h in 200 patients presenting with suspected acute MI. The final diagnosis, based on standard criteria, was adjudicated by two independent cardiologists. RESULTS: One hundred and twenty-five patients (62.5%)were classified as type 1 MI and 75 (37.5%) were type 2 MI. In a multivariable setting, age (relative risk [RR]=1.43, p=0.040), male gender (RR=2.22, p=0.040), T-wave inversion (RR=8.51, p<0.001), ST-segment depression (RR=8.71, p<0.001) and absolute delta hs-cTnT (RR=2.10, p=0.022) were independently associated with type 1 MI. In a receiver operating characteristic curve analysis, the discriminatory power of absolute delta cTnI and hs-cTnT was significantly higher compared to relative c-TnI and hs-cTnT changes. The additive information provided by cTnI and hs-cTnT over and above the information provided by the "clinical" model was only marginal. CONCLUSIONS: The diagnostic information provided by serial measurements of conventional or hs-cTnT is not better than that yielded by a simple clinical scoring model. Absolute changes are more informative than relative troponin changes.

International standardization of diagnostic criteria for vasospastic angina.

The Coronary Vasomotion Disorders International Study Group (COVADIS) was established to develop international standards for the diagnostic criteria of coronary vasomotor disorders. The first symposium held on the 4-5 September 2013 addressed the criteria for vasospastic angina, which included the following (i) nitrate-responsive angina, (ii) transient ischaemic electrocardiogram changes, and (iii) documented coronary artery spasm. Adoption of these diagnostic criteria will improve the clinical diagnosis of this condition and facilitate research in this field.