Paradoxes in cardiology: Revisiting the gap between myths and facts

PULSUS PARADOXUS

In 1669, Lomer described the phenomenon of a decrease in pulse volume on inspiration in a patient with pericardial constriction.¹ Later in 1850, Floyer and William described the same finding in patients with bronchial asthma.^1,2 In 1873, Adolf Kussmaul, in the issue of ‘Berliner Klinische Wochenschrift’, coined the term ‘pulsus paradoxus’ for the peculiar phenomenon observed in 3 patients with constrictive pericarditis (CP).

Pulsus paradoxus is defined as a decrease in systolic blood pressure of >10 mmHg during inspiration. The ‘paradox’ in the term ‘pulsus paradoxus’ is the fact that heart sounds are audible over the precordium, but the pulse disappears and is not felt on inspiration. Pulsus paradoxus is an important physical sign in various cardiac and non-cardiac conditions.² In patients with bronchial asthma, it is considered an ominous sign. In some patients with inapparent hypovolaemia, it can be one of the earliest signs of impending shock.^2,3 Though the cuff sphygmomanometer remains the standard method for clinical demonstration of pulsus paradox, other methods like palpation of central pulses and arterial and pulse oximetry waveform analysis can also be used to demonstrate the paradox.

Mechanism

Under normal physiological conditions, arterial blood pressure falls during inspiration and increases during expiration due to intrathoracic pressure changes during the respiratory cycle, which are transmitted to cardiac chambers. Both these mechanisms lead to a decrease in stroke volume during inspiration. These respiratory changes are altered in patients with CP, acute exacerbation of asthma, and acute pulmonary thromboembolism due to various mechanisms that lead to pulsus paradoxus (Fig. 1). The mechanisms include:

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FIG 1.

Various cardiac and non-cardiac causes and underlying mechanism of pulsus paradoxus. Red arrows indicate the direction of septal displacement and right ventricular encroachment on the left ventricular cavity during inspiration, highlighting reduced left ventricular chamber size/filling

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1. In CP, there is a failure of transmission of intrathoracic pressures to the left cardiac chambers, leading to increased intrapericardial and reduced pulmonary venous pressure.

2. In cardiac tamponade, the increased blood pooling in the lungs and decreased left ventricular (LV) filling due to paradoxical septal motion, along with increased intrapericardial pressure, lead to decreased LV stroke volume, which manifests as pulsus paradoxus.

3. In acute massive pulmonary embolism, pulsus paradoxus is caused by acute right ventricular (RV) dilatation secondary to an embolus in the pulmonary artery, leading to RV dysfunction and underfilling of the LV. Another mechanism involves excessive blood pooling in the lungs during inspiration.

4. Pulsus paradoxus is an ominous sign in acute exacerbation of asthma and one of the most important non-cardiac causes of the paradoxical pulse, which occurs due to exaggeration in the inspiratory–expiratory difference in stroke volume, primarily mediated by intrathoracic pressure on ventricular preload.

5. In patients with chronic obstructive airway disease, hyperinflated lungs lead to air trapping, which interferes with LV filling, causing paradoxical pulse.

FONTAN PARADOX

The Fontan paradox is a specific feature of the surgically created Fontan circuit. Mark de Leval coined the term to define the unique physiological state of systemic venous hypertension in the post-Fontan state.⁴ The ‘Fontan paradox’ is the clinical state of elevated systemic venous pressure coexisting with reduced cardiac output, in the absence of a functional right ventricle in patients with total cavo-pulmonary connection surgery.^4,5 The Fontan circulation is a state of dual paradox. First, there is the physiological paradox, which includes the elevation of systemic venous pressures above pulmonary venous pressures to drive cardiac output. Second, despite deleterious complications of chronically elevated venous pressure, Fontan surgery remains a lifesaving procedure for single ventricle physiology.⁶ A cardiac transplant is the only definitive treatment for a failing Fontan. However, Marc de Leval gave a roadmap for the development of treatment options in the form of assistive devices to reverse the Fontan paradox.⁷ This is still evolving; however, it is possibly a promising treatment in patients with Fontan paradox.

REVERSED PULSUS PARADOXUS

In 1973, Massumi et al. first described the reversed pulsus paradoxus in patients with hypertrophic obstructive cardiomyopathy (HOCM), isorhythmic atrioventricular dissociation, and LV failure patients on positive pressure ventilation.⁸ Reversed pulsus paradoxus refers to a rise in systolic blood pressure during inspiration. The mechanism varies among different aetiologies. In patients on mechanical ventilation, during systole, positive pressure ventilation displaces the LV wall inward to assist LV emptying, causing a mild increase in systolic pressure during inspiration, leading to reversed pulsus paradoxus. A reversed pulsus paradoxus in mechanically ventilated patients is a sensitive indicator of hypovolaemia.⁸ Jain et al. described the reversed pulsus paradoxus mechanism in patients with HOCM. They postulated that there is a decrease in LV outflow tract gradient after deep inspiration due to increased LV transmural gradient, leading to a significant increase in afterload and subsequent decrease in LV outflow tract gradient, leading to a paradoxical increase in systolic blood pressure during deep inspiration. This concept was unrecognized till the Mayo Clinic reported 2 patients with this observation.⁹

OBESITY PARADOX

The obesity paradox is a well-known phenomenon, first described in 1999 by Fleischmann et al. in patients with chronic kidney disease on haemodialysis.¹⁰ Later, it was also observed in chronic heart failure, chronic kidney disease, acute myocardial infarction, peripheral arterial disease, chronic obstructive pulmonary disease, and others. Kamyar KalanterZadeh used the term ‘reverse epidemiology’ for the better survival observed in obese patients with chronic kidney disease. This was attributed to multiple factors, including chronic inflammation and muscle wasting, which are less in obese patients. A few studies have shown that adipose tissue stores lipophilic chemicals, which prevent their toxic or catabolic effects on the body.^11,12 Various biological hypotheses and mechanisms underlying the obesity paradox have been described (Fig. 2). The obesity paradox in patients with heart failure (HF) is extensively discussed and often multifactorial. It can be attributed to hypertension, sleep-disordered breathing, metabolic syndrome, and diastolic dysfunction. The obesity survival paradox implies that HF in obese patients has a better short-term prognosis than HF in lean patients. In addition to the adipose tissue hypothesis as described in patients with chronic kidney disease, the paradox in HF is attributed to cardiorespiratory fitness, which is determined by peak oxygen consumption or VO₂ max. Wang et al. showed that mild obesity is associated with a good short-term prognosis but high mortality in the long term, and the protective effects of heart failure are limited to a better short-term prognosis.¹³

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FIG 2.

Mechanisms of the obesity paradox in cardiovascular diseases (CVD)

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Contrary to the obesity paradox, which suggests a survival benefit in patients with a higher body mass index (BMI), recent studies adjusting for key prognostic variables have shown that this paradox does not hold true. When examining alternative anthropometric indices like waist-to-height ratio, greater adiposity was consistently associated with higher risks of HF hospitalization and cardiovascular mortality. Notably, patients in the highest quintile of waist-to-height ratio had a 39% higher risk of hospitalization for HF compared to those in the lowest quintile, even after adjustment for confounding factors. These findings underscore the importance of considering body fat distribution and ectopic fat, which BMI alone fails to capture, as predictors of adverse outcomes in HF.¹⁴

ANGIOTENSION RECEPTOR BLOCKADE AND MYOCARDIAL INFARCTION PARADOX

Angiotensin receptor blockers (ARBs) selectively antagonize AT1 (angiotensin 1) receptors and help in reduction of BP, and decrease salt and water retention. As per guidelines, ARBs prevent diabetic nephropathy and progression of hypertension and reduce HF events. Despite these benefits, observations from the VALUE trial showed a higher incidence of myocardial infarction (MI) in patients receiving valsartan, which was later described as the ‘ARB MI paradox.’¹⁵

In 2006, ARB MI paradox was described by Strauss and Hall, who stated that anticholinesterase (ACE) inhibitors can prevent subsequent MI and cardiovascular events, whereas ARBs do not prevent subsequent MI or cardiovascular death; hence, ACE inhibitors are recommended over ARBs to prevent MI or cardiovascular death after MI.¹⁶ ACE inhibitors not only antagonize the pathological effects of angiotensin II but also prevent bradykinin breakdown, which induces further cardioprotection. In contrast, angiotensin receptor antagonists selectively inhibit AT1 receptors, inducing an inhibitory effect on the negative feedback mechanism and thereby further increasing plasma angiotensin II levels by almost 200%, which increases the propensity for development of MI in patients treated with ARBs. This is considered the mechanism for the ARB MI paradox.^16,17 Polzin et al.¹⁷ proposed that Sphingosin-1-phosphate is a substance with a cardioprotective effect, which is produced by sphingosine kinases. In patients treated with ACE inhibitors, higher sphingosine concentrations were observed as compared to those treated with ARBs, which partially explains the ‘ARB MI paradox’.¹⁷

However, recent evidence from a meta-analysis involving over 250 000 patients has shown no significant difference in outcomes between ARBs and ACE inhibitors regarding all-cause mortality, cardiovascular death, and MI. Head-to-head trials corroborate these findings, demonstrating that both drug classes confer similar cardiovascular protection, with the added benefit of better tolerability seen with ARBs due to a lower risk of drug withdrawal from adverse effects. This challenges the previously suggested ARB MI paradox and affirms the comparable efficacy of ARBs and ACE inhibitors in reducing cardiovascular mortality.¹⁸

HAEMODYNAMIC PARADOX OF CHRONIC HF

The haemodynamic paradox of chronic HF was a term used in the late 1980s for the fact that exercise intolerance due to chronic HF does not improve even after the improvement in cardiac output (CO). Exercise capacity is determined by peak oxygen consumption (VOmax), which is directly linked to cardiac output. As per the Fick equation, VO₂ max is the product of CO and arteriovenous oxygen difference ( AVO₂). Therefore, in patients with chronic HF, there is no improvement in VO₂ max despite improvement in CO. This is attributed to the proportionate decrease in arteriovenous difference. This is described as the PB ‘haemodyamic paradox’ in HF, which suggests that in chronic HF patients, changes in peripheral oxygen consumption play a critical role in exercise capacity and affect the haemodynamics at peak CO and peak VO₂.¹⁹

SMOKER’S PARADOX

Cigarette smoking affects the cardiovascular system via various mechanisms and is linked to MI, peripheral arterial disease, and sudden cardiac death. Smokers suffer their MI on average a decade earlier than non-smokers. The smoker’s paradox implies that smokers have favourable short-term outcomes after MI.²⁰ However, it has now been established that the smoker’s paradox is not related to smoking but is more related to the baseline characteristics of the patients. This paradox in the thrombolytic era was postulated due to a better response to thrombolysis and the thrombotic nature of occlusion secondary to the hyper-coagulable state, in contrast to the atherosclerotic state in non-smokers. However, in the PCI era, this paradox continued due to lower rates of factors such as diabetes, hypertension, left anterior descending artery involvement, triple vessel disease, and female sex that negatively affect prognosis. Smokers who come with myocardial infarction are younger and hence have a better prognosis. Therefore, it is recommended not to use the term ‘smoker’s paradox’ as it may misguide the patients.

CAMPEAU RADIAL PARADOX

In 1989, Lucien Campeau, a Canadian cardiologist, introduced trans-radial access as an alternative to transfemoral access for coronary angiography.²¹ The trans-radial approach for coronary interventions has reduced the use of transfemoral access. However, the increased use of radial access has led to decreased efficiency for gaining femoral access and paradoxically increased the rate of vascular complications when femoral access is attempted. This is a real-world scenario worldwide known as the ‘Campeau radial paradox.’²² As per Kopin et al., radial access use has significantly reduced the use of femoral access, but femoral access cannot be avoided in complex coronary interventions.²² Azzalini et al.²³ suggested that cardiology training programs must include femoral teaching and minimal transfemoral access to maintain efficiency and reduce complications.²¹

YY PARADOX

YY paradox was described by two authors, Yajnik and Yudnik, who had similar body mass indices (BMIs) but different body fat percentages, as demonstrated on a 3D body scan. As BMI is an important variable for the assessment of obesity, the YY paradox must be taken into consideration while defining obesity and assessing patients.²⁴ The YY paradox was also demonstrated by Sengar and Mill²⁴ in 301 Indian women, having the same BMI but different body fat measured by bioelectric impedance fat monitor and anthropometric techniques. The YY paradox is an important phenomenon as it has varied implications in patients with cardiac diseases, such as the impact of obesity on cardiac conditions like HF, acute coronary syndrome, and hypertension.

PARADOXICAL LOW-GRADIENT AORTIC STENOSIS

Paradoxical low gradient aortic stenosis was described by Hachicha et al.²⁵ in patients with severe symptomatic aortic stenosis (AS) with aortic valve area <1 cm², indexed aortic valve area <0.6 cm²/m² of body surface area, indexed stroke volume <35 mL/m², and mean aortic valve gradient <40 mmHg with normal LV systolic function (LVEF >50%).²⁵ The paradox is a preserved ejection fraction despite a paradoxical combination of low-flow and low-gradient aortic stenosis. As per ACC/AHA 2020 guidelines for valvular heart disease management, paradoxical low gradient severe aortic stenosis is classified as stage D3. Paradoxical low gradient AS is attributed to a small thickened LV, age, diastolic dysfunction, and hypertension. The outcomes are better in patients with paradoxical low gradient AS as compared to low flow low gradient severe AS.²⁶ Therefore, it is important to critically evaluate symptoms in patients with aortic stenosis, and if there is discordance in the echo-cardiographic valve area and gradients with symptoms, stroke volume can be calculated echocardiographically to avoid under assessing the severity of AS. Even cardiac CT or cardiac MRI can be used to confirm the diagnosis of this paradoxical entity. As these patients have a good prognosis after aortic valve replacement, this symptoms and gradients paradox should be kept in mind to avoid missing the paradoxical low gradient severe aortic stenosis.^25,26

CARDIOVASCULAR DISEASES (CVD) PARADOX

Despite tremendous advances in the field of cardiology in recent years, the prevalence of CVD is still increasing. This paradox is a well-known phenomenon described by Fuster and Mearns in 2009.²⁷ From 1995 to 2005, it was observed that the incidence of initial diagnosis of coronary artery disease (CAD) had reduced, but the prevalence increased due to a significant decrease in age-related mortality, leading to a substantial economic burden on treatment.²⁸ However, there are other contributing factors to this paradox, which include increasing incidence of risk factors of CVD like obesity, diabetes mellitus, dyslipidaemia, hypertension, obstructive sleep apnoea, smoking, and others. The healthcare cost is increasing worldwide due to the availability of expensive new treatments and due to longer survival of patients due to advanced treatments, along with hospitalizations. Fuster and Mearns suggested that promoting cardiovascular health may reduce CVD incidence and treatment costs worldwide.²⁷

FRENCH PARADOX

The French paradox is the concept postulated by French epidemiologists in the 1980s, which explains the lower incidence of CAD and cardiovascular mortality despite higher intake of cholesterol and saturated fats in the French population.²⁹ This was observed in the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study. As per data from the MONICA project conducted by the WHO, France is at a lower risk of CAD and associated mortality. The French paradox is attributed to multiple factors, including a diet rich in vegetables and drinking patterns despite a high intake of saturated fats. Lower CAD incidence as per the French paradox implies that primary prevention of CAD with a diet rich in fruits and vegetables, regular exercise, and smoking cessation should be promoted.^29,30

EAST ASIAN PARADOX

East Asian people have a higher risk of bleeding with warfarin as compared to the western population.³¹ Therefore, race-specific targets have been proposed for therapeutic international normalized ratio (INR).³¹ As per Young-Hoon Jeong, there is a huge ethnic variability in thrombogenicity and response to antiplatelet therapy owing to platelet reactivity.³² Multiple studies have shown high platelet reactivity in the East Asian population due to high prevalence of CYP2C19 loss-of-function alleles. Therefore, established antiplatelet therapy dosages as per guidelines may lead to more bleeding in the East Asian population. This East Asian paradox demands a tailored, race-specific antiplatelet therapy for patients with acute coronary syndrome and chronic CAD, due to racial differences in antiplatelet reactivity.³²

TRUE PHYSIOLOGICAL PARADOX: THE KUSSMAUL SIGN

The Kussmaul sign is the paradoxical increase in jugular venous pressure during inspiration. It is considered a ‘true physiologic paradox’ and was originally described by Adolf Kussmaul, a German physician, in 1873, in a patient with CP.³³ However, it can be seen in only one-third of patients with CP. Other causes include RV dysfunction, restrictive cardiomyopathy, and massive pulmonary embolism. The mechanism for the Kussmaul sign is impaired RV filling leading to elevated right atrial pressures and venous pressures during inspiration, ultimately causing a paradoxical increase in JVP.³⁴

ANNULUS PARADOX

The term ‘Annulus paradox’ was first proposed by Ha et al. to describe the inverse relation between the ratio of early diastolic transmitral inflow velocity (E) to early diastolic mitral annular tissue Doppler velocity (E2) (E/E2) and to the pulmonary capillary wedge pressure (PCWP) in patients with constrictive pericarditis (CP).³⁵ In patients with CP, the E/E' is not elevated despite increased ventricular filling pressures. In CP, there is an exaggerated longitudinal motion of the mitral annulus. As the severity of CP increases, the mitral annular longitudinal motion is increasingly accentuated, leading to a decreased E/E' ratio. However, the ventricular filling pressures are elevated due to restricted expansion of the heart, due to pericardial constriction.³⁵ This leads to the development of the annular paradox, which is almost always present in clinically significant pericardial constriction.

SYSTOLIC PARADOX IN HYPERTROPHIC CARDIOMYOPATHY (HCM)

Haland et al.³⁶ described the systolic paradox in patients with HCM where the LV ejection fraction (LVEF) is usually normal and remains normal till end-stage disease. However, the global longitudinal strain (GLS) is significantly reduced despite normal LVEF. This systolic paradox in patients with HCM can be explained by the smaller ventricular volumes secondary to increased wall thickness in HCM, leading to an altered equation for LVEF. In HCM, the reduced ventricular compliance shifts the Frank–Starling pressure–volume curve to the left, and enddiastolic pressure and preload are higher despite the lower enddiastolic volume. Reduced compliance and myocardial fibrosis lead to a reduction in GLS. However, the LVEF remains normal.³⁶

HIGH-DENSITY LIPOPROTEIN CHOLESTEROL (HDL-C) PARADOX

HDL-C is considered cardioprotective due to its atheroprotective ability, which is due to reverse cholesterol transport. However, recent data from two observational studies, Cardiovascular Health in Ambulatory Care Research Team (CANHEART) and Copenhagen Heart Studies (Copenhagen City Heart Study and the Copenhagen General Population Study), demonstrated a significant U-shaped relationship between HDL-C and all-cause mortality.^37,38 Low HDL is associated with increased hazard risk of all-cause and cardiovascular mortality. However, the CANHEART study showed that high HDL-C levels (>90 mg/dl) were associated with significantly increased hazard risk for non-cancer and non-cardiovascular mortality.³⁷ The genes HNF4A (hepatocyte nuclear factor-4), SCARB1 (scavenger receptor B class I), and LAG3 (lymphocyte activation gene-3) are associated with high HDL-C and increased risk of MI as per data from various genetic studies. Dysfunctional HDL not only decreases reverse cholesterol transport but can have pro-inflammatory, pro-apoptotic, pro-oxidative, and pro-thrombotic effects. Therefore, the ‘HDL paradox’ states that although low HDL-C remains a significant factor for increased cardiovascular risk, high HDL-C levels (>90 mg/dl) are not cardioprotective.³⁹

ELECTROCARDIOGRAM–ECHOCARDIOGRAPHY (ECG– ECHO) HYPERTROPHY PARADOX IN INFILTRATIVE CARDIOMYOPATHY

In the presence of LV hypertrophy, an ECG shows increased LV QRS amplitude due to increased ventricular mass. However, in patients with infiltrative cardiomyopathies like amyloidosis, although echocardiography demonstrates significant thickening of the ventricular muscle mass, the ECG does not show increased voltages (Fig. 3). This is because in infiltrative cardiomyopathy, the hypertrophy is not due to myocyte hypertrophy, but due to infiltration of the myocardium by non-contractile substances like amyloid and granulomas. Therefore, the hypertrophy is not reflected in the surface ECG. This is the ECG–ECHO paradox of infiltrative cardiomyopathy.⁴⁰

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FIG 3.

Electrocardiogram–echocardiography hypertrophy paradox in infiltrative cardiomyopathy showing significant thickening of the ventricular muscle mass in echocardiography whereas the electrocardiogram showed low voltage complexes

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ASIAN INDIAN PARADOX

Asian Indian paradox signifies the higher burden of CVD among Asian Indians despite a lower incidence of conventional CVD risk factors like smoking, obesity, hypertension, and dyslipidaemia as compared to western countries. The excess burden of premature death from CAD among Asian Indians cannot be fully explained despite the higher prevalence of conditions like insulin resistance, metabolic syndrome, glucose intolerance, and diabetes.⁴¹ The CAD in Indians study showed that the rate of CVD is 3–4 times higher in the Indian population in the USA, despite a similar or lower prevalence of major conventional risk factors except for diabetes.⁴² This is attributed to genetic factors unrelated to conventional risk factors. This explains the need for lower treatment thresholds for Asian Indians. Considering the Asian Indian paradox, Enas et al. proposed that treatment thresholds for conventional risk factors should be lowered by 10% to 20% for the Asian Indian population.⁴³