Female (n = 1967)
Male (n = 2005)
p value
Age, years
84.0 ± 6.6
81.6 ± 7.5
<0.001
Body mass index, kg/m2
25.7 ± 5.4
26.3 ± 4.5
<0.001
Logistic EuroSCORE, %
21.4 ± 13
22.2 ± 15
0.97
Clinical history
Coronary artery disease
918 (47.9 %)
1341 (69.0 %)
<0.001
Chronic obstructive pulmonary disease
397 (20.3 %)
503 (25.1 %)
0.003
Peripheral vascular disease
278 (14.2 %)
521 (26.1 %)
<0.001
Creatinine before procedure >200 mmol/l
120 (6.1 %)
220 (11.0 %)
<0.001
Cerebrovascular disease
191 (9.8 %)
198 (9.9 %)
0.91
Echocardiographic findings
Mean gradient, mm Hg
51.0 ± 17.7
45.4 ± 14.8
<0.001
Effective orifice area indexed, cm2/m2
0.4 ± 0.2
0.4 ± 0.2
0.041
Ejection fraction, %
56.6 ± 13.3
50.1 ± 14.3
<0.001
Transfemoral TAVI approach
1536 (78.7 %)
1365 (68.4 %)
<0.001
Edwards SAPIEN/Medtronic CoreValve
73.2 %, 26.8 %
60.4 %, 39.6 %
<0.001
Echocardiographic findings, postprocedural
Effective orifice area indexed, cm2/m2
1.1 ± 0.3
1.0 ± 0.3
0.13
Ejection fraction, %
58.2 ± 11.6
52.9 ± 12.9
<0.001
Pulmonary artery pressure, mm Hg
40.5 ± 12.1
41.2 ± 13.2
0.31
Moderate to severe aortic regurgitation
196 (11.8 %)
294 (17.1 %)
<0.001
In the FRANCE 2 registry, female patients were older (84 vs. 81.6 years; p < 0.001), with less frequent history of CAD (47.9 % vs. 69 %; p < 0.001), chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), or renal failure (creatinine >200 μmol/l: 6.1 % vs. 11.0 %; p < 0.001) [4].
In contrast, the UK registry found higher female rates of COPD (25.1 % vs. 20.8 %; p = 0.04) and chronic renal disease (6.8 % vs. 3.7 %; p = 0.006) [7].
In the Italian Observational Multicenter Registry (OBSERVANT Research Group), female TAVI patients had a different risk profile from males, with greater age (82.4 vs. 81.1 years; p = 0.005), lower body weight (67.6 vs. 74.5 kg; p < 0.001), and lower preoperative hemoglobin level (11.4 vs. 11.8 g/dL; p < 0.001) but with similar New York Heart Association (NYHA) class (class III, 45 % vs. 43.4 %; class IV, 15.5 % vs. 13.8 %), frailty score (2 (partially self-sufficient), 24.8 % vs. 16.2 %) and European system for cardiac operative risk evaluation (EuroSCORE) (14.6 vs. 15.9; NS), and less frequent renal dysfunction, COPD, arteriopathy, or history of cardiovascular surgery or PCI (p < 0.01) [6].
The major findings of recent meta-analyses were significant sex differences in terms of age, CAD, COPD, and PVD [13, 15] (Table 8.2). In O’Connor’s meta-analysis, 48.6 % (n = 5502) of the 11,310 patients included in the final cohort were women. Men had higher rates of risk factors than women, with higher prevalences of diabetes and of history of myocardial infarction, PCI, coronary artery bypass graft, PVD, poor left ventricular systolic function (left ventricular ejection fraction <30 %) and three-vessel coronary artery disease, higher logistic EuroSCORE, and greater prevalence of pulmonary disease [1].
Age (year) | EuroSCORE (%) | COPD (%) | Previous MI (%) | Previous PCI (%) | Previous cardiac surgery (%) | NYHA III/IV | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
F | M | F | M | F | M | F | M | F | M | F | M | F | M | |
Hayashida [3] | 83.8 | 82.4 | 22.3 | 26.2 | 38.2 | 36.4 | 7.6 | 21.7 | 25.2 | 35.6 | 13.7 | 26.4 | 86.3 | 82.9 |
Buja [5] | 82 | 80 | 23 | 23 | 17 | 26 | 13 | 32 | 22 | 36 | 6.3 | 28 | 74 | 66 |
Al-Lamee [9] | 82.6 | 80.8 | 21 | 21.8 | 21.8 | 25.1 | 13 | 29.5 | 17 | 18 | 12.7 | 40.9 | 20.1 | 19 |
Sherif [11] | 82.8 | 80.3 | 21 | 20 | 20.8 | 28.3 | 11.5 | 21.9 | 30.2 | 40.5 | 13.9 | 33.6 | 90.7 | 85 |
Williams [12] | 84.5 | 82.9 | 27.5 | 30.7 | 22.5 | 15 | 18.4 | 32.5 | 27.2 | 38.2 | 19 | 59.7 | 93.9 | 94.5 |
Zhao [13] | 82.1 | 80.6 | 22.7 | 24 | 24.2 | 38.6 | 19.5 | 34.3 | 27.3 | 44.1 | n.r | n.r | 79.9 | 75.3 |
O’Connor [15] | 83.3 | 81.6 | 22.2 | 23.9 | 28.2 | 31.4 | 14.6 | 28.6 | 17.6 | 23.4 | 14.1 | 41.1 | n.r | n.r |
The difference in clinical presentation between men and women may partly be due to women having lower rates of specialist referral and thus receiving medical care later than men. They wait longer before consulting a doctor [16].
8.1.2 Left Ventricle Evolution
Several studies have emphasized the existence of sex differences in the left ventricle adaptation to AS. On average, women with AS develop thicker ventricles with better conservation of ejection fraction and less fibrosis than male counterparts [15]. Hence, despite being uniformly labeled as “severe AS patients” when presenting for aortic valve replacement (AVR), women and men may show markedly different phenotypes when the complete physiological picture of ventricular performance and valvulo-arterial impedance is considered.
Pressure overload leading to cardiac remodeling is largely influenced by gender; for example, hypertrophy is more frequently associated with the left ventricular dilation and systolic dysfunction in males, whereas geometry is more favorable to conserving systolic pump performance in women. Initial studies suggested that the loss of the left ventricular mass after AVR is more frequent and rapid in women, allowing better normalization of ventricle biomechanics than in men. Taken together, these translational data point to the intriguing possibility that women with AS may exhibit a positive differential treatment response to TAVI.
8.2 Specific Female Anatomical Features for TAVI
The literature is unanimous in finding fundamental sex differences in ultrasound data and the size of arterial approaches.
8.2.1 Mean Aortic Valve Gradient
In the FRANCE 2 registry, mean aortic valve gradient was greater in women than in men (51 vs. 45 mmHg; p < 0.001), as was mean ejection fraction (56 % vs. 50 %; p < 0.001). Findings were similar in the other registry reports and in O’Connor’s meta-analysis (61 % vs 55 %; p < 0.001) [1]. Overall, mean aortic orifice diameter is 21 mm in women and 23 mm in men, which probably explains the observed difference in choice of valve for AVR. Thus, percentage use of CoreValve and SAPIEN implants was, respectively, 35.2 % and 64.8 % in women and 31.4 % and 67.9 % in men (p < 0.001) in the 11,310 patients analyzed by O’Connor. Small (23 mm) valves are more often used in female patients (31.2 % vs. 10.8 %; p < 0.001) [15]. The FRANCE 2 results are in agreement with the above: women, 26.8 % CoreValve and 73.2 % SAPIEN; men, 39.6 % and 60.4 %, respectively; p < 0.001 [4].
8.2.2 Access
The most frequently used approach is femoral, but its safety greatly depends on iliofemoral axis assessment. Vascular axis diameters should be measured and tortuosity and calcification assessed. For this, CT angiography provides precious precise information. Minimum femoral dimensions are defined by the manufacturer’s specifications based on introducer sheath size, which, in published studies, was 6 mm for 18Fr sheaths for the Medtronic CoreValve and 6–7 mm for Edwards SAPIEN XT. However, these sheath diameters are based on the devices’ internal diameters. Moreover, excessive calcification at the femoral access site constitutes a risk factor independently of any major vascular complication.
The approach was more often femoral in women in the FRANCE 2 study (78.7 % vs. 68.4 % in men; p < 0.001), probably due to a higher rate of peripheral vascular disease in males (14.2 % in women vs. 26.1 % in men; p < 0.001) [4]. However, femoral approaches were globally smaller in women: 7.2 vs. 7.9 mm on the left and 7.5 vs. 7.7 mm on the right (p < 0.001) [1].
The presence and degree of femoral and aortoiliac atheroma are an important factor to be taken into account in selecting the approach. Framingham’s data are useful here: prevalence of abdominal aortic plaque, and of any aortic plaque, was higher in women than in men (p < 0.02). Total plaque volume, both absolute and normalized to BSA, was larger in women than in men on thoracoabdominal aortic cardiac MRI (p < 0.05) [17].
8.2.3 Coronary and Aortic Valve Calcifications
There are differences in the aortic valve itself, not only in terms of orifice size but also of degree of calcification. Because calcium is detectable noninvasively with CT imaging, it is possible to use the extent and distribution of calcification in cardiac valves, coronary arteries, and aorta as a diagnostic tool in risk stratification.
A significant gender difference in total coronary and aortic valve calcification in patients with severe AS was recently reported [18]. Men had more severe aortic and coronary calcification than women. Valvular calcification in AS patients has been linked to systemic calcified atherosclerosis. The identification of oxidized lipoproteins, inflammatory cells, and proteins activated by macrophages in aortic valve calcification suggests a similarity to the pathogenesis of coronary artery calcification. Furthermore, highly calcified stenotic aortic valves show greater oxidized low-density lipoprotein concentrations as well as increased expression of metalloproteinases [18].
The persistence of gender difference in coronary calcification in severe AS suggests that this cardioprotection against calcification continues beyond the menopause, and perhaps calcification itself may be either a delayed process or a process that continues once initiated.
8.3 Technical Issues and Complications
8.3.1 Procedural Device Success
Procedural device success rates are reportedly similar in women and men, with 97 % success [1]. The majority of registries and trials performed TAVI via the transfemoral approach [3–10], and this was more common in women than in men in the FRANCE 2 series (78.7 % vs. 68.4 %; p < 0.001) and in O’Connor’s meta-analysis (70.4 % vs. 67.9 %; p = 0.004). In the majority of studies, implanted valves included the SAPIEN and SAPIEN XT devices in 23-, 26-, and 29-mm sizes (Edwards Lifesciences) and the CoreValve device in 23-, 26-, 29-, and 31-mm sizes (Medtronic).
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