Catherine N. Marti

Endothelial Dysfunction, Arterial Stiffness, and Heart Failure

Outcomes for heart failure (HF) patients remain suboptimal. No known therapy improves mortality in acute HF and HF with preserved ejection fraction; the most recent HF trial results have been negative or neutral. Improvement in surrogate markers has not necessarily translated into better outcomes. To translate breakthroughs with potential therapies into clinical benefit, a better understanding of the pathophysiology establishing the foundation of benefit is necessary. Vascular function plays a central role in the development and progression of HF. Endothelial function and nitric oxide availability affect myocardial function, systemic and pulmonary hemodynamics, and coronary and renal circulation. Arterial stiffness modulates ventricular loading conditions and diastolic function, key components of HF with preserved ejection. Endothelial function and arterial stiffness may therefore serve as important physiological targets for new HF therapies and facilitate patient selection for improved application of existing agents.

Developing Therapies for Heart Failure with Preserved Ejection Fraction: Current State and Future Directions

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

Soluble guanylate cyclase: a potential therapeutic target for heart failure.

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)—soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO–sGC–cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO–sGC–cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO–sGC–cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

Heart Failure in Patients With Human Immunodeficiency Virus Infection Epidemiology, Pathophysiology, Treatment, and Future Research

With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus type 1 (HIV-1) infection has become a chronic disease with longer life expectancy.1 The HIV Outpatient Study showed that, with the addition of antiretroviral therapy (ART), mortality declined from 29.4 to 8.8 per 100 person-years.2 More recent data indicate that the proportions of patients expected to survive 5, 10, and 15 years after seroconversion in the HAART era are 99%, 93%, and 89%, respectively.3 With the increased life expectancy and decreased morbidity from opportunistic infections, the recognition and importance of chronic complications associated with HIV-1 infection are becoming more evident. Cardiac diseases are common complications found in these patients. The spectrum of heart diseases varies significantly between developed and developing countries and, in developed countries, between pre-HAART and post-HAART eras.4 Among them, HIV-associated cardiomyopathy, broadly defined as a decreased left ventricular (LV) ejection fraction or dilated LV by imaging studies, with or without symptoms of heart failure, is currently recognized as a major long-term complication of HIV-1 infection in developing countries; however, it is still prevalent in developed countries.4 Many questions regarding its pathogenesis and treatment remain unanswered. The epidemiology of HIV-associated cardiomyopathy has changed since the first report in 1986.5 The advent of HAART has significantly altered both the incidence and prevalence of this disease, and the definition of HIV-associated cardiomyopathy has also evolved from one of primarily systolic dysfunction to now reflect the growing recognition of diastolic dysfunction in these patients. The incidence of HIV-associated cardiomyopathy is difficult to ascertain because very few studies actually evaluated this measure. In the pre-ART era, HIV-associated cardiomyopathy was defined as symptomatic, systolic dysfunction with a dilated LV and was seen almost exclusively in patients with advanced HIV disease and AIDS. These older studies, …

Soluble Tumor Necrosis Factor Receptors and Heart Failure Risk in Older Adults Health, Aging, and Body Composition (Health ABC) Study

Background— Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type 1 (sTNF-R1) and type 2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear. Methods and Results— Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age, 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF-R2 levels was 3.14 (2.42–4.06), 1.46 (1.25–1.76), and 3.43 (2.95–4.02) ng/mL, respectively. During a median follow-up of 11.4 (6.9–11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02–1.61 per log2 increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15–2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80–1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2; interaction P =0.531, 0.091, and 0.795, respectively) and in both sexes (TNF, sTNF-R1, sTNF-R2; interaction P =0.491, 0.672, and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95% CI, 1.03–3.18; P =0.038 for preserved versus HR, 0.90; 95% CI, 0.56–1.44; P =0.667 for reduced ejection fraction; interaction P =0.05). Conclusions— In older adults, elevated levels of sTNF-R1 are associated with increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.Background— Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type 1 (sTNF-R1) and type 2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear. Methods and Results— Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age, 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF-R2 levels was 3.14 (2.42–4.06), 1.46 (1.25–1.76), and 3.43 (2.95–4.02) ng/mL, respectively. During a median follow-up of 11.4 (6.9–11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02–1.61 per log2 increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15–2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80–1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2; interaction P=0.531, 0.091, and 0.795, respectively) and in both sexes (TNF, sTNF-R1, sTNF-R2; interaction P=0.491, 0.672, and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95% CI, 1.03–3.18; P=0.038 for preserved versus HR, 0.90; 95% CI, 0.56–1.44; P=0.667 for reduced ejection fraction; interaction P=0.05). Conclusions— In older adults, elevated levels of sTNF-R1 are associated with increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.

Echocardiographic Assessment of Pulmonary Artery Systolic Pressure and Outcomes in Ambulatory Heart Failure Patients

Background Pulmonary hypertension (PH) in patients with heart failure (HF) is associated with worse outcomes and is rapidly being recognized as a therapeutic target. To facilitate pragmatic research efforts, data regarding the prognostic importance of noninvasively assessed pulmonary artery systolic pressure (PASP) in stable ambulatory patients with HF are needed. Methods and Results We examined the association between echocardiographic PASP and outcomes in 417 outpatients with HF (age, 54±13 years; 60.7% men; 50.4% whites; 24.9% with preserved ejection fraction). Median PASP was 36 mm Hg (interquartile range [IQR]: 29, 46). After a median follow‐up of 2.6 years (IQR: 1.7, 3.9) there were 72 major events (57 deaths; 9 urgent heart transplants; and 6 ventricular assist device implantations) and 431 hospitalizations for HF. In models adjusting for clinical risk factors and therapy, a 10‐mm Hg higher PASP was associated with 37% higher risk (95% CI: 18, 59; P<0.001) for major events, and 11% higher risk (95% CI: 1, 23; P=0.039) for major events or HF hospitalization. The threshold that maximized the likelihood ratio for both endpoints was 48 mm Hg; those with PASP ≥48 mm Hg (N=84; 20.1%) had an adjusted hazard ratio of 3.33 (95% CI: 1.96, 5.65; P<0.001) for major events and 1.47 (95% CI: 1.02, 2.11; P=0.037) for major events or HF hospitalization. Reduced right ventricular systolic function had independent prognostic utility over PASP for adverse outcomes. Right atrial pressure and transtricuspid gradient both contributed to risk. Conclusions Elevated PASP, determined by echocardiography, identifies ambulatory patients with HF at increased risk for adverse events.

Nitrate Therapy for Heart Failure: Benefits and Strategies to Overcome Tolerance

Combination therapy with hydralazine and nitrates can improve outcomes in patients with heart failure and low ejection fraction. However, this combination is underused in clinical practice for several reasons, including side effects related to hydralazine and polypharmacy. Some of the benefits seen with hydralazine, including afterload reduction and attenuation of nitrate tolerance, have also been observed with angiotensin-converting enzyme inhibitors. Demonstrating similar clinical benefits with nitrates plus angiotensin-converting enzyme inhibitor therapy alone, in the absence of hydralazine, may represent an opportunity to improve heart failure care by increasing the use of nitrates. In this paper, we summarize data that support studying such an approach.

Soluble Tumor Necrosis Factor Receptors and Heart Failure Risk in Older AdultsClinical Perspective

Background— Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type 1 (sTNF-R1) and type 2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear. Methods and Results— Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age, 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF-R2 levels was 3.14 (2.42–4.06), 1.46 (1.25–1.76), and 3.43 (2.95–4.02) ng/mL, respectively. During a median follow-up of 11.4 (6.9–11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02–1.61 per log2 increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15–2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80–1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2; interaction P =0.531, 0.091, and 0.795, respectively) and in both sexes (TNF, sTNF-R1, sTNF-R2; interaction P =0.491, 0.672, and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95% CI, 1.03–3.18; P =0.038 for preserved versus HR, 0.90; 95% CI, 0.56–1.44; P =0.667 for reduced ejection fraction; interaction P =0.05). Conclusions— In older adults, elevated levels of sTNF-R1 are associated with increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.Background— Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type 1 (sTNF-R1) and type 2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear. Methods and Results— Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age, 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF-R2 levels was 3.14 (2.42–4.06), 1.46 (1.25–1.76), and 3.43 (2.95–4.02) ng/mL, respectively. During a median follow-up of 11.4 (6.9–11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02–1.61 per log2 increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15–2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80–1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2; interaction P=0.531, 0.091, and 0.795, respectively) and in both sexes (TNF, sTNF-R1, sTNF-R2; interaction P=0.491, 0.672, and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95% CI, 1.03–3.18; P=0.038 for preserved versus HR, 0.90; 95% CI, 0.56–1.44; P=0.667 for reduced ejection fraction; interaction P=0.05). Conclusions— In older adults, elevated levels of sTNF-R1 are associated with increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.

Acute heart failure: patient characteristics and pathophysiology.

The number of hospitalizations for acute heart failure (HF) continues to increase and it remains the most common discharge diagnosis among Medicare beneficiaries. Prognosis after hospitalization for HF is poor, with high in-hospital mortality and even higher post-discharge mortality and rehospitalization rates. It is a complex clinical syndrome that varies widely with respect to clinical presentation and underlying pathophysiology. This paper reviews what is documented in the literature regarding the known pathophysiologic mechanisms reported in patients hospitalized for HF.

Incident Heart Failure in Relation to Vascular Disease: Insights from the Health, Aging, and Body Composition Study

The contribution of heart failure (HF) unrelated to vascular disease to the overall HF burden in older adults is not well characterized. This was investigated in this study.