Left-sided heart failure (LHF) causes pulmonary hypertension and right-sided heart failure (RHF) as a result of “back pressure”

Pulmonary hypertension and right ventricle (RV) systolic dysfunction occurring with normal left ventricle (LV) systolic function is synonymous with isolated RHF

A single hemodynamic assessment demonstrating a mean pulmonary artery pressure > 25 mm Hg, and a pulmonary capillary wedge pressure (PCWP) < 15 mm Hg is sufficient to diagnose isolated RHF (ie, rule out biventricular heart failure [HF])

Failing to realize that bilateral pleural effusions are virtually pathognomonic for biventricular HF

Failing to realize that left atrial enlargement, with a normal mitral, valve is pathognomonic for LHF

Labeling an edematous patient as euvolemic

Acknowledging that a patient has LHF but deciding that the severity of a symptom or sign (eg, pulmonary hypertension, RV failure, exercise limitation) is out of proportion to the pulmonary capillary wedge pressure (PCWP), LVEDP, or the diagnostic filling abnormality seen on echo, before a trial of euvolemia

Confusing failure to diurese (not achieving a negative fluid balance despite loop diuretic administration) with failure of diuresis (achieving a negative fluid balance that unfortunately does not improve the patient’s condition)

Equating renal and serum indices that suggest “prerenal” azotemia (eg, Na ⁺ -avid urine, blood urea nitrogen (BUN)/creatinine (CR) > 20) with intravascular volume depletion (forgetting they are also produced by cardiorenal physiology) and volume overload

Considering pulmonary vasodilatior therapy for a patient with LHF because the RV failure is “out of proportion” to the degree of LV failure

Diagnosing acute respiratory distress syndrome (ARDS) (which requires “no evidence of pulmonary venous hypertension”) in a patient with bilateral pleural effusions

It is the job of the pulmonologist to evaluate and manage unexplained pulmonary hypertension, RHF, and exercise limitation

• •
  

  Unexplained means not obvious from pulmonary function tests (PFTS) and/or echocardiogram

The most common cause of unexplained pulmonary hypertension, RHF, and exercise limitation is “occult left heart failure”

Occult left heart failure describes the situation where other physicians, sometimes cardiologists, have concluded that a patient is not suffering from biventricular HF, often despite obvious pathognomonic signs (eg, bilateral pleural effusions, elevated PCWP pressure, left atrial enlargement, and peripheral edema) ( Fig. 6.1 )

Encapsulated case of occult left-sided heart failure (LHF). (A) Initial pulmonary evaluation for gradually worsening dyspnea on exertion with peripheral edema (NYHA III), revealing moderate restriction on pulmonary function tests (PFTs), a normal chest x-ray, and a right-sided heart catheterization demonstrating LHF (mean pulmonary artery pressure > 25 mm Hg with a pulmonary capillary wedge pressure (PCWP) > 15 mm Hg). Cardiology mistakenly concludes that the patient’s physical limitation is out of proportion to the magnitude of his left and right pressure elevations. This reasoning is flawed because the severity of heart failure is graded clinically and it is not possible to conclude that symptoms are “out of proportion to” a single resting echocardiogram or cardiac catheterization measurement. PCWP systematically underestimates left ventricular end-diastolic pressure (LVEDP), and LVEDP may rise dramatically with exercise in the decompensated individual with heart failure with a preserved ejection fraction (HFpEF). (B) The primary care physician is mistakenly concerned that his rising creatinine-indicated acute kidney injury (AKI), erroneously attributing it to intravascular volume depletion, despite edema. Pulmonary follow-up shows dramatically improved exercise tolerance (NHYA I), improved PFTs and a stable/improving creatinine with only ~ 6 lbs of net fluid loss. This case also highlights the importance of discontinuing rennin-angiotensin system inhibition during diuresis in patients with significant chronic kidney disease (CKD) (autoregulation already difficult enough for the kidneys in this setting).

Missed or “occult” LHF is most commonly a phenomenon of diastolic heart failure (a.k.a. heart failure with a preserved ejection fraction [HFpEF])

• •
  

  Patients with systolic dysfunction are less likely to have their decompensated heart failure “missed” when they present with new or worsening pulmonary hypertension, RHF, and/or exercise limitation

Occult LHF should be excluded by an empiric trial of euvolemia (which is always indicated) before invasive testing (eg, cardiac catheterization) and/or extensive work up (eg, cardiopulmonary exercise testing)

Biventricular HF from diastolic dysfunction mimics a myriad of pulmonary disease presentations; for example:

• •
  

  Group I pulmonary arterial hypertension (idiopathic pulmonary arterial hypertension [IPAH]-like “small vessel disease”)

  
  
  
  
  • •
    

    Patient presents with exercise limitation, increased pulmonary artery systolic (PAS) pressure on echocardiogram, and normal LV systolic function

  
  
  
  
• •
  

  Worsening chronic obstructive pulmonary disease (COPD) with cor pulmonale

  
  
  
  
  • •
    

    COPD patient presents with increased dyspnea on exertion and increased lower extremity edema

  
  
  
  
• •
  

  Exacerbation of interstitial lung disease (ILD)

  
  
  
  
  • •
    

    ILD patient presents with increased interstitial markings, worse oxygenation, more restriction, and increased lower extremity edema

  
  
  
  
• •
  

  Indolent lymphoma

  
  
  
  
  • •
    

    Patient presents with fluorodeoxyglucose (FDG)-avid mediastinal adenopathy

  
  

Similarly, biventricular HF from diastolic dysfunction mimics many ICU presentations; for example:

• •
  

  Acute pulmonary embolism with RV dysfunction

  
  
  
  
  • •
    

    Patient presents with hypotension, new RV dysfunction, and normal LV systolic function

  
  
  
  
• •
  

  ARDS

  
  
  
  
  • •
    

    Intubated patient develops worsening compliance, oxygenation, and diffuse infiltrates

  
  
  
  
• •
  

  Ondine’s curse

  
  
  
  
  • •
    

    Patient presents with sudden, unexplained central hypoventilation

  
  

Patients with lung disease, preserved LV systolic function, and peripheral edema pose a significant diagnostic challenge:

• •
  

  Isolated RHF (from cor pulmonale) vs biventricular HF (from diastolic dysfunction)

  
  
• •
  

  The stakes are high ( hospice for cor pulmonale vs diuretics for LHF )

Critically ill hypotensive patients with RV dysfunction and preserved LV systolic function also pose a significant diagnostic challenge:

• •
  

  Isolated RHF vs biventricular HF (from LV diastolic dysfunction)

  
  
• •
  

  Stakes are high ( lytics for presumed massive PE, pulmonary vasodilator therapy for IPAH or diuretics for LHF )

Acute and chronic respiratory failure is always impacted by LHF, because interstitial edema:

• •
  

  Decreases compliance

  
  
• •
  

  Increases airway resistance (submucosal edema)

  
  
• •
  

  Worsens obesity-related hypoventilation

Definition of LHF:

• •
  

  LHF is synonymous with biventricular HF

  
  
  
  
  • •
    

    Isolated LHF does not exist (not compatible with human physiology)

  
  
  
  
• •
  

  LHF is defined as an LVEDP > 15 mm Hg (normal < 12 mm Hg) regardless of the mechanism:

  
  
  
  
  • •
    

    Primary cardiac causes (eg, myocardial infarction [MI], arrhythmia) or volume overload (eg, anuric renal failure)

  
  
  
  
• •
  

  LHF, regardless of the mechanism, ultimately involves:

  
  
  
  
  • •
    

    Decreased LV cardiac output (CO) leading to increased pressure in the left ventricle at the end of diastole, or an elevated LVEDP

  
  

LHF occurs as a consequence of either systolic or diastolic dysfunction:

• •
  

  Systolic dysfunction equals impaired LV squeeze (a.k.a. heart failure with reduced ejection fraction [HFrEF])

  
  
  
  
  • •
    

    Systolic dysfunction occurs in people with a cardiomyopathy, most commonly from ischemic heart disease, hypertension (HTN), alcohol, and viral or idiopathic disease

  
  
  
  
• •
  

  Diastolic dysfunction equals impaired LV filling, despite a normal or high ejection fraction (a.k.a. HFpEF)

  
  
  
  
  • •
    

    Diastolic dysfunction occurs in people experiencing poor ventricular compliance (eg, stiff ventricle) as seen with LVH and hypertensive heart disease, and shortened diastole (ie, filling time) as seen in tachycardia

    
    
  • •
    

    Diastolic dysfunction represents a functional, dynamic failure that can occur in any normal heart if appropriately stressed

    
    
  • •
    

    Diastolic dysfunction is often provoked, unmasked, or exacerbated by:

    
    
    
    
    • •
      

      Hypoxia (stiffens the ventricle and causes tachycardia)

      
      
    • •
      

      Tachycardia (shortens diastole, ie, the time allowed for ventricular filling)

      
      
    • •
      

      Hypertension (stiffens the ventricle (LVH) and decreases CO directly by afterload)

      
      
    • •
      

      Total body volume overload (increased preload)

      
      
      
      
      • •
        

        Total body volume overload is commonly caused by:

        
        
        
        
        • •
          

          Impaired natriuresis (as in chronic kidney disease [CKD] or acute kidney injury [AKI])

          
          
        • •
          

          Intravenous sodium loading (as occurs during resuscitation)

        
        

      
      

    
    

  
  

Regardless of the mechanism of the LHF (ie, systolic or diastolic dysfunction), RHF occurs via a neurohormonal reflex (a.k.a. the biventricular HF reflex ) ( Fig. 6.2 ):

• •
  

  Increased LVEDP causes an increase in left atrial (LA) pressure and pulmonary venous (PV) pressure directly, via “back pressure”

  
  
• •
  

  Increased PV pressure triggers a neurohormonal reflex that causes pulmonary artery vasoconstriction leading to an increase in PA pressure, ensuring and maintaining forward blood flow through the lungs ( Fig. 6.3 )

  
  

  
  

  
  

  

  
  

  
  

  Schematic describing the determinants of pulmonary blood flow via the “waterfall hypothesis.” Said differently, the distensible nature of the pulmonary vasculature, behaving like a “starling resistor,” means that direct, backward transmission of pressure (a.k.a. “back pressure”) from the pulmonary veins to the pulmonary arteries would only occur after forward blood flow stopped. This is not compatible with human physiology (and does not occur). The only time left sided cardiac pressures are directly and rapidly transmitted to the right side is during tamponade physiology.

  
  

  (Adapted from Westerhof N et al. Physiol Rev 2006;86:1263–1308.)

  
  
  
  
• •
  

  Increased PA pressure then increases right ventricular end-diastolic pressure (RVEDP) directly (via increased afterload), causing right heart failure

  
  
• •
  

  Increased RVEDP leads to an increased right atrial pressure (RAP) and central venous pressure (CVP) directly, via “back pressure,” leading to peripheral edema and pleural effusions

Flow diagram depicting the pathophysiology of biventricular heart failure (HF) (heart failure with preserved ejection fraction [HFpEF] and heart failure with reduced ejection fraction [HFrEF]), where black arrows denote direct “back pressure,” blue arrow denote “mechanical effect,” and red arrows denote “neurohormonal signaling.” The biventricular HF reflex describes the pulmonary vascular aspect of the neurohormonal signaling that is responsible for pulmonary hypertension and right-sided heart failure (RHF). The diagram shows that transudative pleural effusions are pathognomonic for biventricular HF (ie, do not occur with isolated RHF) by requiring both an elevated pulmonary venous pressure (causing pulmonary edema that weeps into the pleural space) and an elevated central venous pressure (CVP) (to prevent thoracic lymphatic drainage of the fluid). The diagram highlights that individuals whose heart failure leaves them with LVEDP values in the 15–18 mm Hg range will be clinically and radiographically indistinguishable from patients with pulmonary vascular disease and isolated RHF (ie, pulmonary hypertension, peripheral edema, and exercise limitation).

This neurohormonal reflex maintains forward blood flow from pulmonary arteries to pulmonary veins despite pulmonary venous hypertension (which threatens to stop forward flow by removing the right-to-left pressure gradient) ( Fig. 6.4 )

• •
  

  This reflex also ensures that, as LVEDP rises, peripheral edema occurs before (and preferentially to) pulmonary edema

(A) Neurohormonal reflex of biventricular heart failure (HF) demonstrated in an isolated perfused dog lung lobe. In this model, left ventricular end-diastolic pressure (LVEDP) increase is simulated by pulmonary venous occlusion, which leads to a nearly instantaneous linear rise in pulmonary artery pressure. (B) The same experimental model as in A after simultaneous occlusion of both the pulmonary vein and artery to obtain an equilibration pressure. A model where the pulmonary artery and vein behave like a solid conduit (ie, back pressure model) predicts that the equilibrated pressure, after simultaneous occlusion of both pulmonary artery and vein, should equal the pulmonary venous pressure at the time of occlusion (obtained by backward extrapolation). Instead, the actual equilibrated pressure is higher than predicted because of pulmonary arterial tone generated by the biventricular HF reflex.

(Adapted from Linehan, JH, Dawson CA, Rickaby DA. Distribution of vascular resistance and compliance in a dog lung lobe. J Applied Physio: Respir, Enviro and Exer Physio 53(1):158–68, 1982.)

The biventricular HF reflex is the mechanism by which LV diastolic dysfunction gives rise to RV systolic dysfunction, an echocardiogram finding often misconstrued as pathognomonic for pulmonary vascular disease ( Fig. 6.5 )

Encapsulated case showing new right ventricle (RV) systolic dysfunction misinterpreted as acute pulmonary embolism in a patient admitted with heart failure with preserved ejection fraction (HFpEF). Repeat studies were obtained 5 days later because the patient was deemed to be euvolemic (by the absence of peripheral edema). His chest x-ray and computed tomography (CT) scan demonstrate persistent bilateral pulmonary embolisms pleural effusions, illustrating the point that that peripheral edema resolves before pleural fluid during diuresis. A lateral film with close inspection of the costophrenic angles is the simplest screen for euvolemia (after peripheral edema resolves) in a patient with biventricular heart failure. Note : CT angiography was ultimately obtained by the medicine SVC, after transfer from the intensive care unit, given persistent (but unfounded) concerns for pulmonary embolism based on the original echocardiogram finding and the disbelief that RV systolic function could be caused by left ventricle (LV) diastolic dysfunction (which is actually quite common).

The biventricular HF reflex maintains forward flow and is protective against pulmonary edema in the face of LVEDP elevations

As LVEDP rises, left atrial and pulmonary venous pressure rise via “back pressure,” leading to pulmonary edema

If increased pulmonary venous pressure were then directly transmitted to the pulmonary arteries in a continued “back pressure” fashion, the pulmonary vascular pressure gradient from right to left would disappear and blood would not flow forward (this does not occur)

Instead, an increase in pulmonary venous pressure reflexively triggers an increase in pulmonary artery tone (either a little or a lot) via a neurohormonal reflex

Traditionally, if the increase in mPAP is just enough to overcome the increase in LVEDP and maintain forward flow, the patient is said to have “passive pulmonary hypertension”

• •
  

  Where the transpulmonary gradient (mPAP-LVEDP) is ≤ 12 mm Hg

Conversely, if the mPAP is significantly elevated, the patient is said to have “out-of-proportion” or “reactive” pulmonary hypertension

• •
  

  Where the transpulmonary gradient (mPAP-LVEDP) > 12 mm Hg

Thus the “passive” vs “reactive” designation given to the pulmonary hypertension seen with LHF is arbitrary and not physiologic as implied

• •
  

  So-called passive patients have a more blunted biventricular HF reflex

  
  
  
  
  • •
    

    Making them prone to pulmonary edema

  
  
  
  
• •
  

  So-called reactive patients have a more robust biventricular HF reflex

  
  
  
  
  • •
    

    Making them prone to excessive peripheral edema and ascites (RHF symptoms) protecting them against pulmonary edema ( Fig. 6.6 )

    
    

    
    

    
    

    

    
    

    
    

    (A) The normal relationship between mean pulmonary artery pressure (mPAP) and left ventricle end-diastolic pressure (LVEDP) when LVEDP is normal (< 12 mm Hg). (B) The relationship between mPAP and LVEDP when it is high (> 15 mm Hg) in individuals with a “blunted” or “passive” biventricular HF reflex, resulting in a modest elevation in mPAP, just enough to keep it above the waterfall point ensuring forward flow. (C) The relationship between mPAP and LVEDP when LVEDP is high (> 15 mm Hg) in individuals with a “robust” or “reactive” biventricular HF reflex, resulting in a large elevation in mPAP, keeping it well above the “waterfall point.” (D) The fictitious scenario known as “back pressure,” where LVEDP rises above the waterfall point such that it can directly affect pulmonary artery pressure (doing so only after forward flow stops).

    
    

  
  

The passive vs reactive designation has no implications on management

Additionally, the terms cause significant confusion:

• •
  

  “Passive” is misconstrued as “back pressure”

  
  
• •
  

  “Reactive” is misconstrued as “vasoreactive”

  
  
• •
  

  “Out of proportion” is misconstrued to imply a need for specific pulmonary vasodilator therapy (actually contraindicated)

Scatter plot below, shows that a PCWP of 25 may generate a pulmonary artery systolic (PAS) pressure anywhere from ~38 mm Hg to ~ 99 mm Hg Fig. 6.7

Scatterplot of the pulmonary capillary wedge pressure (PCWP) and the pulmonary artery systolic (PAS) pressure of 1000 patients with left-sided heart failure. The data demonstrate the enormous individual variability in pulmonary artery pressure for any given PCWP ( or left ventricle end-diastolic pressure [LVEDP]) (ie, enormous variability in the biventricular heart failure reflex).

(Adapted from Drazner et al. J Heart and Lung Transplant 18:11.)

The range in PAS pressures among people is explained by individual variability in the biventricular HF reflex— not small vessel vascular remodeling, hypoxic vasoconstriction, or back pressure

• •
  

  This variability makes the designation “out of proportion” impossible to make

Normal LVEDP is 3–8 mm Hg (< 12 mm Hg)

When LVEDP and pulmonary venous pressure (PVP) rise to > 15 mm Hg, the biventricular HF reflex is triggered, increasing mPAP by vasoconstriction, and to varying degrees, vascular remodeling

Elevated mPAP leads to an increased RVEDP (often with RV systolic dysfunction) and subsequently right atrial pressure (RAP) and CVP

• •
  

  Ensuring continued right-to-left pulmonary blood flow

  
  
• •
  

  Causing peripheral edema before pulmonary edema

When LVEDP and PVP rise > 18 mm Hg, interstitial edema ensues

When LVEDP and PVP rise > 25 mm Hg, alveolar edema occurs

When sustained elevations of both CVP and PVP occur, bilateral pleural effusions accumulate

When biventricular HF continues, further sustained elevations of CVP lead to accumulation of ascites

The biventricular HF reflex, though poorly characterized, occurs when elevated LVEDP (> 15 mm Hg) causes pulmonary venous hypertension, which triggers both:

• •
  

  An instantaneous increase in mPAP involving PA vasoconstriction (likely via serotonergic neurons) and

  
  
• •
  

  A sustained increase in mPAP, likely driven by hormonal changes in pulmonary artery endothelial cells such as:

  
  
  
  
  • •
    

    Increased endothelin synthesis, decreased nitric oxide synthesis, and decreased prostacyclin synthesis

  
  

These hormonal changes act on pulmonary artery smooth muscle cells, causing:

• •
  

  Hypertrophy, hyperplasia, and increased tone

  
  
• •
  

  Together these changes lead to varying degrees of pulmonary vascular (small vessel) remodeling with luminal narrowing and complete occlusion

The instantaneous (vasoconstrictive) increase in pulmonary artery tone seen in biventricular HF is vulnerable to reversal with pulmonary vasodilators (eg, IV prostacyclin)

• •
  

  Causing sudden pulmonary edema, failure of forward blood flow through the heart, and death