Heart failure
Definition [1]
Heart failure (HF), as defined by the American College of Cardiology (ACC) and the American Heart Association (AHA), is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood.
Stages of heart failure [2]
Stage A: At risk for heart failure
People at risk for heart failure but do not yet have symptoms or structural or functional heart disease
Risk factors for people in this stage include:
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Obesity
-
Exposure to cardiotoxic agents
-
Genetic variants for cardiomyopathy
-
Family history of cardiomyopathy
Stage B: Pre-heart failure
People without current or previous symptoms of heart failure but with:
-
Structural heart disease
-
Increased filling pressures in the heart
-
Other risk factors
Stage C: Symptomatic heart failure
People with current or previous symptoms of heart failure
Stage D: Advanced heart failure
People with heart failure symptoms that disrupt daily life functions or lead to hospitalization
NYHA Functional Classification [2]
Class Patient Symptoms
I. No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or shortness of breath.
II. Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, shortness of breath, or chest pain.
III. Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, shortness of breath, or chest pain.
IV. Symptoms of heart failure at rest. Any physical activity causes further discomfort.
Signs and symptoms [3]
History
History of previous heart failure (LR+ 5.8)
PND (LR+ 2.6)
Atrial fibrillation (LR+ 3.8)
Clinical impression of heart failure by the physician (LR+ 4.4)
Signs
Jugular venous distention (LR+ 5.1)
S3 or third heart sound (LR+ 11)
Hepatojugular reflux (LR+6)
Rales (LR+ 2.8)
Edema alone: nonspecific
Edema plus Jugular venous distention: Likely cardiogenic edema
Bendopnea [4]
Bendopnea was assessed by asking patients to bend forward and report any shortness of breath within 30 seconds.
Increase intrathroacic pressure
Increase pulmonary vascular resistance
Increase intraabdominal pressure
Increase Venous return
AI-generated photos
Framingham criteria [6]
( Sensitivity ranges from 92% to 97%, while specificity ranges from 78% to 79%, depending on the specific study and definition of heart failure. )
2 Major or 1 Major + 2 minor
Major criteria
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Acute pulmonary edema
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Cardiomegaly
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Hepatojugular reflux
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JVP distension
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Paroxysmal nocturnal dyspnea or orthopnea
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Rales
-
Third heart sound gallop
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Subacute loss weight > 4.5 kg in 5 days in response to treatment
Minor criteria
-
Ankle edema
-
Dyspnea on exertion
-
Hepatomegaly
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Nocturnal cough
-
Pleural effusion
-
Tachycardia > 120 beats per minute
Precipitating causes
MNEMONIC: HAPPI TREMOR
Hypertension
Anemia, Arrhythmia
Pulmonary embolism
Pregnacy
Infection
Thyrotoxicosis
Renal disease
Endocarditis
Myocardial infarction
Oral salt intake, overload
Drugs: noncompliance,
Salt-water retention: Pioglitazone, Alpha blockers
Cardiotoxicity: Doxorubicin, Trastuzumab
Rheumatic heart disease
Hemodynamic Profiles in Patients With Heart Failure [5]
Warm and Dry
Cold and Dry
Warm and Wet
Cold and Wet
Congestion
Estimated PCWP ≥22 mm Hg
Inadequate perfusion
Estimated CI ≤2.2 l/min/m2
- +
-
+
Diuretics
Inotropic agents
Physical Exam Findings for Detection of Elevated Intracardiac Pressures in Patients With Known or Suspected HF [9,10]
Finding | Sensitivity (%) | Specificity (%) |
|---|---|---|
Bilateral pulmonary rales | 12 - 60 | 78 - 96 |
Edema (≥2+) | 10 - 50 | 78 - 96 |
Hepatojugular reflux | 24 - 84 | 83 - 98 |
JVP ≥8 cmH2O | 10 - 58 | 92 - 97 |
Orthopnea (≥2 pillows) | 42.8 | 87.5 |
PND | 42.8 | 89.8 |
S3 | 12 - 37 | 85 - 99 |
S4 | 5 - 71 | 50 - 97 |
Perfusion
include narrow pulse pressure, cool extremities, a global assessment of cold made by the clinician,
Proportional pulse pressure [7]
Proportional pulse pressure can be a maker of low CI.
Proportional pulse pressure = (systolic pressure – diastolic pressure)/systolic pressure
A proportional pulse pressure of less than 25% had 91% sensitivity and 83% specificity for a cardiac index of less than 2.2 L/min/㎡m². However, in the ESCAPE trial, PPP < 25% was found infrequently, with 16 out of 188 cases showing a sensitivity of 10%, a specificity of 96%, a positive predictive value (PPV) of 87.5, a negative predictive value (NPV) of 28, and a likelihood ratio (LR+) of 2.54. (8)
Chest X-rays (9)
Chest X-ray was moderately specific (76–83%) but insensitive (67–68%).
CXR Finding | Sensitivity (%) | Specificity (%) |
|---|---|---|
Cardiomegaly | 54 - 64 | 71 - 79 |
Bilateral pleural effusions | 1 - 20 | 95 - 99 |
Alveolar edema | 2 - 12 | 97 - 99 |
Interstitial edema | 18 - 29 | 93 - 95 |
NT-proBNP
Acute
NT-proBNP
Rule-out
≤ 300 pg/ml
Age-adjusted
Rule-in
<50
≥450 pg/ml
50-74
≥ 900 pg/ml
≥ 75
≥ 1800 pg/ml
Chronic
≤ 125 pg/ml
≥ 125 pg/ml
≥ 250 pg/ml
≥ 500 pg/ml
Noncardiac causes of elevated BNPs
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Advance age
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Anemia
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Renal failure
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Pulmonary: severe pneumonia, pulmonary hypertension
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Critical illness
-
Bacterial sepsis
-
Severe burns
-
Toxic-metabolic insults e.g., cancer chemotherapy and envenomation
* Obesity may lead to an underestimation of BNP levels.
Furosemide [11]
Mechanism: inhibits Na-K-2Cl symporter
Pharmacokinetic
Absorption: Bioavailability about 50% (varies), onset 1-2 hours to peak effect.
Distribution: Bind to albumin > 90%, Vd 0.07-0.2 L/kg
Metabolism: By the liver (approximately 10%)
Excretion: By the kidneys via filtration and tubular secretion, the total time of therapeutic effect is 6-8 hours
Dose equivalence: 40 mg of furosemide = 20 mg of torsemide = 1 mg of bumetanide
For patients with acute decompensated heart failure
The initial dose is 20-40 mg administered intravenously or an equivalent dose greater than the total daily oral maintenance dose of furosemide that the patient is currently taking. Diuretic dose adjustments should be based on the patient's clinical response.
Continuous dose VS Bolus dose
Low dose diuretic VS High dose diuretic (2.5X) [13]
The Diuretic Strategies in Patients with Acute Decompensated Heart Failure (Dose trial): In a double-blind, randomized trial with a prospective 2x2 factorial design, 308 patients suffering from acute decompensated heart failure were administered intravenous furosemide. The treatment involved either a bolus every 12 hours or a continuous infusion, with dosages determined based on either the patient's previous oral dose or 2.5 times that dose. After 48 hours, adjustments to the doses were permitted. The primary endpoints included patients' global assessment of symptoms, measured by the area under the curve (AUC) on a visual-analogue scale over 72 hours, and changes in serum creatinine levels.
Comparing bolus to continuous infusion showed no significant differences in symptom assessment (mean AUC: 4236 ± 1440 vs. 4373 ± 1404; P = 0.47) or in creatinine levels (0.05 ± 0.3 mg/dL vs. 0.07 ± 0.3 mg/dL; P = 0.45). A trend suggested greater improvement in the high-dose group (mean AUC: 4430 ± 1401 vs. 4171 ± 1436; P = 0.06), but no significant difference in their creatinine levels (0.08 ± 0.3 mg/dL vs. 0.04 ± 0.3 mg/dL; P = 0.21). The high-dose strategy led to increased diuresis and better outcomes in some secondary measures, along with transient worsening of renal function.
In patients with acute decompensated heart failure, there were no significant differences in symptom assessment or renal function changes between bolus and continuous diuretic therapy, nor between high-dose and low-dose therapy.
Diuretic resistance
FeNa
Normal
Heart failure (decreased maximum effect)
Renal failure (increased dose to achieve ordinary response)
Diuretic concentration
Drug pharmacology: Poor absorption, Dose, and Sodium intake
Extra renal: Renal blood flow, Central venous congestion, Hypoalbuminemia
Intra Renal: Reduced GFR, increased proximal tubule sodium reabsorption, hypochloromic alkalosis
Rebound phenomenon (Postdiuretic Sodium Retention) (11)
A decrease in sodium excretion below baseline after the effect of the loop diuretic has worn off. Volume depletion activates the sodium retaining mechanism.
Braking phenomenon (12)
Diuretic braking refers to a sudden decrease in urine production following repeated diuretic administration, leading to a loss of responsiveness to the diuretic.
The observed effects result from both changes in blood flow at the glomerulus and adaptive responses in the distal nephron. In a groundbreaking study conducted on rats by Kaissling, treatment with furosemide was linked to cellular hypertrophy in the distal convoluted tubule, the connecting tubule, and the cortical collecting duct.
TOLVAPTAN [14]
Mechanism: Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist.
Pharmacokinetic
Absorption: Bioavailability about 40%, peak concentration 2-4 hours, elimination half-life 12 hours
Distribution: Bind to albumin > 99%, 3L/kg; Healthy subjects: 3L/kg; slightly higher in heart failure patients.
Metabolism: Metabolism is exclusively by the CYP3A4 enzyme in the liver. Avoid concomitant use of Tolvaptan with strong CYP3A inducers. Metabolites are inactive.
Excretion: Fecal elimination is minimal, with less than 1% of tolvaptan being excreted unchanged in the urine.
At the initiation of Tolvaptan
1. Discontinue fluid restriction and allow the patient to drink when they feel thirsty.
2. Monitor sodium (Na) levels every 6 hours for the first 36 hours, then every 12 hours thereafter.
3. Review the use of Tolvaptan at 3, 6, and 9 days.
4. Be aware that correcting hyponatremia too quickly (e.g., greater than 12 mEq/L in 24 hours) can lead to osmotic demyelination.
Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure. The EVEREST Outcome Trial:
Patients were randomly assigned within 48 hours of admission to receive oral tolvaptan (30 mg once daily, n = 2072) or a placebo (n = 2061) for at least 60 days, in addition to standard therapy.
The primary endpoints included all-cause mortality (assessed for superiority and noninferiority) and the composite of cardiovascular death or hospitalization for heart failure (assessed for superiority). Secondary outcomes included changes in dyspnea, body weight, and edema.
During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 patients (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The mortality difference remained within the noninferiority margin (P < .001). The composite of cardiovascular death or hospitalization occurred in 42.0% of the tolvaptan group and 40.2% of the placebo group (hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary outcomes showed that tolvaptan improved dyspnea, body weight, and edema but had no impact on cardiovascular mortality or heart failure hospitalization. In patients with hyponatremia, serum sodium levels significantly increased. The overall Kansas City Cardiomyopathy Questionnaire score did not improve, though effects on body weight and serum sodium persisted after discharge. Increased thirst and dry mouth were noted, but major adverse events occurred at similar rates in both groups.
In summary, Tolvaptan initiated for acute heart failure treatment did not affect long-term mortality or morbidity.
Acetazolamide [16]
Mechanism: Acetazolamide is a diuretic and carbonic anhydrase inhibitor medication.
Pharmacokinetic
Absorption: Well absorbed orally.
Distribution: Carbonic anhydrase inhibitors, such as acetazolamide, bind tightly to carbonic anhydrase. Therefore, tissues rich in these enzymes, such as the kidneys and red blood cells, will have higher concentrations of carbonic anhydrase inhibitors, including acetazolamide.
Metabolism: Acetazolamide does not undergo metabolic alteration.
Excretion: The plasma half-life is between 6 and 9 hours, with renal excretion being the primary method of elimination.
Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR trial): In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro–B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed.
A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17-1.82; P < 0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups.
In summary, adding acetazolamide to loop diuretic therapy for patients with acute decompensated heart failure led to a higher rate of successful decongestion.
Spironolactone [15]
Efficacy and Safety of Spironolactone in Acute Heart Failure The ATHENA-HF Randomized Clinical Trial:
This double-blind and placebo (or low-dose)-controlled randomized clinical trial was conducted in 22 US acute care hospitals among patients with AHF who were previously receiving no or low-dose (12.5 mg or 25 mg daily) spironolactone and had NT-proBNP levels of 1000 pg/mL or more or B-type natriuretic peptide levels of 250 pg/mL or more, regardless of ejection fraction.
Participants were randomized to receive either high-dose spironolactone (100 mg) or a placebo, or 25 mg of spironolactone (usual care) daily for 96 hours.
The primary end point was the change in NT-proBNP levels from baseline to 96 hours. Secondary end points included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety end points included hyperkalemia and changes in renal function.
A total of 360 patients were randomized into two groups. There was no significant difference in log NT-proBNP reduction between the high-dose spironolactone group (-0.55, 95% CI, -0.92 to -0.18) and the usual care group (-0.49, 95% CI, -0.98 to -0.14; P = .57). Additionally, secondary endpoints, including day-30 mortality and heart failure hospitalization rates, were similar between the groups.
In conclusion, the ATHENA-HF trial demonstrated that adding 100 mg of spironolactone daily to standard diuretic therapy did not improve outcomes in patients with worsening heart failure. The short treatment duration of just four days may not have allowed enough time for the accumulation of its active metabolite, canrenone.
References
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