In the past, cardiovascular research in chronic heart failure (HF) was traditionally focussed on the analysis of circulatory regulation of the arterial tone. From the development of the neurohormonal model of chronic HF with the predominance of vasoconstrictive factors like catecholamines and angiotensin II 1 to the recent research projects centered around endothelial function in chronic HF, 2-4 it was the arterial side of the circulation that received the greatest attention.

Arterial endothelial dysfunction in chronic HF is characterized by a reduced endothelium-dependent vasodilation. Especially during exercise, small resistance vessels exhibit a blunted vasodilatory capacity that contributes to increased systemic vascular resistance and peripheral hypoperfusion. 3,4 The functional relevance of arterial endothelial function has been confirmed in clinical intervention studies. 5

The reasons for the preponderance of studies on arterial endothelial dysfunction are diverse: first of all, the methodological arsenal to assess arterial endothelial function in chronic HF is extremely well developed, ranging from in vitro models of isolated aortic or arteriolar rings to in vivo hemodynamic measurements of arterial resistance and quantitative measurement of endothelial function by noninvasive (strain-gauge plethysmography, Doppler ultrasound) and invasive methods (Doppler guide-wires, quantitative angiography). The thin vascular wall, lack of a robust muscular media, and high compliance make the assessment of isolated venous rings difficult. 6 In vivo studies of venous function often are hampered by the influence of factors like posture, circulating blood volume, and right ventricular function. These methodological factors may have added to the prejudice that preload regulation is less important for cardiac function and exercise tolerance compared with reduction of peripheral vascular resistance and afterload.

In this issue, Welsch et al (JCR. 2002;22:321-326) report that forearm venous capacitance and venous outflow were significantly reduced in patients with chronic HF and showed inverse correlations with exercise tolerance as assessed by 6-minute walking test. Their work helps to bring venous function back to our attention as a potential factor for hemodynamic function and exercise capacity in HF. However, several important questions still need to be answered.

First, not only the indices of venous function but also forearm arterial inflow and vascular resistance correlated with exercise tolerance. It remains unclear whether reduced venous outflow during plethysmography can be regarded as an independent predictor of exercise capacity or whether it is reduced as a result of reduced arterial inflow-indicating a pathologic arterial vascular function. The present study does not answer the question if changes in venous function occur independently from arterial function in chronic HF. In a recent clinical trial, Nightingale et al 7 reported a preserved venous endothelial function as assessed by radionuclide forearm venous plethysmography, even in the presence of arterial endothelial dysfunction. 7 They argued that the veins and the arteries are different with regard to the regional basal nitric oxide (NO) generation by the endothelium: although arterial endothelium has a high basal NO production, it is extremely low in veins. 6 This is the result of a reduced endothelial cell NO synthase expression in veins-possibly as a result of the lower local flow velocity. On the other hand, venous endothelium has been shown to generate lower amounts of reactive oxygen species as a result of a reduced response of the NAD(P)H oxidase system to angiotensin II thus reducing local NO breakdown. 8 These differences in local reactive oxygen species concentration would explain Nightingale's results.

Second, one fourth of the chronic HF patients were on nitrates and 19 of 20 were on diuretics. These two classes of HF drugs reduce venous vascular tone or total blood volume thereby affecting the filling pressures of the venous capacitance vessels. It is not reported whether patients on nitrates, for instance, had a lower forearm venous outflow as compared to chronic HF patients without preload-reducing medications.

Third, invasive hemodynamics, coronary status, ejection fraction are not reported, making it difficult to distinguish whether patients in the present study were in systolic or diastolic HF. Ideally, invasive measurements of right and left ventricular filling pressures and cardiac output should be correlated with parameters of venous function to prove the concept that reduced venous outflow as measured by strain gauge plethysmography indeed lowers ventricular preload and cardiac output.

Last, the majority of the study subjects were African Americans and three fourths of them had hypertensive heart disease. This study cohort is not representative of typical chronic HF populations in which ischemic cardiomyopathy is the predominant cause of HF. 9

These limitations, however, should not deter us from addressing venous function as a study parameter but should rather stimulate future research projects. Measurement of venous function in chronic HF is an area with many undiscovered countries waiting to be explored. However, greater scrutiny with regard to intervening factors (eg, arterial vascular tone, backward failure with elevated pulmonary pressure, intravascular volume, medications) is necessary to analyze in which way changes in venous function are related to the condition or intervention to be examined.

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