Calcific diseases of the cardiovascular system, such as atherosclerotic calcification and calcific aortic valve disease, are widespread and clinically significant, causing substantial morbidity and mortality. Vascular cells, like bone cells, interact with their matrix substrate through molecular signals, and through biomechanical signals, such as traction forces transmitted from cytoskeleton to matrix. The interaction of contractile vascular cells with their matrix may be one of the most important factors controlling pathological mineralisation of the artery wall and cardiac valves. In many respects, the matricrine and matrix mechanical changes in calcific vasculopathy and valvulopathy resemble those occurring in embryonic bone development and normal bone mineralisation. The matrix proteins provide a microenvironment for propagation of crystal growth and provide mechanical cues to the cells that direct differentiation. Small contractions of the cytoskeleton may tug on integrin links to sites on matrix proteins, and thereby sense the stiffness, possibly through deformation of binding proteins causing release of differentiation factors such as products of the members of the transforming growth factor-β superfamily. Inflammation and matrix characteristics are intertwined: inflammation alters the matrix such as through matrix metalloproteinases, while matrix mechanical properties affect cellular sensitivity to inflammatory cytokines. The adhesive properties of the matrix also regulate self-organisation of vascular cells into patterns through reaction-diffusion phenomena and left-right chirality. In this review, we summarise the roles of extracellular matrix proteins and biomechanics in the development of inflammatory cardiovascular calcification.

Previously considered a degenerative process, cardiovascular calcification is now established as an active process that is regulated in several ways by lipids, phospholipids, and lipoproteins. These compounds serve many of the same functions in vascular and valvular calcification as they do in skeletal bone calcification. Hyperlipidemia leads to accumulation of lipoproteins in the subendothelial space of cardiovascular tissues, which leads to formation of mildly oxidized phospholipids, which are known bioactive factors in vascular cell calcification. One lipoprotein of particular interest is Lp(a), which showed genome-wide significance for the presence of aortic valve calcification and stenosis. It carries an important enzyme, autotaxin, which produces lysophosphatidic acid (LPA), and thus has a key role in inflammation among other functions. Matrix vesicles, extruded from the plasma membrane of cells, are the sites of initiation of mineral formation. Phosphatidylserine, a phospholipid in the membranes of matrix vesicles, is believed to complex with calcium and phosphate ions, creating a nidus for hydroxyapatite crystal formation in cardiovascular as well as in skeletal bone mineralization. This review focuses on the contributions of lipids, phospholipids, lipoproteins, and autotaxin in cardiovascular calcification, and discusses possible therapeutic targets.

Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.

Heart failure (HF) with borderline ejection fraction was first defined in 2013 in the American College of Cardiology/American Heart Association guidelines as the presence of the typical symptoms of HF and a left ventricular ejection fraction (LVEF) of 41% to 49%. In 2016, the European Society of Cardiology specified HF with mid-range ejection fraction (HFmrEF) as LVEF of 40% to 49%. This range of LVEF is less well studied compared with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Although there are effective, guideline-directed medical therapies for patients with HFrEF, no therapies thus far show measurable benefit in HFpEF. Patients with HFmrEF have a clinical profile and prognosis that are closer to those of patients with HFpEF than those of HFrEF, with certain distinctions. Whether these patients represent a unique and dynamic HF group that may benefit from targeted therapies known to be beneficial in patients with HFrEF, such as neurohormonal blockade, requires further study. This review summarizes what is known about the clinical epidemiology, pathophysiology, and prognosis for patients with HFmrEF and how these features compare with the more well-studied HF groups. Although recommended treatments currently focus on aggressive management of comorbidities, we summarize the studies that identify a potential signal for beneficial therapies. Future studies are needed to not only better characterize the HFmrEF population but to also determine effective management strategies to reduce the high cardiovascular morbidity and mortality burden on this phenotype of patients with HF.

Purpose of review

To describe the epidemiology, pathophysiology, management, and prognosis of patients with heart failure with mid-range ejection fraction (HFmrEF).

Recent findings

In 2013, The American Heart Association (AHA)/American College of Cardiology (ACC) assigned an ejection fraction (EF) range to heart failure with reduced ejection fraction (HFrEF, EF ≤ 40%) and heart failure with preserved ejection fraction (HFpEF, EF ≥50%). This classification created a "gray zone" of patients with EFs between 41% and 49% that ultimately came to be known as heart failure with borderline or mid-range ejection fraction. HFmrEF patients represent a group with heterogeneous clinical characteristics that at times resembles HFrEF, at others HFpEF, and at others still a unique phenotype altogether. No randomized controlled trials exist in those with HFmrEF, though HFrEF and HFpEF studies that include overlap suggest some potential benefit of beta blockers, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. Mortality rates among the HFmrEF population are significant, and are similar to those in patients with HFrEF and HFpEF. HFmrEF is a complex disorder that remains poorly understood. Future research is needed to better elucidate the pathophysiology, management, and prognosis of this condition.

Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guideline-directed medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

Introduction: Asian-American/Pacific Islanders (AAPIs) and Hispanics are two of the most rapidly growing minorities, but both are poorly represented in the cardiovascular literature. In light of national quality improvement efforts to ensure adherence to cardiovascular therapy guidelines, this study examines guideline adherence and outcomes in AAPIs and Hispanics compared to non-Hispanic Whites (NHW) in a quaternary care center after percutaneous coronary intervention (PCI). Methods: 1,896 AAPI, Hispanics, and NHW adults from February 28, 2012 to December 30, 2020 who underwent emergent or elective PCI were included. The primary endpoint was the prescription of post-PCI guideline-directed medical therapy including aspirin, statins, P2Y12 receptor blockers, and cardiopulmonary rehabilitation. Secondary endpoints included comorbidity burden, post-PCI morbidity and mortality, and prior PCI. Analyses were adjusted for age, sex, and insurance type. Results: Hispanics had the lowest median age and the highest rates of government insurance. Hispanics had lower odds of either ACE inhibitor or ARB prescription versus NHW (OR = 0.75, p = 0.03). Odds of ticagrelor prescriptions were lower for both Hispanics (OR = 0.56, p = 0.01) and AAPIs (OR = 0.62, p = 0.02) versus NHW. However, odds of clopidogrel prescriptions were higher for Hispanics than NHW (OR = 1.57, p = 0.01), while AAPIs trended towards the same (OR = 1.42, p = 0.05). No differences were found for statin or cardiopulmonary rehabilitation prescriptions. AAPIs and Hispanics had significantly higher risks of diabetes (OR = 2.28 and 1.8 respectively, p < 0.01) and of being on dialysis (OR = 2.25 and 2.52 respectively, p < 0.01) than NHW. AAPIs also had higher odds of hypertension than NHW (OR = 1.51, p = 0.01). Hispanics had significantly higher risk of post-PCI mortality versus NHW (OR = 2.12, p < 0.01). Conclusions: AAPIs and Hispanics had lower odds of ticagrelor prescription than NHW, and Hispanics had higher odds of clopidogrel prescription. Hispanics also had higher odds of mortality post-PCI. Further, AAPIs and Hispanics had higher comorbidity burdens. This study suggests that despite quality improvement efforts, work remains to be done to narrow health disparities.

Background

Since January 2020, COVID-19 has affected more than 100 million people in the U.S. Previous studies on racial and ethnic disparities related to characteristics and outcomes of COVID-19 patients have been insightful. However, appropriate epidemiologic age-standardization of the disease burden and disparities for hospitalization data are lacking.

Objective

To identify and describe racial and ethnic disparities for primary COVID-19 hospitalizations in the U.S. in 2020.

Methods

In this nationally representative observational study, we use the National Inpatient Sample to quantify racial and ethnic disparities in COVID-19 hospitalizations. Descriptive statistics for patient characteristics, common comorbidities, age-standardized hospitalization rates, inpatient complications, and mortality among COVID-19 hospitalizations were contrasted by race and ethnicity.

Results

There were 1,058,815 primary COVID-19 hospitalizations in 2020. Of those, 47.2% were female, with median age of 66 (IQR, 54, 77). Overall inpatient mortality rate was 11.1%. When compared to White patients, Black, Hispanic, and Native American patients had higher age-standardized hospitalization rate ratios of 2.42 (95% CI 2.40-2.43), 2.26 (2.25-2.28), and 2.51 (2.46-2.56), respectively. Non-White patients had increased age-adjusted rates for procedures and complications. Factors associated with inpatient mortality include age, male sex, Hispanic or Native American race or ethnicity, lower income, Medicaid, heart failure, arrhythmias, coagulopathy, and chronic liver disease.

Conclusions

Marginalized populations in the U.S. had over twice the COVID-19 hospitalization rate relative to White patients. Age-adjusted mortality rates were highest for Black, Hispanic, and Native American patients. Careful consideration for vulnerable populations is encouraged during highly communicable respiratory pandemics.