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18 Pathophysiology of Heart Failure 183

which may lead to dysregulation of cellular oxidative lymphatic flow as microvascular filtration increases. The
VetBooks.ir stress, thereby contributing to the progressive nature of proposed mechanism is believed to be subsequent to
“tethering” of the initial lymphatics to surrounding struc-
heart failure. Mitochondrial reactive oxygen species may
produce mitochondrial damage, activation of mitogen‐
volume increases, thus increasing the radius and filtration of
activated protein kinases, cardiac hypertrophy and fibro- tures which pull the lymph vessels open as the interstitial
sis, again suggesting that alterations in organelles of the lymphatics.
metabolism may contribute to ventricular remodeling. Stage 2 occurs when the lymphatics’ capacity to
The reactive oxygen species and mitochondrial damage remove the interstitial fluid is overwhelmed. During
are also strong mediators of autophagy in certain settings this stage, fluid and colloid accumulate in the intersti-
and may serve as an additional mechanism for remode- tial areas around bronchioles, arterioles, and venules.
ling and progression to heart failure. Fluid accumulation occurs within the peribronchial
and perivascular interstitial space (versus adjacent to
the alveolar capillary membrane) because of its more
Hemodynamics of Heart Failure negative pressure and more compliant properties. The
and Development of Pulmonary Edema
enlarged lymphatics and free fluid form cuffs around
Progressive disturbances of systolic and diastolic the bronchioles and pulmonary blood vessels and may
function may ultimately lead to development of systemic subsequently compress the small airways and blood
or pulmonary venous congestion as a consequence of vessels. Gas exchange may be relatively unaffected in
elevated venous pressure. Increased plasma volume (via the early stages of edema if there is no increase in the
sodium and water retention) and reduced venous capaci- alveolar‐capillary membrane thickness along the thin
tance (via venoconstriction) no longer augment systolic side of the interstitial space. But as capillary filtrate
function in the failing heart and instead merely precipi- continues to accumulate, the less compliant interstit-
tate clinical signs associated with congestion. ium around the alveolar‐capillary septa also fills, the
Pulmonary capillary wedge pressures exceeding interstitial pressure rises, and alveolar flooding begins
25 mmHg are likely to precipitate signs of left‐sided heart (stage 3). Arterial oxygenation decreases and in severe
failure, including cough and increased respiratory rate and cases death may ensue.
effort. Pulmonary edema develops when the movement of
fluid from the blood to the interstitial space, and in some
instances to the alveoli, exceeds the return of fluid from the Therapeutic Implications
interstitial space to the blood and its drainage through the
lymphatics. There is normally a continuous exchange of Understanding of the pathophysiologic mechanisms
fluid, colloid, and solutes from the vasculature into the of heart failure enables development of therapeutic
interstitial space so a pathologic state exists only when strategies to provide symptomatic benefit and slow
there is an increase in the net flux of fluid, colloid, and sol- the natural history of disease progression. With the
utes from the vasculature into the interstitial space. The long‐standing recognition that fluid retention and
total microvascular filtration rate can change as a result of poor pump function contribute to pulmonary and
changes in filtration surface area, membrane permeability systemic venous congestion and low cardiac output,
to water, hydrostatic and colloidal osmotic pressures, and the initial therapeutic strategies were to reduce
membrane permeability to protein. Lymphatic flow will preload and afterload while augmenting contractility.
similarly be dictated by the hydrostatic pressure of the We continue to use these strategies today via the
interstitium, the pumping pressure within the lymphatics, administration of diuretics and inodilators to combat
the systemic venous pressure, and the resistance to flow. many forms of heart failure. With further advances in
During stage 1 of pulmonary edema development, the the understanding of cardiac remodeling, agents
interstitial volume remains normal due to the compensatory capable of blocking critical neurohormonal pathways,
increase in lymphatic flow. In most tissues, the increase in including ACE inhibitors, beta‐blockers, and aldos-
the hydrostatic interstitial pressure with the development of terone antagonists, were developed to prolong sur-
interstitial edema would serve to inhibit microvascular fil- vival without imposing significant alterations in
tration and enhance lymph flow. However, the interstitial cardiac loading conditions. And with further advances
pressure rarely reaches high enough values to use this pro- in the understanding of myocyte loss, altered gene
tective mechanism because (a) the increase in the interstitial expression, dysregulation of excitation‐contraction
compliance allows large volume increases with small pres- coupling, degradation of the extracellular matrix and
sure increases and (b) alveolar flooding occurs at relatively deranged cardiac metabolism, new therapeutic agents
low interstitial pressures (2–3 mmHg). The more protective will continue to be identified in an effort to one day
mechanism in the lung is the decreased resistance to halt the inevitable cycle that leads to heart failure.