■ Genes that encode nuclear membrane proteins

HEART FAILURE ■
(laminin)
Muscular dystrophies
DEFINITION
➢ RHD as major cause of HF in Africa & Asia, esp in younger
➢ A complex clinical syndrome that results from structural or
pts
functional impairment of ventricular filling or ejection of
➢ HTN: as major cause in African and African-American
blood (ACCF/AHA, 2022)
populations
➢ Chagas’ disease is still a major cause of HF in South
EPIDEMIOLOGY America.
➢ >20 million cases worldwide
➢ Prevalence:
❖ Overall prevalence in adult population in developed
countries is 2%
❖ Rises with age; affects 6-10% of people >65 y/o
❖ Women comprises atleast ½ of HF cases due to longer
life expectancy; but incidence of HF is lower than in men
❖ In north america & europe: lifetime risk in developing
HF is approx. 1 out of 5 for a 40 y/o
➢ HF was once thought to arise primarily in the setting of a
depressed LV EF; but studies have shown that approx. ½ of
pts who develop HF have a normal or preserved EF (EF
≥50%).
➢ Categorization:
❖ Reduced EF (HFrEF; formerly systolic failure)
❖ HF with a preserved EF (HRpEF; formerly diastolic
failure)

PROGNOSIS
➢ 30–40% of pts die within 1 year of dx; 60–70% die within 5
years, mainly from worsening HF or as a sudden event (i.e.
ventricular arrhythmia).
➢ Patients with sx at rest NYHA class IV have a 30–70%
ETIOLOGY annual mortality rate,
➢ Any condition that leads to an alteration in LV structure or ➢ Patients with sx with moderate activity NYHA class II have
fXN can predispose a pt to develop HF an annual mortality rate of 5–10%.
➢ CAD: predominant cause in men & women; 60-75% of cases
of HF
➢ Hypertension: 75% of pts, often assoc. w/ CAD
➢ HF w/ a depressed EF:
○ 20-30% of cases of HF; exact etiology not known
○ Pts referred to as having nonischemic, dilated, or
idiopathic cardiomyopathy if the cause is unknown
➢ Dilated cardiomyopathy:
○ may be due to prior viral infection or toxin exposure
○ or 2ry to genetic defects; mutations in..
■ genes that encode cytoskeletal proteins (desmin,
cardiac myosin, vinculin)
 BASIC MECHANISMS OF HF
HF w/ a Reduced Ejection Fraction (HFrEF)
➢ LV remodeling in response to:
○ Myocyte hypertrophy
○ Alterations in the contractile properties of myocyte
○ Progressive loss of myocytes due to necrosis, apoptosis
and autophagy
○ B-adrenergic desensitization
○ Abnormal myocardial energetics & metabolism
○ Reorganization of ECM = dissolution of structural
PATHOGENESIS collagen weave >> replacement by an interstitial
collagen matrix
➢ The biologic stimuli for the changes above include
mechanical stretch of the myocyte, circulating
neurohormones (e.g., norepinephrine) inflammatory
cytokines (e.g., TNF), other peptides and growth factors (e.g.,
endothelin), & ROS (e.g., superoxide).
➢ Transcriptional and posttranscriptional changes in genes &
proteins that regulates excitation-coupling & cross-bridge
interaction:
○ Due to sustained neurohormonal activation and
mechanical overload
○ include decreased fxn of SERCA2A >> decreased ca2+
uptake into the SR, &
○ hyperphosphorylation of the ryanodine receptor, leading
➢ Index event = initiates either the damage of heart muscle to ca2+ leakage from the SR.
causing loss of functioning cardiac myocytes OR disruption  Changes that occur in the crossbridges include:
of myocardium ability to contract o decreased expression of α-myosin heavy chain
➢ LV dysfunction may remain asymp due to compensatory o increased expression of β-myosin heavy chain
mechanisms to preserve LV fxn: o myocytolysis; disruption of the cytoskeletal links
1. Activation of RAAS and adrenergic nervous system between the sarcomeres and ECM.
2. Increased myocardial contractility o Result = impaired ability of the myocyte to contract >>
3. Activation of vasodilatory molecules (ie., ANP & BNP, depressed LV systolic fxn
bradykinin, prostaglandins [PGE2 and PGI2], and NO) to  Impaired myocardial relaxation is caused by:
counteract excessive peripheral vascular vasoconstriction o Myocardial relaxation is ATP-dependent process >>
➢ Transition to symptomatic HF by increasing activation of Reductions in ATP concentration >> slowed relaxation
neurohormonal, adrenergic, and cytokine systems >> LV
remodeling
 omyocardial stiffness 2ry to cardiac hypertrophy &
increased myocardial collagen content may contribute to
diastolic failure.
o As occurs in ischemia
 Factors contributing to elevated LV end-diastole pressure:
o Delayed LV filling due to reduced compliance
o Inc in HR >> shortens time for diastolic filling
o Inc pulmonary capillary pressure >> dyspnea

Left Ventricular Remodeling

 Refers to the changes in LV mass, volume, & shape and the  May occur in pts w/ abdominal obesity or ascites; and
composition of the heart that occur after cardiac injury patients with pulmonary disease
and/or abnormal hemodynamic loading conditions
 Mechanical burdens contribute to the progression of HF Paroxysmal Nocturnal Dyspnea (PND)
 LV dilation >> LY wall thinning + increase in afterload >>  Acute episodes of severe SOB & coughing;
functional afterload mismatch = decreased stroke volume  Generally, occur at night and awaken the patient from sleep,
o LV dilation may also cause tethering of the papillary usually 1–3 h after the patient sleep
muscles with resulting incompetence of the mitral valve  Sx: coughing or wheezing, possibly due to inc pressure in
>> MR the bronchial >> airway compression + interstitial
 High end-diastolic wall stress may lead to: pulmonary edema = increased airway resistance.
o hypoperfusion of the subendocardium, w/ resultant  Often have persistent coughing & wheezing even even at
worsening of LV fxn upright position.
o inc oxidative stress, w/ resultant activation of genes that  Cardiac asthma is closely r/t PND, is characterized by
are sensitive to free radical generation (e.g., TNF) wheezing 2ry to bronchospasm
o sustained expression of stretch activation of hypertrophic
signaling pathways Cheyne-Stokes Respiration
 Aka periodic respiration or cyclic respiration
 present in 40% of patients with advanced HF; assoc. w/ low
ACC/AHA Stages of HF CO

CLINICAL MANIFESTATIONS
General Symptoms
 Cardinal symptoms of HF = fatigue and SOB
 Dyspnea:
o Exertional dyspnea on early stages; may occur at rest as
disease progresses
o Most important mechanism is pulmonary congestion w/
accumulation of interstitial fluid
o Pulmonary congestion activates juxtacapillary J
receptors >> rapid, shallow breathing (cardiac dyspnea)
o Contributing factors: dec pulmonary compliance, inc
airway resistance, respiratory muscle and/or diaphragm
fatigue, & anemia
Orthopnea
 Dyspnea in a recumbent position
 Later manifestation of HF
 Due to redistribution of fluid from the splanchnic circulation
& lower limbs into the central circulation during
recumbency >> increase in pulmonary capillary pressure.
 Nocturnal cough is a common sx;frequently overlooked
symptom of HF
 Generally is relieved by sitting upright or sleeping with
additional pillows.
 caused by an increased sensitivity of the respiratory center to  Pulmonary edema = rales may be heard widely over both
arterial Pco2 & a lengthy circulatory time lung fields and may be accompanied by
 Apneic phase = arterial Po2 falls and arterial Pco2 rises. expiratory wheezing (cardiac asthma)
 Changes in ABG stimulate respiratory center >>  Rales absent in chronic HF due to inc lymphatic drainage of
hyperventilation and hypocapnia >> recurrence of apnea alveolar fluid
 Pleural effusion:
Other symptoms: o Due to elevation of pleural capillary pressure >> fluid
 Acute pulmonary edema sx transudation into pleural cavity
 GI: nausea, early satiety assoc. w/ abdominal pain & fullness o occur most commonly w/ biventricular failure
r/t edema of bowel wall and/or congested liver (RUQ pain) o if unilateral, occur more in the R pleural space
 CNS: confusion, disorientation, sleep & mood disturbances
 Nocturia Cardiac examination
 If (+) cardiomegaly: PMI displaced below 5 th ICS &/or
lateral to MCL; palpable over two interspaces
 Severe LV hypertrophy leads to a sustained PMI.
 Some pts has audible and palpable S3 at the apex
o most commonly present in pts w/ volume overload who
have tachycardia & tachypnea
o often signifies severe hemodynamic compromise
 Patients with enlarged or RVH may have a sustained and
prolonged left parasternal impulse extending throughout
systole
 S4 is not a specific indicator of HF; usually present in pts w/
diastolic dysfunction
 The murmurs of MR and TR are frequently present in
patients with advanced HF
PHYSICAL EXAMINATION
General appearance and vital signs: Abdomen & extremities
 Mild – mod HF = no distress at rest; feels uncomfortable  In r/t hepatomegaly:
when lying flat for a few min o enlarged liver is frequently tender and may pulsate
 Severe HF= SOB; needs to sit upright; labored breathing during systole if TR is present
 SBP = normal or high in early HF; reduced in advanced HF o Ascites, a late sign, occurs as a consequence of increased
due to severe LV dysfunction pressure in the hepatic veins and the veins draining the
 Pulse pressure diminished peritoneum.
 Sinus tachycardia o Jaundice = due to impaired hepatic fxn 2ry to hepatic
 Cyanosis of lips and nail beds = r/t peripheral congestion & hepatocellular hypoxemia & is assoc. w/
vasoconstriction inc in direct & indirect bilirubin
 Peripheral edema:
Jugular veins o Cardinal sx but nonspecific
 Provides estimation of right atrial pressure o Usually symmetric and dependent in HF; occurs
 JVP best appreciated w/ recumbent position & head tilted at predominantly in the ankles and the pretibial region in
45° ambulatory pts
 Quantified in cmH20 (normal: ≤8 cm) o At sacral area in bedridden pts
 Measure by estimating height of venous column of blood o Long-standing edema assoc. w/ indurated & pigmented
above sternal angle in cm then add 5vm skin
 Early stages of HF, the venous pressure may be normal at
rest but may become abnormally elevated with sustained Cardiac cachexia
(~15 s) pressure on the abdomen (positive abdominojugular  In severe chronic HF; w/ marked wt loss & cachexia
reflux)  If (+), has poor overall prognosis
 Giant v waves indicate the presence of TR

Pulmonary examination
 Transudation of fluid from the intravascular space into the
alveoli = crackles (rales/crepitations)
 Assessment of LV Function
 2D echo/doppler:
o semiquantitative assessment of LV size and fxn
o to

determine presence/absence of valvular &/or regional

wall motion abnormalities (indicative of a prior MI)
o L atrial enlargement + LVH + impaired LV diastolic
DIAGNOSIS & LABORATORY TESTS filling = useful for the assessment of HF with a preserved
General assessment: EF
 Clinical history o To assess RV size and pulmonary pressures to evaluate
 Physical exam findings and manage cor pulmonale
 ECG findings (any abnormality)  MRI:
o For analysis of cardiac anatomy & fxn
Routine laboratory testing o Gold standard for assessing LV mass & volumes
 In pts w/ new-onset HF and those chronic HF & acute o Used for evaluating patients with HF, both in terms of
decompensation: assessing LV structure and for determining the cause of

ECG:
 Routine 12-lead ECG
 Uses:
o assess cardiac rhythm
o determine the presence of LVH or prior MI (presence
or absence of Q-waves)
o determine QRS width to know if patient may benefit
from resynchronization therapy
 It is repeated when there is a clinical indication, such as a
suspicion for arrhythmia, ischemia or myocardial injury,
conduction, or other cardiac abnormalities

Chest X-Ray
 To assess cardiac size and shape, as well as the state of the
pulmonary vasculature, and may identify noncardiac causes
of the pt’s sx
 Some patients with acute HF have evidence of pulmonary
HTN interstitial edema, and/or pulmonary edema HF (e.g., amyloidosis, ischemic cardiomyopathy,
hemochromatosis)
 Ejection fraction (EF): RECOMMENDATIONS FOR DIAGNOSTIC
o most useful index of LV fxn TESTS
o easy to measure by noninvasive testing
o measurement is limited by alterations in afterload and/or
preload
o If EF is normal (≥50%), systolic fxn is usually adequate
o If EF is significantly depressed (<30–40%), contractility
is usually depressed.
o Myocardial strain rate imaging using speckle tracking =
shown to add incremental value to standard
measurements of LV EF and to have prognostic value.

Biomarkers
 Both BNP & N-terminal pro-BNP (NT-proBNP):
o released from the failing heart
o relatively sensitive markers for the presence of HFrEF
o elevated in HfpEF; albeit to a lesser degree
 BNP or NT-proBNP is useful to support clinical decision-
making in ambulatory pts w/ dyspnea
 Limitations: natriuretic peptide levels increase w/ age &
renal impairment, more elevated in women, & can be
elevated in right HF from any cause
 BNP levels may increase in patients taking ARNIs.
 Levels can be falsely low in obese patients.
 Other biomarkers, such as soluble ST-2 and galectin-3, are
newer biomarkers that can be used to determine the
prognosis of HF patients

Exercise testing
 To assess the need for cardiac transplantation in patients
with advanced HF
 A peak O2 uptake (vo2) <14 mL/kg/min is assoc. w/ a
relatively poor prognosis.
 vo2 <14 mL/kg/min may have better survival when
transplanted than when treated medically
(ESC
Guidelines)

DIFFERENTIAL DIAGNOSIS
HF resembles but should be distinguished from:
 1. Conditions in which there is circulatory congestion 2ry to undergoes vascular remodeling, vasoconstriction, and
abnormal salt and water retention but no disturbance of destruction.
cardiac structure or function (e.g., renal failure) o Result = pulmonary artery pressures and RV afterload
2. Noncardiac causes of pulmonary edema (e.g., ARDS). increases, setting the stage for cor pulmonale
 RV can only handle volume overload; so sustained pressure
 A very low BNP or NT-proBNP may be helpful in excluding a overload eventually leads to RV dysfunction and failure
cardiac cause of dyspnea in this setting.  Acute cor pulmonale occurs..
 Ankle edema may arise 2ry to varicose veins, obesity, renal o after a sudden and severe stimulus (e.g., massive
disease, or gravitational effects. pulmonary embolus)
 If HFpEF, it may be difficult to determine the relative o with RV dilatation and failure but no RV hypertrophy
contribution of HF to the dyspnea that occurs in chronic lung  Chronic cor pulmonale: slow progression assoc. w
disease and/or obesity compensatory RVH that lowers wall tension and preserves
RV function >> RV dilation >> increase in RV wall tension
>> overt dysfunction
COR PULMONALE o Acute decompensation of compensated chronic cor
Definition pulmonale is a common clinical occurrence.
 Aka pulmonary heart disease o Triggers include:
 Broadly defined by altered RV structure and/or fxn in the  worsening hypoxia
context of chronic lung disease  acidemia (e.g., exacerbation of COPD)
 Triggered by the presence of pulmonary HTN  acute pulmonary embolus
 Although RV dysfunction is an important sequela of  atrial tachyarrhythmia
HFpEF and HFrEF, this is not considered as cor pulmonale.  hypervolemia
 mechanical ventilation that compresses blood
Etiology vessels assoc. w/alveoli >> further increasing RV
afterload

Pathophysiology
 Pulmonary HTN + increased RV afterload = alteration of
RV structure (i.e., dilation with or without hypertrophy) and
fxn
 In lung parenchymal diseases, primary pulmonary vascular
disorders, or chronic (alveolar) hypoxia, the circulatory bed
References:
Harrison
Goldman & Schafer
Schwartz
2022 AHA/ACC/HFSA Heart Failure Guidelines
ESC Guidelines