Enter Stage A, Exit Stage D: A Curtain Call for Delay in Heart Failure Prevention

By 1990, the end of the decade in which the CARDIA study was initiated, heart failure (HF) was the cause of death for approximately 38,000 people per year in the United States.¹ The Centers for Disease Control (CDC) had shown that crude death rates for HF were proportionate to age – 31.6 per 100,000 persons for those aged 65-74 years – and that these rates for people older than 65 years increased substantially from 1980-1990.¹ CDC data also revealed race-specific variations in age-adjusted death rates for HF; African-American men were dying earlier and in the greatest numbers.¹ From National Health and Nutrition Examination Survey (NHANES) data from the same decade, we learned that for younger individuals – aged 55-74 years – the overall 10-year and 15-year mortality rates from HF were > 55%.² The authors of this NHANES analysis posed a series of provocative questions regarding the contributions of smoking, lipids, and hypertension to the development of HF and inquired how the course of prevalent HF is shaped by these and other risk factors.²

Since then, the CARDIA study has aimed to answer these and other questions regarding the evolution of cardiovascular risk factors and diseases in one of the youngest cohorts to be longitudinally observed. In this issue of Circulation: Heart Failure, Gidding et al.³ describe the antecedents and progression of the American College of Cardiology (ACC)/American Heart Association (AHA) heart failure stages over 25 years in a cohort of generally healthy young African-American and white women and men. The authors hypothesized that HF would become more prevalent and severe over time, African-Americans would be more adversely affected, and obesity would be associated with these findings. They sought to expand our knowledge on the predictive capacity of the pre-symptomatic HF stages by observing young adults.

In this study, 2,189 participants had complete Year 5 and Year 30 examination and echocardiographic data, including standardized measurements of cardiovascular risk factors through physical, laboratory, and exercise-related examinations and psychosocial and behavioral assessments. At Year 5 (ages 22-37 years, mean 30.1 years), 79% of the cohort was classified as Stage 0, 16% as Stage A, and 5% as Stage B – even at these young ages, 21% of the overall cohort was already at risk for HF. Similarly, an alarming 20% of the 22-25 year olds in this Year 5 cohort were at risk for HF. At Year 30 (age 47-62 years, mean 55.2 years), 69% of the overall cohort was at risk for or had HF – 42% were Stage A, 26% were Stage B, and 1% were Stage C/D. For the entire cohort, 62% of those classified as Stage 0 at baseline had progressed to Stages A-D by Year 30 – making them either at risk for or having HF. At Year 5, African-American women and men already had higher prevalences of more advanced HF stages compared to white women and men, a disparity that persisted at Year 30.

In their important paper, the authors present the distributions of 27 demographic and risk factor characteristics of the study cohort at both Years 5 and 30. We can simplify and contextualize these findings by aligning them with the AHA’s Life’s Simple 7 (LS7) – 7 factors that represent ideal cardiovascular health, promoted by the AHA and, when optimal, have definitively been shown to reduce morbidity and mortality from cardiovascular disease, stroke, and heart failure in global populations.⁴ Using this LS7 construct, here is how the CARDIA cohort fared:

1. Manage Blood Pressure: At both Years 5 and 30, overall cohort participants with HF Stages A-D had significantly higher systolic and diastolic blood pressures.

2. Control Cholesterol: At Year 30, participants’ total cholesterol declined across progressive HF stages, although values for nearly every stage were higher compared to those from Year 5.

3. Reduce Blood Sugar: By Year 30, 12.5% of the overall cohort had developed diabetes, compared to a prevalence of 0.2% at Year 5.

4. Get Active: Participants’ self-reported physical activity fell over 25 years with the Year 30 Stage C/D cohort having the lowest physical activity scores.

5. Eat Better: No diet-related data were disclosed.

6. Lose Weight: At Year 5, 23% of Stage A participants were obese (BMI ≥ 30 kg/m²) with that proportion rising to 72% at Year 30. At Year 5, the mean BMI of the original CARDIA cohort was 25.4 kg/m².

7. Stop Smoking: 23.1% of the overall cohort was smoking at Year 5; by Year 30, only 12.0% of participants identified as active smokers.

Studies from other diverse longitudinal cohorts, like Framingham Offspring⁵, Atherosclerosis Risk in Communities (ARIC)⁶, Multi-Ethnic Study of Atherosclerosis (MESA)⁷, and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL)⁸, have demonstrated lower HF risks and incidences in participants with optimal LS7 scores. By nearly every metric, this CARDIA cohort failed to achieve ideal cardiovascular health, resulting in nearly half of the cohort living with Stage A HF at Year 30.

In the same decade as the CDC’s aforementioned warning regarding rising HF prevalence and mortality, mortality from coronary heart disease declined.¹ Complex modeling studies attributed the largest influences on this decline to the expansion of secondary prevention efforts, like thrombolysis, percutaneous and surgical coronary interventions, and the use of angiotensin-converting enzyme inhibitors and statins. Primary prevention and risk factor reduction had taken a backseat to the development and implementation of evidence-based medical therapies for acute coronary syndromes.^9,10 Heart failure prevalence continued to increase, likely due to a combination of factors including advances in medical therapy for myocardial infarction, an increasing incidence of HF, a growing awareness of the disease, an aging population, and a rising prevalence of obesity and diabetes. Despite the rising HF prevalence, age-adjusted rates for HF-related cardiovascular death in the U.S. declined in the late 20^th century. However, since 2012, we have seen a startling trend toward a rise in HF-related cardiovascular death rates with a disproportionately high mortality in younger adults (aged 35-64 years) and African-Americans.¹¹ This Gidding et al. analysis is a time capsule – an indictment of the primary prevention failures of our past and a warning call for the impending HF mortality burden of our future.

These data from CARDIA and from many other cohorts make it abundantly clear that young adulthood is a critical time for cardiovascular risk factor education, prevention, and treatment when appropriate. However, there are considerable barriers to actualizing these interventions. First, there is a dearth of evidence regarding cardiovascular disease risk factor modification in 20-50 year olds. Recent large randomized trials like SPRINT¹² and other ongoing trials continue to exclude adults aged < 50 years due to their low average cardiovascular disease risk, resultant high costs associated with their inclusion, and failure to achieve outcomes of interest in this population. We agree with the authors’ conclusion that continuing to follow our current system of clinical trial design with the focus on event-driven endpoints will bias us against discovering impactful interventions to reduce long-term cardiovascular disease risks in young adults.

Second, we, as cardiologists, cannot do this alone. We do not typically care for patients like these CARDIA cohort participants at Year 5, aged 22-37 years, and often not even until after Year 30. These vulnerable younger adults are cared for by primary care providers, obstetrician/gynecologists, and often by no one at all. With frequently changing preventive health goalposts – like blood pressure and lipid targets and physical activity and diet recommendations – more people at risk for and with disease become identified, and an already overburdened health care workforce struggles to assume more responsibility for surveillance and action. But, there are models for success. We have learned that health outreach centered outside of our practices and around a community mainstay, in one case the barbershop, can be very effective in achieving significant and durable HF risk factor modification in a vulnerable population.^13,14 We must invest in collaborative efforts with primary care providers, community health workers, other cardiovascular team professionals, and the interested lay public to deliver simple, cost-effective, and scalable preventive interventions to our patients much earlier in their lives.

Lastly, we are at our own Year 30 crossroads. Undoubtedly, there have been outstanding advances in secondary prevention and treatment of HF over three decades, and expanded HF prevention and treatment indications for therapies like angiotensin-neprilysin inhibitors and sodium-glucose co-transporter-2 inhibitors are under investigation and highly anticipated. At the same time, under our watch, our highest risk patients are being denied potentially life-saving cardiovascular therapies¹⁵ and our youngest generations are at risk to become casualties of a new kind of tobacco epidemic.¹⁶ The future of HF prevention will be defined by the disparities created by the lacks of evidence-based interventions, longitudinal preventive care, and our own activism.

When it comes to young adults, our health care system is built to focus our attentions on short-term needs over lifetime risk management. At each visit, we should not only thoughtfully assess the cardiovascular risk profile of the individual in front of us but also envision the stage she/he is standing on at Year 30. And, before each day’s curtain call, we should take direction from the authors of the 2013 ACCF/AHA HF guideline – HF “stages are progressive and inviolate; once a patient moves to a higher stage, regression…is not observed.”¹⁷